Mark Holodniy

All Publications

• Risk Factors for Extrapulmonary Tuberculosis Among US Veterans, 1990-2022. Open forum infectious diseases Oda, G., Lucero-Obusan, C., Schirmer, P., Chung, J., Holodniy, M. 2024; 11 (12): ofae698

  Abstract

  To determine factors that put US veterans with active tuberculosis at risk for extrapulmonary tuberculosis (EPTB) compared with pulmonary tuberculosis.We included veterans with laboratory-confirmed tuberculosis from 1990-2022 in our retrospective cohort study. Multivariable logistic regression was used to estimate the association of demographic and clinical risk factors with EPTB.Of 7493 veterans aged 20-100 years (median, 58 years) with laboratory-confirmed tuberculosis, 1397 (19%) had EPTB. The most common EPTB infection among veterans was pleural (31.4%), while meningitis carried the highest mortality risk at 90 days. Factors independently associated with EPTB among veterans were non-Hispanic black race/ethnicity, diabetes mellitus, human immunodeficiency virus infection, severe kidney disease, and all-cause mortality within 90 days after tuberculosis diagnosis.Our study demonstrated several risk factors for EPTB among US veterans. Healthcare providers should be educated regarding patient populations at risk for EPTB, especially given the challenges in diagnosing this disease and the importance of instituting early treatment to prevent severe illness and death.

  View details for DOI 10.1093/ofid/ofae698

  View details for PubMedID 39679355

  View details for PubMedCentralID PMC11639626

• Clinically Defined Lymphogranuloma Venereum among US Veterans with Human Immunodeficiency Virus, 2016-2023. Microorganisms Oda, G., Chung, J., Lucero-Obusan, C., Holodniy, M. 2024; 12 (7)

  Abstract

  We applied lymphogranuloma venereum (LGV) clinical case criteria to a cohort of 1381 Veterans positive for HIV and Chlamydia trachomatis (CT) from 2016 from 2023 and analyzed variables to ascertain risk factors for LGV and factors associated with the use of standard treatment regimens. In total, 284/1381 (20.6%) met the criteria for LGV. A total of 179/284 (63%) were probable cases, and 105/284 (37%) were possible cases (those meeting clinical criteria but with concurrent sexually transmitted infections (STI) associated with LGV-like symptoms). None had confirmatory CT L1-L3 testing. A total of 230 LGV cases (81%) presented with proctitis, 71 (25%) with ulcers, and 57 (20.1%) with lymphadenopathy. In total, 66 (23.2%) patients had >1 symptom of LGV. A total of 43 (15%) LGV cases were hospitalized. Primary risk factors for LGV were male birth sex (p = 0.004), men who have sex with men (p < 0.001), and the presence of STIs other than gonorrhea or syphilis (p = 0.011). In total, 124/284 (43.7%) LGV cases received standard recommended treatment regimens. Probable cases were more likely to receive standard treatment than possible cases (p = 0.003). We report that 20.6% of CT cases met clinical criteria for LGV among HIV-infected Veterans and that less than half of cases received recommended treatment regimens, indicating that LGV is likely underestimated and inadequately treated among this US population.

  View details for DOI 10.3390/microorganisms12071327

  View details for PubMedID 39065095

  View details for PubMedCentralID PMC11278903

• Early trajectories of virological and immunological biomarkers and clinical outcomes in patients admitted to hospital for COVID-19: an international, prospective cohort study. The Lancet. Microbe Jensen, T. O., Murray, T. A., Grandits, G. A., Jain, M. K., Grund, B., Shaw-Saliba, K., Matthay, M. A., Abassi, M., Ardelt, M., Baker, J. V., Chen, P., Dewar, R. L., Goodman, A. L., Hatlen, T. J., Highbarger, H. C., Holodniy, M., Lallemand, P., Laverdure, S., Leshnower, B. G., Looney, D., Moschopoulos, C. D., Mugerwa, H., Murray, D. D., Mylonakis, E., Nagy-Agren, S., Rehman, M. T., Rupert, A., Stevens, R., Turville, S., Weintrob, A., Wick, K., Lundgren, J., Ko, E. R. 2024

  Abstract

  Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of viral replication and immune dysregulation. We aimed to characterise biomarker trajectories and their associations with clinical outcomes.In this international, prospective cohort study, patients admitted to hospital with COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 platform trial within the Accelerating COVID-19 Therapeutic Interventions and Vaccines programme between Aug 5, 2020 and Sept 30, 2021 were included. Participants were included from 108 sites in Denmark, Greece, Poland, Singapore, Spain, Switzerland, Uganda, the UK, and the USA, and randomised to placebo or one of four neutralising monoclonal antibodies: bamlanivimab (Aug 5 to Oct 13, 2020), sotrovimab (Dec 16, 2020, to March 1, 2021), amubarvimab-romlusevimab (Dec 16, 2020, to March 1, 2021), and tixagevimab-cilgavimab (Feb 10 to Sept 30, 2021). This trial included an analysis of 2149 participants with plasma nucleocapsid antigen, anti-nucleocapsid antibody, C-reactive protein (CRP), IL-6, and D-dimer measured at baseline and day 1, day 3, and day 5 of enrolment. Day-90 follow-up status was available for 1790 participants. Biomarker trajectories were evaluated for associations with baseline characteristics, a 7-day pulmonary ordinal outcome, 90-day mortality, and 90-day rate of sustained recovery.The study included 2149 participants. Participant median age was 57 years (IQR 46-68), 1246 (58·0%) of 2149 participants were male and 903 (42·0%) were female; 1792 (83·4%) had at least one comorbidity, and 1764 (82·1%) were unvaccinated. Mortality to day 90 was 172 (8·0%) of 2149 and 189 (8·8%) participants had sustained recovery. A pattern of less favourable trajectories of low anti-nucleocapsid antibody, high plasma nucleocapsid antigen, and high inflammatory markers over the first 5 days was observed for high-risk baseline clinical characteristics or factors related to SARS-CoV-2 infection. For example, participants with chronic kidney disease demonstrated plasma nucleocapsid antigen 424% higher (95% CI 319-559), CRP 174% higher (150-202), IL-6 173% higher (144-208), D-dimer 149% higher (134-165), and anti-nucleocapsid antibody 39% lower (60-18) to day 5 than those without chronic kidney disease. Participants in the highest quartile for plasma nucleocapsid antigen, CRP, and IL-6 at baseline and day 5 had worse clinical outcomes, including 90-day all-cause mortality (plasma nucleocapsid antigen hazard ratio (HR) 4·50 (95% CI 3·29-6·15), CRP HR 3·37 (2·30-4·94), and IL-6 HR 5·67 (4·12-7·80). This risk persisted for plasma nucleocapsid antigen and CRP after adjustment for baseline biomarker values and other baseline factors.Patients admitted to hospital with less favourable 5-day biomarker trajectories had worse prognosis, suggesting that persistent viral burden might drive inflammation in the pathogenesis of COVID-19, identifying patients that might benefit from escalation of antiviral or anti-inflammatory treatment.US National Institutes of Health.

  View details for DOI 10.1016/S2666-5247(24)00015-6

  View details for PubMedID 38815595

• An update on drug-drug interactions in older adults living with human immunodeficiency virus (HIV). Expert review of clinical pharmacology Linfield, R. Y., Nguyen, N. N., Laprade, O. H., Holodniy, M., Chary, A. 2024

  Abstract

  People with HIV are living longer due to advances in antiretroviral therapy. With improved life expectancy comes an increased lifetime risk of comorbid conditions - such as cardiovascular disease and cancer - and polypharmacy. Older adults, particularly those living with HIV, are more vulnerable to drug interactions and adverse effects, resulting in negative health outcomes.Antiretrovirals are involved in many potential drug interactions with medications used to treat common comorbidities and geriatric conditions in an aging population of people with HIV. We review the mechanisms and management of significant drug-drug interactions involving antiretroviral medications and non-antiretroviral medications commonly used among older people living with HIV. The management of these interactions may require dose adjustments, medication switches to alternatives, enhanced monitoring, and considerations of patient- and disease-specific factors.Clinicians managing comorbid conditions among older people with HIV must be particularly vigilant to side effect profiles, drug-drug interactions, pill burden, and cost when optimizing treatment. To support healthier aging among people living with HIV, there is a growing need for antiretroviral stewardship, multidisciplinary care models, and advances that promote insight into the correlations between an individual, their conditions, and their medications.

  View details for DOI 10.1080/17512433.2024.2350968

  View details for PubMedID 38753455

• Immunomodulators for immunocompromised patients hospitalized for COVID-19: a meta-analysis of randomized controlled trials. EClinicalMedicine Siempos, I. I., Kalil, A. C., Belhadi, D., Veiga, V. C., Cavalcanti, A. B., Branch-Elliman, W., Papoutsi, E., Gkirgkiris, K., Xixi, N. A., Kotanidou, A., Hermine, O., Porcher, R., Mariette, X. 2024; 69: 102472

  Abstract

  Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19.The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care).Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61-1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64-1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09-0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality.Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19.Hellenic Foundation for Research and Innovation.

  View details for DOI 10.1016/j.eclinm.2024.102472

  View details for PubMedID 38361992

  View details for PubMedCentralID PMC10867612

• Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Aggarwal, N. R., Nordwall, J., Braun, D. L., Chung, L., Coslet, J., Der, T., Eriobu, N., Ginde, A. A., Hayanga, A. J., Highbarger, H., Holodniy, M., Horcajada, J. P., Jain, M. K., Kim, K., Laverdure, S., Lundgren, J., Natarajan, V., Nguyen, H. H., Pett, S. L., Phillips, A., Poulakou, G., Price, D. A., Robinson, P., Rogers, A. J., Sandkovsky, U., Shaw-Saliba, K., Sturek, J. M., Trautner, B. W., Waters, M., Reilly, C. 2024

  Abstract

  Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials.A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models.Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time.Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.

  View details for DOI 10.1093/cid/ciad780

  View details for PubMedID 38376212

• Epidemiology of the 2022 Mpox Outbreak in the US Veterans Health Administration. The Journal of infectious diseases Lucero-Obusan, C., Oda, G., Schirmer, P., Edson, C., Trevino, C., Elbeik, T., Holodniy, M. 2023

  Abstract

  In May 2022, mpox cases were reported in non-endemic countries, including the United States. We examined mpox infections in the Veterans Health Administration (VHA).Mpox diagnostic and whole genome sequencing (WGS) results, demographics, risk factors, hospitalizations, exposures, deaths, pharmacy, and immunization data were obtained from VHA data sources (5/23/22-5/31/23).Of 1,144 Veterans tested, 251 (21.9%) were presumptive positive for Non Variola Orthopox (NVO) or NVO and Monkeypox virus (MPXV) confirmed positive. Incidence rate was 7.5 per 100,000 Veterans in care, with highest rate observed in Veterans aged 25-34 (13.83 cases per 100,000). Higher odds of NVO or NVO/MPXV positivity was associated with maleness, non-Hispanic Black race/ethnicity, syphilis or HIV positivity, or genital/rectal sample site, while older age and vaccination with JYNNEOS or vaccinia (smallpox) had lower odds. Among 209 with confirmatory testing, 90.4% reported intimate contact and/or an epi link; 84.5% were men who have sex with men (MSM); 24.2% received tecovirimat; and 8.1% were hospitalized with 1 death. Eighty-six sequenced samples had evaluable WGS results. All were clade IIb, representing 10 different lineages from 20 states and the District of Columbia.Mpox affected younger, MSM, non-Hispanic Black and HIV+/syphilis + males among US Veterans. Viral diversity was noted across geographic regions. At risk Veterans would benefit from vaccination and risk reduction strategies for mpox and other STIs.

  View details for DOI 10.1093/infdis/jiad600

  View details for PubMedID 38134309

• Effect of Neutralizing Monoclonal Antibody Treatment on Early Trajectories of Virologic and Immunologic Biomarkers in Patients Hospitalized With COVID-19. The Journal of infectious diseases Jensen, T. O., Grandits, G. A., Jain, M. K., Murray, T. A., Grund, B., Shaw-Saliba, K., Matthay, M. A., Abassi, M., Ardelt, M., Baker, J. V., Chen, P., Dewar, R. L., Goodman, A. L., Hatlen, T. J., Highbarger, H. C., Holodniy, M., Lallemand, P., Laverdure, S., Leshnower, B. G., Looney, D., Moschopoulos, C. D., Mugerwa, H., Murray, D. D., Mylonakis, E., Nagy-Agren, S., Rehman, M. T., Rupert, A., Stevens, R. A., Turville, S., Weintrob, A., Wick, K., Lundgren, J., Ko, E. R. 2023

  Abstract

  Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood.Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), anti-nucleocapsid antibody, C-reactive protein, interleukin-6, and d-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models.Analysis included 2149 participants enrolled between August 2020 and September 2021. Treatment resulted in 20% lower levels of plasma N-Ag compared with placebo (95% confidence interval, 12%-27%; P < .001), and a steeper rate of decline through the first 5 days (P < .001). The treatment difference did not vary between subgroups, and no difference was observed in trajectories of other biomarkers or the day 5 pulmonary ordinal scale.Our study suggests that nmAb has an antiviral effect assessed by plasma N-Ag among hospitalized patients with COVID-19, with no blunting of the endogenous anti-nucleocapsid antibody response. No effect on systemic inflammation or day 5 clinical status was observed.NCT04501978.

  View details for DOI 10.1093/infdis/jiad446

  View details for PubMedID 37948759

• Risk of Hospitalization and Mortality Following Medically Attended Norovirus Infection-Veterans Health Administration, 2010-2018. Open forum infectious diseases Cates, J., Cardemil, C. V., Mirza, S. A., Lopman, B., Hall, A. J., Holodniy, M., Lucero-Obusan, C. 2023; 10 (11): ofad556

  Abstract

  While prior studies have suggested a role for norovirus gastroenteritis in contributing to severe morbidity and mortality, the importance of norovirus as a causal pathogen for hospitalization and mortality remains poorly understood. We estimated the effect of laboratory-confirmed norovirus infection on hospitalization and mortality among a national cohort of veterans who sought care within the Veterans Affairs health care system.We analyzed electronic health record data from a cohort study of adults who were tested for norovirus within the Veterans Affairs system between 1 January 2010 and 31 December 2018. Adjusted risk ratios (aRRs) for hospitalization and mortality were estimated using log-binomial regression models, adjusting for age, Clostridioides difficile, underlying medical conditions, and nursing home residence.In total, 23 196 veterans had 25 668 stool samples tested for norovirus; 2156 samples (8.4%) tested positive. Testing positive for norovirus infection, compared with testing negative, was associated with a slight increased risk of hospitalization (aRR, 1.13 [95% confidence interval, 1.06-1.21]) and a significant increased risk of mortality within 3 days after the norovirus test (2.14 [1.10-4.14]). The mortality aRR within 1 week and 1 month were reduced to 1.40 (95% confidence interval, .84-2.34) and 0.97 (.70-1.35), respectively.Older veterans with multiple comorbid conditions were at a slight increased risk of hospitalization and significant increased risk of mortality in the 3 days after a norovirus-positive test, compared with those testing negative. Clinicians should be aware of these risks and can use these data to inform clinical management for veterans with norovirus.

  View details for DOI 10.1093/ofid/ofad556

  View details for PubMedID 38023542

  View details for PubMedCentralID PMC10667024

• Nationwide Genomic Surveillance and Response to COVID-19: The VA SeqFORCE and SeqCURE Consortiums. Federal practitioner : for the health care professionals of the VA, DoD, and PHS Krishnan, J., Woods, C. W., Holodniy, M., Nicholson, B. P., Marconi, V. C., Ammons, M. C., Jinadatha, C., Pyarajan, S., Wang-Rodriguez, J., Garcia, A. P., Battles, J. K. 2023; 40 (11 Suppl 5): S44-S47

  Abstract

  The US Department of Veterans Affairs (VA) has dedicated significant resources toward countering the COVID-19 pandemic. Sequencing for Research Clinical and Epidemiology (SeqFORCE) and Sequencing Collaborations United for Research and Epidemiology (SeqCURE) were developed as clinical and research consortiums, respectively, focused on the genetic COVID-19 surveillance.Through genetic sequencing, VA SeqFORCE and SeqCURE collaborations contributed to the COVID-19 pandemic response and scientific understanding. Future directions for each program include the assessment of the unique impact of COVID-19 on the veteran population, as well as the adaptation of these programs to future infectious disease threats. We foresee the use of these established platforms beyond infectious diseases.VA SeqFORCE and SeqCURE were established as clinical and research programs dedicated to sequencing COVID-19 as part of ongoing clinical and surveillance efforts. In the future, we anticipate that having these programs embedded within the largest integrated health care system in the US will enable the study of pathogens and pandemics beyond COVID-19 and at an unprecedented scale. The investment in these programs will form an integral part of our nation's response to emerging infectious diseases, with future applications to precision medicine and beyond.

  View details for DOI 10.12788/fp.0417

  View details for PubMedID 38577303

  View details for PubMedCentralID PMC10988620

• Integrative analyses highlight functional regulatory variants associated with neuropsychiatric diseases. Nature genetics Guo, M. G., Reynolds, D. L., Ang, C. E., Liu, Y., Zhao, Y., Donohue, L. K., Siprashvili, Z., Yang, X., Yoo, Y., Mondal, S., Hong, A., Kain, J., Meservey, L., Fabo, T., Elfaki, I., Kellman, L. N., Abell, N. S., Pershad, Y., Bayat, V., Etminani, P., Holodniy, M., Geschwind, D. H., Montgomery, S. B., Duncan, L. E., Urban, A. E., Altman, R. B., Wernig, M., Khavari, P. A. 2023

  Abstract

  Noncoding variants of presumed regulatory function contribute to the heritability of neuropsychiatric disease. A total of 2,221 noncoding variants connected to risk for ten neuropsychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, borderline personality disorder, major depression, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder and schizophrenia, were studied in developing human neural cells. Integrating epigenomic and transcriptomic data with massively parallel reporter assays identified differentially-active single-nucleotide variants (daSNVs) in specific neural cell types. Expression-gene mapping, network analyses and chromatin looping nominated candidate disease-relevant target genes modulated by these daSNVs. Follow-up integration of daSNV gene editing with clinical cohort analyses suggested that magnesium transport dysfunction may increase neuropsychiatric disease risk and indicated that common genetic pathomechanisms may mediate specific symptoms that are shared across multiple neuropsychiatric diseases.

  View details for DOI 10.1038/s41588-023-01533-5

  View details for PubMedID 37857935

  View details for PubMedCentralID 4112379

• Effectiveness of Smallpox Vaccination to Prevent Mpox in Military Personnel. The New England journal of medicine Titanji, B. K., Eick-Cost, A., Partan, E. S., Epstein, L., Wells, N., Stahlman, S. L., Devineni, P., Munyoki, B., Pyarajan, S., Balajee, A., Smith, J., Woods, C. W., Holodniy, M., Davey, V. J., Bonomo, R. A., Young-Xu, Y., Marconi, V. C. 2023; 389 (12): 1147-1148

  View details for DOI 10.1056/NEJMc2300805

  View details for PubMedID 37733313

• Epidemiology of Coccidioidomycosis in the Veterans Health Administration, 2013-2022. Journal of fungi (Basel, Switzerland) Lucero-Obusan, C., Deka, R., Schirmer, P., Oda, G., Holodniy, M. 2023; 9 (7)

  Abstract

  We describe the epidemiology of coccidioidomycosis among a national cohort of Veterans. Using electronic health record data from adults tested for coccidioidomycosis between 1 January 2013 and 31 December 2022, we analyzed differences in baseline demographics (age, sex, race/ethnicity, birth country, comorbidities, residence, and Charlson Comorbidity Index score) between 4204 coccidioidomycosis-test-positive and 63,322 test-negative Veterans. Log-binomial regression models with adjusted risk ratios (aRRs) were used to evaluate risk factors associated with coccidioidomycosis including dissemination, hospitalization, and mortality. Case counts and incidence rates were highest in select counties in Arizona and California where Coccidioides is endemic. Coccidioidomycosis-positive Veterans were younger, more likely to be male, and Philippine-born. The risk factors most highly associated with being coccidioidomycosis-positive included Native Hawaiian/Pacific Islander (aRR 1.068 [95%CI: 1.039-1.098]), Asian (aRR 1.060 [95%CI: 1.037-1.083]), Black (aRR 1.029 [95%CI: 1.022-1.036]), American Indian/Alaska Native (aRR 1.026 [95%CI: 1.004-1.048]) race, and Hispanic/Latino ethnicity (aRR 1.021 [95%CI: 1.013-1.028]). Black race (aRR: 1.058 [95%CI: 1.037-1.081]) and Hispanic/Latino ethnicity (aRR 1.018 [95%CI: 1.0003-1.036]) were also associated with disseminated coccidioidomycosis, strengthening the evidence for the association of coccidioidomycosis, including severe infections, with specific racial and ethnic groups. There were no statistically significant differences in hospitalization within 45 days of testing or 30-day all-cause mortality. Improving our understanding of coccidioidomycosis risk factors is important for targeted prevention strategies and to reduce delays in diagnosis and ineffective treatment.

  View details for DOI 10.3390/jof9070731

  View details for PubMedID 37504720

  View details for PubMedCentralID PMC10381299

• Early Outcomes of SARS-CoV-2 Infection in a Multisite Prospective Cohort of Inpatient Veterans. Open forum infectious diseases Ross, J. M., Sugimoto, J. D., Timmons, A., Adams, J., Deardoff, K., Korpak, A., Liu, C., Moore, K., Wilson, D., Bedimo, R., Chang, K. M., Cho, K., Crothers, K., Garshick, E., Gaziano, J. M., Holodniy, M., Hunt, C. M., Isaacs, S. N., Le, E., Jones, B. E., Shah, J. A., Smith, N. L., Lee, J. S. 2023; 10 (7): ofad330

  Abstract

  Over 870 000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have occurred among Veterans Health Administration users, and 24 000 have resulted in death. We examined early outcomes of SARS-CoV-2 infection in hospitalized veterans.In an ongoing, prospective cohort study, we enrolled veterans age ≥18 tested for SARS-CoV-2 and hospitalized at 15 Department of Veterans Affairs medical centers between February 2021 and June 2022. We estimated adjusted odds ratios (aORs), adjusted incidence rate ratios (aIRRs), and adjusted hazard ratios (aHRs) for maximum illness severity within 30 days of study entry (defined using the 4-category VA Severity Index for coronavirus disease 2019 [COVID-19]), as well as length of hospitalization and rehospitalization within 60 days, in relationship with demographic characteristics, Charlson comorbidity index (CCI), COVID-19 vaccination, and calendar period of enrollment.The 542 participants included 329 (61%) who completed a primary vaccine series (with or without booster; "vaccinated"), 292 (54%) enrolled as SARS-CoV-2-positive, and 503 (93%) men, with a mean age of 64.4 years. High CCI scores (≥5) occurred in 61 (44%) vaccinated and 29 (19%) unvaccinated SARS-CoV-2-positive participants. Severe illness or death occurred in 29 (21%; 6% died) vaccinated and 31 (20%; 2% died) unvaccinated SARS-CoV-2-positive participants. SARS-CoV-2-positive inpatients per unit increase in CCI had greater multivariable-adjusted odds of severe illness (aOR, 1.21; 95% CI, 1.01-1.45), more hospitalization days (aIRR, 1.06; 95% CI, 1.03-1.10), and rehospitalization (aHR, 1.07; 95% CI, 1.01-1.12).In a cohort of hospitalized US veterans with SARS-CoV-2 infection, those with a higher CCI had more severe COVID-19 illness, more hospital days, and rehospitalization, after adjusting for vaccination status, age, sex, and calendar period.

  View details for DOI 10.1093/ofid/ofad330

  View details for PubMedID 37484899

  View details for PubMedCentralID PMC10358428

• Trends in Follow-up Testing Among Patients Positive for Chlamydia and Gonorrhea in the Veterans Health Administration, 2013 to 2019 SEXUALLY TRANSMITTED DISEASES Schirmer, P., Sharma, A., Lucero-Obusan, C., Oda, G., Holodniy, M. 2023; 50 (5): 258-264

  Abstract

  The Centers for Disease Control and Prevention (CDC) recommends testing patients with chlamydia (CT)/gonorrhea (GC) for other sexually transmitted infections (STIs) and repeating CT/GC testing 3 to 12 months later. We assessed repeat CT/GC testing and testing for HIV/syphilis in accordance with CDC guidelines in the US Veterans Health Administration.Molecular laboratory testing for CT/GC during January 1, 2013-December 31, 2020 was retrieved from Veterans Health Administration data sources. Patients were evaluated for syphilis, HIV, and repeat CT/GC testing within 1 year after a positive CT/GC test result. Differences of CT/GC-positive patients associated with receiving recommended testing were assessed using χ2 /Fisher exact tests.A total of 41,630 of 1,005,761 CT (4.1%) and 17,649 of 1,013,198 GC (1.7%) results were positive. Median ages of positive CT/GC patients were 29 and 36 years, respectively. Repeat testing rates for CT/GC within 90 to 119 days were 3.9% and 2.9%, and rates within 90 to 365 days were 32.8% and 34.7%, with 8.6% and 15% being positive again, respectively. Guideline-compatible repeat testing in known HIV-positive patients nearly doubled (75.7% for CT and 67.8% for GC). The CDC-recommended HIV testing was performed for 72.4% and 65.5% CT and GC first positives, respectively, whereas syphilis testing was completed for 66.5% and 60.5% CT and GC, respectively. Compared with 25- to 34-year-old patients with CT or GC, those younger than 25 years had higher odds of guideline-discordant repeat testing but had lower odds of not receiving HIV/syphilis testing.Nearly two-thirds of patients did not receive recommended repeat testing, and nearly one-third were not tested for HIV/syphilis. Veterans Health Administration providers may benefit from additional education on CDC-recommended sexually transmitted infection guidelines and testing recommendations.

  View details for DOI 10.1097/OLQ.0000000000001765

  View details for Web of Science ID 000970797300003

  View details for PubMedID 36649595

  View details for PubMedCentralID PMC10097481

• The US Department of Veterans Affairs Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD): A Biorepository Addressing National Health Threats. Open forum infectious diseases Harley, J. B., Pyarajan, S., Partan, E. S., Epstein, L., Wertheim, J. A., Diwan, A., Woods, C. W., Davey, V., Blair, S., Clark, D. H., Kaufman, K. M., Khan, S., Chepelev, I., Devine, A., Cameron, P., McCann, M. F., Ammons, M. C., Bolz, D. D., Battles, J. K., Curtis, J. L., Holodniy, M., Marconi, V. C., Searles, C. D., Beenhouwer, D. O., Brown, S. T., Moorman, J. P., Yao, Z. Q., Rodriguez-Barradas, M. C., Mohapatra, S., Molina De Rodriguez, O. Y., Padiernos, E. B., McIndoo, E. R., Price, E., Burgoyne, H. M., Robey, I., Schwenke, D. C., Shive, C. L., Przygodzki, R. M., Ramoni, R. B., Krull, H. K., Bonomo, R. A. 2022; 9 (12): ofac641

  Abstract

  The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has demonstrated the need to share data and biospecimens broadly to optimize clinical outcomes for US military Veterans.In response, the Veterans Health Administration established VA SHIELD (Science and Health Initiative to Combat Infectious and Emerging Life-threatening Diseases), a comprehensive biorepository of specimens and clinical data from affected Veterans to advance research and public health surveillance and to improve diagnostic and therapeutic capabilities.VA SHIELD now comprises 12 sites collecting de-identified biospecimens from US Veterans affected by SARS-CoV-2. In addition, 2 biorepository sites, a data processing center, and a coordinating center have been established under the direction of the Veterans Affairs Office of Research and Development. Phase 1 of VA SHIELD comprises 34 157 samples. Of these, 83.8% had positive tests for SARS-CoV-2, with the remainder serving as contemporaneous controls. The samples include nasopharyngeal swabs (57.9%), plasma (27.9%), and sera (12.5%). The associated clinical and demographic information available permits the evaluation of biological data in the context of patient demographics, clinical experience and management, vaccinations, and comorbidities.VA SHIELD is representative of US national diversity with a significant potential to impact national healthcare. VA SHIELD will support future projects designed to better understand SARS-CoV-2 and other emergent healthcare crises. To the extent possible, VA SHIELD will facilitate the discovery of diagnostics and therapeutics intended to diminish COVID-19 morbidity and mortality and to reduce the impact of new emerging threats to the health of US Veterans and populations worldwide.

  View details for DOI 10.1093/ofid/ofac641

  View details for PubMedID 36601554

  View details for PubMedCentralID PMC9801224

• Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial. The Lancet. Respiratory medicine Wolfe, C. R., Tomashek, K. M., Patterson, T. F., Gomez, C. A., Marconi, V. C., Jain, M. K., Yang, O. O., Paules, C. I., Palacios, G. M., Grossberg, R., Harkins, M. S., Mularski, R. A., Erdmann, N., Sandkovsky, U., Almasri, E., Pineda, J. R., Dretler, A. W., de Castilla, D. L., Branche, A. R., Park, P. K., Mehta, A. K., Short, W. R., McLellan, S. L., Kline, S., Iovine, N. M., El Sahly, H. M., Doernberg, S. B., Oh, M. D., Huprikar, N., Hohmann, E., Kelley, C. F., Holodniy, M., Kim, E. S., Sweeney, D. A., Finberg, R. W., Grimes, K. A., Maves, R. C., Ko, E. R., Engemann, J. J., Taylor, B. S., Ponce, P. O., Larson, L., Melendez, D. P., Seibert, A. M., Rouphael, N. G., Strebe, J., Clark, J. L., Julian, K. G., de Leon, A. P., Cardoso, A., de Bono, S., Atmar, R. L., Ganesan, A., Ferreira, J. L., Green, M., Makowski, M., Bonnett, T., Beresnev, T., Ghazaryan, V., Dempsey, W., Nayak, S. U., Dodd, L. E., Beigel, J. H., Kalil, A. C. 2022; 10 (9): 888-899

  Abstract

  Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.Between Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).In hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.National Institute of Allergy and Infectious Diseases.

  View details for DOI 10.1016/S2213-2600(22)00088-1

  View details for PubMedID 35617986

  View details for PubMedCentralID PMC9126560

• Exposure Sources Among Veterans With Elevated Blood Lead Levels, United States, 2015‒2021. American journal of public health Oda, G., Sharma, A., Lucero-Obusan, C., Schirmer, P., Holodniy, M. 2022; 112 (S7): S670-S678

  Abstract

  Objectives. To determine characteristics and sources of exposure in veterans with elevated blood lead levels (BLLs). Methods. We included users of US Veterans Health Administration care aged 18 years or older tested for BLL from October 2015 to September 2021. Prevalence of BLL 10 micrograms per deciliter (µg/dL) or higher and 25 µg/dL or higher was determined within demographic groups. Logistic regression analysis measured association of International Classification of Diseases, Tenth Revision, Clinical Modification‒coded conditions with elevated BLL. Electronic notes were reviewed for exposure sources. Results. Among 1007 unique veterans with BLL 10 µg/dL or higher, prevalence of BLL 10 µg/dL or higher and 25 µg/dL or higher peaked at 4.9 and 1.3 per 100 000 veterans, respectively (fiscal year 2019), and was highest in non-Hispanic White men and those aged 25 to 34 years. Conditions predicted by elevated BLL were attention-deficit/hyperactivity disorder (ADHD) and nausea or vomiting. Firearms represented 70.1% of occupational and 85.9% of nonoccupational exposures. Toxicology consults occurred in 17 of 298 (6%) with BLL 25 µg/dL or higher. Conclusions. Firearms were the largest exposure source among veterans with elevated BLL. Clinicians should be alert for potential conditions (including ADHD and nausea or vomiting in our study) associated with lead exposure. Standardization of care regarding toxicology referral practices is warranted. (Am J Public Health. 2022;112(S7):S670-S678. https://doi.org/10.2105/AJPH.2022.306936).

  View details for DOI 10.2105/AJPH.2022.306936

  View details for PubMedID 36179285

• Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19 : A Randomized Controlled Trial. Annals of internal medicine Barkauskas, C., Mylonakis, E., Poulakou, G., Young, B. E., Vock, D. M., Siegel, L., Engen, N., Grandits, G., Mosaly, N. R., Vekstein, A. M., Rogers, R., Shehadeh, F., Kaczynski, M., Mylona, E. K., Syrigos, K. N., Rapti, V., Lye, D. C., Hui, D. S., Leither, L., Knowlton, K. U., Jain, M. K., Marines-Price, R., Osuji, A., Overcash, J. S., Kalomenidis, I., Barmparessou, Z., Waters, M., Zepeda, K., Chen, P., Torbati, S., Kiweewa, F., Sebudde, N., Almasri, E., Hughes, A., Bhagani, S. R., Rodger, A., Sandkovsky, U., Gottlieb, R. L., Nnakelu, E., Trautner, B., Menon, V., Lutaakome, J., Matthay, M., Robinson, P., Protopapas, K., Koulouris, N., Kimuli, I., Baduashvili, A., Braun, D. L., Günthard, H. F., Ramachandruni, S., Kidega, R., Kim, K., Hatlen, T. J., Phillips, A. N., Murray, D. D., Jensen, T. O., Padilla, M. L., Accardi, E. X., Shaw-Saliba, K., Dewar, R. L., Teitelbaum, M., Natarajan, V., Laverdure, S., Highbarger, H. C., Rehman, M. T., Vogel, S., Vallée, D., Crew, P., Atri, N., Schechner, A. J., Pett, S., Hudson, F., Badrock, J., Touloumi, G., Brown, S. M., Self, W. H., North, C. M., Ginde, A. A., Chang, C. C., Kelleher, A., Nagy-Agren, S., Vasudeva, S., Looney, D., Nguyen, H. H., Sánchez, A., Weintrob, A. C., Grund, B., Sharma, S., Reilly, C. S., Paredes, R., Bednarska, A., Gerry, N. P., Babiker, A. G., Davey, V. J., Gelijns, A. C., Higgs, E. S., Kan, V., Matthews, G., Thompson, B. T., Legenne, P., Chandra, R., Lane, H. C., Neaton, J. D., Lundgren, J. D. 2022; 175 (9): 1266-1274

  Abstract

  Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection.To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone.Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978).Multinational, multicenter trial.Adults hospitalized with COVID-19.Intravenous ensovibep, 600 mg, or placebo.Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90.An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR < 1 would favor ensovibep).The trial was prematurely stopped because of futility, limiting power for the primary outcome.Compared with placebo, ensovibep did not improve clinical outcomes for hospitalized participants with COVID-19 receiving standard care, including remdesivir; no safety concerns were identified.National Institutes of Health.

  View details for DOI 10.7326/M22-1503

  View details for PubMedID 35939810

  View details for PubMedCentralID PMC9384272

• The Association of Baseline Plasma SARS-CoV-2 Nucleocapsid Antigen Level and Outcomes in Patients Hospitalized With COVID-19. Annals of internal medicine 2022

  Abstract

  Levels of plasma SARS-CoV-2 nucleocapsid (N) antigen may be an important biomarker in patients with COVID-19 and enhance our understanding of the pathogenesis of COVID-19.To evaluate whether levels of plasma antigen can predict short-term clinical outcomes and identify clinical and viral factors associated with plasma antigen levels in hospitalized patients with SARS-CoV-2.Cross-sectional study of baseline plasma antigen level from 2540 participants enrolled in the TICO (Therapeutics for Inpatients With COVID-19) platform trial from August 2020 to November 2021, with additional data on day 5 outcome and time to discharge.114 centers in 10 countries.Adults hospitalized for acute SARS-CoV-2 infection with 12 days or less of symptoms.Baseline plasma viral N antigen level was measured at a central laboratory. Delta variant status was determined from baseline nasal swabs using reverse transcriptase polymerase chain reaction. Associations between baseline patient characteristics and viral factors and baseline plasma antigen levels were assessed using both unadjusted and multivariable modeling. Association between elevated baseline antigen level of 1000 ng/L or greater and outcomes, including worsening of ordinal pulmonary scale at day 5 and time to hospital discharge, were evaluated using logistic regression and Fine-Gray regression models, respectively.Plasma antigen was below the level of quantification in 5% of participants at enrollment, and 1000 ng/L or greater in 57%. Baseline pulmonary severity of illness was strongly associated with plasma antigen level, with mean plasma antigen level 3.10-fold higher among those requiring noninvasive ventilation or high-flow nasal cannula compared with room air (95% CI, 2.22 to 4.34). Plasma antigen level was higher in those who lacked antispike antibodies (6.42 fold; CI, 5.37 to 7.66) and in those with the Delta variant (1.73 fold; CI, 1.41 to 2.13). Additional factors associated with higher baseline antigen level included male sex, shorter time since hospital admission, decreased days of remdesivir, and renal impairment. In contrast, race, ethnicity, body mass index, and immunocompromising conditions were not associated with plasma antigen levels. Plasma antigen level of 1000 ng/L or greater was associated with a markedly higher odds of worsened pulmonary status at day 5 (odds ratio, 5.06 [CI, 3.41 to 7.50]) and longer time to hospital discharge (median, 7 vs. 4 days; subhazard ratio, 0.51 [CI, 0.45 to 0.57]), with subhazard ratios similar across all levels of baseline pulmonary severity.Plasma samples were drawn at enrollment, not hospital presentation. No point-of-care test to measure plasma antigen is currently available.Elevated plasma antigen is highly associated with both severity of pulmonary illness and clinically important patient outcomes. Multiple clinical and viral factors are associated with plasma antigen level at presentation. These data support a potential role of ongoing viral replication in the pathogenesis of SARS-CoV-2 in hospitalized patients.U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

  View details for DOI 10.7326/M22-0924

  View details for PubMedID 36037469

  View details for PubMedCentralID PMC9447373

• Effectiveness of mRNA COVID-19 vaccines against Omicron and Delta variants in a matched test-negative case-control study among US veterans. BMJ open Young-Xu, Y., Zwain, G. M., Izurieta, H. S., Korves, C., Powell, E. I., Smith, J., Balajee, A., Holodniy, M., Beenhouwer, D. O., Rodriguez-Barradas, M. C., Brown, S. T., Marconi, V. C. 2022; 12 (8): e063935

  Abstract

  To estimate the effectiveness of messenger RNA (mRNA) booster doses during the period of Delta and Omicron variant dominance.We conducted a matched test-negative case-control study to estimate the vaccine effectiveness (VE) of three and two doses of mRNA vaccines against infection (regardless of symptoms) and against COVID-19-related hospitalisation and death.Veterans Health Administration.We used electronic health record data from 114 640 veterans who had a SARS-CoV-2 test during November 2021-January 2022. Patients were largely 65 years or older (52%), male (88%) and non-Hispanic white (59%).First positive result for a SARS-CoV-2 PCR or antigen test.Against infection, booster doses had higher estimated VE (64%, 95% CI 63 to 65) than two-dose vaccination (12%, 95% CI 10 to 15) during the Omicron period. For the Delta period, the VE against infection was 90% (95% CI 88 to 92) among boosted vaccinees, higher than the VE among two-dose vaccinees (54%, 95% CI 50 to 57). Against hospitalisation, booster dose VE was 89% (95% CI 88 to 91) during Omicron and 94% (95% CI 90 to 96) during Delta; two-dose VE was 63% (95% CI 58 to 67) during Omicron and 75% (95% CI 69 to 80) during Delta. Against death, the VE with a booster dose was 94% (95% CI 90 to 96) during Omicron and 96% (95% CI 87 to 99) during Delta.Among an older, mostly male, population with comorbidities, we found that an mRNA vaccine booster was highly effective against infection, hospitalisation and death. Although the effectiveness of booster vaccination against infection was moderately higher against Delta than against the Omicron SARS-CoV-2 variant, effectiveness against severe disease and death was similarly high against both variants.

  View details for DOI 10.1136/bmjopen-2022-063935

  View details for PubMedID 35922100

• Risk Factors for Acute Gastroenteritis Among Patients Hospitalized in 5 Veterans Affairs Medical Centers, 2016-2019. Open forum infectious diseases Balachandran, N., Cates, J., Kambhampati, A. K., Marconi, V. C., Whitmire, A., Morales, E., Brown, S. T., Lama, D., Rodriguez-Barradas, M. C., Moronez, R. G., Domiguez, G. R., Beenhouwer, D. O., Poteshkina, A., Matolek, Z. A., Holodniy, M., Lucero-Obusan, C., Agarwal, M., Cardemil, C., Parashar, U., Mirza, S. A. 2022; 9 (8): ofac339

  Abstract

  In the United States, ∼179 million acute gastroenteritis (AGE) episodes occur annually. We aimed to identify risk factors for all-cause AGE, norovirus-associated vs non-norovirus AGE, and severe vs mild/moderate AGE among hospitalized adults.We enrolled 1029 AGE cases and 624 non-AGE controls from December 1, 2016, to November 30, 2019, at 5 Veterans Affairs Medical Centers. Patient interviews and medical chart abstractions were conducted, and participant stool samples were tested using the BioFire Gastrointestinal Panel. Severe AGE was defined as a modified Vesikari score of ≥11. Multivariate logistic regression was performed to assess associations between potential risk factors and outcomes; univariate analysis was conducted for norovirus-associated AGE due to limited sample size.Among 1029 AGE cases, 551 (54%) had severe AGE and 44 (4%) were norovirus positive. Risk factors for all-cause AGE included immunosuppressive therapy (adjusted odds ratio [aOR], 5.6; 95% CI, 2.7-11.7), HIV infection (aOR, 3.9; 95% CI, 1.8-8.5), severe renal disease (aOR, 3.1; 95% CI, 1.8-5.2), and household contact with a person with AGE (aOR, 2.9; 95% CI, 1.3-6.7). Household (OR, 4.4; 95% CI, 1.6-12.0) and non-household contact (OR, 5.0; 95% CI, 2.2-11.5) with AGE was associated with norovirus-associated AGE. Norovirus positivity (aOR, 3.4; 95% CI, 1.3-8.8) was significantly associated with severe AGE.Patients with immunosuppressive therapy, HIV, and severe renal disease should be monitored for AGE and may benefit from targeted public health messaging regarding AGE prevention. These results may also direct future public health interventions, such as norovirus vaccines, to specific high-risk populations.

  View details for DOI 10.1093/ofid/ofac339

  View details for PubMedID 35949407

  View details for PubMedCentralID PMC9356693

• Evaluation of independent self-collected blood specimens for COVID-19 antibody detection among the US veteran population. Diagnostic microbiology and infectious disease Mohammed, T., Brewer, J. V., Pyatt, M., Whitbourne, S. B., Gaziano, J. M., Edson, C., Holodniy, M. 2022; 104 (2): 115770

  Abstract

  Feasibility of home blood sample collection methods for the presence of SARS-CoV-2 antibodies from VA Million Veteran Program (MVP) participants was tested to determine COVID-19 infection or vaccination status. Participants (n = 312) were randomly assigned to self-collect blood specimens using the Neoteryx Mitra Clamshell (n = 136) or Tasso-SST (n = 176) and asked to rate their experience. Mitra tip blood was eluted and Tasso tubes were centrifuged. All samples were stored at -80 °C until tested with InBios SCoV-2 Detect™ IgG ELISA, BioRad Platelia SARS-CoV-2 Total Ab Assay, Abbott SARS-CoV-2 IgG and AdviseDx SARS-CoV-2 IgG II assays. Participants rated both devices equally. The Abbott assay had the highest sensitivity (87% Mitra, 98% Tasso-SST) for detecting known COVID infection and/or vaccination. The InBios assay with Tasso-SST had the best sensitivity (97%) and specificity (80%) for detecting known COVID-19 infection and/or vaccination. Veterans successfully collected their own specimens with no strong preference for either device.

  View details for DOI 10.1016/j.diagmicrobio.2022.115770

  View details for PubMedID 35985109

• Association of Secretor Status and Recent Norovirus Infection With Gut Microbiome Diversity Metrics in a Veterans Affairs Population. Open forum infectious diseases Johnson, J. A., Read, T. D., Petit, R. A., Marconi, V. C., Meagley, K. L., Rodriguez-Barradas, M. C., Beenhouwer, D. O., Brown, S. T., Holodniy, M., Lucero-Obusan, C. A., Schirmer, P., Ingersoll, J. M., Kraft, C. S., Neill, F. H., Atmar, R. L., Kambhampati, A. K., Cates, J. E., Mirza, S. A., Hall, A. J., Cardemil, C. V., Lopman, B. A. 2022; 9 (5): ofac125

  Abstract

  Norovirus infection causing acute gastroenteritis could lead to adverse effects on the gut microbiome. We assessed the association of microbiome diversity with norovirus infection and secretor status in patients from Veterans Affairs medical centers. Alpha diversity metrics were lower among patients with acute gastroenteritis but were similar for other comparisons.

  View details for DOI 10.1093/ofid/ofac125

  View details for PubMedID 35434176

• Effectiveness of mRNA-based vaccines during the emergence of SARS-CoV-2 Omicron variant. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Sharma, A., Oda, G., Holodniy, M. 2022

  Abstract

  BACKGROUND: We evaluated effectiveness of mRNA-based vaccines following emergence of SARS-CoV-2 Omicron variant.METHODS: Recipients of a third dose of BNT162b2 or mRNA-1273 ≥ 180 days after the primary series were matched to primary series recipients and unvaccinated persons. Participants were followed from December 1, 2021 to March 12, 2022. Outcomes were documented SARS-CoV-2 infection, COVID-19 hospitalization, and COVID-19 death. Effectiveness was calculated from 100-day risks estimated with the Kaplan-Meier estimator.RESULTS: BNT162b2 and mRNA-1273 groups respectively included 221,267 and 187,507 third dose recipients matched to equal numbers of primary series recipients and unvaccinated persons. Compared to no vaccination, effectiveness of a third dose of BNT162b2 was 47.8% (95% confidence interval [CI]: 45.2-50.3), 81.8% (95% CI 79.2-84.2), and 89.6% (95% CI 85.0-93.6) against documented infection, hospitalization, and death, respectively. Effectiveness of a third dose of BNT162b2 compared to the primary series was 30.1% (95% CI 26.2-33.7), 61.4% (95% CI 55.0-67.1), and 78.8% (95% CI 67.9-87.5) against documented infection, hospitalization, and death, respectively.Effectiveness of a third dose of mRNA-1273 compared to no vaccination was 61.9% (95% CI 59.4-64.4), 87.9% (95% CI 85.3-90.2), and 91.4% (95% CI 86.4-95.6) against documented infection, hospitalization, and death, respectively. Effectiveness of a third dose of mRNA-1273 compared to the primary series was 37.1% (95% CI 32.2-41.7), 63.5% (95% CI 53.7-71.6), and 75.0% (95% CI 55.4-88.0) against documented infection, hospitalization, and death, respectively.CONCLUSIONS: BNT162b2 and mRNA-1273 were effective against COVID-19 following emergence of Omicron variant. A third dose provided additional protection over the primary series.

  View details for DOI 10.1093/cid/ciac325

  View details for PubMedID 35475889

• Public health surveillance in the U.S. Department of Veterans Affairs: evaluation of the Praedico surveillance system. BMC public health Lucero-Obusan, C., Oda, G., Mostaghimi, A., Schirmer, P., Holodniy, M. 2022; 22 (1): 272

  Abstract

  Early threat detection and situational awareness are vital to achieving a comprehensive and accurate view of health-related events for federal, state, and local health agencies. Key to this are public health and syndromic surveillance systems that can analyze large data sets to discover patterns, trends, and correlations of public health significance. In 2020, Department of Veterans Affairs (VA) evaluated its public health surveillance system and identified areas for improvement.Using the Centers for Disease Control and Prevention (CDC) Guidelines for Evaluating Public Health Surveillance Systems, we assessed the ability of the Praedico Surveillance System to perform public health surveillance for a variety of health issues and evaluated its performance compared to an enterprise data solution (VA Corporate Data Warehouse), legacy surveillance system (VA ESSENCE) and a national, collaborative syndromic surveillance platform (CDC NSSP BioSense).Review of system attributes found that the system was simple, flexible, and stable. Representativeness, timeliness, sensitivity, and Predictive Value Positive were acceptable but could be further improved. Data quality issues and acceptability present challenges that potentially affect the overall usefulness of the system.Praedico is a customizable surveillance and data analytics platform built on big data technologies. Functionality is straightforward, with rapid query generation and runtimes. Data can be graphed, mapped, analyzed, and shared with key decision makers and stakeholders. Evaluation findings suggest that future development and system enhancements should focus on addressing Praedico data quality issues and improving user acceptability. Because Praedico is designed to handle big data queries and work with data from a variety of sources, it could be enlisted as a tool for interdepartmental and interagency collaboration and public health data sharing. We suggest that future system evaluations include measurements of value and effectiveness along with additional organizations and functional assessments.

  View details for DOI 10.1186/s12889-022-12578-2

  View details for PubMedID 35144575

• SARS-CoV-2 Illness Severity and Early Hospitalization Outcomes in a Multicenter Prospective Cohort Study Among Veterans IDWeek Ross, J., Sugimoto, J., Timmons, A., Moore, K., Adams, J., Wilson, D., Liu, C., Deardoff, K., Korpak, A., Chang, K., Cho, K., Crothers, K., Gaziano, M., Holodniy, M., Hunt, C., Isaacs, S., Jones, B., Le, E., Shah, J., Smith, N., Lee, J. 2022: S197
• Trends in Follow-up Testing among Patients Positive for Chlamydia and Gonorrhea in the Veterans Health Administration (VHA), 2013-2019 IDWeek Schirmer, P., Sharma, A., Lucero-Obusan, C., Oda, G., Holodniy, M. 2022: S906

  View details for DOI 10.1093/ofid/ofac492.1839

• Receipt of Influenza Vaccination as Predictor of COVID-19 Vaccination among United States Veterans IDWeek Oda, G., Sharma, A., Lucero-Obusan, C., Schirmer, P., Holodniy, M. 2022: S780

  View details for DOI 10.1093/ofid/ofac492.1592

• Implementation of large-scale laboratory-based detection of COVID-19 in the Veterans Health Administration, March 2020 - February 2021. Diagnostic microbiology and infectious disease Sharma, A., Oda, G., Icardi, M., Mole, L., Holodniy, M. 1800; 102 (3): 115617

  Abstract

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presented numerous operational challenges to healthcare delivery networks responsible for implementing large scale detection of Coronavirus Disease 2019 (COVID-19), the infection caused by SARS-CoV-2. We describe testing performance, review data quality metrics, and summarize experiences during the scale up of laboratory-based detection of COVID-19 in the Veterans Health Administration, the largest healthcare system in the United States. During March 2020 to February 2021, we observed rapid increase in testing volume, decreases in test turnaround time, improvements in testing of hospitalized persons, changes in test positivity, and varying utilization of different tests. Though performance metrics improved over time, surges challenged testing capacity and data quality remained suboptimal. Future planning efforts should focus on fortifying supply chains for consumables and equipment repair, optimizing distribution of testing workload across laboratories, and improving informatics to accurately monitor operations and intent for testing during a public health emergency.

  View details for DOI 10.1016/j.diagmicrobio.2021.115617

  View details for PubMedID 35007825

• Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial. The Lancet. Respiratory medicine Kalil, A. C., Mehta, A. K., Patterson, T. F., Erdmann, N., Gomez, C. A., Jain, M. K., Wolfe, C. R., Ruiz-Palacios, G. M., Kline, S., Regalado Pineda, J., Luetkemeyer, A. F., Harkins, M. S., Jackson, P. E., Iovine, N. M., Tapson, V. F., Oh, M. D., Whitaker, J. A., Mularski, R. A., Paules, C. I., Ince, D., Takasaki, J., Sweeney, D. A., Sandkovsky, U., Wyles, D. L., Hohmann, E., Grimes, K. A., Grossberg, R., Laguio-Vila, M., Lambert, A. A., Lopez de Castilla, D., Kim, E., Larson, L., Wan, C. R., Traenkner, J. J., Ponce, P. O., Patterson, J. E., Goepfert, P. A., Sofarelli, T. A., Mocherla, S., Ko, E. R., Ponce de Leon, A., Doernberg, S. B., Atmar, R. L., Maves, R. C., Dangond, F., Ferreira, J., Green, M., Makowski, M., Bonnett, T., Beresnev, T., Ghazaryan, V., Dempsey, W., Nayak, S. U., Dodd, L., Tomashek, K. M., Beigel, J. H. 2021

  Abstract

  Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19.We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475.Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group.Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo.The National Institute of Allergy and Infectious Diseases (USA).

  View details for DOI 10.1016/S2213-2600(21)00384-2

  View details for PubMedID 34672949

  View details for PubMedCentralID PMC8523116

• Reduced Mortality With Ondansetron Use in SARS-CoV-2-Infected Inpatients. Open forum infectious diseases Bayat, V., Ryono, R., Phelps, S., Geis, E., Sedghi, F., Etminani, P., Holodniy, M. 2021; 8 (7): ofab336

  Abstract

  Background: The coronavirus disease 2019 (COVID-19) pandemic has led to a surge in clinical trials evaluating investigational and approved drugs. Retrospective analysis of drugs taken by COVID-19 inpatients provides key information on drugs associated with better or worse outcomes.Methods: We conducted a retrospective cohort study of 10 741 patients testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within 3 days of admission to compare risk of 30-day all-cause mortality in patients receiving ondansetron using multivariate Cox proportional hazard models. All-cause mortality, length of hospital stay, adverse events such as ischemic cerebral infarction, and subsequent positive COVID-19 tests were measured.Results: Administration of ≥8 mg of ondansetron within 48 hours of admission was correlated with an adjusted hazard ratio for 30-day all-cause mortality of 0.55 (95% CI, 0.42-0.70; P < .001) and 0.52 (95% CI, 0.31-0.87; P = .012) for all and intensive care unit-admitted patients, respectively. Decreased lengths of stay (9.2 vs 11.6; P < .001), frequencies of subsequent positive SARS-CoV-2 tests (53.6% vs 75.0%; P = .01), and long-term risks of ischemic cerebral ischemia (3.2% vs 6.1%; P < .001) were also noted.Conclusions: If confirmed by prospective clinical trials, our results suggest that ondansetron, a safe, widely available drug, could be used to decrease morbidity and mortality in at-risk populations.

  View details for DOI 10.1093/ofid/ofab336

  View details for PubMedID 34307731

• Respiratory co-infections with COVID-19 in the Veterans Health Administration, 2020. Diagnostic microbiology and infectious disease Schirmer, P. n., Lucero-Obusan, C. n., Sharma, A. n., Sohoni, P. n., Oda, G. n., Holodniy, M. n. 2021; 100 (1): 115312

  Abstract

  Reporting of Coronavirus disease 2019 (COVID-19) co-infections with other respiratory pathogens has varied. We evaluated 825,280 molecular and/or viral culture respiratory assays within the Veterans Health Administration from September 29, 2019 to May 31, 2020. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detected in 10,222 of 174,746 (5.8%) individuals. 30,063 (17.2%) of 174,746 individuals tested for SARS-CoV-2 had additional respiratory pathogen testing; co-infection was identified in 56 of 3757 (1.5%) individuals positive for SARS-CoV-2. Among those negative for SARS-CoV-2, 1022 of 26,306 (3.9%) were positive for at least 1 respiratory pathogen. Compared to COVID-19 mono-infection, individuals with COVID-19 co-infection had lower odds of being female. Compared to non-COVID-19 respiratory pathogen infection, individuals with COVID-19 co-infection had lower odds of being female, were hospitalized more frequently, had higher odds of death, and were younger at death. Our findings suggest COVID-19 co-infections were rare; however, not all COVID-19 patients were concurrently tested for other respiratory pathogens and seasonal decreases in other respiratory pathogens were occurring as COVID-19 emerged.

  View details for DOI 10.1016/j.diagmicrobio.2021.115312

  View details for PubMedID 33561606

  View details for PubMedCentralID PMC7816561

• COVID-19 At-Home Capillary Blood Specimen Collection Pilot – Gaining Insight into Independent Self- Collection of Blood Specimens and COVID-19 Within the Veteran Population IDWeek Mohammed, T., Brewer, J., Pyatt, M., Casas, J., Whitbourne, S., Gaziano, M., Edson, C., Holodniy, M. 2021: 593-594

  View details for DOI 10.1093/ofid/ofab466.1199

• Risk Factors for Acute Gastroenteritis Among Patients Hospitalized in 5 Veterans Affairs Medical Centers, 2016–19 IDWeek Balachandran, N., Cates, J., Kambhampati, A., Marconi, V., Brown, S., Rodriguez–Barradas, M., Beenhouwer, D., Holodniy, M., Lucero-Obusan, C., Cardemil, C., Parashar, U., Mirza, S. 2021: S451

  View details for DOI 10.1093/ofid/ofab466.899

• Diphtheria in Veterans Health Administration (VHA), 2000-2021 IDWeek Schirmer, P., Lucero-Obusan, C., Sharma, A., Oda, G., Holodniy, M. 2021: S692

  View details for DOI 10.1093/ofid/ofab466.1393

• COVID-19 Vaccine Breakthrough Hospitalizations and Deaths in the Veterans Health Administration IDWeek Oda, G., Sharma, A., Lucero-Obusan, C., Schirmer, P., Holodniy, M., Edson, C., Khaksar, R. 2021: S61–S62

  View details for DOI 10.1093/ofid/ofab466.098

• Influenza Surveillance in the Veterans Health Administration (VHA): 2020-2021 Season IDWeek Lucero, C., Schirmer, P., Oda, G., Holodniy, M. 2021: S803

  View details for DOI 10.1093/ofid/ofab466.1636

• Adapting the Surveillance Platform for Enteric and Respiratory Infectious Organisms at United States Veterans Affairs Medical Centers (SUPERNOVA) for COVID-19 Among Hospitalized Adults: Surveillance Protocol. Frontiers in public health Meites, E., Bajema, K. L., Kambhampati, A., Prill, M., Marconi, V. C., Brown, S. T., Rodriguez-Barradas, M. C., Beenhouwer, D. O., Holodniy, M., Lucero-Obusan, C., Cardemil, C., Cates, J., Surie, D. 2021; 9: 739076

  Abstract

  Introduction: Early in the COVID-19 pandemic, the Centers for Disease Control and Prevention (CDC) rapidly initiated COVID-19 surveillance by leveraging existing hospital networks to assess disease burden among hospitalized inpatients and inform prevention efforts. Materials and Methods: The Surveillance Platform for Enteric and Respiratory Infectious Organisms at Veterans Affairs Medical Centers (SUPERNOVA) is a network of five United States Veterans Affairs Medical Centers which serves nearly 400,000 Veterans annually and conducts laboratory-based passive and active monitoring for pathogens associated with acute gastroenteritis and acute respiratory illness among hospitalized Veterans. This paper presents surveillance methods for adapting the SUPERNOVA surveillance platform to prospectively evaluate COVID-19 epidemiology during a public health emergency, including detecting, characterizing, and monitoring patients with and without COVID-19 beginning in March 2020. To allow for case-control analyses, patients with COVID-19 and patients with non-COVID-19 acute respiratory illness were included. Results: SUPERNOVA included 1,235 participants with COVID-19 and 707 participants with other acute respiratory illnesses hospitalized during February through December 2020. Most participants were male (93.1%), with a median age of 70 years, and 45.8% non-Hispanic Black and 32.6% non-Hispanic White. Among those with COVID-19, 28.2% were transferred to an intensive care unit, 9.4% received invasive mechanical ventilation, and 13.9% died. Compared with controls, after adjusting for age, sex, and race/ethnicity, COVID-19 case-patients had significantly higher risk of mortality, respiratory failure, and invasive mechanical ventilation, and longer hospital stays. Discussion: Strengths of the SUPERNOVA platform for COVID-19 surveillance include the ability to collect and integrate multiple types of data, including clinical and illness outcome information, and SARS-CoV-2 laboratory test results from respiratory and serum specimens. Analysis of data from this platform also enables formal comparisons of participants with and without COVID-19. Surveillance data collected during a public health emergency from this key U.S. population of Veterans will be useful for epidemiologic investigations of COVID-19 spectrum of disease, underlying medical conditions, virus variants, and vaccine effectiveness, according to public health priorities and needs.

  View details for DOI 10.3389/fpubh.2021.739076

  View details for PubMedID 34778173

  View details for PubMedCentralID PMC8585926

• From implementation to sustainment: A large-scale adverse event disclosure support program generated through embedded research in the Veterans Health Administration. Healthcare (Amsterdam, Netherlands) Elwy, A. R., Maguire, E. M., McCullough, M., George, J., Bokhour, B. G., Durfee, J. M., Martinello, R. A., Wagner, T. H., Asch, S. M., Gifford, A. L., Gallagher, T. H., Walker, Y., Sharpe, V. A., Geppert, C., Holodniy, M., West, G. 2021; 8 Suppl 1: 100496

  Abstract

  In 2008, the Veterans Health Administration published a groundbreaking policy on disclosing large-scale adverse events to patients in order to promote transparent communication in cases where harm may not be obvious or even certain. Without embedded research, the evidence on whether or not implementation of this policy was generating more harm than good among Veteran patients was unknown. Through an embedded research-operations partnership, we conducted four research projects that led to the development of an evidence-based large-scale disclosure toolkit and disclosure support program, and its implementation across VA healthcare. Guided by the Consolidated Framework for Implementation Research, we identified specific activities corresponding to planning, engaging, executing, reflecting and evaluating phases in the process of implementation. These activities included planning with operational leaders to establish a shared research agenda; engaging with stakeholders to discuss early results, establishing buy-in of our efforts and receiving feedback; joining existing operational teams to execute the toolkit implementation; partnering with clinical operations to evaluate the toolkit during real-time disclosures; and redesigning the toolkit to meet stakeholders' needs. Critical lessons learned for implementation success included a need for stakeholder collaboration and engagement, an organizational culture involving a strong belief in evidence, a willingness to embed researchers in clinical operation activities, allowing for testing and evaluation of innovative practices, and researchers open to constructive feedback. At the conclusion of the research, VA operations worked with the researchers to continue to support efforts to spread, scale-up and sustain toolkit use across the VA healthcare system, with the final goal to establish long-term sustainability.

  View details for DOI 10.1016/j.hjdsi.2020.100496

  View details for PubMedID 34175102

• Comparative Effectiveness and Antibody Responses to Moderna and Pfizer-BioNTech COVID-19 Vaccines among Hospitalized Veterans - Five Veterans Affairs Medical Centers, United States, February 1-September 30, 2021. MMWR. Morbidity and mortality weekly report Bajema, K. L., Dahl, R. M., Evener, S. L., Prill, M. M., Rodriguez-Barradas, M. C., Marconi, V. C., Beenhouwer, D. O., Holodniy, M., Lucero-Obusan, C., Brown, S. T., Tremarelli, M., Epperson, M., Mills, L., Park, S. H., Rivera-Dominguez, G., Morones, R. G., Ahmadi-Izadi, G., Deovic, R., Mendoza, C., Jeong, C., Schrag, S. J., Meites, E., Hall, A. J., Kobayashi, M., McMorrow, M., Verani, J. R., Thornburg, N. J., Surie, D. 2021; 70 (49): 1700-1705

  Abstract

  The mRNA COVID-19 vaccines (Moderna and Pfizer-BioNTech) provide strong protection against severe COVID-19, including hospitalization, for at least several months after receipt of the second dose (1,2). However, studies examining immune responses and differences in protection against COVID-19-associated hospitalization in real-world settings, including by vaccine product, are limited. To understand how vaccine effectiveness (VE) might change with time, CDC and collaborators assessed the comparative effectiveness of Moderna and Pfizer-BioNTech vaccines in preventing COVID-19-associated hospitalization at two periods (14-119 days and ≥120 days) after receipt of the second vaccine dose among 1,896 U.S. veterans at five Veterans Affairs medical centers (VAMCs) during February 1-September 30, 2021. Among 234 U.S. veterans fully vaccinated with an mRNA COVID-19 vaccine and without evidence of current or prior SARS-CoV-2 infection, serum antibody levels (anti-spike immunoglobulin G [IgG] and anti-receptor binding domain [RBD] IgG) to SARS-CoV-2 were also compared. Adjusted VE 14-119 days following second Moderna vaccine dose was 89.6% (95% CI = 80.1%-94.5%) and after the second Pfizer-BioNTech dose was 86.0% (95% CI = 77.6%-91.3%); at ≥120 days VE was 86.1% (95% CI = 77.7%-91.3%) for Moderna and 75.1% (95% CI = 64.6%-82.4%) for Pfizer-BioNTech. Antibody levels were significantly higher among Moderna recipients than Pfizer-BioNTech recipients across all age groups and periods since vaccination; however, antibody levels among recipients of both products declined between 14-119 days and ≥120 days. These findings from a cohort of older, hospitalized veterans with high prevalences of underlying conditions suggest the importance of booster doses to help maintain long-term protection against severe COVID-19.†.

  View details for DOI 10.15585/mmwr.mm7049a2

  View details for PubMedID 34882654

• Effectiveness of COVID-19 mRNA Vaccines Against COVID-19-Associated Hospitalization - Five Veterans Affairs Medical Centers, United States, February 1-August 6, 2021. MMWR. Morbidity and mortality weekly report Bajema, K. L., Dahl, R. M., Prill, M. M., Meites, E., Rodriguez-Barradas, M. C., Marconi, V. C., Beenhouwer, D. O., Brown, S. T., Holodniy, M., Lucero-Obusan, C., Rivera-Dominguez, G., Morones, R. G., Whitmire, A., Goldin, E. B., Evener, S. L., Tremarelli, M., Tong, S., Hall, A. J., Schrag, S. J., McMorrow, M., Kobayashi, M., Verani, J. R., Surie, D. 2021; 70 (37): 1294-1299

  Abstract

  COVID-19 mRNA vaccines (Pfizer-BioNTech and Moderna) have been shown to be highly protective against COVID-19-associated hospitalizations (1-3). Data are limited on the level of protection against hospitalization among disproportionately affected populations in the United States, particularly during periods in which the B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19, predominates (2). U.S. veterans are older, more racially diverse, and have higher prevalences of underlying medical conditions than persons in the general U.S. population (2,4). CDC assessed the effectiveness of mRNA vaccines against COVID-19-associated hospitalization among 1,175 U.S. veterans aged ≥18 years hospitalized at five Veterans Affairs Medical Centers (VAMCs) during February 1-August 6, 2021. Among these hospitalized persons, 1,093 (93.0%) were men, the median age was 68 years, 574 (48.9%) were non-Hispanic Black (Black), 475 were non-Hispanic White (White), and 522 (44.4%) had a Charlson comorbidity index score of ≥3 (5). Overall adjusted vaccine effectiveness against COVID-19-associated hospitalization was 86.8% (95% confidence interval [CI] = 80.4%-91.1%) and was similar before (February 1-June 30) and during (July 1-August 6) SARS-CoV-2 Delta variant predominance (84.1% versus 89.3%, respectively). Vaccine effectiveness was 79.8% (95% CI = 67.7%-87.4%) among adults aged ≥65 years and 95.1% (95% CI = 89.1%-97.8%) among those aged 18-64 years. COVID-19 mRNA vaccines are highly effective in preventing COVID-19-associated hospitalization in this older, racially diverse population of predominately male U.S. veterans. Additional evaluations of vaccine effectiveness among various age groups are warranted. To prevent COVID-19-related hospitalizations, all eligible persons should receive COVID-19 vaccination.

  View details for DOI 10.15585/mmwr.mm7037e3

  View details for PubMedID 34529636

  View details for PubMedCentralID PMC8445376

• COVID-19 Infections Among Healthcare Personnel in the United States Veterans Health Administration, March - August, 2020. Journal of occupational and environmental medicine Oda, G., Sharma, A., Lucero-Obusan, C., Schirmer, P., Sohoni, P., Holodniy, M. 2020

  Abstract

  OBJECTIVE: We investigated COVID-19 infection and death among healthcare personnel (HCP) in the U.S. Veterans Health Administration.METHODS: HCP with positive SARS-CoV-2 RT-PCR tests between March 1-August 31, 2020 were included. Risk ratios were calculated for sex, age, race/ethnicity, Veteran status, occupation category, facility of employment by inpatient COVID-19 test percent positivity and death.RESULTS: 5,925 HCP were COVID-19-infected out of 131,606 tested (4.5% positivity). Highest risk for COVID-19 infection included: HCP working in hospitals with >15% inpatient COVID-19 test positivity, nursing staff, non-Hispanic Black and Hispanic or Latino HCP and HCP who were Veterans. Among 18 HCP who died after COVID-19 infection, male sex, age ≥65 years, and Veteran status were significant risk factors.CONCLUSIONS: Robust national surveillance testing methods are needed to accurately monitor HCP COVID-19 infections and deaths to improve HCP safety.

  View details for DOI 10.1097/JOM.0000000000002109

  View details for PubMedID 33315723

• Candida auris in the US Department of Veterans' Affairs (VA) Lucero-Obusan, C., Schirmer, P., Oda, G., Holodniy, M. CAMBRIDGE UNIV PRESS. 2020: S146

  View details for DOI 10.1017/ice.2020.663

  View details for Web of Science ID 000621851500193

• Lessons Learned From a Decade of Dental Lookback Investigations in the Department of Veterans' Affairs (VA): 2009-2019 Schirmer, P., Lucero-Obusan, C., Oda, G., West, G., Holodniy, M. CAMBRIDGE UNIV PRESS. 2020: S310-S311

  View details for DOI 10.1017/ice.2020.900

  View details for Web of Science ID 000621851501132

• Prevalence of Drug-Resistant Mycobacterium tuberculosis in the Veterans Health Administration (VHA) Oda, G., Lucero-Obusan, C., Schirmer, P., Holodniy, M. CAMBRIDGE UNIV PRESS. 2020: S357-S359

  View details for DOI 10.1017/ice.2020.979

  View details for Web of Science ID 000621851501211

• Lack of Evidence of Transmission of Bloodborne Viruses by Improperly Reprocessed Fiberoptic Endoscopes Sellick, J., Oda, G., Schirmer, P., Lucero-Obusan, C., Holodniy, M. CAMBRIDGE UNIV PRESS. 2020: S309-S310

  View details for DOI 10.1017/ice.2020.898

  View details for Web of Science ID 000621851501130

• A SARS-CoV-2 Prediction Model from Standard Laboratory Tests. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Bayat, V., Phelps, S., Ryono, R., Lee, C., Parekh, H., Mewton, J., Sedghi, F., Etminani, P., Holodniy, M. 2020

  Abstract

  BACKGROUND: With the limited availability of testing for the presence of the SARS-CoV-2 virus and concerns surrounding the accuracy of existing methods, other means of identifying patients are urgently needed. Previous studies showing a correlation between certain laboratory tests and diagnosis suggest an alternative method based on an ensemble of tests.METHODS: We have trained a machine learning model to analyze the correlation between SARS-CoV-2 test results and 20 routine laboratory tests collected within a 2-day period around the SARS-CoV-2 test date. We used the model to compare SARS-CoV-2 positive and negative patients.RESULTS: In a cohort of 75,991 veteran inpatients and outpatients who tested for SARS-CoV-2 in the months of March through July, 2020, 7,335 of whom were positive by RT-PCR or antigen testing, and who had at least 15 of 20 lab results within the window period, our model predicted the results of the SARS-CoV-2 test with a specificity of 86.8%, a sensitivity of 82.4%, and an overall accuracy of 86.4% (with a 95% confidence interval of [86.0%, 86.9%]).CONCLUSIONS: While molecular-based and antibody tests remain the reference standard method for confirming a SARS-CoV-2 diagnosis, their clinical sensitivity is not well known. The model described herein may provide a complementary method of determining SARS-CoV-2 infection status, based on a fully independent set of indicators, that can help confirm results from other tests as well as identify positive cases missed by molecular testing.

  View details for DOI 10.1093/cid/ciaa1175

  View details for PubMedID 32785701

• Remdesivir for the Treatment of Covid-19 - Preliminary Report. The New England journal of medicine Beigel, J. H., Tomashek, K. M., Dodd, L. E., Mehta, A. K., Zingman, B. S., Kalil, A. C., Hohmann, E., Chu, H. Y., Luetkemeyer, A., Kline, S., Lopez de Castilla, D., Finberg, R. W., Dierberg, K., Tapson, V., Hsieh, L., Patterson, T. F., Paredes, R., Sweeney, D. A., Short, W. R., Touloumi, G., Lye, D. C., Ohmagari, N., Oh, M. D., Ruiz-Palacios, G. M., Benfield, T., Fätkenheuer, G., Kortepeter, M. G., Atmar, R. L., Creech, C. B., Lundgren, J., Babiker, A. G., Pett, S., Neaton, J. D., Burgess, T. H., Bonnett, T., Green, M., Makowski, M., Osinusi, A., Nayak, S., Lane, H. C. 2020

  Abstract

  Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious.We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%).Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACCT-1 ClinicalTrials.gov number, NCT04280705.).

  View details for DOI 10.1056/NEJMoa2007764

  View details for PubMedID 32445440

  View details for PubMedCentralID PMC7262788

• Remdesivir for the treatment of COVID-19 - Final Report (Adaptive COVID-19 Treatment Trial (ACTT-1)) The New England Journal of Medicine Study Team, M. 2020

  Abstract

  Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious.We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%).Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACCT-1 ClinicalTrials.gov number, NCT04280705.).

  View details for DOI 10.1056/NEJMoa2007764

  View details for PubMedCentralID PMC7262788

• Molecular testing for acute respiratory tract infections: clinical and diagnostic recommendations from the IDSA's Diagnostics Committee. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Hanson, K. E., Azar, M. M., Banerjee, R., Chou, A., Colgrove, R. C., Ginocchio, C. C., Hayden, M. K., Holodiny, M., Jain, S., Koo, S., Levy, J., Timbrook, T. T., Caliendo, A. M., Diagnostics Committee of the Infectious Diseases Society of America (IDSA) 2020

  Abstract

  The clinical signs and symptoms of acute respiratory tract infections (RTIs) are not pathogen specific. Highly sensitive and specific nucleic acid amplification tests have become the diagnostic reference standard for viruses and translation of bacterial assays from basic research to routine clinical practice represents an exciting advance in respiratory medicine. Most recently, molecular diagnostics have played an essential role in the global health response to the novel coronavirus pandemic. How best to use newer molecular tests for RTI in combination with clinical judgment and traditional methods can be bewildering given the plethora of available assays and rapidly evolving technologies. Here, we summarize the current state of the art with respect to the diagnosis of viral and bacterial RTIs, provide a practical framework for diagnostic decision-making using selected patient-centered vignettes, and make recommendations for future studies to advance the field.

  View details for DOI 10.1093/cid/ciaa508

  View details for PubMedID 32369578

• Covid-19 Testing, Hospital Admission, and Intensive Care Among 2,026,227 United States Veterans Aged 54-75 Years. medRxiv : the preprint server for health sciences Rentsch, C. T., Kidwai-Khan, F., Tate, J. P., Park, L. S., King, J. T., Skanderson, M., Hauser, R. G., Schultze, A., Jarvis, C. I., Holodniy, M., Re, V. L., Akgün, K. M., Crothers, K., Taddei, T. H., Freiberg, M. S., Justice, A. C. 2020

  Abstract

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes coronavirus disease 2019 (Covid-19), an evolving pandemic. Limited data are available characterizing SARS-Cov-2 infection in the United States.To determine associations between demographic and clinical factors and testing positive for coronavirus 2019 (Covid-19+), and among Covid-19+ subsequent hospitalization and intensive care.Retrospective cohort study including all patients tested for Covid-19 between February 8 and March 30, 2020, inclusive. We extracted electronic health record data from the national Veterans Affairs Healthcare System, the largest integrated healthcare system in the United States, on 2,026,227 patients born between 1945 and 1965 and active in care. Exposures: Demographic data, comorbidities, medication history, substance use, vital signs, and laboratory measures. Laboratory tests were analyzed first individually and then grouped into a validated summary measure of physiologic injury (VACS Index). Main Outcomes and Measures: We evaluated which factors were associated with Covid-19+ among all who tested. Among Covid-19+ we identified factors associated with hospitalization or intensive care. We identified independent associations using multivariable and conditional multivariable logistic regression with multiple imputation of missing values.Among Veterans aged 54-75 years, 585/3,789 (15.4%) tested Covid-19+. In adjusted analysis (C-statistic=0.806) black race was associated with Covid-19+ (OR 4.68, 95% CI 3.79-5.78) and the association remained in analyses conditional on site (OR 2.56, 95% CI 1.89-3.46). In adjusted models, laboratory abnormalities (especially fibrosis-4 score [FIB-4] >3.25 OR 8.73, 95% CI 4.11-18.56), and VACS Index (per 5-point increase OR 1.62, 95% CI 1.43-1.84) were strongly associated with hospitalization. Associations were similar for intensive care. Although significant in unadjusted analyses, associations with comorbid conditions and medications were substantially reduced and, in most cases, no longer significant after adjustment.Black race was strongly associated with Covid-19+, but not with hospitalization or intensive care. Among Covid-19+, risk of hospitalization and intensive care may be better characterized by laboratory measures and vital signs than by comorbid conditions or prior medication exposure.

  View details for DOI 10.1101/2020.04.09.20059964

  View details for PubMedID 32511595

  View details for PubMedCentralID PMC7276022

• Risk for In-Hospital Complications Associated with COVID-19 and Influenza - Veterans Health Administration, United States, October 1, 2018-May 31, 2020. MMWR. Morbidity and mortality weekly report Cates, J. n., Lucero-Obusan, C. n., Dahl, R. M., Schirmer, P. n., Garg, S. n., Oda, G. n., Hall, A. J., Langley, G. n., Havers, F. P., Holodniy, M. n., Cardemil, C. V. 2020; 69 (42): 1528–34

  Abstract

  Coronavirus disease 2019 (COVID-19) is primarily a respiratory illness, although increasing evidence indicates that infection with SARS-CoV-2, the virus that causes COVID-19, can affect multiple organ systems (1). Data that examine all in-hospital complications of COVID-19 and that compare these complications with those associated with other viral respiratory pathogens, such as influenza, are lacking. To assess complications of COVID-19 and influenza, electronic health records (EHRs) from 3,948 hospitalized patients with COVID-19 (March 1-May 31, 2020) and 5,453 hospitalized patients with influenza (October 1, 2018-February 1, 2020) from the national Veterans Health Administration (VHA), the largest integrated health care system in the United States,* were analyzed. Using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes, complications in patients with laboratory-confirmed COVID-19 were compared with those in patients with influenza. Risk ratios were calculated and adjusted for age, sex, race/ethnicity, and underlying medical conditions; proportions of complications were stratified among patients with COVID-19 by race/ethnicity. Patients with COVID-19 had almost 19 times the risk for acute respiratory distress syndrome (ARDS) than did patients with influenza, (adjusted risk ratio [aRR] = 18.60; 95% confidence interval [CI] = 12.40-28.00), and more than twice the risk for myocarditis (2.56; 1.17-5.59), deep vein thrombosis (2.81; 2.04-3.87), pulmonary embolism (2.10; 1.53-2.89), intracranial hemorrhage (2.85; 1.35-6.03), acute hepatitis/liver failure (3.13; 1.92-5.10), bacteremia (2.46; 1.91-3.18), and pressure ulcers (2.65; 2.14-3.27). The risks for exacerbations of asthma (0.27; 0.16-0.44) and chronic obstructive pulmonary disease (COPD) (0.37; 0.32-0.42) were lower among patients with COVID-19 than among those with influenza. The percentage of COVID-19 patients who died while hospitalized (21.0%) was more than five times that of influenza patients (3.8%), and the duration of hospitalization was almost three times longer for COVID-19 patients. Among patients with COVID-19, the risk for respiratory, neurologic, and renal complications, and sepsis was higher among non-Hispanic Black or African American (Black) patients, patients of other races, and Hispanic or Latino (Hispanic) patients compared with those in non-Hispanic White (White) patients, even after adjusting for age and underlying medical conditions. These findings highlight the higher risk for most complications associated with COVID-19 compared with influenza and might aid clinicians and researchers in recognizing, monitoring, and managing the spectrum of COVID-19 manifestations. The higher risk for certain complications among racial and ethnic minority patients provides further evidence that certain racial and ethnic minority groups are disproportionally affected by COVID-19 and that this disparity is not solely accounted for by age and underlying medical conditions.

  View details for DOI 10.15585/mmwr.mm6942e3

  View details for PubMedID 33090987

• Baricitinib plus Remdesivir for Hospitalized Adults with COVID-19 (Adaptive COVID-19 Treatment Trial (ACTT-2)) The New England Journal of Medicine Study Team, M. 2020

  View details for DOI 10.1056/NEJMoa2031994

• Assessment and Capability of SARS-CoV-2 Detection in the Veterans Health Administration IDWeek Sharma, A., Oda, G., Holodniy, M. 2020

  View details for DOI 10.1093/ofid/ofaa439.606

• Comparative Assessment of Multiple SARS-CoV-2 Antibody and Neutralization Assays from Blood Samples in COVID-19 Infected Patients IDWeek Dewar, R., Trevino, C., Lallemand, P., Highbarger, H., Elbeik, T., Rehman, T., Holbrook, M., Schmaljohn, C., Lane, C., Chary, A., Holodniy, M. 2020

  View details for DOI 10.1093/ofid/ofaa439.611

• Influenza Surveillance in the U.S. Department of Veterans Affairs (VA): 2019-2020 Season IDWeek Lucero-Obusan, C., Schirmer, P., Oda, G., Holodniy, M. 2020

  View details for DOI 10.1093/ofid/ofaa439.1887

• Gonorrhea Testing and Ceftriaxone Resistance in the Department of Veterans Affairs (VA) IDWeek Schirmer, P., Lucero-Obusan, C., Oda, G., Holodniy, M. 2020

  View details for DOI 10.1093/ofid/ofaa439.1714

• Respiratory Coinfections with COVID-19 in Veterans Health Administration (VA), 2020 IDWeek Schirmer, T., Lucero-Obusan, C., Sharma, A., Sohini, P., Oda, G., Holodniy, M. 2020

  View details for DOI 10.1093/ofid/ofaa439.592

• Respiratory Syncytial Virus (RSV) Surveillance in the Department of Veterans Affairs (VA), 2010-2018 IDWeek Lucero-Obusan, C., Schirmer, T., Oda, G., Holodniy, M. 2020

  View details for DOI 10.1093/ofid/ofaa439.1896

• Covid-19 by Race and Ethnicity: A National Cohort Study of 6 Million United States Veterans. medRxiv : the preprint server for health sciences Rentsch, C. T., Kidwai-Khan, F. n., Tate, J. P., Park, L. S., King, J. T., Skanderson, M. n., Hauser, R. G., Schultze, A. n., Jarvis, C. I., Holodniy, M. n., Re, V. L., Akgün, K. M., Crothers, K. n., Taddei, T. H., Freiberg, M. S., Justice, A. C. 2020

  Abstract

  There is growing concern that racial and ethnic minority communities around the world are experiencing a disproportionate burden of morbidity and mortality from symptomatic SARS-Cov-2 infection or coronavirus disease 2019 (Covid-19). Most studies investigating racial and ethnic disparities to date have focused on hospitalized patients or have not characterized who received testing or those who tested positive for Covid-19.To compare patterns of testing and test results for coronavirus 2019 (Covid-19) and subsequent mortality by race and ethnicity in the largest integrated healthcare system in the United States.Retrospective cohort study.United States Department of Veterans Affairs (VA).5,834,543 individuals in care, among whom 62,098 were tested and 5,630 tested positive for Covid-19 between February 8 and May 4, 2020. Exposures: Self-reported race/ethnicity.We evaluated associations between race/ethnicity and receipt of Covid-19 testing, a positive test result, and 30-day mortality, accounting for a wide range of demographic and clinical risk factors including comorbid conditions, site of care, and urban versus rural residence.Among all individuals in care, 74% were non-Hispanic white (white), 19% non-Hispanic black (black), and 7% Hispanic. Compared with white individuals, black and Hispanic individuals were more likely to be tested for Covid-19 (tests per 1000: white=9.0, [95% CI 8.9 to 9.1]; black=16.4, [16.2 to 16.7]; and Hispanic=12.2, [11.9 to 12.5]). While individuals from minority backgrounds were more likely to test positive (black vs white: OR 1.96, 95% CI 1.81 to 2.12; Hispanic vs white: OR 1.73, 95% CI 1.53 to 1.96), 30-day mortality did not differ by race/ethnicity (black vs white: OR 0.93, 95% CI 0.64 to 1.33; Hispanic vs white: OR 1.07, 95% CI 0.61 to 1.87).Black and Hispanic individuals are experiencing an excess burden of Covid-19 not entirely explained by underlying medical conditions or where they live or receive care. While there was no observed difference in mortality by race or ethnicity, our findings may underestimate risk in the broader US population as health disparities tend to be reduced in VA.

  View details for DOI 10.1101/2020.05.12.20099135

  View details for PubMedID 32511524

  View details for PubMedCentralID PMC7273292

• COVID-19-associated hospitalization rates and severe outcomes among Veterans from 5 Veteran Affairs Medical Centers, February 27-July 17, 2020: Hospital-Based Surveillance. JMIR public health and surveillance Cardemil, C. V., Dahl, R. n., Prill, M. M., Cates, J. n., Brown, S. n., Perea, A. n., Marconi, V. n., Bell, L. n., Rodriguez-Barradas, M. n., Rivera-Dominguez, G. n., Beenhouwer, D. n., Poteshkina, A. n., Holodniy, M. n., Lucero-Obusan, C. n., Balachandran, N. n., Hall, A. J., Kim, L. n., Langley, G. n. 2020

  Abstract

  COVID-19 has disproportionately affected older adults and certain racial and ethnic groups in the US. Data quantifying the disease burden, as well as describing clinical outcomes during hospitalization among these groups, is needed.We aimed to describe interim COVID-19 hospitalization rates and severe clinical outcomes by age group and race and ethnicity among Veterans in a multi-site surveillance network.We implemented a multisite COVID-19 surveillance platform in 5 Veterans Affairs Medical Centers (VAMCs: Atlanta, Bronx, Houston, Palo Alto, and Los Angeles), collectively serving >396,000 patients annually. From February 27- July 17 2020, we actively identified SARS-CoV-2 positive inpatient cases through screening of admitted patients and review of laboratory test results. We manually abstracted medical charts for demographics, underlying medical conditions, and clinical outcomes of COVID-19 hospitalized patients. We calculated hospitalization incidence and incidence rate ratios, and relative risk (RR) for invasive mechanical ventilation, intensive care unit (ICU) admission, and death after adjusting for age, race and ethnicity, and underlying medical conditions.We identified 621 laboratory-confirmed hospitalized COVID-19 cases. Median age was 70 years, 66% were aged ≥65 years, and 94% were male. Most COVID-19 diagnoses were among non-Hispanic Blacks (52%), followed by non-Hispanic Whites (25%) and Hispanic or Latinos (18%). Hospitalization rates were highest among Veterans aged ≥85 years, Hispanic or Latino, and non-Hispanic Black (430, 317 and 298 per 100,000, respectively); Veterans aged ≥85 years had a 14-fold increased rate of hospitalization compared with Veterans aged 18-29 years (95% CI: 5.7-34.6), while Hispanic or Latino and Black Veterans had a 4.6 and 4.2-fold increased rate of hospitalization compared with non-Hispanic White Veterans (95% CI: 3.6-5.9), respectively. Overall, 11.6% of patients required invasive mechanical ventilation, 26.6% were admitted to the intensive care unit (ICU), and 16.9% died in hospital. The adjusted RR for invasive mechanical ventilation and ICU admission did not differ by age group or race/ethnicity, but Veterans aged ≥65 had a 4.5-fold increased risk of death while hospitalized with COVID-19 compared with those aged <65 years (95% CI: 2.4-8.6).COVID-19 surveillance at 5 VAMCs across the US demonstrated higher hospitalization rates and severe outcomes in older Veterans, and higher hospitalization rates in Hispanic or Latino and non-Hispanic Black Veterans compared to non-Hispanic White Veterans. These data highlight the need for targeted prevention and timely treatment for Veterans, with special attention to increasing age, Hispanic or Latino and non-Hispanic Black Veterans.

  View details for DOI 10.2196/24502

  View details for PubMedID 33338028

• Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. The New England journal of medicine Kalil, A. C., Patterson, T. F., Mehta, A. K., Tomashek, K. M., Wolfe, C. R., Ghazaryan, V. n., Marconi, V. C., Ruiz-Palacios, G. M., Hsieh, L. n., Kline, S. n., Tapson, V. n., Iovine, N. M., Jain, M. K., Sweeney, D. A., El Sahly, H. M., Branche, A. R., Regalado Pineda, J. n., Lye, D. C., Sandkovsky, U. n., Luetkemeyer, A. F., Cohen, S. H., Finberg, R. W., Jackson, P. E., Taiwo, B. n., Paules, C. I., Arguinchona, H. n., Goepfert, P. n., Ahuja, N. n., Frank, M. n., Oh, M. D., Kim, E. S., Tan, S. Y., Mularski, R. A., Nielsen, H. n., Ponce, P. O., Taylor, B. S., Larson, L. n., Rouphael, N. G., Saklawi, Y. n., Cantos, V. D., Ko, E. R., Engemann, J. J., Amin, A. N., Watanabe, M. n., Billings, J. n., Elie, M. C., Davey, R. T., Burgess, T. H., Ferreira, J. n., Green, M. n., Makowski, M. n., Cardoso, A. n., de Bono, S. n., Bonnett, T. n., Proschan, M. n., Deye, G. A., Dempsey, W. n., Nayak, S. U., Dodd, L. E., Beigel, J. H. 2020

  Abstract

  Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known.We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15.A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003).Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).

  View details for DOI 10.1056/NEJMoa2031994

  View details for PubMedID 33306283

• Patterns of COVID-19 testing and mortality by race and ethnicity among United States veterans: A nationwide cohort study. PLoS medicine Rentsch, C. T., Kidwai-Khan, F. n., Tate, J. P., Park, L. S., King, J. T., Skanderson, M. n., Hauser, R. G., Schultze, A. n., Jarvis, C. I., Holodniy, M. n., Lo Re, V. n., Akgün, K. M., Crothers, K. n., Taddei, T. H., Freiberg, M. S., Justice, A. C. 2020; 17 (9): e1003379

  Abstract

  There is growing concern that racial and ethnic minority communities around the world are experiencing a disproportionate burden of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19). We investigated racial and ethnic disparities in patterns of COVID-19 testing (i.e., who received testing and who tested positive) and subsequent mortality in the largest integrated healthcare system in the United States.This retrospective cohort study included 5,834,543 individuals receiving care in the US Department of Veterans Affairs; most (91%) were men, 74% were non-Hispanic White (White), 19% were non-Hispanic Black (Black), and 7% were Hispanic. We evaluated associations between race/ethnicity and receipt of COVID-19 testing, a positive test result, and 30-day mortality, with multivariable adjustment for a wide range of demographic and clinical characteristics including comorbid conditions, health behaviors, medication history, site of care, and urban versus rural residence. Between February 8 and July 22, 2020, 254,595 individuals were tested for COVID-19, of whom 16,317 tested positive and 1,057 died. Black individuals were more likely to be tested (rate per 1,000 individuals: 60.0, 95% CI 59.6-60.5) than Hispanic (52.7, 95% CI 52.1-53.4) and White individuals (38.6, 95% CI 38.4-38.7). While individuals from minority backgrounds were more likely to test positive (Black versus White: odds ratio [OR] 1.93, 95% CI 1.85-2.01, p < 0.001; Hispanic versus White: OR 1.84, 95% CI 1.74-1.94, p < 0.001), 30-day mortality did not differ by race/ethnicity (Black versus White: OR 0.97, 95% CI 0.80-1.17, p = 0.74; Hispanic versus White: OR 0.99, 95% CI 0.73-1.34, p = 0.94). The disparity between Black and White individuals in testing positive for COVID-19 was stronger in the Midwest (OR 2.66, 95% CI 2.41-2.95, p < 0.001) than the West (OR 1.24, 95% CI 1.11-1.39, p < 0.001). The disparity in testing positive for COVID-19 between Hispanic and White individuals was consistent across region, calendar time, and outbreak pattern. Study limitations include underrepresentation of women and a lack of detailed information on social determinants of health.In this nationwide study, we found that Black and Hispanic individuals are experiencing an excess burden of SARS-CoV-2 infection not entirely explained by underlying medical conditions or where they live or receive care. There is an urgent need to proactively tailor strategies to contain and prevent further outbreaks in racial and ethnic minority communities.

  View details for DOI 10.1371/journal.pmed.1003379

  View details for PubMedID 32960880

• Incidence, etiology, and severity of acute gastroenteritis among prospectively enrolled patients in 4 Veterans Affairs hospitals and outpatient centers, 2016-18. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Cardemil, C. V., Balachandran, N. n., Kambhampati, A. n., Grytdal, S. n., Dahl, R. M., Rodriguez-Barradas, M. C., Vargas, B. n., Beenhouwer, D. O., Evangelista, K. V., Marconi, V. C., Meagley, K. L., Brown, S. T., Perea, A. n., Lucero-Obusan, C. n., Holodniy, M. n., Browne, H. n., Gautam, R. n., Bowen, M. D., Vinjé, J. n., Parashar, U. D., Hall, A. J. 2020

  Abstract

  Acute gastroenteritis (AGE) burden, etiology, and severity in adults is not well-characterized. We implemented a multisite AGE surveillance platform in 4 Veterans Affairs Medical Centers (Atlanta, Bronx, Houston and Los Angeles), collectively serving >320,000 patients annually.From July 1, 2016-June 30, 2018, we actively identified AGE inpatient cases and non-AGE inpatient controls through prospective screening of admitted patients and passively identified outpatient cases through stool samples submitted for clinical diagnostics. We abstracted medical charts and tested stool samples for 22 pathogens via multiplex gastrointestinal PCR panel followed by genotyping of norovirus- and rotavirus-positive samples. We determined pathogen-specific prevalence, incidence, and modified Vesikari severity scores.We enrolled 724 inpatient cases, 394 controls, and 506 outpatient cases. Clostridioides difficile and norovirus were most frequently detected among inpatients (cases vs controls: C. difficile, 18.8% vs 8.4%; norovirus, 5.1% vs 1.5%; p<0.01 for both) and outpatients (norovirus: 10.7%; C. difficile: 10.5%). Incidence per 100,000 population was highest among outpatients (AGE: 2715; C. difficile: 285; norovirus: 291) and inpatients ≥65 years old (AGE: 459; C. difficile: 91; norovirus: 26). Clinical severity scores were highest for inpatient norovirus, rotavirus, and Shigella/EIEC cases. Overall, 12% of AGE inpatient cases had ICU stays and 2% died; 3 deaths were associated with C. difficile and 1 with norovirus. C. difficile and norovirus were detected year-round with a fall/winter predominance.C. difficile and norovirus were leading AGE pathogens in outpatient and hospitalized US Veterans, resulting in severe disease. Clinicians should remain vigilant for bacterial and viral causes of AGE year-round.

  View details for DOI 10.1093/cid/ciaa806

  View details for PubMedID 32584956

• Companion and complementary diagnostics for infectious diseases. Expert review of molecular diagnostics Dailey, P. J., Elbeik, T. n., Holodniy, M. n. 2020

  Abstract

  Introduction: Companion diagnostics (CDx) are important in oncology therapeutic decision-making, but specific regulatory approved CDx for infectious disease treatment are officially lacking. While not approved as CDx, several ID diagnostics are used as CDx. The diagnostics community, manufacturers, and regulatory agencies have made major efforts to ensure that diagnostics for new antimicrobials are available at or near release of new agents.Areas covered: This review highlights the status of Complementary and companion diagnostic (c/CDx) in the infectious disease literature, with focus on genotypic antimicrobial resistance testing against pathogens as a class of diagnostic tests.Expert opinion: CRISPR, sepsis markers, and narrow spectrum antimicrobials, in addition to current and emerging technologies, present opportunities for infectious disease c/CDx. Challenges include slow guideline revision, high costs for regulatory approval, lengthy buy in by agencies, discordant pharmaceutical/diagnostic partnerships, and higher treatment costs. The number of patients and available medications used to treat different infectious diseases is well suited to support competing diagnostic tests. However, newer approaches to treatment (for example narrow spectrum antibiotics), may be well suited for a small number of patients, i.e. a niche market in support of a CDx. The current emphasis is rapid and point-of-care (POC) diagnostic platforms as well as changes in treatment.

  View details for DOI 10.1080/14737159.2020.1724784

  View details for PubMedID 32031431

• Notes from the Field: Unexplained Dermatologic, Respiratory, and Ophthalmic Symptoms Among Health Care Personnel at a Hospital - West Virginia, November 2017-January 2018. MMWR. Morbidity and mortality weekly report Lucas, T. J., Holodniy, M., de Perio, M. A., Perkins, K. M., Benowitz, I., Jackson, D., Kracalik, I., Grant, M., Oda, G., Powell, K. M. 2019; 68 (44): 1006-1007

  View details for DOI 10.15585/mmwr.mm6844a2

  View details for PubMedID 31697654

• Validation of Acute Gastroenteritis-related International Classification of Diseases, Clinical Modification Codes in Pediatric and Adult US Populations. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Pindyck, T., Hall, A. J., Tate, J. E., Cardemil, C. V., Kambhampati, A. K., Wikswo, M. E., Payne, D. C., Grytdal, S., Boom, J. A., Englund, J. A., Klein, E. J., Halasa, N., Selvarangan, R., Staat, M. A., Weinberg, G. A., Beenhouwer, D. O., Brown, S. T., Holodniy, M., Lucero-Obusan, C., Marconi, V. C., Rodriguez-Barradas, M. C., Parashar, U. 2019

  Abstract

  International Classification of Diseases diagnostic codes are used to estimate acute gastroenteritis (AGE) disease burden. We validated AGE-related codes in pediatric and adult populations using 2 multiregional active surveillance platforms. The sensitivity of AGE codes was similar (54% and 58%) in both populations and increased with addition of vomiting-specific codes.

  View details for DOI 10.1093/cid/ciz846

  View details for PubMedID 31626687

• Treatment for Gulf War Illness (GWI) with KPAX002 (methylphenidate hydrochloride + GWI nutrient formula) in subjects meeting the Kansas case definition: A prospective, open-label trial (revision 2). Journal of psychiatric research Holodniy, M., Kaiser, J. D. 2019; 118: 14–20

  Abstract

  This study tested the safety, tolerability, and efficacy of KPAX002-a combination of methylphenidate hydrochloride plus a micronutrient formula designed to support mitochondrial function-as a treatment for Gulf War Illness (GWI). This open-label trial enrolled 17 subjects meeting the Kansas case definition for GWI. Of the 17 subjects enrolled, 15 qualified for the Intent-to-Treat (ITT) population with 10 subjects completing the trial per protocol. All analyses were on the ITT population. At 12 weeks, subjects taking KPAX002 experienced a mean 25% reduction in their overall GWI symptoms severity as measured by the GWI Symptoms Assessment Tool (SAT) (p < 0.001). Visual analog scale scores were also significantly reduced for fatigue (p = 0.019), cognitive symptoms (p = 0.006), sleep problems (p = 0.026), and pain (p = 0.05). Twelve weeks of KPAX002 administration resulted in a significant improvement in GWI symptoms with an acceptable side effect profile. A larger randomized, double-blinded, placebo-controlled trial is necessary to determine if the observed benefit can be replicated.

  View details for DOI 10.1016/j.jpsychires.2019.08.003

  View details for PubMedID 31446218

• Trends in Incidence of Norovirus-associated Acute Gastroenteritis in Four Veterans Affairs Medical Center Populations in the United States, 2011-2015. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Grytdal, S., Browne, H., Collins, N., Vargas, B., Rodriguez-Barradas, M. C., Rimland, D., Beenhouwer, D. O., Brown, S. T., Bidwell Goetz, M., Lucero-Obusan, C., Holodniy, M., Kambhampati, A., Parashar, U., Vinjé, J., Lopman, B., Hall, A. J., Cardemil, C. V. 2019

  Abstract

  Norovirus is an important cause of epidemic acute gastroenteritis (AGE), yet the burden of endemic disease in adults has not been well documented. We estimated the prevalence and incidence of outpatient and community-acquired inpatient norovirus AGE at 4 Veterans Affairs Medical Centers (VAMC) (Atlanta, Bronx, Houston, and Los Angeles) and examined trends over 4 surveillance years.From November 2011 to September 2015, stool specimens collected within 7 days of AGE symptom onset for clinician-requested diagnostic testing were tested for norovirus and positive samples were genotyped. Incidence was calculated by multiplying norovirus prevalence among tested specimens by AGE-coded outpatient encounters and inpatient discharges, and dividing by the number of unique patients served.Of 1,603 stool specimens, 6% tested were positive for norovirus; GII.4 viruses (GII.4 New Orleans [17%] and GII.4 Sydney [47%]) were the most common genotypes. Overall prevalence and outpatient and inpatient community-acquired incidence followed a seasonal pattern, with higher median rates during November-April (9.2%, 376/100,000, and 45/100,000 respectively) compared to May-October (3.0%, 131/100,000 and 13/100,000, respectively). An alternate-year pattern was also detected, with highest peak prevalence, outpatient, and inpatient community-acquired norovirus incidence rates in the first and third years of surveillance (14-25%, 349-613/100,000, and 43-46/100,000).This multiyear analysis of laboratory-confirmed AGE surveillance from 4 VAMCs demonstrates dynamic intra- and inter-annual variability in prevalence and incidence of outpatient and inpatient community-acquired norovirus in US Veterans, highlighting the burden of norovirus disease in this adult population.

  View details for DOI 10.1093/cid/ciz165

  View details for PubMedID 30901024

• Carbon monoxide poisoning surveillance in the Veterans Health Administration, 2010-2017. BMC public health Oda, G., Ryono, R., Lucero-Obusan, C., Schirmer, P., Holodniy, M. 2019; 19 (1): 190

  Abstract

  BACKGROUND: Exposure to carbon monoxide (CO), the odorless, colorless gas resulting from incomplete combustion of hydrocarbons, is preventable. Despite the significant risk of morbidity and mortality associated with CO poisoning, there currently exists no active national CO surveillance system in the United States (U.S.). Our study aims to use electronic health record data to describe the epidemiology of CO poisoning in the Veterans Health Administration healthcare population.METHODS: We identified unique inpatient and outpatient encounters coded with International Classification of Diseases (ICD) codes for CO poisoning and analyzed relevant demographic, laboratory, treatment, and death data from January 2010 through December 2017 for Veterans across all 50U.S. states and Puerto Rico. Statistical methods used were 95% CI calculations and the two-tailed z test for proportions.RESULTS: We identified 5491 unique patients with CO poisoning, of which 1755 (32%) were confirmed/probable and 3736 (68%) were suspected. Unintentional poisoning was most common (72.9%) overall. Age less than 65years, residence in Midwest U.S. Census region versus South or West, and winter seasonal trend were characteristics associated with confirmed/probable CO poisoning. Twenty-six deaths (1.5%) occurred within 30days of confirmed/probable CO poisoning and were primarily caused by cardiovascular events (42%) or anoxic encephalopathy (15%).CONCLUSIONS: Our findings support the use of ICD-coded data for targeted CO poisoning surveillance, however, improvements are needed in ICD coding to reduce the percentage of cases coded with unknown injury intent and/or CO poisoning source. Prevalence of CO poisoning among Veterans is consistent with other U.S. estimates. Since most cases are unintentional, opportunities exist for provider and patient education to reduce risk.

  View details for PubMedID 30764795

• Clusters of nontuberculous mycobacteria linked to water sources at three Veterans Affairs medical centers. Infection control and hospital epidemiology Oda, G. n., Winters, M. A., Pacheco, S. M., Sikka, M. K., Bleasdale, S. C., Dunn, B. n., Boswell, E. n., Winters, B. n., Bumsted, A. n., Frisch, J. n., Holodniy, M. n. 2019: 1–11

  Abstract

  To characterize nontuberculous mycobacteria (NTM) associated with case clusters at 3 medical facilities.Retrospective cohort study using molecular typing of patient and water isolates.Veterans Affairs Medical Centers (VAMCs).Isolation and identification of NTM from clinical and water samples using culture, MALDI-TOF, and gene population sequencing to determine species and genetic relatedness. Clinical data were abstracted from electronic health records.An identical strain of Mycobacterium conceptionense was isolated from 41 patients at VA Medical Centers (VAMCs A, B, and D), and from VAMC A's ICU ice machine. Isolates were initially identified as other NTM species within the M. fortuitum clade. Sequencing analyses revealed that they were identical M. conceptionense strains. Overall, 7 patients (17%) met the criteria for pulmonary or nonpulmonary infection with NTM, and 13 of 41 (32%) were treated with effective antimicrobials regardless of infection or colonization status. Separately, a M. mucogenicum patient strain from VAMC A matched a strain isolated from a VAMC B ICU ice machine. VAMC C, in a different state, had a 4-patient cluster with Mycobacterium porcinum. Strains were identical to those isolated from sink-water samples at this facility.NTM from hospital water systems are found in hospitalized patients, often during workup for other infections, making attribution of NTM infection problematic. Variable NTM identification methods and changing taxonomy create challenges for epidemiologic investigation and linkage to environmental sources.

  View details for DOI 10.1017/ice.2019.342

  View details for PubMedID 31822316

• Acute Hepatitis A Infections among Veterans in Outbreak States, 2016-2018 ISDS Lucero-Obusan, C., Oda, G., Schirmer, P., Holodniy, M. 2019

  View details for DOI 10.5210/ojphi.v11i1.9947

• Acute Hepatitis A Infection and Vaccination in the Veterans Health Administration ISDS Oda, G., Lucero-Obusan, C., Schirmer, P., Holodniy, M. 2019

  View details for DOI 10.5210/ojphi.v11i1.9845

• Etiology, Severity of Illness, and Risk Factors for Patients Hospitalized with Acute Gastroenteritis from Multi-Site Veteran’s Affairs (VA) Surveillance, 2016–2018: Results from SUPERNOVA IDWeek Cardemil, C., Balachandran, N., Kambhampati, A., Grytdal, S., Rodriguez-Barradas, M., Vargas, B., Beenhouwer, D., Evangelista, K., Marconi, V., Meagley, K., Brown, S., Perea, A., Lucero-Obusan, C., Holodniy, M., Brown, H., Gautum, R., Bowen, M., Vinje, J., Parashar, U., Hall, A. 2019

  View details for DOI 10.1093/ofid/ofz360.2000

• Tuberculosis in the Department of Veterans Affairs: Missed Opportunities for Prevention IDWeek Oda, G., Lucero-Obusan, C., Schirmer, P., Holodniy, M. 2019

  View details for DOI 10.1093/ofid/ofz359.112

• Pertussis Testing in the Department of Veterans Affairs, 2010–2018 IDWeek Schirmer, P., Lucero-Obusan, C., Oda, G., Holodniy, M. 2019

  View details for DOI 10.1093/ofid/ofz360.1504

• Is On-Demand Multilocus Sequence Typing of Methicillin-resistant Staphylococcus aureus (MRSA) and Clostridioides difficile Hospital Isolates Useful for Infection Control Practice? IDWeek Holodniy, M., Winters, M., Aseo, R., Markman, L., Chary, A. 2019

  View details for DOI 10.1093/ofid/ofz360.2146

• Rapid identification of pathogenic bacteria using Raman spectroscopy and deep learning. Nature communications Ho, C. S., Jean, N. n., Hogan, C. A., Blackmon, L. n., Jeffrey, S. S., Holodniy, M. n., Banaei, N. n., Saleh, A. A., Ermon, S. n., Dionne, J. n. 2019; 10 (1): 4927

  Abstract

  Raman optical spectroscopy promises label-free bacterial detection, identification, and antibiotic susceptibility testing in a single step. However, achieving clinically relevant speeds and accuracies remains challenging due to weak Raman signal from bacterial cells and numerous bacterial species and phenotypes. Here we generate an extensive dataset of bacterial Raman spectra and apply deep learning approaches to accurately identify 30 common bacterial pathogens. Even on low signal-to-noise spectra, we achieve average isolate-level accuracies exceeding 82% and antibiotic treatment identification accuracies of 97.0±0.3%. We also show that this approach distinguishes between methicillin-resistant and -susceptible isolates of Staphylococcus aureus (MRSA and MSSA) with 89±0.1% accuracy. We validate our results on clinical isolates from 50 patients. Using just 10 bacterial spectra from each patient isolate, we achieve treatment identification accuracies of 99.7%. Our approach has potential for culture-free pathogen identification and antibiotic susceptibility testing, and could be readily extended for diagnostics on blood, urine, and sputum.

  View details for DOI 10.1038/s41467-019-12898-9

  View details for PubMedID 31666527

• Influenza and Respiratory Syncytial Virus (RSV) Surveillance in the US Department of Veterans Affairs (VA): 2018‐2019 Season. IDWeek Lucero-Obusan, C., Schirmer, P., Oda, G., Holodniy, M. 2019: S792–S793

  View details for DOI 10.1093/ofid/ofz360.1991

• Real-World Impact of Resistance-Associated Substitutions on Re-Treatment after Ledipasvir/Sofosbuvir Virologic Failure in Hepatitis C Patients Backus, L. I., Belperio, P. S., Shahoumian, T., Loomis, T., Winters, M. A., Holodniy, M. WILEY. 2018: 348A

  View details for Web of Science ID 000446020500600

• Effect of Interferon-Free Regimens on Disparities in Hepatitis C Treatment of US Veterans. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research Barnett, P. G., Joyce, V. R., Lo, J. n., Gidwani-Marszowski, R. n., Goldhaber-Fiebert, J. D., Desai, M. n., Asch, S. M., Holodniy, M. n., Owens, D. K. 2018; 21 (8): 921–30

  Abstract

  To determine whether implementation of interferon-free treatment for hepatitis C virus (HCV) reached groups less likely to benefit from earlier therapies, including patients with genotype 1 virus or contraindications to interferon treatment, and groups that faced treatment disparities: African Americans, patients with HIV co-infection, and those with drug use disorder.Electronic medical records of the US Veterans Health Administration (VHA) were used to characterize patients with chronic HCV infection and the treatments they received. Initiation of treatment in 206,544 patients with chronic HCV characterized by viral genotype, demographic characteristics, and comorbid medical and mental illness was studied using a competing events Cox regression over 6 years.With the advent of interferon-free regimens, the proportion treated increased from 2.4% in 2010 to 18.1% in 2015, an absolute increase of 15.7%. Patients with genotype 1 virus, poor response to previous treatment, and liver disease had the greatest increase. Large absolute increases in the proportion treated were observed in patients with HIV co-infection (18.6%), alcohol use disorder (11.9%), and drug use disorder (12.6%) and in African American (13.7%) and Hispanic (13.5%) patients, groups that were less likely to receive interferon-containing treatment. The VHA spent $962 million on interferon-free treatments in 2015, 1.5% of its operating budget.The proportion of patients with HCV treated in VHA increased sevenfold. The VHA was successful in implementing interferon treatment in previously undertreated populations, and this may become the community standard of care.

  View details for PubMedID 30098669

• Incidence of Norovirus and Rotavirus From Multisite Active Surveillance in Veteran’s Affairs Hospitals, December 2016–February 2018: Results From the SUPERNOVA Network IDWeek Cardemil, C., Kambhampati, A., Grytdal, S., Rodriguez-Barradas, M., Vargas, B., Beenhouwer, D., Evangelista, K., Marconi, V., Meagley, K., Brown, S., Perea, A., Lucero-Obusan, C., Holodniy, M., Browne, H., Gautum, R., Bowen, M., Vinje, J., Parshar, U., Hall, A. 2018

  View details for DOI 10.1093/ofid/ofy209.118

• Influenza Surveillance and Outbreaks in the US Department of Veterans Affairs (VA): 2017–2018 Season IDWeek Lucero-Obusan, C., Schirmer, P., Oda, G., Holodniy, M. 2018

  View details for DOI 10.1093/ofid/ofy210.2156

• Gonorrhea and Chlamydia Infections in the Department of Veterans Affairs (VA), 2013–2017 IDWeek Schirmer, P., Lucero-Obusan, C., Oda, G., Holodniy, M. 2018

  View details for DOI 10.1093/ofid/ofy210.1328

• Post-Hurricane Maria Surveillance for Infectious Diseases in the Veterans Affairs San Juan Medical Center, Puerto Rico IDWeek Oda, G., Matanock, A., Hunter, J., Patel, A., Pillai, S., Styles, T., Saavedra, S., Martinez, M., Jones, M., Mecher, C., Ryono, R., Holodniy, M. 2018

  View details for DOI 10.1093/ofid/ofy210.458

• Economically Efficient Hepatitis C Virus Treatment Prioritization Improves Health Outcomes: Hepatitis C Virus Treatment Prioritization. Medical decision making : an international journal of the Society for Medical Decision Making Cipriano, L. E., Liu, S. n., Shahzada, K. S., Holodniy, M. n., Goldhaber-Fiebert, J. D. 2018: 272989X18792284

  Abstract

  The total cost of treating the 3 million Americans chronically infected with hepatitis C virus (HCV) represents a substantial affordability challenge requiring treatment prioritization. This study compares the health and economic outcomes of alternative treatment prioritization schedules.We developed a multiyear HCV treatment budget allocation model to evaluate the tradeoffs of 7 prioritization strategies. We used optimization to identify the priority schedule that maximizes population net monetary benefit (NMB). We compared prioritization schedules in terms of the number of individuals treated, the number of individuals who progress to end-stage liver disease (ESLD), and population total quality-adjusted life years (QALYs). We applied the model to the population of treatment-naive patients with a total annual HCV treatment budget of US$8.6 billion.First-come, first-served (FCFS) treats the fewest people with advanced fibrosis, prevents the fewest cases of ESLD, and gains the fewest QALYs. A schedule developed from optimizing population NMB prioritizes treatment in the first year to patients with moderate to severe fibrosis who are younger than 65 years, followed by older individuals with moderate to severe fibrosis. While this strategy yields the greatest population QALYs, prioritization by disease severity alone prevents more cases of ESLD. Sensitivity analysis indicated that the differences between prioritization schedules are greater when the budget is smaller. A 10% annual treatment price reduction enabled treatment 1 year sooner to several patient subgroups, specifically older patients and those with less severe liver fibrosis.In the absence of a sufficient budget to treat all patients, explicit prioritization targeting younger people with more severe disease first provides the greatest health benefits. We provide our spreadsheet model so that decision makers can compare health tradeoffs of different budget levels and various prioritization strategies with inputs tailored to their population.

  View details for PubMedID 30132410

• Impact of IFNL4-∆G genotype on sustained virologic response in hepatitis C genotype 1 patients treated with direct-acting antivirals. Diagnostic microbiology and infectious disease Backus, L. I., Shahoumian, T. A., Belperio, P. S., Winters, M. n., Prokunina-Olsson, L. n., O'Brien, T. R., Holodniy, M. n. 2018

  Abstract

  In direct acting antiviral (DAA)-treated HCV genotype 1, the sustained virologic response rate with the ∆G/∆G genotype of IFNL4 rs368234815 (86.8%) was significantly lower than with ∆G/TT (95.9%, P = 0.03) or TT/TT (98.6%, P = 0.01). The SVR odds ratio for ∆G/∆G compared to TT/TT was 0.10 (P = 0.03). IFNL4 genotype might predict DAA-response.

  View details for PubMedID 29866411

• Zika virus infection in the Veterans Health Administration (VHA), 2015-2016. PLoS neglected tropical diseases Schirmer, P. L., Wendelboe, A. n., Lucero-Obusan, C. A., Ryono, R. A., Winters, M. A., Oda, G. n., Martinez, M. n., Saavedra, S. n., Holodniy, M. n. 2018; 12 (5): e0006416

  Abstract

  Zika virus (ZIKV) is an important flavivirus infection. Although ZIKV infection is rarely fatal, risk for severe disease in adults is not well described. Our objective was to describe the spectrum of illness in U.S. Veterans with ZIKV infection.Case series study including patients with laboratory-confirmed or presumed positive ZIKV infection in all Veterans Health Administration (VHA) medical centers. Adjusted odds ratios of clinical variables associated with hospitalization and neurologic complications was performed.Of 1,538 patients tested between 12/2015-10/2016 and observed through 3/2017, 736 (48%) were RT-PCR or confirmed IgM positive; 655 (89%) were male, and 683 (93%) from VA Caribbean Healthcare System (VACHCS). Ninety-four (13%) were hospitalized, 91 (12%) in the VACHCS. Nineteen (3%) died after ZIKV infection. Hospitalization was associated with increased Charlson co-morbidity index (adjusted odds ratio [OR] 1.2; 95% confidence interval [CI], 1.1-1.3), underlying connective tissue disease (OR, 29.5; CI, 3.6-244.7), congestive heart failure (OR, 6; CI, 2-18.5), dementia (OR, 3.6; CI, 1.1-11.2), neurologic symptom presentation (OR, 3.9; CI, 1.7-9.2), leukocytosis (OR, 11.8; CI, 4.5-31), thrombocytopenia (OR, 7.8; CI, 3.3-18.6), acute kidney injury (OR, 28.9; CI, 5.8-145.1), or using glucocorticoids within 30 days of testing (OR, 13.3; CI 1.3-133). Patients presenting with rash were less likely to be hospitalized (OR, 0.29; CI, 0.13-0.66). Risk for neurologic complications increased with hospitalization (OR, 5.9; CI 2.9-12.2), cerebrovascular disease (OR 4.9; CI 1.7-14.4), and dementia (OR 2.8; CI 1.2-6.6).Older Veterans with multiple comorbidities or presenting with neurologic symptoms were at increased risk for hospitalization and neurological complications after ZIKV infection.

  View details for PubMedID 29795560

• A joint frailty model provides for risk stratification of HIV-infected patients based on unobserved heterogeneity. Journal of clinical epidemiology Jung, T. H., Kyriakides, T. n., Holodniy, M. n., Esserman, D. n., Peduzzi, P. n. 2018

  Abstract

  To investigate the association between recurrent AIDS-defining events and a semi-competing risk of death in patients with advanced, multi-drug resistant HIV infection and to identify individuals at increased risk for these events using a joint frailty model.368 patients with antiretroviral treatment failure in the OPTIMA Trial randomized to two antiretroviral treatment strategies using a 2x2 factorial design, intensive vs. standard and interruption vs. continuation, and followed for development of AIDS-defining events and death.Participants were heterogeneous for risk of AIDS-defining events and death (p<0.001) and AIDS-defining events were strongly associated with death (p<0.001), irrespective of treatment. The frailty model was used to classify individuals into high- and low-risk groups based on unobserved heterogeneity. Low-risk individuals were unlikely to die (0%) or have an AIDS-defining event (<4%), while high-risk individuals had event rates approaching 70%. About one-third of high-risk individuals had accelerated mortality, all who died before experiencing an AIDS-defining event. High-risk was associated with being immunocompromised and higher predicted 5-year mortality.The joint frailty model permits classification of individuals into risk groups based on unobserved heterogeneity that may be identifiable based on observed covariates, providing advantages over the traditional Cox model.

  View details for PubMedID 29432857

• Healthcare-associated Legionnaires' disease: Limitations of surveillance definitions and importance of epidemiologic investigation. Journal of infection prevention Castellino, L. M., Gamage, S. D., Hoffman, P. V., Kralovic, S. M., Holodniy, M., Bernstein, J. M., Roselle, G. A. 2017; 18 (6): 307-310

  Abstract

  Healthcare-associated Legionnaires' disease (HCA LD) causes significant morbidity and mortality, with varying guidance on prevention. We describe the evaluation of a case of possible HCA LD and note the pitfalls of relying solely on an epidemiologic definition for association of a case with a facility. Our detailed investigation led to the identification of a newLegionella pneumophilaserogroup 1 sequence type, confirmed a healthcare association and helped build the framework for our ongoing preventive efforts. Our experience highlights the role of routine environmental cultures in the assessment of risk for a given facility. As clinicians increasingly rely on urinary antigen testing for the detection ofL. pneumophila, our investigation emphasises the importance of clinical cultures in an epidemiologic investigation.

  View details for DOI 10.1177/1757177417720999

  View details for PubMedID 29344101

  View details for PubMedCentralID PMC5761936

• Mapping MOS-HIV to HUI3 and EQ-5D-3L in Patients With HIV. MDM policy & practice Joyce, V. R., Sun, H., Barnett, P. G., Bansback, N., Griffin, S. C., Bayoumi, A. M., Anis, A. H., Sculpher, M., Cameron, W., Brown, S. T., Holodniy, M., Owens, D. K. 2017; 2 (2): 2381468317716440

  Abstract

  Objectives: The Medical Outcomes Study HIV Health Survey (MOS-HIV) is frequently used in HIV clinical trials; however, scores generated from the MOS-HIV are not suited for cost-effectiveness analyses as they do not assign utility values to health states. Our objective was to estimate and externally validate several mapping algorithms to predict Health Utilities Index Mark 3 (HUI3) and EQ-5D-3L utility values from the MOS-HIV. Methods: We developed and validated mapping algorithms using data from two HIV clinical trials. Data from the first trial (n = 367) formed the estimation data set for the HUI3 (4,610 observations) and EQ-5D-3L (4,662 observations) mapping algorithms; data from the second trial (n = 168) formed the HUI3 (1,135 observations) and EQ-5D-3L (1,152 observations) external validation data set. We compared ordinary least squares (OLS) models of increasing complexity with the more flexible two-part, beta regression, and finite mixture models. We assessed model performance using mean absolute error (MAE) and mean squared error (MSE). Results: The OLS model that used MOS-HIV dimension scores along with squared terms gave the best HUI3 predictions (mean observed 0.84; mean predicted 0.80; MAE 0.0961); the finite mixture model gave the best EQ-5D-3L predictions (mean observed 0.90; mean predicted 0.88; MAE 0.0567). All models produced higher prediction errors at the lower end of the HUI3 and EQ-5D-3L score ranges (<0.40). Conclusions: The proposed mapping algorithms can be used to predict HUI3 and EQ-5D-3L utility values from the MOS-HIV, although greater error may pose a problem in samples where a substantial proportion of patients are in poor health. These algorithms may be useful for estimating utility values from the MOS-HIV for cost-effectiveness studies when HUI3 or EQ-5D-3L data are not available.

  View details for DOI 10.1177/2381468317716440

  View details for PubMedID 30288427

  View details for PubMedCentralID PMC6125043

• Epidemiologic Review of Veterans Health Administration Patients with Isolation of Nontuberculous Mycobacteria after Cardiopulmonary Bypass Procedures. Infection control and hospital epidemiology Oda, G. n., Ryono, R. n., Lucero-Obusan, C. n., Schirmer, P. n., Shanawani, H. n., Jacobs, K. n., Holodniy, M. n. 2017: 1–4

  Abstract

  We evaluated the isolation of postoperative nontuberculous mycobacteria (NTM) associated with heater-cooler devices (HCDs) used during cardiopulmonary bypass (CPB) surgery in the Veterans Health Administration from January 1, 2010, to December 31, 2016. In more than 38,000 CPB procedures, NTM was isolated in 111 patients; 1 Mycobacterium chimaera mediastinitis case and 1 respiratory isolate were found. Infect Control Hosp Epidemiol 2017;1-4.

  View details for DOI 10.1017/ice.2017.148

  View details for PubMedID 28693623

• Dengue, Chikungunya & Zika Virus in VA Caribbean HCS, Nov. 2015-Aug. 2016 ISDS Schirmer, P., Oda, G., Lucero-Obusan, C., Winters, M., Saavedra, S., Martinez, M., Holodniy, M. 2017

  View details for DOI 10.5210/ojphi.v9i1.7680

• Carbon Monoxide Poisoning in the Veterans Health Administration, 2010 - 2016 ISDS Oda, G., Ryono, R., Lucero-Obusan, C., Schirmer, P., Holodniy, M. 2017

  View details for DOI 10.5210/ojphi.v9i1.7710

• Firearm Injury Encounters in the Veterans Health Administration (VHA), 2010-2015 ISDS Lucero-Obusan, C., Wendelboe, A., Schirmer, P., Oda, G., Holodniy, M. 2017

  View details for DOI 10.5210/ojphi.v9i1.7716

• Identical Strain of Mycobacterium conceptionense Isolated from Patients at 2 Veterans Affairs Medical Centers within the Same Metropolitan Area over a 4 Year Period IDWeek Oda, G., Winters, M., Pacheco, S., Sicca, M., Bleasdale, S., Dunn, B., Winters, B., McDuffey, E., Bumsted, A., Holodniy, M. 2017

  View details for DOI 10.1093/ofid/ofx163.504

• Factors for Hospitalizations and Neurologic Complications in Zika Virus Infection in the Department of Veterans Affairs (VA) IDWeek Schirmer, P., Wendelboe, A., Lucero-Obusan, C., Ryono, R., Oda, G., Winters, M., Saavedra, S., Martinez, M., Holodniy, M. 2017

  View details for DOI 10.1093/ofid/ofx163.750

• Comparative Effectiveness of High-Dose vs. Standard-Dose Influenza Vaccines among Veterans: 2015–2016 and 2016–2017 Seasons IDWeek Lucero-Obusan, C., Schirmer, P., Wendelboe, A., Ryono, R., Oda, G., Holodniy, M. 2017

  View details for DOI 10.1093/ofid/ofx163.1162

• Epidemiology and Burden of Influenza in the U.S. Department of Veterans Affairs. Influenza and other respiratory viruses Lucero-Obusan, C. n., Schirmer, P. L., Wendelboe, A. n., Oda, G. n., Holodniy, M. n. 2017

  Abstract

  We describe influenza activity in the US Veterans Affairs (VA) population for the 2010-2011 through 2015-2016 seasons and compare with national CDC FluView data. VA confirmed influenza cases ranged from 1,005-11,506 per season; triage calls from 6,090-10,346; outpatient visits from 3,849-13,406; antiviral prescriptions from 3,650-32,826; hospitalizations from 546-4,673; and deaths in hospitalized patients from 17-139. Peak activity was generally the same as observed nationally by the CDC. For the seasons analyzed, correlation between VA and CDC %ILI visits (r=0.863), influenza hospitalizations (r=0.953), positive tests (r=0.948), and percent of tests positive (r=0.938) was strong. Understanding influenza burden is important for evaluating prevention priorities and resource allocation within VA. This article is protected by copyright. All rights reserved.

  View details for PubMedID 29045064

• Rationale and design of the Drug-Eluting Stents vs Bare-Metal Stents in Saphenous Vein Graft Angioplasty (DIVA) Trial. Clinical cardiology Brilakis, E. S., Banerjee, S. n., Edson, R. n., Shunk, K. n., Goldman, S. n., Holmes, D. R., Bhatt, D. L., Rao, S. V., Smith, M. W., Sather, M. n., Colling, C. n., Kar, B. n., Nielsen, L. n., Conner, T. n., Wagner, T. n., Rangan, B. V., Ventura, B. n., Lu, Y. n., Holodniy, M. n., Shih, M. C. 2017

  Abstract

  VA Cooperative Studies Program #571 (DIVA) was designed to evaluate the efficacy of drug-eluting stents (DES) for reducing aortocoronary saphenous vein bypass graft (SVG) failure when compared with bare-metal stents (BMS) in participants undergoing stenting of de novo SVG lesions. Participants undergoing clinically indicated stenting of de novo SVG lesions were randomized in a 1:1 ratio to DES or BMS. Randomization was stratified by presence/absence of diabetes mellitus and the number of target SVG lesions (1 vs ≥2) within each participating site. At sites that did not routinely administer 12-months of dual antiplatelet therapy after SVG stenting participants without acute coronary syndromes received 1 month of open-label clopidogrel, followed by 11 months of clopidogrel for those assigned to DES and 11 months of placebo for those assigned to BMS. The primary endpoint was the 12-month incidence of target-vessel failure (defined as the composite of cardiac death, target-vessel myocardial infarction, or target-vessel revascularization). Secondary endpoints included the incidence of other clinical endpoints and the incremental cost-effectiveness of DES relative to BMS. Due to lower-than-anticipated target-vessel failure rates, target enrollment was increased from 519 to 762. The study had randomized 599 participants when recruitment ended in December 2015. The DIVA trial will provide clarity on the appropriate stent type for de novo SVG lesions.

  View details for PubMedID 28841230

• A review of drug-drug interactions in older HIV-infected patients. Expert review of clinical pharmacology Chary, A. n., Nguyen, N. N., Maiton, K. n., Holodniy, M. n. 2017: 1–24

  Abstract

  The number of older HIV-infected people is growing due to increasing life expectancies resulting from the use of antiretroviral therapy (ART). Both HIV and aging increase the risk of other comorbidities, such as cardiovascular disease, osteoporosis, and some malignancies, leading to greater challenges in managing HIV with other conditions. This results in complex medication regimens with the potential for significant drug-drug interactions and increased morbidity and mortality. Area covered: We review the metabolic pathways of ART and other medications used to treat medical co-morbidities, highlight potential areas of concern for drug-drug interactions, and where feasible, suggest alternative approaches for treating these conditions as suggested from national guidelines or articles published in the English language. Expert commentary: There is limited evidence-based data on ART drug interactions, pharmacokinetics and pharmacodynamics in the older HIV-infected population. Choosing and maintaining effective ART regimens for older adults requires consideration of side effect profile, individual comorbidities, interactions with concurrent prescriptions and non-prescription medications and supplements, dietary patterns with respect to dosing, pill burden and ease of dosing, cost and affordability, patient preferences, social situation, and ART resistance history. Practitioners must remain vigilant for potential drug interactions and intervene when there is a potential for harm.

  View details for PubMedID 28922979

• Cost-Effectiveness of HIV Preexposure Prophylaxis for People Who Inject Drugs in the United States ANNALS OF INTERNAL MEDICINE Bernard, C. L., Brandeau, M. L., Humphreys, K., Bendavid, E., Holodniy, M., Weyant, C., Owens, D. K., Goldhaber-Fiebert, J. D. 2016; 165 (1): 10-?

  View details for DOI 10.7326/M15-2634

  View details for Web of Science ID 000379215800003

• HIV-1 Protease, Reverse Transcriptase, and Integrase Variation JOURNAL OF VIROLOGY Rhee, S., Sankaran, K., Varghese, V., Winters, M. A., Hurt, C. B., Eron, J. J., Parkin, N., Holmes, S. P., Holodniy, M., Shafer, R. W. 2016; 90 (13): 6058-6070

  Abstract

  HIV-1 protease (PR), reverse transcriptase (RT), and integrase (IN) variability presents a challenge to laboratories performing genotypic resistance testing. This challenge will grow with increased sequencing of samples enriched for proviral DNA such as dried blood spots and increased use of next-generation sequencing (NGS) to detect low-abundance HIV-1 variants. We analyzed PR and RT sequences from >100,000 individuals and IN sequences from >10,000 individuals to characterize variation at each amino acid position, identify mutations indicating APOBEC-mediated G-to-A editing, and identify mutations resulting from selective drug pressure. Forty-seven percent of PR, 37% of RT and 34% of IN positions had one or more amino acid variants with a prevalence ≥1%. Seventy percent of PR, 60% of RT and 60% of IN positions had one or more variants with a prevalence ≥0.1%. Overall 201 PR, 636 RT and 346 IN variants had a prevalence ≥0.1%. The median inter-subtype prevalence-ratio was 2.9-, 2.1- and 1.9-fold for these PR, RT and IN variants, respectively. Only 5.0% of PR, 3.7% of RT and 2.0% of IN variants had a median inter-subtype prevalence-ratio ≥10-fold. Variants at lower prevalences were more likely to differ biochemically and to be part of an electrophoretic mixture compared to high prevalence variants. There were 209 mutations indicative of APOBEC-mediated G-to-A editing and 326 non-polymorphic treatment-selected mutations. Identifying viruses with a high number of APOBEC-associated mutations will facilitate the quality control of dried blood spot sequencing. Identifying sequences with a high proportion of rare mutations will facilitate the quality control of NGS.Most antiretroviral drugs target three HIV-1 proteins: PR, RT, and IN. These proteins are highly variable: many different amino acids can be present at the same position in viruses from different individuals. Some of the amino acid variants cause drug resistance and occur mainly in individuals receiving antiretroviral drugs. Some variants result from a human cellular defense mechanism called APOBEC-mediated hypermutation. Many variants result from naturally occurring mutation. Some variants may represent technical artifacts. We studied PR and RT sequences from >100,000 individuals and IN sequences from >10,000 individuals to quantify variation at each amino acid position in these three HIV-1 proteins. We performed analyses to determine which amino acid variants resulted from antiretroviral drug selection pressure, APOBEC-mediated editing, and naturally occurring variation. Our results provide information essential to clinical, research, and public health laboratories performing genotypic resistance testing by sequencing HIV-1 PR, RT, and IN.

  View details for DOI 10.1128/JVI.00495-16

  View details for Web of Science ID 000378340300019

  View details for PubMedID 27099321

• Are current screening protocols for chronic hepatitis B virus infection adequate? DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE Mortensen, E., Kamali, A., Schirmer, P. L., Lucero-Obusan, C., Winston, C. A., Oda, G., Winters, M. A., Durfee, J., Martinello, R. A., Davey, V. J., Holodniy, M. 2016; 85 (2): 159-167

  Abstract

  Chronic hepatitis B virus (HBV) infection screening usually includes only HBV surface antigen (HBsAg) testing; HBV core and surface antibody (anti-HBc, anti-HBs) assays, indicating resolved infection and immunity, are not routinely performed. Yet, serum HBV DNA is measurable in approximately 10% of HBsAg-negative/anti-HBc-positive cases, representing occult HBV infection (OBI). Patient blood samples from 2 Veterans Affairs medical center look-back investigations were screened for HBV infection using HBsAg enzyme immunoassays. Supplementary testing included anti-HBc and anti-HBs enzyme immunoassays. For anti-HBc-positive samples, HBV DNA testing was performed. Background OBI prevalence was further estimated at these 2 facilities based on HBV serology testing results from 1999-2012. Finally, a literature review was performed to determine OBI prevalence in the published literature. Of 1887 HBsAg-negative cohort patients, 98 (5.2%) were anti-HBc positive/anti-HBs negative; and 175 (9.3%), anti-HBc positive/anti-HBs positive. Six of 273 were HBV DNA positive, representing 0.3% of the total tested and 2.2% who were anti-HBc positive/anti-HBs negative or anti-HBc positive/anti-HBs positive. Among 32,229 general population veterans at these 2 sites who had any HBV testing, 4/108 (3.7%) were HBV DNA positive, none of whom were part of the cohort. In 129 publications with HBsAg-negative patients, 1817/1,209,426 (0.15%) had OBI. However, excluding blood bank studies with greater than 1000 patients, the OBI rate increased to 1800/17,893 (10%). OBI is not rare and has implications for transmission and disease detection. HBsAg testing alone is insufficient for detecting all chronic HBV infections. These findings may impact blood donation, patient HBV screening, follow-up protocols for patients assumed to have cleared the infection, and initiation of immunosuppression in patients with distant or undetected HBV.

  View details for DOI 10.1016/j.diagmicrobio.2015.12.005

  View details for Web of Science ID 000376822600007

  View details for PubMedID 27009896

• Epidemiologic Review of Carbapenem-Resistant Enterobacteriaceae, Duodenoscopes, and Endoscopic Ultrasonography in the Department of Veterans Affairs INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY Ryono, R. A., Schirmer, P. L., Lucero-Obusan, C., Oda, G., Dominitz, J. A., Holodniy, M. 2016; 37 (6): 725-?

  View details for DOI 10.1017/ice.2016.45

  View details for Web of Science ID 000376541900020

  View details for PubMedID 26954589

• Phylogeny of Zika Virus in Western Hemisphere, 2015. Emerging infectious diseases Lanciotti, R. S., Lambert, A. J., Holodniy, M., Saavedra, S., Signor, L. D. 2016; 22 (5): 933-5

  View details for DOI 10.3201/eid2205.160065

  View details for PubMedID 27088323

• Chikungunya Fever Cases Identified in the Veterans Health Administration System, 2014 PLOS NEGLECTED TROPICAL DISEASES Perti, T., Lucero-Obusan, C. A., Schirmer, P. L., Winters, M. A., Holodniy, M. 2016; 10 (5)

  Abstract

  During December 2013, the first locally transmitted chikungunya virus (CHIKV) infections in the Americas were reported in the Caribbean. Although CHIKV infection is rarely fatal, risk for severe disease increases with age and medical comorbidities. Herein we describe characteristics of Veterans Health Administration (VHA) patients with CHIKV infection and, among those with infections diagnosed in Puerto Rico, investigated risk factors for hospitalization.We queried VHA's national electronic medical records to identify patients with CHIKV testing during 2014. Demographics, clinical history, laboratory results, and outcomes were abstracted. We investigated risk factors for hospitalization among patients with laboratory-confirmed CHIKV infection in Puerto Rico.We identified 180 laboratory-confirmed CHIKV infections; 148 (82.2%) were diagnosed in Puerto Rico, and 32 (17.8%) were diagnosed among returning travelers elsewhere in the United States. In Puerto Rico, where more patients were hospitalized (55.4% versus 20.0%) and died (4.1% versus 0%), risk for hospitalization increased with age (relative risk [RR]/each 10-year increase, 1.19; 95% confidence interval [CI], 1.06-1.32) and, adjusted for age, increased among patients with congestive heart failure (RR, 1.58; 95% CI, 1.25-1.99), chronic kidney disease (RR, 1.52; 95% CI, 1.19-1.94), diabetes mellitus (RR, 1.39; 95% CI, 1.06-1.84), or chronic lung disease (RR, 1.37; 95% CI, 1.03-1.82).CHIKV infection is an emerging problem among Veterans residing in or visiting areas with CHIKV transmission. Although overall mortality rates are low, clinicians in affected areas should be aware that older patients and patients with comorbidities may be at increased risk for severe disease.

  View details for DOI 10.1371/journal.pntd.0004630

  View details for Web of Science ID 000377769300020

  View details for PubMedID 27144588

  View details for PubMedCentralID PMC4856344

• Multifunctional coatings to simultaneously promote osseointegration and prevent infection of orthopaedic implants. Biomaterials Raphel, J., Holodniy, M., Goodman, S. B., Heilshorn, S. C. 2016; 84: 301-314

  Abstract

  The two leading causes of failure for joint arthroplasty prostheses are aseptic loosening and periprosthetic joint infection. With the number of primary and revision joint replacement surgeries on the rise, strategies to mitigate these failure modes have become increasingly important. Much of the recent work in this field has focused on the design of coatings either to prevent infection while ignoring bone mineralization or vice versa, to promote osseointegration while ignoring microbial susceptibility. However, both coating functions are required to achieve long-term success of the implant; therefore, these two modalities must be evaluated in parallel during the development of new orthopaedic coating strategies. In this review, we discuss recent progress and future directions for the design of multifunctional orthopaedic coatings that can inhibit microbial cells while still promoting osseointegration.

  View details for DOI 10.1016/j.biomaterials.2016.01.016

  View details for PubMedID 26851394

• Genetic Variation in the IL-6 and HLA-DQB1 Genes Is Associated with Spontaneous Clearance of Hepatitis C Virus Infection JOURNAL OF IMMUNOLOGY RESEARCH Waldron, P. R., Belitskaya-Levy, I., Chary, A., Won, J., Winters, M., Monto, A., Ryan, J., Lazzeroni, L. C., Holodniy, M. 2016

  Abstract

  Background. Millions of people are infected with hepatitis C virus (HCV) worldwide and 30% spontaneously clear the infection. Reasons for HCV clearance without antiviral treatment are not well understood. Methods. Blood was collected for DNA analysis from patients with chronic HCV infection or evidence of spontaneous clearance. To overcome anticipated limitations of small sample size, primary analyses consisted of a candidate gene analysis of 12 preselected genes based on known association with host immunologic response to HCV infection. To further reduce the impact of multiple testing on power, a single likelihood ratio test was conducted for each gene using all associated SNPs assayed on the Illumina Quad 610/660W chip. Step-down permutation methods were used to adjust for multiple testing in all analyses. Results. Ninety-five and 62 patients with HCV chronic infection or spontaneous clearance, respectively, were included for analysis. HLA-DQB1 (p = 1.76⁎10(-5)) and IL-6 (p = 0.0007) genes were significantly associated with spontaneous HCV clearance. IL-28B was not significantly associated with spontaneous clearance (p = 0.17). Conclusion. Our whole-gene analytic strategy identified a previously unreported association of IL-6 with spontaneous clearance of HCV infection. We also confirmed the finding that HLA-DQB1 is associated with spontaneous resolution of HCV infection.

  View details for DOI 10.1155/2016/6530436

  View details for Web of Science ID 000377874400001

  View details for PubMedID 27340680

  View details for PubMedCentralID PMC4909898

• Cost-Effectiveness of Treatments for Genotype 1 Hepatitis C Virus Infection in Non-VA and VA Populations Medical Decision Making Policy and Practice Liu, S., Barnett, P. G., Holodniy, M., Lo, J., Joyce, V. R., Gadwani, R., Asch, S. M., Owens, D. K., Goldhaber-Fiebert, J. D. 2016; 1 (1): 1-12

  View details for DOI 10.1177/2381468316671946

• Epidemiologic Review of Carbapenem-Resistant Enterobacteriaceae and Duodenoscopes in the Department of Veterans Affairs. Open forum infectious diseases Ryono, R., Schirmer, P., Lucero-Obusan, C., Oda, G., Dominitz, J., Holodniy, M. 2015; 2: 107-?

  View details for DOI 10.1093/ofid/ofv131.27

  View details for PubMedID 27437409

• Prevalence of Direct Acting Antiviral (DAA) Resistance in the Department of Veterans Affairs (VA) Holodniy, M., Winters, M. A., Backus, L. I., Belperio, P. S., Morgan, T. R., Ross, D. WILEY-BLACKWELL. 2015: 1391A-1392A

  View details for Web of Science ID 000367013200020

• Emergence of Hemagglutinin Mutations During the Course of Influenza Infection SCIENTIFIC REPORTS Cushing, A., Kamali, A., Winters, M., Hopmans, E. S., Bell, J. M., Grimes, S. M., Xia, L. C., Zhang, N. R., Moss, R. B., Holodniy, M., Ji, H. P. 2015; 5

  Abstract

  Influenza remains a significant cause of disease mortality. The ongoing threat of influenza infection is partly attributable to the emergence of new mutations in the influenza genome. Among the influenza viral gene products, the hemagglutinin (HA) glycoprotein plays a critical role in influenza pathogenesis, is the target for vaccines and accumulates new mutations that may alter the efficacy of immunization. To study the emergence of HA mutations during the course of infection, we employed a deep-targeted sequencing method. We used samples from 17 patients with active H1N1 or H3N2 influenza infections. These patients were not treated with antivirals. In addition, we had samples from five patients who were analyzed longitudinally. Thus, we determined the quantitative changes in the fractional representation of HA mutations during the course of infection. Across individuals in the study, a series of novel HA mutations directly altered the HA coding sequence were identified. Serial viral sampling revealed HA mutations that either were stable, expanded or were reduced in representation during the course of the infection. Overall, we demonstrated the emergence of unique mutations specific to an infected individual and temporal genetic variation during infection.

  View details for DOI 10.1038/srep16178

  View details for Web of Science ID 000364140000001

  View details for PubMedID 26538451

  View details for PubMedCentralID PMC4633648

• Reuse of Insulin Pens Among Multiple Patients at 2 Veterans Affairs Medical Centers INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY Schirmer, P., Winston, C. A., Lucero-Obusan, C., Winters, M., Lesse, A., de Comarmond, C., Oda, G., Martinello, R. A., Holodniy, M. 2015; 36 (10): 1121-1129

  Abstract

  OBJECTIVE To determine whether reuse of insulin pens among multiple patients resulted in transmission of bloodborne pathogens (BBP). DESIGN Retrospective cohort study. SETTING Two Veterans Affairs medical centers. PATIENTS Veterans who received insulin via insulin pens from 2010 to 2013. METHODS Patients were identified through electronic health records, notified of possible exposure, and serotested for human immunodeficiency virus, hepatitis C virus (HCV), and hepatitis B virus. Newly discovered case patients were assessed in relation to potential proximate patients to determine viral strain relatedness by HCV envelope (env) gene sequencing. RESULTS Of 1,791 hospitalized veterans who received insulin via insulin pen, 1,155 were tested for at least 1 viral infection after exposure. Of these, 67 patients were newly diagnosed with 1 or more viral BBPs. For human immunodeficiency virus and hepatitis B virus no additional strain testing of case or proximate patients was possible; 8 HCV cases and 45 proximates (40 unique patients; 5 patients were positive for 2 genotypes) were identified as needing strain testing. Only 3 cases and their 19 proximates had samples available for further testing. None of the 26 remaining proximate patients had blood available for further testing. Median genetic distance between the HCV env sequences of those available for additional testing ranged from 14% to 24%, indicating nonrelatedness. CONCLUSIONS Our investigation revealed that exposure to insulin pen reuse did not result in HCV transmission among patients who had viral genetic analysis performed. Analysis for any additional potential transmission of blood-borne pathogens was limited by the available samples. Infect Control Hosp Epidemiol 2015;00(0):1-9.

  View details for DOI 10.1017/ice.2015.165

  View details for Web of Science ID 000361919700001

  View details for PubMedID 26198627

• Reply to Young et al. Clinical infectious diseases Desai, M., Joyce, V., Bendavid, E., Olshen, R. A., Hlatky, M., Chow, A., Holodniy, M., Barnett, P., Owens, D. K. 2015; 61 (7): 1207-1208

  View details for DOI 10.1093/cid/civ517

  View details for PubMedID 26123931

• Acute cardiac injury events <= 30 days after laboratory-confirmed influenza virus infection among US veterans, 2010-2012 BMC CARDIOVASCULAR DISORDERS Ludwig, A., Lucero-Obusan, C., Schirmer, P., Winston, C., Holodniy, M. 2015; 15

  Abstract

  Cardiac injury is a known potential complication of influenza infection. Because U.S. veterans cared for at the U.S. Department of Veterans Affairs are older and have more cardiovascular disease (CVD) risk factors than the general U.S. population, veterans are at risk for cardiac complications of influenza infection. We investigated biomarkers of cardiac injury characteristics and associated cardiac events among veterans who received cardiac biomarker testing ≤30 days after laboratory-confirmed influenza virus infection.Laboratory-confirmed influenza cases among veterans cared for at U.S. Department of Veterans Affairs' facilities for October 2010-December 2012 were identified using electronic medical records (EMRs). Influenza confirmation was based on respiratory specimen viral culture or antigen or nucleic acid detection. Acute cardiac injury (ACI) was defined as an elevated cardiac biomarker (troponin I or creatinine kinase isoenzyme MB) >99 % of the upper reference limit occurring ≤30 days after influenza specimen collection. EMRs were reviewed for demographics, CVD history and risk factors, and ACI-associated cardiac events.Among 38,197 patients with influenza testing results, 4,469 (12 %) had a positive result; 600 of those patients had cardiac biomarker testing performed ≤30 days after influenza testing, and 143 (24 %) had one or more elevated cardiac biomarkers. Among these 143, median age was 73 years (range 44-98 years), and 98 (69 %) were non-Hispanic white. All patients had one or more CVD risk factors, and 98 (69 %) had a history of CVD. Eighty-six percent of ACI-associated events occurred within 3 days of influenza specimen collection date. Seventy patients (49 %) had documented or probable acute myocardial infarction, 8 (6 %) acute congestive heart failure, 6 (4 %) myocarditis, and 4 (3 %) atrial fibrillation. Eleven (8 %) had non-cardiac explanations for elevated cardiac biomarkers, and 44 (31 %) had no documented explanation. Sixty-eight (48 %) patients had received influenza vaccination during the related influenza season.Among veterans with laboratory-confirmed influenza infection and cardiac biomarker testing ≤30 days after influenza testing, approximately 25 % had evidence of ACI, the majority within 3 days. Approximately half were myocardial infarctions. Our findings emphasize the importance of considering ACI associated with influenza infection among patients at high risk, including this older population with prevalent CVD risk factors.

  View details for DOI 10.1186/s12872-015-0095-0

  View details for Web of Science ID 000362062900002

  View details for PubMedID 26423142

  View details for PubMedCentralID PMC4589211

• Risk of Cardiovascular Events Associated With Current Exposure to HIV Antiretroviral Therapies in a US Veteran Population. Clinical infectious diseases Desai, M., Joyce, V., Bendavid, E., Olshen, R. A., Hlatky, M., Chow, A., Holodniy, M., Barnett, P., Owens, D. K. 2015; 61 (3): 445-452

  Abstract

   To characterize the association of antiretroviral drug combinations on risk of cardiovascular events. Certain antiretroviral medications for human immunodeficiency virus (HIV) have been implicated in increasing risk of cardiovascular disease. However, antiretroviral drugs are typically prescribed in combination. We characterized the association of current exposure to antiretroviral drug combinations on risk of cardiovascular events including myocardial infarction, stroke, percutaneous coronary intervention, and coronary artery bypass surgery. We used the Veterans Health Administration Clinical Case Registry to analyze data from 24 510 patients infected with HIV from January 1996 through December 2009. We assessed the association of current exposure to 15 antiretroviral drugs and 23 prespecified combinations of agents on the risk of cardiovascular event by using marginal structural models and Cox models extended to accommodate time-dependent variables. Over 164 059 person-years of follow-up, 934 patients had a cardiovascular event. Current exposure to abacavir, efavirenz, lamivudine, and zidovudine was significantly associated with increased risk of cardiovascular event, with odds ratios ranging from 1.40 to 1.53. Five combinations were significantly associated with increased risk of cardiovascular event, all of which involved lamivudine. One of these-efavirenz, lamivudine, and zidovudine-was the second most commonly used combination and was associated with a risk of cardiovascular event that is 1.60 times that of patients not currently exposed to the combination (odds ratio = 1.60, 95% confidence interval, 1.25-2.04). In the VA cohort, exposure to both individual drugs and drug combinations was associated with modestly increased risk of a cardiovascular event.

  View details for DOI 10.1093/cid/civ316

  View details for PubMedID 25908684

• Incidence of Medically-Attended Norovirus-Associated Acute Gastroenteritis in Four Veteran's Affairs Medical Center Populations in the United States, 2011-2012 PLOS ONE Grytdal, S. P., Rimland, D., Shirley, S. H., Rodriguez-Barradas, M. C., Goetz, M. B., Brown, S. T., Lucero-Obusan, C., Holodniy, M., Graber, C., Parashar, U., Vinje, J., Lopman, B. 2015; 10 (5)

  Abstract

  An estimated 179 million acute gastroenteritis (AGE) illnesses occur annually in the United States. The role of noroviruses in hospital-related AGE has not been well-documented in the U. S. We estimated the population incidence of community- acquired outpatient and inpatient norovirus AGE encounters, as well as hospital-acquired inpatient norovirus AGE among inpatients at four Veterans Affairs (VA) Medical Centers (VAMCs). Fifty (4%) of 1,160 stool specimens collected ≤7 days from symptom onset tested positive for norovirus. During a one year period, the estimated incidence of outpatient, community- and hospital-acquired inpatient norovirus AGE was 188 cases, 11 cases, and 54 cases/ 100,000 patients, respectively. This study demonstrates the incidence of outpatient and community- and hospital-acquired inpatient norovirus AGE among the VA population seeking care at these four VAMCs.

  View details for DOI 10.1371/journal.pone.0126733

  View details for Web of Science ID 000356444000030

  View details for PubMedID 25996826

• Long-term Persistence of Zoster Vaccine Efficacy CLINICAL INFECTIOUS DISEASES Morrison, V. A., Johnson, G. R., Schmader, K. E., Levin, M. J., Zhang, J. H., Looney, D. J., Betts, R., Gelb, L., Guatelli, J. C., Harbecke, R., Pachucki, C., Keay, S., Menzies, B., Griffin, M. R., Kauffman, C. A., Marques, A., Toney, J., Boardman, K., Su, S., Li, X., Chan, I. F., Parrino, J., Annunziato, P., Oxman, M. N., Shingles Prevention Study Grp 2015; 60 (6): 900-909

  Abstract

  The Shingles Prevention Study (SPS) demonstrated zoster vaccine efficacy through 4 years postvaccination. A Short-Term Persistence Substudy (STPS) demonstrated persistence of vaccine efficacy for at least 5 years. A Long-Term Persistence Substudy (LTPS) was undertaken to further assess vaccine efficacy in SPS vaccine recipients followed for up to 11 years postvaccination. Study outcomes were assessed for the entire LTPS period and for each year from 7 to 11 years postvaccination.Surveillance, case determination, and follow-up were comparable to those in SPS and STPS. Because SPS placebo recipients were offered zoster vaccine before the LTPS began, there were no unvaccinated controls. Instead, SPS and STPS placebo results were used to model reference placebo groups.The LTPS enrolled 6867 SPS vaccine recipients. Compared to SPS, estimated vaccine efficacy in LTPS decreased from 61.1% to 37.3% for the herpes zoster (HZ) burden of illness (BOI), from 66.5% to 35.4% for incidence of postherpetic neuralgia, and from 51.3% to 21.1% for incidence of HZ, and declined for all 3 outcome measures from 7 through 11 years postvaccination. Vaccine efficacy for the HZ BOI was significantly greater than zero through year 10 postvaccination, whereas vaccine efficacy for incidence of HZ was significantly greater than zero only through year 8.Estimates of vaccine efficacy decreased over time in the LTPS population compared with modeled control estimates. Statistically significant vaccine efficacy for HZ BOI persisted into year 10 postvaccination, whereas statistically significant vaccine efficacy for incidence of HZ persisted only through year 8.

  View details for DOI 10.1093/cid/ciu918

  View details for Web of Science ID 000351051600013

  View details for PubMedID 25416754

  View details for PubMedCentralID PMC4357816

• Acute and chronic immune biomarker changes during interferon/ribavirin treatment in HIV/HCV co-infected patients JOURNAL OF VIRAL HEPATITIS Jain, M. K., Adams-Huet, B., Terekhova, D., Kushner, L. E., Bedimo, R., Li, X., Holodniy, M. 2015; 22 (1): 25-36

  Abstract

  Chronic viral infections lead to persistent immune activation, which is alleviated by eradicating or suppressing the infection. To understand the effects of interferon treatment on immune system activation by chronic infections, we evaluated kinetic patterns of a broad spectrum of serum biomarkers during HCV treatment in HIV/HCV co-infected patients. HCV viral load and 50 biomarkers were analysed at baseline and 27 time points during pegylated interferon-alpha and ribavirin (IFN/RBV) treatment of 12 HIV/HCV co-infected patients. We evaluated biomarker changes from baseline for each time point and biomarker correlations with clinical parameters, treatment response and liver histopathology. IL-1α, IL-12p40, IL-1RA, IP-10, MIG, MIP-1α/1β, HGF, sCD40L, TRAIL and leptin increased in the first day. IL-12p70, IL-17A, IL-10, GROα, IL-8, MCP-3, IL-4 and M-CSF peaked later during week 1. IL-1α, HGF, IP-10, MIP-1α, TRAIL, sCD40L, IL-10, IL-12p70, MCP-3, FGFb, ENA-78, TGF-β, IL-2, IFN-γ, IL-6, IL-15, IL-7 and PDGF-BB decreased below baseline over the course of treatment. Higher BMI, baseline HCV viral load and leptin levels were associated with lack of sustained virologic response. ENA-78 was associated with sustained viral response. Positive correlations were found between liver inflammation and baseline CD4 count, sVCAM and HGF; fibrosis stage and HGF; liver steatosis, BMI and leptin. Our findings suggest IFN/RBV treatment initially increases levels of several biomarkers, but eventually leads to a decline in many immune markers. These findings shed light on the relationship between IFN treatment and immune activation by chronic viral infections, such as HCV.

  View details for DOI 10.1111/jvh.12226

  View details for Web of Science ID 000346826600005

  View details for PubMedID 24506344

• Surveillance for Opioid Overdose in the Veterans Health Administration, 2004-2014 ISDS Winston, C., Holodniy, M. 2015

  View details for DOI 10.5210/ojphi.v7i1.5725

• Pertussis Surveillance in Veterans Affairs Medical Centers in Western United States – 2010-2014 ISDS Schirmer, P., Mercier, R., Lucero-Obusan, C., Oda, G., Holodniy, M. 2015

  View details for DOI 10.5210/ojphi.v7i1.5716

• Evaluation of Praedico™, A Next Generation Big Data Biosurveillance Application Mark Holodniy Holodniy, M., Winston, C., Lucero-Obusan, C., Oda, G., Mostaghimi, A., Pavlin, J., Etminani, P., Lee, C., Sedghi, F. 2015

  View details for DOI 10.5210/ojphi.v7i1.5799

• Challenges in Surveillance for Chikungunya Virus (CHIKV) Infection ISDS Lucero-Obusan, C., Schirmer, P., Oda, G., Holodniy, M. 2015

  View details for DOI 10.5210/ojphi.v7i1.5702

• Epidemiologic Review of Carbapenem-Resistant Enterobacteriaceae and Duodenoscopes in the Department of Veterans Affairs IDWeek Ryono, R., Schirmer, P., Lucero-Obusan, C., Oda, G., Dominitz, J., Holodniy, M. 2015

  View details for DOI 10.1093/ofid/ofv131.27

• Peripheral Blood Mononuclear Cell Gene Expression Remains Broadly Altered Years after Successful Interferon-Based Hepatitis C Virus Treatment. Journal of immunology research Waldron, P. R., Holodniy, M. 2015; 2015: 958231-?

  Abstract

  Background. Inflammatory gene expression in peripheral blood mononuclear cells (PBMCs) is altered in chronic Hepatitis C Virus (HCV) infection. Duration of changes after pegylated interferon- (peg-IFN-) based HCV treatment is unclear. Methods. PBMC mRNA expression of 184 inflammatory response genes was analyzed (nCounter GX Human Inflammation Kit, Nanostring) from peg-IFN treatment nonresponders (NR, n = 18), sustained virologic responders (SVR, n = 22), and spontaneous clearers (SC, n = 15). Logistic regression was used for comparison. Results. Median time from last treatment was 2 and 2.7 years in SVR and NR, respectively (p = NS). Mean mRNA counts were significantly different for 42 and 29 genes comparing SVR to SC patients and NR to SC, respectively, and no genes comparing SVR to NR. Differential expression of 24 genes was significantly different in both SVR and NR groups compared to SC. Among these 24 acute and chronic inflammatory cascade genes, significant upregulation was noted for proinflammatory transcription regulators Fos, CEBPB, and MyD88 in SVR and NR compared to SC. HDAC4 was significantly downregulated in SVR and NR compared to the SC group. Conclusions. PBMC inflammatory gene expression patterns in SVR resemble NR more than SC patients. A generalized inflammatory response persists in PBMCs long after successful peg-IFN treatment for HCV infection.

  View details for DOI 10.1155/2015/958231

  View details for PubMedID 26568966

  View details for PubMedCentralID PMC4629046

• Sofosbuvir-Based Treatment Regimens for Chronic, Genotype 1 Hepatitis C Virus Infection in US Incarcerated Populations A Cost-Effectiveness Analysis ANNALS OF INTERNAL MEDICINE Liu, S., Watcha, D., Holodniy, M., Goldhaber-Fiebert, J. D. 2014; 161 (8): 546-U43

  Abstract

  Prevalence of chronic hepatitis C virus (HCV) infection is high among incarcerated persons in the United States. New, short-duration, high-efficacy therapies may expand treatment eligibility in this population.To assess the cost-effectiveness of sofosbuvir for HCV treatment in incarcerated populations.Markov model.Published literature and expert opinion.Treatment-naive men with chronic, genotype 1 HCV monoinfection.Lifetime.Societal.No treatment, 2-drug therapy (pegylated interferon and ribavirin), or 3-drug therapy with either boceprevir or sofosbuvir. For inmates with short remaining sentences (<1.5 years), only no treatment or sofosbuvir 3-drug therapy was feasible; for those with long sentences (≥1.5 years; mean, 10 years), all strategies were considered. After release, eligible persons could receive sofosbuvir 3-drug therapy.Discounted costs (in 2013 U.S. dollars), discounted quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios.The strategies yielded 13.12, 13.57, 14.43, and 15.18 QALYs, respectively, for persons with long sentences. Sofosbuvir produced the largest absolute reductions in decompensated cirrhosis (16%) and hepatocellular carcinoma (9%), resulting in 2.1 additional QALYs at an added cost exceeding $54,000 compared with no treatment. For persons with short sentences, sofosbuvir cost $25,700 per QALY gained compared with no treatment; for those with long sentences, it dominated other treatments, costing $28,800 per QALY gained compared with no treatment.High reinfection rates in prison attenuated cost-effectiveness for persons with long sentences.Data on sofosbuvir's long-term effectiveness and price are limited. The analysis did not consider women, Hispanic persons, or patients co-infected with HIV or hepatitis B virus.Sofosbuvir-based treatment is cost-effective for incarcerated persons, but affordability is an important consideration.National Institutes of Health.

  View details for DOI 10.7326/M14-0602

  View details for Web of Science ID 000343906800014

  View details for PubMedCentralID PMC4313741

• MicroRNA and hepatitis C virus-challenges in investigation and translation: a review of the literature DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE Waldron, P. R., Holodniy, M. 2014; 80 (1): 1-12

  Abstract

  Investigations into the role of microRNA (miRNA) in hepatitis C virus (HCV) infection, disease pathogenesis and host immune and treatment response have potential to produce innovations in diagnosis, prognosis and therapy. However, investigational challenges remain in generating clinically useful and reproducible results. We review the literature with a primary emphasis on methods and technologies used to construct our current understanding of miRNA and HCV disease. A second emphasis is to understand potential clinical research applications and provide clarification of previous study results. Many miRNA have key roles in viral and immunopathogenesis of HCV infection across multiple tissue compartments. Controversy exists among published studies regarding relative measurements, temporal changes and biological significance of specific miRNA and HCV infection. To reconcile diverging data, additional research into optimal sample processing, in vitro models, techniques for microarray differential expression of miRNAs, practices for sample result normalization, and effect of HCV genotype variation on expression are all necessary. Microarray and miRNA isolation techniques should be selected based on ability to generate reproducible results in the sample type of interest. More direct comparisons of efficacy and reliability of various multiplex microarrays and an improved consensus around miRNA normalization and quantitation are necessary so that data can be compared across studies.

  View details for DOI 10.1016/j.diagmicrobio.2014.05.024

  View details for Web of Science ID 000342118900001

  View details for PubMedID 24996839

• Human pegivirus RNA is found in multiple blood mononuclear cells in vivo and serum-derived viral RNA-containing particles are infectious in vitro JOURNAL OF GENERAL VIROLOGY Chivero, E. T., Bhattarai, N., Rydze, R. T., Winters, M. A., Holodniy, M., Stapleton, J. T. 2014; 95: 1307-1319

  Abstract

  Human Pegivirus (HPgV; previously called GB virus C/hepatitis G virus) has limited pathogenicity despite causing persistent infection, and is associated with prolonged survival in HIV-infected individuals. Although HPgV RNA is found in and produced by T and B lymphocytes, the primary permissive cell type(s) are unknown. We quantified HPgV RNA in highly purified CD4+ and CD8+ T cells, including naïve, central memory, and effector memory populations, and in B cells (CD19+), NK cells (CD56+) cells and monocytes (CD14+) using real time RT-PCR. Single genome sequencing was performed on virus within individual cell types to estimate genetic diversity among cell populations. HPgV RNA was present in CD4+ and CD8+ T lymphocytes (9 of 9 subjects), B lymphocytes (7 of 10), NK cells and monocytes (both 4 of 5). HPgV RNA levels were higher in naïve (CD45RA+) CD4+ cells than in central memory and effector memory cells (p<0.01). HPgV sequences were highly conserved between patients (0.117 ± 0.02 substitutions per site; range 0.58-0.14) and within subjects (0.006 ± 0.003 substitutions per site; range 0.006-0.010). The non-synonymous/synonymous substitution ratio was 0.07 suggesting low selective pressure. CFSE-labeled HPgV RNA-containing particles precipitated by a commercial exosome isolation reagent delivered CSFE to uninfected monocytes, NK cells, T and B lymphocytes, and HPgV RNA was transferred to peripheral blood mononuclear cells with evidence of subsequent viral replication. Thus, HPgV RNA-containing serum particles including microvesicles may contribute to delivery of HPgV to PBMCs in vivo, explaining the apparent broad tropism of this persistent human RNA virus.

  View details for DOI 10.1099/vir.0.063016-0

  View details for PubMedID 24668525

• Effect of Management Strategies and Clinical Status on Costs of Care for Advanced HIV AMERICAN JOURNAL OF MANAGED CARE Barnett, P. G., Chow, A., Joyce, V. R., Bayoumi, A. M., Griffin, S. C., Sun, H., Holodniy, M., Brown, S. T., Cameron, D. W., Sculpher, M., Youle, M., Anis, A. H., Owens, D. K. 2014; 20 (5): E129-E137

  Abstract

  To determine the association between preexisting characteristics and current health and the cost of different types of advanced human immunodeficiency virus (HIV) care.Treatment-experienced patients failing highly active antiretroviral treatment (ART) in the United States, Canada, and the United Kingdom were factorial randomized to an antiretroviral-free period and ART intensification. Cost was estimated by multiplying patient-reported utilization by a unit cost.A total of 367 participants were followed for a mean of 15.3 quarters (range 1-26). Medication accounted for most (61.8%) of the $26,832 annual cost. Cost averaged $4147 per quarter for ART, $1981 for inpatient care, $580 for outpatient care, and $346 for other medications. Cost for inpatient stays, outpatient visits, and other medications was 171% higher (P <.01) and cost of ART was 32% lower (P <.01) when cluster of differentiation 4 (CD4) count was <50 cells/μL compared with periods when CD4 count was >200 cells/μL. Some baseline characteristics, including low CD4 count, high viral load, and HIV from injection drug use with hepatitis C coinfection, had a sustained effect on cost.The association between health status and cost depended on the type of care. Indicators of poor health were associated with higher inpatient and concomitant medication costs and lower cost for ART medication. Although ART has supplanted hospitalization as the most important cost in HIV care, some patients continue to incur high hospitalization costs in periods when they are using less ART. The cost of interventions to improve the use of ART might be offset by the reduction of other costs.

  View details for Web of Science ID 000339146800002

• The VACS Index Accurately Predicts Mortality and Treatment Response among Multi-Drug Resistant HIV Infected Patients Participating in the Options in Management with Antiretrovirals (OPTIMA) Study PLOS ONE Brown, S. T., Tate, J. P., Kyriakides, T. C., Kirkwood, K. A., Holodniy, M., Goulet, J. L., Angus, B. J., Cameron, D. W., Justice, A. C. 2014; 9 (3)

  Abstract

  The VACS Index is highly predictive of all-cause mortality among HIV infected individuals within the first few years of combination antiretroviral therapy (cART). However, its accuracy among highly treatment experienced individuals and its responsiveness to treatment interventions have yet to be evaluated. We compared the accuracy and responsiveness of the VACS Index with a Restricted Index of age and traditional HIV biomarkers among patients enrolled in the OPTIMA study.Using data from 324/339 (96%) patients in OPTIMA, we evaluated associations between indices and mortality using Kaplan-Meier estimates, proportional hazards models, Harrel's C-statistic and net reclassification improvement (NRI). We also determined the association between study interventions and risk scores over time, and change in score and mortality.Both the Restricted Index (c = 0.70) and VACS Index (c = 0.74) predicted mortality from baseline, but discrimination was improved with the VACS Index (NRI = 23%). Change in score from baseline to 48 weeks was more strongly associated with survival for the VACS Index than the Restricted Index with respective hazard ratios of 0.26 (95% CI 0.14-0.49) and 0.39(95% CI 0.22-0.70) among the 25% most improved scores, and 2.08 (95% CI 1.27-3.38) and 1.51 (95%CI 0.90-2.53) for the 25% least improved scores.The VACS Index predicts all-cause mortality more accurately among multi-drug resistant, treatment experienced individuals and is more responsive to changes in risk associated with treatment intervention than an index restricted to age and HIV biomarkers. The VACS Index holds promise as an intermediate outcome for intervention research.

  View details for DOI 10.1371/journal.pone.0092606

  View details for Web of Science ID 000333675600053

  View details for PubMedID 24667813

  View details for PubMedCentralID PMC3965438

• GBV-C Viremia and Clinical Events in Advanced HIV Infection JOURNAL OF MEDICAL VIROLOGY Sahni, H., Kirkwood, K., Kyriakides, T. C., Stapleton, J., Brown, S. T., Holodniy, M. 2014; 86 (3): 426-432

  Abstract

  GB Virus C (GBV-C) is a non-pathogenic flavivirus, commonly found in HIV infected patients. Studies suggest a survival benefit of GBV-C viremia in HIV infection. Impact of GBV-C viremia was evaluated on clinical outcome in multidrug-resistant HIV. The OPTIMA study enrolled advanced multidrug-resistant HIV patients with a CD4 count ≤300 cells/mm(3) . This study included a subset of OPTIMA patients. Primary endpoints included AIDS events or death. GBV-C status was assessed at baseline and last time point on study by real-time PCR. Cox proportional hazards models were used to determine if CD4 count (100/mm(3) ), treatment assignment, presence or disappearance of GBV-C viremia, GBV-C viral load level and Hepatitis C virus antibody status were associated with outcome. Of 288 patients (98% male, baseline mean age 48 years, HIV viral load 4.67 log10 /ml, and CD4 127 cells/mm(3) ), 62 (21.5%) had detectable GBV-C viremia. The mortality rate for GBV-C infected subjects was lower, 19/62 (30.7%) versus 87/226 (38.5%), and time to death shorter (HR 0.67, 95% CI 0.41-1.11), but the results were not significantly different. The time to development of AIDS events was not different (HR 0.90, 95% CI 0.52-1.53). Among covariates, only CD4 count (HR 0.28, CI 0.19-0.42) had a significant survival effect. A trend in decreased mortality was seen in GBV-C+ patients with CD4 <100/mm(3) in multivariate analyses. GBV-C co-infection in multidrug-resistant HIV infected patients was associated with a trend in improved survival but not decreased AIDS events. Analysis was limited by cohort size. J. Med. Virol. © 2013 Wiley Periodicals, Inc.

  View details for DOI 10.1002/jmv.23845

  View details for Web of Science ID 000329461000008

  View details for PubMedID 24249700

• CD4 counts and mortality in virologically suppressed US veterans. Journal of the International Association of Providers of AIDS Care Drechsler, H., Zhang, S., Holodniy, M., Bedimo, R. 2014; 13 (2): 120-126

  Abstract

  We used the Veterans Health Administration (VA) HIV Clinical Case Registry (CCR) to evaluate the association between annual CD4 averages and all-cause mortality in HIV-infected veterans during their initial episode of suppressive highly active antiretroviral therapy (HAART). We observed 1083 deaths in 14 769 patients. Unadjusted mortality rates in the top and bottom CD4 quintiles differed significantly from the mid CD4 strata. Mortality in the top CD4 quintile (≥720 cells/mm(3)) was 14.1/1000 patient-years, 95% confidence interval (CI): 10.1-18.2, compared with 20.4 (CI: 15.5-25.3) in the next lower CD4 stratum (530-719 cells/mm(3)). This difference was significant in Cox proportional hazards model, controlling for demographics, hepatitis co-infections, low-level viremia, HAART adherence, and refill rates of individual antiretrovirals (HR: 1.4, CI: 1.13-1.73). Our results support early HAART initiation as advocated by the current US treatment guidelines for HIV infection.

  View details for DOI 10.1177/2325957413512153

  View details for PubMedID 24378517

• Public Health Practice Is Not Research. American journal of public health Otto, J. L., Holodniy, M., Defraites, R. F. 2014

  Abstract

  Scientific and clinical activities undertaken by public health agencies may be misconstrued as medical research. Most discussions of regulatory and legal oversight of medical research focus on activities involving either patients in clinical practice or volunteers in clinical trials. These discussions often exclude similar activities that constitute or support core functions of public health practice. As a result, public health agencies and practitioners may be held to inappropriate regulatory standards regarding research. Through the lens of the Departments of Defense and Veterans Affairs, and using several case studies from these departments, we offer a framework for the adjudication of activities common to research and public health practice that could assist public health practitioners, research oversight authorities, and scientific journals in determining whether such activities require regulatory review and approval as research. (Am J Public Health. Published online ahead of print February 13, 2014: e1-e7. doi:10.2105/AJPH.2013.301663).

  View details for DOI 10.2105/AJPH.2013.301663

  View details for PubMedID 24524499

• Application of a non-amplification-based technology to detect invasive fungal pathogens DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE Hsu, J. L., Binkley, J., Clemons, K. V., Stevens, D. A., Nicolls, M. R., Holodniy, M. 2014; 78 (2): 137-140

  Abstract

  Current diagnostic techniques for fungal diseases could be improved with respect to sensitivity, specificity, and timeliness. To address this clinical need, we adapted a non-amplification-based nucleic acid detection technology to identify fungal pathogens. We demonstrate a high-specificity, detection sensitivity, reproducibility, and multiplex capacity for detecting fungal strains.

  View details for DOI 10.1016/j.diagmicrobio.2013.11.013

  View details for Web of Science ID 000330149700007

  View details for PubMedID 24359934

• Incidence of norovirus-associated acute gastroenteritis in four Veteran's Affairs Medical Center populations in the United States, 2011-2012 IDWeek Grytdal, S., Rimland, D., Shirley, H., Rodriguez-Barradas, M., Goetz, M., Brown, S., Lucero-Obusan, C., Holodniy, M., Graeber, C., Parashar, U., Vinje, J., Lopman, B. 2014

  View details for DOI 10.1093/ofid/ofu051.132

• USE OF DRIED BLOOD SPOT SAMPLES IN HCV-, HBV-, AND INFLUENZA-RELATED EPIDEMIOLOGICAL STUDIES DRIED BLOOD SPOTS: APPLICATIONS AND TECHNIQUES Gakhar, H., Holodniy, M., Li, W., Lee, M. S. 2014: 95-113

  View details for Web of Science ID 000467383000009

• Meeting Mandatory Infectious Disease Reporting Requirements: The Department of Veterans Affairs’ Plan ISDS Selzer, B., Lin, A., Oda, G., Holodniy, M. 2014

  View details for DOI 10.5210/ojphi.v6i1.5126

• Influenza Surveillance in the Department of Veterans Affairs (VA): 2012-2013 Influenza Season ISDS Lucero-Obusan, C., Winters, M., Schirmer, P., Oda, G., Martinello, R., Davey, V., Holodniy, M. 2014

  View details for DOI 10.5210/ojphi.v6i1.5121

• Carbapenem-Resistant Enterobacteriaceae (CRE) Distribution within the Veterans Affairs Healthcare System: 2013 IDWeek Ryono, R., Oda, G., Shankar, G., Schirmer, P., Holodniy, M. 2014

  View details for DOI 10.1093/ofid/ofu052.221

• Opportunities for Improved Detection and Treatment of Latent Tuberculosis Infection Among Veterans — Western United States, January 2010–July 2013 IDWeek Perti, T., Schirmer, P., Winston, C., Weiss, E., Cavanaugh, J., Lucero-Obusan, C., Holodniy, M. 2014

  View details for DOI 10.1093/ofid/ofu052.1236

• Combining Surveillance Systems: Effective Merging of US Veteran and Military Health Data PLOS ONE Pavlin, J. A., Burkom, H. S., Elbert, Y., Lucero-Obusan, C., Winston, C. A., Cox, K. L., Oda, G., Lombardo, J. S., Holodniy, M. 2013; 8 (12)

  Abstract

  The U.S. Department of Veterans Affairs (VA) and Department of Defense (DoD) had more than 18 million healthcare beneficiaries in 2011. Both Departments conduct individual surveillance for disease events and health threats.We performed joint and separate analyses of VA and DoD outpatient visit data from October 2006 through September 2010 to demonstrate geographic and demographic coverage, timeliness of influenza epidemic awareness, and impact on spatial cluster detection achieved from a joint VA and DoD biosurveillance platform.Although VA coverage is greater, DoD visit volume is comparable or greater. Detection of outbreaks was better in DoD data for 58% and 75% of geographic areas surveyed for seasonal and pandemic influenza, respectively, and better in VA data for 34% and 15%. The VA system tended to alert earlier with a typical H3N2 seasonal influenza affecting older patients, and the DoD performed better during the H1N1 pandemic which affected younger patients more than normal influenza seasons. Retrospective analysis of known outbreaks demonstrated clustering evidence found in separate DoD and VA runs, which persisted with combined data sets.The analyses demonstrate two complementary surveillance systems with evident benefits for the national health picture. Relative timeliness of reporting could be improved in 92% of geographic areas with access to both systems, and more information provided in areas where only one type of facility exists. Combining DoD and VA data enhances geographic cluster detection capability without loss of sensitivity to events isolated in either population and has a manageable effect on customary alert rates.

  View details for DOI 10.1371/journal.pone.0084077

  View details for Web of Science ID 000329116700096

  View details for PubMedID 24386335

• Cost-Effectiveness of Newer Antiretroviral Drugs in Treatment-Experienced Patients With Multidrug-Resistant HIV Disease. Journal of acquired immune deficiency syndromes Bayoumi, A. M., Barnett, P. G., Joyce, V. R., Griffin, S. C., Sun, H., Bansback, N. J., Holodniy, M., Sanders, G., Brown, S. T., Kyriakides, T. C., Angus, B., Cameron, D. W., Anis, A. H., Sculpher, M., Owens, D. K. 2013; 64 (4): 382-391

  Abstract

  Newer antiretroviral drugs provide substantial benefits but are expensive. The cost-effectiveness of using antiretroviral drugs in combination for patients with multidrug-resistant HIV disease was determined.A cohort state-transition model was built representing treatment-experienced patients with low CD4 counts, high viral load levels, and multidrug-resistant virus. The effectiveness of newer drugs (those approved in 2005 or later) was estimated from published randomized trials. Other parameters were estimated from a randomized trial and from the literature. The model had a lifetime time horizon and used the perspective of an ideal insurer in the United States. The interventions were combination antiretroviral therapy, consisting of 2 newer drugs and 1 conventional drug, compared with 3 conventional drugs. Outcome measures were life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness.Substituting newer antiretroviral drugs increased expected survival by 3.9 years in advanced HIV disease. The incremental cost-effectiveness ratio of newer, compared with conventional, antiretroviral drugs was $75,556/QALY gained. Sensitivity analyses showed that substituting only one newer antiretroviral drug cost $54,559 to $68,732/QALY, depending on assumptions about efficacy. Substituting 3 newer drugs cost $105,956 to $117,477/QALY. Cost-effectiveness ratios were higher if conventional drugs were not discontinued.In treatment-experienced patients with advanced HIV disease, use of newer antiretroviral agents can be cost-effective, given a cost-effectiveness threshold in the range of $50,000 to $75,000 per QALY gained. Newer antiretroviral agents should be used in carefully selected patients for whom less expensive options are clearly inferior.

  View details for DOI 10.1097/QAI.0000000000000002

  View details for PubMedID 24129369

• Safety of Zoster Vaccine in Elderly Adults Following Documented Herpes Zoster JOURNAL OF INFECTIOUS DISEASES Morrison, V. A., Oxman, M. N., Levin, M. J., Schmader, K. E., Guatelli, J. C., Betts, R. F., Gelb, L. D., Pachucki, C. T., Keay, S. K., Menzies, B., Griffin, M. R., Kauffman, C. A., Marques, A. R., Toney, J. F., Simberkoff, M. S., Serrao, R., Arbeit, R. D., Gnann, J. W., Greenberg, R. N., Holodniy, M., Keitel, W. A., Yeh, S. S., Davis, L. E., Crawford, G. E., Neuzil, K. M., Johnson, G. R., Zhang, J. H., Harbecke, R., Chan, I. S., Keller, P. M., Williams, H. M., Boardman, K. D., Silber, J. L., Annunziato, P. W. 2013; 208 (4): 559-563

  Abstract

  Background. After completion of the Shingles Prevention Study (SPS; Department of Veterans Affairs Cooperative Studies Program Number 403), SPS participants who had initially received placebo were offered investigational zoster vaccine without charge. This provided an opportunity to determine the relative safety of zoster vaccine in older adults following documented herpes zoster (HZ).Methods. A total of 13 681 SPS placebo recipients who elected to receive zoster vaccine were followed for serious adverse events (SAE) for 28 days after vaccination. In contrast to the SPS, a prior episode of HZ was not a contraindication to receiving zoster vaccine. The SPS placebo recipients who received zoster vaccine included 420 who had developed documented HZ during the SPS.Results. The mean interval between the onset of HZ and the receipt of zoster vaccine in the 420 recipients with prior HZ was 3.61 years (median interval, 3.77 years [range, 3-85 months]); the interval was <5 years for approximately 80% of recipients. The proportion of vaccinated SPS placebo recipients with prior HZ who developed ≥1 SAE (0.95%) was not significantly different from that of vaccinated SPS placebo recipients with no prior history of HZ (0.66%), and the distribution of SAEs in the 2 groups was comparable.Conclusions. These results demonstrate that the general safety of zoster vaccine in older persons is not altered by a recent history of documented HZ, supporting the safety aspect of the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommendation to administer zoster vaccine to all persons ≥60 years of age with no contraindications, regardless of a prior history of HZ.

  View details for DOI 10.1093/infdis/jit182

  View details for Web of Science ID 000322412100005

  View details for PubMedID 23633406

• Concurrent outbreaks with co-infection of norovirus and Clostridium difficile in a long-term-care facility EPIDEMIOLOGY AND INFECTION Ludwig, A., Sato, K., Schirmer, P., Maniar, A., Lucero-Obusan, C., Fleming, C., Ryono, R., Oda, G., Winters, M., Holodniy, M. 2013; 141 (8): 1598-1603

  Abstract

  SUMMARY We describe an outbreak of simultaneous Clostridium difficile and norovirus infections in a long-term-care facility. Thirty patients experienced acute gastroenteritis, and four had co-infection with identical C. difficile 027 and genotype II.4 New Orleans norovirus strains. Co-occurring infection requires improved understanding of risk factors, clinical impact, and testing strategies.

  View details for DOI 10.1017/S0950268813000241

  View details for Web of Science ID 000321763100004

  View details for PubMedID 23433360

• PREDICTING INFLUENZA ADMISSIONS AMONG VETERANS FROM TELEPHONE TRIAGE Winston, C., Lucero-Obusan, C., Schirmer, P., Holodniy, M. OXFORD UNIV PRESS INC. 2013: S111

  View details for Web of Science ID 000319870300439

• Health-related Quality of Life Assessment after Antiretroviral Therapy: A Review of the Literature. Drugs Gakhar, H., Kamali, A., Holodniy, M. 2013; 73 (7): 651-672

  Abstract

  Antiretroviral (ARV) treatment for HIV infection has resulted in significant improvement in immunologic and virologic parameters, as well as a reduction in AIDS-defining illnesses and death. Over 25 medications are approved for use, usually in combination regimens of three or four ARVs. Several ARVs are now available as combinatorial products, which have been associated with better adherence. However, while ARV therapy has prolonged life, ARVs also pose a challenge for quality of life as they can cause significant side effects in addition to the potential for drug toxicity and interaction. Given the many complications, side effects and symptoms of HIV/AIDS in addition to associated medical and psychiatric co-morbidities, the need to understand and assess how these interactions may affect health-related quality of life (HRQOL) has grown. Numerous instruments (some validated, others not) are available and have been applied to understanding how ARV treatment affects HRQOL in those with HIV infection, both in clinical trials and clinical practice. In general, ARV treatment improves HRQOL, but this is dependent on the population being studied, the HRQOL instrument being used and the timeframe during which HRQOL has been studied. This article provides a review of the literature on quality of-life assessment as it relates to ARV treatment in developed countries and briefly reviews the HRQOL instruments used, how they have been applied to ARV utilization, and where future research should be applied in HRQOL assessment and HIV infection.

  View details for DOI 10.1007/s40265-013-0040-4

  View details for PubMedID 23591907

• Risk of Cardiovascular Disease from Antiretroviral Therapy for HIV: A Systematic Review PLOS ONE Bavinger, C., Bendavid, E., Niehaus, K., Olshen, R. A., Olkin, I., Sundaram, V., Wein, N., Holodniy, M., Hou, N., Owens, D. K., Desai, M. 2013; 8 (3)

  Abstract

  Recent studies suggest certain antiretroviral therapy (ART) drugs are associated with increases in cardiovascular disease.We performed a systematic review and meta-analysis to summarize the available evidence, with the goal of elucidating whether specific ART drugs are associated with an increased risk of myocardial infarction (MI).We searched Medline, Web of Science, the Cochrane Library, and abstract archives from the Conference on Retroviruses and Opportunistic Infections and International AIDS Society up to June 2011 to identify published articles and abstracts.Eligible studies were comparative and included MI, strokes, or other cardiovascular events as outcomes.Eligibility screening, data extraction, and quality assessment were performed independently by two investigators.Random effects methods and Fisher's combined probability test were used to summarize evidence.Twenty-seven studies met inclusion criteria, with 8 contributing to a formal meta-analysis. Findings based on two observational studies indicated an increase in risk of MI for patients recently exposed (usually defined as within last 6 months) to abacavir (RR 1.92, 95% CI 1.51-2.42) and protease inhibitors (PI) (RR 2.13, 95% CI 1.06-4.28). Our analysis also suggested an increased risk associated with each additional year of exposure to indinavir (RR 1.11, 95% CI 1.05-1.17) and lopinavir (RR 1.22, 95% CI 1.01-1.47). Our findings of increased cardiovascular risk from abacavir and PIs were in contrast to four published meta-analyses based on secondary analyses of randomized controlled trials, which found no increased risk from cardiovascular disease.Although observational studies implicated specific drugs, the evidence is mixed. Further, meta-analyses of randomized trials did not find increased risk from abacavir and PIs. Our findings that implicate specific ARTs in the observational setting provide sufficient evidence to warrant further investigation of this relationship in studies designed for that purpose.

  View details for DOI 10.1371/journal.pone.0059551

  View details for Web of Science ID 000317418500051

  View details for PubMedID 23555704

  View details for PubMedCentralID PMC3608726

• Cost-Effectiveness Analysis of Risk-Factor Guided and Birth-Cohort Screening for Chronic Hepatitis C Infection in the United States PLOS ONE Liu, S., Cipriano, L. E., Holodniy, M., Goldhaber-Fiebert, J. D. 2013; 8 (3)

  Abstract

  No consensus exists on screening to detect the estimated 2 million Americans unaware of their chronic hepatitis C infections. Advisory groups differ, recommending birth-cohort screening for baby boomers, screening only high-risk individuals, or no screening. We assessed one-time risk assessment and screening to identify previously undiagnosed 40-74 year-olds given newly available hepatitis C treatments.A Markov model evaluated alternative risk-factor guided and birth-cohort screening and treatment strategies. Risk factors included drug use history, blood transfusion before 1992, and multiple sexual partners. Analyses of the National Health and Nutrition Examination Survey provided sex-, race-, age-, and risk-factor-specific hepatitis C prevalence and mortality rates. Nine strategies combined screening (no screening, risk-factor guided screening, or birth-cohort screening) and treatment (standard therapy-peginterferon alfa and ribavirin, Interleukin-28B-guided (IL28B) triple-therapy-standard therapy plus a protease inhibitor, or universal triple therapy). Response-guided treatment depended on HCV genotype. Outcomes include discounted lifetime costs (2010 dollars) and quality adjusted life-years (QALYs). Compared to no screening, risk-factor guided and birth-cohort screening for 50 year-olds gained 0.7 to 3.5 quality adjusted life-days and cost $168 to $568 per person. Birth-cohort screening provided more benefit per dollar than risk-factor guided screening and cost $65,749 per QALY if followed by universal triple therapy compared to screening followed by IL28B-guided triple therapy. If only 10% of screen-detected, eligible patients initiate treatment at each opportunity, birth-cohort screening with universal triple therapy costs $241,100 per QALY. Assuming treatment with triple therapy, screening all individuals aged 40-64 years costs less than $100,000 per QALY.The cost-effectiveness of one-time birth-cohort hepatitis C screening for 40-64 year olds is comparable to other screening programs, provided that the healthcare system has sufficient capacity to deliver prompt treatment and appropriate follow-on care to many newly screen-detected individuals.

  View details for DOI 10.1371/journal.pone.0058975

  View details for Web of Science ID 000316549400032

  View details for PubMedID 23533595

  View details for PubMedCentralID PMC3606430

• Dengue Surveillance in Veterans Affairs Healthcare Facilities, 2007-2010 PLOS NEGLECTED TROPICAL DISEASES Schirmer, P. L., Lucero-Obusan, C. A., Benoit, S. R., Santiago, L. M., Stanek, D., Dey, A., Martinez, M., Oda, G., Holodniy, M. 2013; 7 (3)

  Abstract

  Although dengue is endemic in Puerto Rico (PR), 2007 and 2010 were recognized as epidemic years. In the continental United States (US), outside of the Texas-Mexico border, there had not been a dengue outbreak since 1946 until dengue re-emerged in Key West, Florida (FL), in 2009-2010. The objective of this study was to use electronic and manual surveillance systems to identify dengue cases in Veterans Affairs (VA) healthcare facilities and then to clinically compare dengue cases in Veterans presenting for care in PR and in FL.Outpatient encounters from 1/2007-12/2010 and inpatient admissions (only available from 10/2009-12/2010) with dengue diagnostic codes at all VA facilities were identified using VA's Electronic Surveillance System for Early Notification of Community-based Epidemics (ESSENCE). Additional case sources included VA data from Centers for Disease Control and Prevention BioSense and VA infection preventionists. Case reviews were performed. Categorical data was compared using Mantel-Haenszel or Fisher Exact tests and continuous variables using t-tests. Dengue case residence was mapped.Two hundred eighty-eight and 21 PR and FL dengue cases respectively were identified. Of 21 FL cases, 12 were exposed in Key West and 9 were imported. During epidemic years, FL cases had significantly increased dengue testing and intensive care admissions, but lower hospitalization rates and headache or eye pain symptoms compared to PR cases. There were no significant differences in clinical symptoms, laboratory abnormalities or outcomes between epidemic and non-epidemic year cases in FL and PR. Confirmed/probable cases were significantly more likely to be hospitalized and have thrombocytopenia or leukopenia compared to suspected cases.Dengue re-introduction in the continental US warrants increased dengue surveillance and education in VA. Throughout VA, under-testing of suspected cases highlights the need to emphasize use of diagnostic testing to better understand the magnitude of dengue among Veterans.

  View details for DOI 10.1371/journal.pntd.0002040

  View details for Web of Science ID 000316943800005

  View details for PubMedID 23516642

  View details for PubMedCentralID PMC3597482

• Immune biomarker differences and changes comparing HCV mono-infected, HIV/HCV co-infected, and HCV spontaneously cleared patients. PloS one Kushner, L. E., Wendelboe, A. M., Lazzeroni, L. C., Chary, A., Winters, M. A., Osinusi, A., Kottilil, S., Polis, M. A., Holodniy, M. 2013; 8 (4)

  Abstract

  Immune biomarkers are implicated in HCV treatment response, fibrosis, and accelerated pathogenesis of comorbidities, though only D-dimer and C-reactive protein have been consistently studied. Few studies have evaluated HIV/HCV co-infection, and little longitudinal data exists describing a broader antiviral cytokine response.Fifty immune biomarkers were analyzed at baseline (BL) and HCV end of treatment follow-up(FU) time point using the Luminex 50-plex assay in plasma samples from 15 HCV-cleared, 24 HCV mono- and 49 HIV/HCV co-infected patients receiving antiretroviral treatment, who either did or did not receive pegylated-interferon/ribavirin HCV treatment. Biomarker levels were compared among spontaneous clearance patients, mono- and co-infected, untreated and HCV-treated, and sustained virologic responders (SVR) and non-responders (NR) at BL and FU using nonparametric analyses. A Bonferroni correction, adjusting for tests of 50 biomarkers, was used to reduce Type I error.Compared to HCV patients at BL, HIV/HCV patients had 22 significantly higher and 4 significantly lower biomarker levels, following correction for multiple testing. There were no significantly different BL levels when comparing SVR and NR in mono- or co-infected patients; however, FU levels changed considerably in co-infected patients, with seven becoming significantly higher and eight becoming significantly lower in SVR patients. Longitudinally between BL and FU, 13 markers significantly changed in co-infected SVR patients, while none significantly changed in co-infected NR patients. There were also no significant changes in longitudinal analyses of mono-infected patients achieving SVR or mono-infected and co-infected groups deferring treatment.Clear differences exist in pattern and quantity of plasma immune biomarkers among HCV mono-infected, HIV/HCV co-infected, and HCV-cleared patients; and with SVR in co-infected patients treated for HCV. Though >90% of patients were male and co-infected had a larger percentage of African American patients, our findings may have implications for better understanding HCV pathogenesis, treatment outcomes, and future therapeutic targets.

  View details for DOI 10.1371/journal.pone.0060387

  View details for PubMedID 23593207

  View details for PubMedCentralID PMC3617231

• Is there cross talk between HIV-1 5 ' RT drug resistance mutations (DRMs) and connection/RNase H (3 ' RT) mutations? Rhee, S. Y., Varghese, V., Winters, M. A., Holodniy, M., Shafer, R. W. INT MEDICAL PRESS LTD. 2013: A67

  View details for Web of Science ID 000335229500059

• Immune biomarker differences and changes comparing HCV mono-infected, HIV/HCV co-infected, and HCV spontaneously cleared patients. PloS one Kushner, L. E., Wendelboe, A. M., Lazzeroni, L. C., Chary, A., Winters, M. A., Osinusi, A., Kottilil, S., Polis, M. A., Holodniy, M. 2013; 8 (4)

  View details for DOI 10.1371/journal.pone.0060387

  View details for PubMedID 23593207

• Influenza treatment and prophylaxis with neuraminidase inhibitors: a review. Infection and drug resistance Kamali, A., Holodniy, M. 2013; 6: 187-198

  Abstract

  Influenza virus is a pathogen that causes morbidity and mortality worldwide. Whereas vaccination is important for prevention of disease, given its limitations, antiviral therapy is at the forefront of treatment and also plays a role in prevention. Currently, two classes of antiviral medications, the adamantanes and the neuraminidase inhibitors, are approved for treatment. Given the resistance patterns of circulating influenza, adamantanes are not recommended. Within the US, two neuraminidase inhibitors are currently approved for both treatment and prevention, while worldwide there are four available. In this review, we will briefly discuss the epidemiology and pathology of influenza and then discuss neuraminidase inhibitors: their mechanism of action, resistance, development, and future applications.

  View details for DOI 10.2147/IDR.S36601

  View details for PubMedID 24277988

  View details for PubMedCentralID PMC3838482

• Risk of cardiovascular disease from antiretroviral therapy for HIV: a systematic review. PloS one Bavinger, C., Bendavid, E., Niehaus, K., Olshen, R. A., Olkin, I., Sundaram, V., Wein, N., Holodniy, M., Hou, N., Owens, D. K., Desai, M. 2013; 8 (3)

  Abstract

  Recent studies suggest certain antiretroviral therapy (ART) drugs are associated with increases in cardiovascular disease.We performed a systematic review and meta-analysis to summarize the available evidence, with the goal of elucidating whether specific ART drugs are associated with an increased risk of myocardial infarction (MI).We searched Medline, Web of Science, the Cochrane Library, and abstract archives from the Conference on Retroviruses and Opportunistic Infections and International AIDS Society up to June 2011 to identify published articles and abstracts.Eligible studies were comparative and included MI, strokes, or other cardiovascular events as outcomes.Eligibility screening, data extraction, and quality assessment were performed independently by two investigators.Random effects methods and Fisher's combined probability test were used to summarize evidence.Twenty-seven studies met inclusion criteria, with 8 contributing to a formal meta-analysis. Findings based on two observational studies indicated an increase in risk of MI for patients recently exposed (usually defined as within last 6 months) to abacavir (RR 1.92, 95% CI 1.51-2.42) and protease inhibitors (PI) (RR 2.13, 95% CI 1.06-4.28). Our analysis also suggested an increased risk associated with each additional year of exposure to indinavir (RR 1.11, 95% CI 1.05-1.17) and lopinavir (RR 1.22, 95% CI 1.01-1.47). Our findings of increased cardiovascular risk from abacavir and PIs were in contrast to four published meta-analyses based on secondary analyses of randomized controlled trials, which found no increased risk from cardiovascular disease.Although observational studies implicated specific drugs, the evidence is mixed. Further, meta-analyses of randomized trials did not find increased risk from abacavir and PIs. Our findings that implicate specific ARTs in the observational setting provide sufficient evidence to warrant further investigation of this relationship in studies designed for that purpose.

  View details for DOI 10.1371/journal.pone.0059551

  View details for PubMedID 23555704

  View details for PubMedCentralID PMC3608726

• IL28B polymorphism is not associated with HCV protease diversity in patients co-infected with HIV and HCV treated with pegylated interferon and ribavirin JOURNAL OF MEDICAL VIROLOGY Osinusi, A., Chary, A., Winters, M. A., Naggie, S., Masur, H., Polis, M. A., Kottilil, S., Holodniy, M. 2012; 84 (10): 1522-1527

  Abstract

  Recent studies have demonstrated that IL28B polymorphisms predict therapeutic responses in chronic hepatitis C virus (HCV)-treated patients; however, the effect on HCV viral diversity, particularly on the HCV protease gene, is not clear. This study sought to evaluate the effect of IL28B polymorphisms on HCV diversity at NS3/4 protease region, which may influence therapeutic response to an HCV protease inhibitor based regimen. Twenty-two patients co-infected with HIV and HCV genotype 1, treatment-naïve on stable HIV antiretroviral therapy initiating interferon-based treatment were evaluated. Plasma HCV NS3 gene diversity was analyzed by clonal analysis at baseline and end of treatment. IL28B (rs12979860) genotypes were tested for associations with virologic outcomes and diversity parameters. There was similar baseline NS3 diversity in patients with CC (favorable) genotype compared to those with CT/TT (unfavorable) genotypes. There was no significant association between IL28B genotype and baseline NS3 nucleotide p-distance, dS-dN, amino acid p-distance, or nucleotide changes. Among patients without a sustained virologic response, between baseline and follow-up there was a significant trend towards decreased diversity after treatment among patients with favorable genotype, which was not observed in unfavorable genotypes. In patients treated with peginterferon/ribavirin therapy, IL28B polymorphism was not associated with enhanced NS3 diversity at baseline. Among non-SVR patients with the less favorable genotype, there was no change in diversity after treatment. This suggests that IL28B genotype is unlikely to have a negative impact on subsequent HCV PI efficacy in patients co-infected with HIV and HCV patients who have previously failed HCV therapy.

  View details for DOI 10.1002/jmv.23376

  View details for Web of Science ID 000308106500003

  View details for PubMedID 22930497

• Cost Effectiveness of Screening Strategies for Early Identification of HIV and HCV Infection in Injection Drug Users PLOS ONE Cipriano, L. E., Zaric, G. S., Holodniy, M., Bendavid, E., Owens, D. K., Brandeau, M. L. 2012; 7 (9)

  Abstract

  To estimate the cost, effectiveness, and cost effectiveness of HIV and HCV screening of injection drug users (IDUs) in opioid replacement therapy (ORT).Dynamic compartmental model of HIV and HCV in a population of IDUs and non-IDUs for a representative U.S. urban center with 2.5 million adults (age 15-59).We considered strategies of screening individuals in ORT for HIV, HCV, or both infections by antibody or antibody and viral RNA testing. We evaluated one-time and repeat screening at intervals from annually to once every 3 months. We calculated the number of HIV and HCV infections, quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs).Adding HIV and HCV viral RNA testing to antibody testing averts 14.8-30.3 HIV and 3.7-7.7 HCV infections in a screened population of 26,100 IDUs entering ORT over 20 years, depending on screening frequency. Screening for HIV antibodies every 6 months costs $30,700/QALY gained. Screening for HIV antibodies and viral RNA every 6 months has an ICER of $65,900/QALY gained. Strategies including HCV testing have ICERs exceeding $100,000/QALY gained unless awareness of HCV-infection status results in a substantial reduction in needle-sharing behavior.Although annual screening for antibodies to HIV and HCV is modestly cost effective compared to no screening, more frequent screening for HIV provides additional benefit at less cost. Screening individuals in ORT every 3-6 months for HIV infection using both antibody and viral RNA technologies and initiating ART for acute HIV infection appears cost effective.

  View details for DOI 10.1371/journal.pone.0045176

  View details for PubMedID 23028828

• Development of Elvitegravir Resistance and Linkage of Integrase Inhibitor Mutations with Protease and Reverse Transcriptase Resistance Mutations PLOS ONE Winters, M. A., Lloyd, R. M., Shafer, R. W., Kozal, M. J., Miller, M. D., Holodniy, M. 2012; 7 (7)

  Abstract

  Failure of antiretroviral regimens containing elvitegravir (EVG) and raltegravir (RAL) can result in the appearance of integrase inhibitor (INI) drug-resistance mutations (DRMs). While several INI DRMs have been identified, the evolution of EVG DRMs and the linkage of these DRMs with protease inhibitor (PI) and reverse transcriptase inhibitor (RTI) DRMs have not been studied at the clonal level. We examined the development of INI DRMs in 10 patients failing EVG-containing regimens over time, and the linkage of INI DRMs with PI and RTI DRMs in these patients plus 6 RAL-treated patients. A one-step RT-nested PCR protocol was used to generate a 2.7 kB amplicon that included the PR, RT, and IN coding region, and standard cloning and sequencing techniques were used to determine DRMs in 1,277 clones (mean 21 clones per time point). Results showed all patients had multiple PI, NRTI, and/or NNRTI DRMs at baseline, but no primary INI DRM. EVG-treated patients developed from 2 to 6 strains with different primary INI DRMs as early as 2 weeks after initiation of treatment, predominantly as single mutations. The prevalence of these strains fluctuated and new strains, and/or strains with new combinations of INI DRMs, developed over time. Final failure samples (weeks 14 to 48) typically showed a dominant strain with multiple mutations or N155H alone. Single N155H or multiple mutations were also observed in RAL-treated patients at virologic failure. All patient strains showed evidence of INI DRM co-located with single or multiple PI and/or RTI DRMs on the same viral strand. Our study shows that EVG treatment can select for a number of distinct INI-resistant strains whose prevalence fluctuates over time. Continued appearance of new INI DRMs after initial INI failure suggests a potent, highly dynamic selection of INI resistant strains that is unaffected by co-location with PI and RTI DRMs.

  View details for DOI 10.1371/journal.pone.0040514

  View details for Web of Science ID 000306548900028

  View details for PubMedID 22815755

• Predictive value of HIV-1 replication capacity and phenotypic susceptibility scores in antiretroviral treatment-experienced patients HIV MEDICINE Bedimo, R., Kyriakides, T., Brown, S., Weidler, J., Lie, Y., Coakley, E., Holodniy, M. 2012; 13 (6): 345-351

  Abstract

  The aim of the study was to determine the prognostic value of HIV replication capacity (RC) for subsequent antiretroviral (ARV) treatment response in ARV-experienced patients.RC and phenotypic resistance testing were performed at baseline and week 12 on plasma samples from patients randomized to undergo a 12-week ARV drug-free period (ARDFP) or initiate immediate salvage therapy (no-ARDFP group) in the Options in Management with Antiretrovirals (OPTIMA) trial. Dichotomous and incremental phenotypic susceptibility scores (dPSSs and iPSSs, respectively) were calculated. The predictive value of RC and PSS for ARV therapy response and/or ARDFP was evaluated using multivariate regression analysis and Pearson correlations.In 146 no-ARDFP subjects, baseline RC (50.8%) did not change at week 12 and was not correlated with CD4 cell count or viral load changes at week 12 (P=0.33 and P=0.79, respectively) or at week 24 (P=0.96 and P=0.14, respectively). dPSS predicted virological but not CD4 cell count response to ARV therapy at weeks 12, 24 and 48 (P=0.002, P<0.001 and P=0.005, respectively). RC was significantly correlated with dPSS and iPSS at baseline, but did not increase their predictive value. In the 137 ARDFP patients, RC increased significantly (from 52.4 to 85.8%), but did not predict CD4 cell count and viral load changes during ARDFP (P=0.92 and P=0.26, respectively). RC after ARDFP did not predict subsequent CD4 cell count and viral load changes 12 weeks following ARV treatment reinitiation (P=0.90 and P=0.29, respectively).We found no additional predictive value of replication capacity for virological or immunological responses (above what PSS provides) in patients undergoing salvage ARV treatment.

  View details for DOI 10.1111/j.1468-1293.2011.00981.x

  View details for Web of Science ID 000304762200004

  View details for PubMedID 22276745

• Results from a Large-Scale Epidemiologic Look-Back Investigation of Improperly Reprocessed Endoscopy Equipment INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY Holodniy, M., Oda, G., Schirmer, P. L., Lucero, C. A., Khudyakov, Y. E., Xia, G., Lin, Y., Valdiserri, R., Duncan, W. E., Davey, V. J., Cross, G. M. 2012; 33 (7): 649-656

  Abstract

  To determine whether improper high-level disinfection practices during endoscopy procedures resulted in bloodborne viral infection transmission. Retrospective cohort study. Four Veterans Affairs medical centers (VAMCs). Veterans who underwent colonoscopy and laryngoscopy (ear, nose, and throat [ENT]) procedures from 2003 to 2009. Patients were identified through electronic health record searches and serotested for human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV). Newly discovered case patients were linked to a potential source with known identical infection, whose procedure occurred no more than 1 day prior to the case patient's procedure. Viral genetic testing was performed for case/proximate pairs to determine relatedness. Of 10,737 veterans who underwent endoscopy at 4 VAMCs, 9,879 patients agreed to viral testing. Of these, 90 patients were newly diagnosed with 1 or more viral bloodborne pathogens (BBPs). There were no case/proximate pairings found for patients with either HIV or HBV; 24 HCV case/proximate pairings were found, of which 7 case patients and 8 proximate patients had sufficient viral load for further genetic testing. Only 2 of these cases, both of whom underwent laryngoscopy, and their 4 proximates agreed to further testing. None of the 4 remaining proximate patients who underwent colonoscopy agreed to further testing. Mean genetic distance between the 2 case patients and 4 proximate patients ranged from 13.5% to 19.1%. Our investigation revealed that exposure to improperly reprocessed ENT endoscopes did not result in viral transmission in those patients who had viral genetic analysis performed. Any potential transmission of BBPs from colonoscopy remains unknown.

  View details for DOI 10.1086/666345

  View details for Web of Science ID 000304998300001

  View details for PubMedID 22669224

• Comparative Assessment of Antimicrobial Usage Measures in the Department of Veterans Affairs INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY Schirmer, P. L., Mercier, R. C., Ryono, R. A., Nguyen, N., Lucero, C. A., Oda, G., Holodniy, M. 2012; 33 (4): 409-411

  Abstract

  We compared 2 data sources--antimicrobial orders and bar-coded medication administration (BCMA)--for calculating the number of grams used, grams used based on defined daily dose, and days of therapy at one Veterans Affairs Medical Center for 2009-2010. The number of grams used calculated from BCMA data provided the most informative antimicrobial utilization measure.

  View details for DOI 10.1086/664759

  View details for Web of Science ID 000301716700016

  View details for PubMedID 22418639

• Outcomes Associated with a Cognitive-Behavioral Chronic Pain Management Program Implemented in Three Public HIV Primary Care Clinics JOURNAL OF BEHAVIORAL HEALTH SERVICES & RESEARCH Trafton, J. A., Sorrell, J. T., Holodniy, M., Pierson, H., Link, P., Combs, A., Israelski, D. 2012; 39 (2): 158-173

  Abstract

  In patients with HIV/AIDS, chronic pain is common and analgesics pose serious risks. Cognitive-behavioral therapies (CBT) provide an alternative. This study evaluated feasibility and impact of a CBT-based pain management program in three public primary care clinics for HIV patients. The program included a workbook and 12-weeks of group CBT sessions. HIV-positive patients with chronic moderate to severe pain were invited to participate in the program and were assessed at enrollment, 6, 12, and 24 weeks. Despite only moderate group attendance, program enrollment was associated with significant improvements in pain intensity, pain-related functioning, anxiety and acceptance, and mental health. At 24 weeks, effect sizes for pain outcomes were -0.83 for pain intensity and -0.43 for functioning. The pattern of change in outcomes was consistent with predictions based on cognitive-behavioral theory. Effects were observed at all clinics. Adding CBT-based pain management into primary care may provide important benefits for patients with HIV/AIDS.

  View details for Web of Science ID 000303000000006

  View details for PubMedID 21947662

• Quantitation of hepatitis C virus RNA in peripheral blood mononuclear cells in HCV-monoinfection and HIV/HCV-coinfection JOURNAL OF MEDICAL VIROLOGY Chary, A., Winters, M. A., Eisen, R., Knight, T. H., Asmuth, D. M., Holodniy, M. 2012; 84 (3): 431-437

  Abstract

  Peripheral blood mononuclear cells (PBMCs) represent an extrahepatic hepatitis C virus (HCV) reservoir, the significance of which is unclear due to limited studies and varying test methodologies. In this study, a commercial viral load assay for measuring cell-associated PBMC HCV RNA was evaluated. HCV RNA was extracted from PBMCs, sorted CD14+, and CD19+ cells and corresponding plasma samples using the Abbott m2000 and Real-Time HCV assay. Test performance and influence of HIV seropositivity on plasma and PBMC HCV RNA were studied. Among 51 patients, 67 and 62 unique patient samples had detectable plasma and PBMC HCV viral load, respectively. The median PBMC viral load was 535 IU/1 M cells (range 29-5,190). CD19+ cells had significantly higher viral load than CD14+ cells (median log(10) HCV viral load 2.63 vs. 1.50 IU/ml; P< 0.001). Stability of PBMC viral load over time was demonstrated in untreated patients; all patients with an undetectable plasma HCV viral load after HCV treatment also demonstrated undetectable PBMC viral load. Repeated testing in nine samples yielded consistent PBMC viral load, differing by only 1.3-fold (range 1.0-1.7-fold). Among samples with detectable plasma HCV RNA, the correlation between PBMC and plasma viral load was moderate (r = 0.66) and was greater among HCV mono-infected compared to HIV/HCV co-infected subjects (r = 0.80 vs. 0.52). Measurement of cell-associated PBMC HCV RNA using a commercial assay demonstrated promising test characteristics. Differences in PBMC HCV viral load based on HIV-coinfection status and the significance of greater copy number in B-cells requires further study.

  View details for DOI 10.1002/jmv.23210

  View details for Web of Science ID 000299071300008

  View details for PubMedID 22246828

• New Protease Inhibitors for the Treatment of Chronic Hepatitis C A Cost-Effectiveness Analysis ANNALS OF INTERNAL MEDICINE Liu, S., Cipriano, L. E., Holodniy, M., Owens, D. K., Goldhaber-Fiebert, J. D. 2012; 156 (4): 279-U68

  Abstract

  Chronic hepatitis C virus is difficult to treat and affects approximately 3 million Americans. Protease inhibitors increase the effectiveness of standard therapy, but they are costly. A genetic assay may identify patients most likely to benefit from this treatment advance.To assess the cost-effectiveness of new protease inhibitors and an interleukin (IL)-28B genotyping assay for treating chronic hepatitis C virus.Decision-analytic Markov model.Published literature and expert opinion.Treatment-naive patients with chronic, genotype 1 hepatitis C virus monoinfection.Lifetime.Societal.Strategies are defined by the use of IL-28B genotyping and type of treatment (standard therapy [pegylated interferon with ribavirin]; triple therapy [standard therapy and a protease inhibitor]). Interleukin-28B-guided triple therapy stratifies patients with CC genotypes to standard therapy and those with non-CC types to triple therapy.Discounted costs (in 2010 U.S. dollars) and quality-adjusted life-years (QALYs); incremental cost-effectiveness ratios.For patients with mild and advanced fibrosis, universal triple therapy reduced the lifetime risk for hepatocellular carcinoma by 38% and 28%, respectively, and increased quality-adjusted life expectancy by 3% and 8%, respectively, compared with standard therapy. Gains from IL-28B-guided triple therapy were smaller. If the protease inhibitor costs $1100 per week, universal triple therapy costs $102,600 per QALY (mild fibrosis) or $51,500 per QALY (advanced fibrosis) compared with IL-28B-guided triple therapy and $70,100 per QALY (mild fibrosis) and $36,300 per QALY (advanced fibrosis) compared with standard therapy.Results were sensitive to the cost of protease inhibitors and treatment adherence rates.Data on the long-term comparative effectiveness of the new protease inhibitors are lacking.Both universal triple therapy and IL-28B-guided triple therapy are cost-effective when the least-expensive protease inhibitor are used for patients with advanced fibrosis.Stanford University.

  View details for PubMedID 22351713

• Ultrasensitive detection of rare mutations using next-generation targeted resequencing NUCLEIC ACIDS RESEARCH Flaherty, P., Natsoulis, G., Muralidharan, O., Winters, M., Buenrostro, J., Bell, J., Brown, S., Holodniy, M., Zhang, N., Ji, H. P. 2012; 40 (1)

  Abstract

  With next-generation DNA sequencing technologies, one can interrogate a specific genomic region of interest at very high depth of coverage and identify less prevalent, rare mutations in heterogeneous clinical samples. However, the mutation detection levels are limited by the error rate of the sequencing technology as well as by the availability of variant-calling algorithms with high statistical power and low false positive rates. We demonstrate that we can robustly detect mutations at 0.1% fractional representation. This represents accurate detection of one mutant per every 1000 wild-type alleles. To achieve this sensitive level of mutation detection, we integrate a high accuracy indexing strategy and reference replication for estimating sequencing error variance. We employ a statistical model to estimate the error rate at each position of the reference and to quantify the fraction of variant base in the sample. Our method is highly specific (99%) and sensitive (100%) when applied to a known 0.1% sample fraction admixture of two synthetic DNA samples to validate our method. As a clinical application of this method, we analyzed nine clinical samples of H1N1 influenza A and detected an oseltamivir (antiviral therapy) resistance mutation in the H1N1 neuraminidase gene at a sample fraction of 0.18%.

  View details for DOI 10.1093/nar/gkr861

  View details for Web of Science ID 000298733500002

  View details for PubMedID 22013163

  View details for PubMedCentralID PMC3245950

• Effect of Treatment Interruption and Intensification of Antiretroviral Therapy on Health-Related Quality of Life in Patients with Advanced HIV: A Randomized, Controlled Trial MEDICAL DECISION MAKING Joyce, V. R., Barnett, P. G., Chow, A., Bayoumi, A. M., Griffin, S. C., Sun, H., Holodniy, M., Brown, S. T., Kyriakides, T. C., Cameron, D. W., Youle, M., Sculpher, M., Anis, A. H., Owens, D. K. 2012; 32 (1): 70-82

  Abstract

  The effect of antiretroviral therapy (ART) interruption or intensification on health-related quality of life (HRQoL) in advanced HIV patients is unknown.To assess the impact of temporary treatment interruption and intensification of ART on HRQoL.A 2 x 2 factorial open label randomized controlled trial.Hospitals in the United States, Canada, and the United Kingdom.Multidrug resistant (MDR) HIV patients.Patients were randomized to receive a 12-wk interruption or not, and ART intensification or standard ART.The Health Utilities Index (HUI3), EQ-5D, standard gamble (SG), time tradeoff (TTO), visual analog scale (VAS), and the Medical Outcomes Study HIV Health Survey (MOS-HIV).There were no significant differences in HRQoL among the four groups during follow-up; however, there was a temporary significant decline in HRQoL on some measures within the interruption group during interruption (HUI3 -0.05, P = 0.03; VAS -5.9, P = 0.002; physical health summary -2.9, P = 0.001; mental health summary -1.9, P = 0.02). Scores declined slightly overall during follow-up. Multivariate analysis showed significantly lower HRQoL associated with some clinical events. Limitations. The results may not apply to HIV patients who have not experienced multiple treatment failures or who have not developed MDR HIV.Temporary ART interruption and ART intensification provided neither superior nor inferior HRQoL compared with no interruption and standard ART. Among surviving patients, HRQoL scores declined only slightly over years of follow-up in this advanced HIV cohort; however, approximately one-third of patients died during the trial follow up. Lower HRQoL was associated with adverse clinical events.

  View details for DOI 10.1177/0272989X10397615

  View details for PubMedID 21383086

• HIV-HBV vaccine escape mutant infection with loss of HBV surface antibody and persistent HBV viremia on tenofovir/emtricitabine without antiviral resistance JOURNAL OF CLINICAL VIROLOGY Schirmer, P., Winters, M., Holodniy, M. 2011; 52 (3): 261-264

  Abstract

  We report a case of acute hepatitis B virus genotype A vaccine escape mutant infection with loss of HBV vaccine-induced seropositivity in a HIV-1 infected patient. His HBV is unresponsive to tenofovir/emtricitabine treatment demonstrated by persistent viremia despite lacking known resistance mutations and while having an undetectable HIV-1 viral load.

  View details for DOI 10.1016/j.jcv.2011.07.014

  View details for Web of Science ID 000296556800021

  View details for PubMedID 21840252

• Use of dried clinical samples for storing and detecting influenza RNA INFLUENZA AND OTHER RESPIRATORY VIRUSES Winters, M., Lloyd, R., Shahidi, A., Brown, S., Holodniy, M. 2011; 5 (6): 413-417

  Abstract

  Most clinical samples collected for diagnostic influenza testing and monitoring require refrigerated or frozen storage or shipment, which imparts logistic and cost burdens. The ability to store and ship dried clinical specimens under ambient conditions for influenza testing would significantly reduce costs and protect samples from improper storage or equipment failure, especially in remote or resource-limited areas.To evaluate the collection and storage of dried clinical samples on a transport matrix (ViveST™, ST) for influenza RNA testing by real-time reverse-transcription PCR (RT-PCR).Viral transport medium from swab or sputum samples was applied to ST, dried, and stored under ambient conditions from 2 days to 6 months. Additional aliquots of samples were frozen. Testing of frozen and ST-stored samples was performed using the WHO/CDC real-time influenza A (H1N1) RT-PCR protocol and compared to the Luminex xTAG RVP assay.ST-stored samples yielded slightly higher threshold cycle values (median 2·54 cycles) compared to frozen samples tested in parallel. This difference was consistent regardless of viral input. There was no significant difference in signal recovery between samples stored for 1 week versus samples stored for 3 weeks, or from three samples stored for 6 months. Qualitatively, clinical specimens stored on ST were 100% concordant (36/36) with frozen samples for detecting the presence of influenza A RNA.ST-processed dried specimens produced similar rates of seasonal or novel 2009 HIN1 influenza RNA detection compared to conventional sample processing and thus presents a viable alternative to refrigerated or frozen samples.

  View details for DOI 10.1111/j.1750-2659.2011.00253.x

  View details for Web of Science ID 000296080300009

  View details for PubMedID 21668673

• Diagnosing invasive fungal disease in critically ill patients CRITICAL REVIEWS IN MICROBIOLOGY Hsu, J. L., Ruoss, S. J., Bower, N. D., Lin, M., Holodniy, M., Stevens, D. A. 2011; 37 (4): 277-312

  Abstract

  Fungal infections are increasing, with a changing landscape of pathogens and emergence of new groups at risk for invasive disease. We review current diagnostic techniques, focusing on studies in critically ill patients. Microbiological cultures, the current "gold standard", demonstrate poor sensitivity, thus diagnosis of invasive disease in the critically ill is difficult. This diagnostic dilemma results in under- or over-treatment of patients, potentially contributing to poor outcomes and antifungal resistance. While other current diagnostic tests perform moderately well, many lack timeliness, efficacy, and are negatively affected by treatments common to critically ill patients. New nucleic acid-based research is promising.

  View details for DOI 10.3109/1040841X.2011.581223

  View details for Web of Science ID 000295616800001

  View details for PubMedID 21749278

• IL28B POLYMORPHISM IS NOT ASSOCIATED WITH HCV PROTEASE DIVERSITY IN HIV/HCV-COINFECTED PATIENTS TREATED WITH AN INTERFERON-BASED REGIMEN 62nd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) Osinusi, A., Chary, A., Kottilil, S., Winters, M. A., Naggie, S., Masur, H., Polis, M. A., Holodniy, M. WILEY-BLACKWELL. 2011: 815A–815A

  View details for Web of Science ID 000295578003193

• Enhanced health event detection and influenza surveillance using a joint Veterans Affairs and Department of Defense biosurveillance application BMC MEDICAL INFORMATICS AND DECISION MAKING Lucero, C. A., Oda, G., Cox, K., Maldonado, F., Lombardo, J., Wojcik, R., Holodniy, M. 2011; 11

  Abstract

  The establishment of robust biosurveillance capabilities is an important component of the U.S. strategy for identifying disease outbreaks, environmental exposures and bioterrorism events. Currently, U.S. Departments of Defense (DoD) and Veterans Affairs (VA) perform biosurveillance independently. This article describes a joint VA/DoD biosurveillance project at North Chicago-VA Medical Center (NC-VAMC). The Naval Health Clinics-Great Lakes facility physically merged with NC-VAMC beginning in 2006 with the full merger completed in October 2010 at which time all DoD care and medical personnel had relocated to the expanded and remodeled NC-VAMC campus and the combined facility was renamed the Lovell Federal Health Care Center (FHCC). The goal of this study was to evaluate disease surveillance using a biosurveillance application which combined data from both populations.A retrospective analysis of NC-VAMC/Lovell FHCC and other Chicago-area VAMC data was performed using the ESSENCE biosurveillance system, including one infectious disease outbreak (Salmonella/Taste of Chicago-July 2007) and one weather event (Heat Wave-July 2006). Influenza-like-illness (ILI) data from these same facilities was compared with CDC/Illinois Sentinel Provider and Cook County ESSENCE data for 2007-2008.Following consolidation of VA and DoD facilities in North Chicago, median number of visits more than doubled, median patient age dropped and proportion of females rose significantly in comparison with the pre-merger NC-VAMC facility. A high-level gastrointestinal alert was detected in July 2007, but only low-level alerts at other Chicago-area VAMCs. Heat-injury alerts were triggered for the merged facility in June 2006, but not at the other facilities. There was also limited evidence in these events that surveillance of the combined population provided utility above and beyond the VA-only and DoD-only components. Recorded ILI activity for NC-VAMC/Lovell FHCC was more pronounced in the DoD component, likely due to pediatric data in this population. NC-VAMC/Lovell FHCC had two weeks of ILI activity exceeding both the Illinois State and East North Central Regional baselines, whereas Hines VAMC had one and Jesse Brown VAMC had zero.Biosurveillance in a joint VA/DoD facility showed potential utility as a tool to improve surveillance and situational awareness in an area with Veteran, active duty and beneficiary populations. Based in part on the results of this pilot demonstration, both agencies have agreed to support the creation of a combined VA/DoD ESSENCE biosurveillance system which is now under development.

  View details for DOI 10.1186/1472-6947-11-56

  View details for Web of Science ID 000295781100001

  View details for PubMedID 21929813

  View details for PubMedCentralID PMC3188469

• Determinants of the Cost of Health Services Used by Veterans With HIV MEDICAL CARE Barnett, P. G., Chow, A., Joyce, V. R., Bayoumi, A. M., Griffin, S. C., Nosyk, B., Holodniy, M., Brown, S. T., Sculpher, M., Anis, A. H., Owens, D. K. 2011; 49 (9): 848-856

  Abstract

  The effect of adherence, treatment failure, and comorbidities on the cost of HIV care is not well understood.To characterize the cost of HIV care including combination antiretroviral treatment (ART).Observational study of administrative data.Total 1896 randomly selected HIV-infected patients and 288 trial participants with multidrug-resistant HIV seen at the US Veterans Health Administration (VHA).Comorbidities, cost, pharmacy, and laboratory data.Many HIV-infected patients (24.5%) of the random sample did not receive ART. Outpatient pharmacy accounted for 62.8% of the costs of patients highly adherent with ART, 32.2% of the cost of those with lower adherence, and 6.2% of the cost of those not receiving ART. Compared with patients not receiving ART, high adherence was associated with lower hospital cost, but no greater total cost. Individuals with a low CD4 count (<50 cells/mm) incurred 1.9 times the cost of patients with counts >500. Most patients had medical, psychiatric, or substance abuse comorbidities. These conditions were associated with greater cost. Trial participants were less likely to have psychiatric and substance abuse comorbidities than the random sample of VHA patients with HIV.Patients receiving combination ART had higher medication costs but lower acute hospital cost. Poor control of HIV was associated with higher cost. The cost of psychiatric, substance abuse, rehabilitation, and long-term care and medications other than ART, often overlooked in HIV studies, was substantial.

  View details for DOI 10.1097/MLR.0b013e31821b34c0

  View details for Web of Science ID 000294206700015

  View details for PubMedID 21610542

• Interferon combination therapy for HIV/hepatitis C virus coinfection IMMUNOTHERAPY Chary, A., Holodniy, M. 2011; 3 (9): 1087-1102

  Abstract

  IFN-α has been the cornerstone of chronic hepatitis C virus (HCV) treatment for over a decade. Yet, rates of sustained virologic response of HCV infection to interferon-based therapy, particularly in difficult-to-treat populations, have been disappointingly low. This is particularly true in HIV/HCV coinfection, in which less than a third of patients typically respond to therapy. New HCV protease inhibitors, most of which will need to be administered with pegylated interferon, are in development, but comprehensive, long-term data for their use in coinfected patients is not yet available. Understanding the basis of this population's poor response to interferon-based therapy is crucial to future exploration of new therapeutic options, immunotherapy and prognosis in HIV/HCV-coinfected population.

  View details for DOI 10.2217/IMT.11.105

  View details for Web of Science ID 000296293800011

  View details for PubMedID 21913831

• One-year outcomes of community-acquired and healthcare-associated pneumonia in the Veterans Affairs Healthcare System INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES Hsu, J. L., Siroka, A. M., Smith, M. W., Holodniy, M., Meduri, G. U. 2011; 15 (6): E382-E387

  Abstract

  While studies have demonstrated higher medium-term mortality for community-acquired pneumonia (CAP), mortality and costs have not been characterized for healthcare-associated pneumonia (HCAP) over a 1-year period.We conducted a retrospective cohort study to evaluate mortality rates and health system costs for patients with CAP or HCAP during initial hospitalization and for 1 year after hospital discharge. We selected 50 758 patients admitted to the Veterans Affairs (VA) healthcare system between October 2003 and May 2007. Main outcome measures included hospital, post-discharge, and cumulative mortality rates and cost during initial hospitalization and at 12 months following discharge.Hospital and 1-year HCAP mortality were nearly twice that of CAP. HCAP was an independent predictor for hospital mortality (odds ratio (OR) 1.62, 95% confidence interval (CI) 1.49-1.76) and 1-year mortality (OR 1.99, 95% CI 1.87-2.11) when controlling for demographics, comorbidities, pneumonia severity, and factors associated with multidrug-resistant infection, including immune suppression, previous antibiotic treatment, and aspiration pneumonia. HCAP patients consistently had higher mortality in each stratum of the Charlson-Deyo-Quan comorbidity index. HCAP patients incurred significantly greater cost during the initial hospital stay and in the following 12 months. Demographics and comorbid conditions, particularly aspiration pneumonia, accounted for 19-33% of this difference.HCAP represents a distinct category of pneumonia with particularly poor survival up to 1 year after hospital discharge. While comorbidities, pneumonia severity, and risk factors for multidrug-resistant infection may interact to produce even higher mortality compared to CAP, they alone do not explain the observed differences.

  View details for DOI 10.1016/j.ijid.2011.02.002

  View details for Web of Science ID 000290588800003

  View details for PubMedID 21393043

  View details for PubMedCentralID PMC3095751

• ONE-YEAR OUTCOMES OF COMMUNITY-ACQUIRED AND HEALTH CARE-ASSOCIATED PNEUMONIA IN THE VETERANS AFFAIRS HEALTH CARE SYSTEM Hsu, J. L., Siroka, A. M., Smith, M. W., Holodniy, M., Meduri, G. U. OXFORD UNIV PRESS INC. 2011: S101

  View details for Web of Science ID 000294114600395

• Clinically Significant Drug Interactions in Younger and Older Human Immunodeficiency Virus-Positive Patients Receiving Antiretroviral Therapy PHARMACOTHERAPY Yiu, P., Nguyen, N. N., Holodniy, M. 2011; 31 (5): 480-489

  Abstract

  To characterize clinically significant drug interactions (CSDIs) in younger and older human immunodeficiency virus (HIV)-positive patients who were receiving antiretroviral therapy.Retrospective medical record review.HIV specialty clinic at a Veterans Affairs medical center.A total of 110 younger (age < 50 yrs) and older (age ≥ 50 yrs) HIV-positive patients receiving antiretroviral therapy during 2007.Demographic, clinical, and prescription drug data were collected. Pharmacokinetic and pharmacodynamic drug interactions were identified, assigned a severity grade, and evaluated for management according to two sources. Interactions with a grade of 2 (monitoring or timing of doses recommended), 3 (therapy modification recommended), or 4 (contraindicated) were considered CSDIs. Among 36 younger and 74 older patients, 763 CSDIs were identified. At least one CSDI was present in 83.3% and 89.2% of younger and older patients, respectively (p=0.56), with most having both antiretroviral and nonantiretroviral CSDIs. Younger and older patients, respectively, had a median of 3 and 5.5 total CSDIs/patient (p=0.09), 2 and 3 antiretroviral CSDIs/patient (p=0.65), and 0.5 and 2.5 nonantiretroviral CSDIs/patient (p=0.04). The proportions of grade 2, 3, and 4 CSDIs were 74.1%, 25.0%, and 0.9%, respectively, in younger patients and 73.1%, 26.1%, and 0.7%, respectively, in older patients (p=0.92). Younger patients had more CSDIs involving antihistamine, erectile dysfunction, and hormone or corticosteroid agents (p<0.01), whereas older patients had more CSDIs involving antihypertensive and antidiabetic agents (p<0.001). Management and outcomes of grades 3 and 4 antiretroviral CSDIs did not differ significantly by age. A list of frequently mismanaged interactions is provided.Clinically significant drug interactions were prevalent in younger and older HIV-positive patients receiving antiretroviral therapy, among which nonantiretroviral interactions should not be overlooked. Knowledge of the drug classes frequently involved in CSDIs by age group and types of CSDIs that are commonly mismanaged may help clinicians optimize care for HIV-infected patients.

  View details for Web of Science ID 000290184000005

  View details for PubMedID 21923429

• Results of Antiretroviral Treatment Interruption and Intensification in Advanced Multi-Drug Resistant HIV Infection from the OPTIMA Trial PLOS ONE Holodniy, M., Brown, S. T., Cameron, D. W., Kyriakides, T. C., Angus, B., Babiker, A., Singer, J., Owens, D. K., Anis, A., Goodall, R., Hudson, F., Piaseczny, M., Russo, J., Schechter, M., Deyton, L., Darbyshire, J. 2011; 6 (3)

  Abstract

  Guidance is needed on best medical management for advanced HIV disease with multidrug resistance (MDR) and limited retreatment options. We assessed two novel antiretroviral (ARV) treatment approaches in this setting.We conducted a 2×2 factorial randomized open label controlled trial in patients with a CD4 count≤300 cells/µl who had ARV treatment (ART) failure requiring retreatment, to two options (a) re-treatment with either standard (≤4 ARVs) or intensive (≥5 ARVs) ART and b) either treatment starting immediately or after a 12-week monitored ART interruption. Primary outcome was time to developing a first AIDS-defining event (ADE) or death from any cause. Analysis was by intention to treat. From 2001 to 2006, 368 patients were randomized. At baseline, mean age was 48 years, 2% were women, median CD4 count was 106/µl, mean viral load was 4.74 log(10) copies/ml, and 59% had a prior AIDS diagnosis. Median follow-up was 4.0 years in 1249 person-years of observation. There were no statistically significant differences in the primary composite outcome of ADE or death between re-treatment options of standard versus intensive ART (hazard ratio 1.17; CI 0.86-1.59), or between immediate retreatment initiation versus interruption before re-treatment (hazard ratio 0.93; CI 0.68-1.30), or in the rate of non-HIV associated serious adverse events between re-treatment options.We did not observe clinical benefit or harm assessed by the primary outcome in this largest and longest trial exploring both ART interruption and intensification in advanced MDR HIV infection with poor retreatment options.Clinicaltrials.gov NCT00050089.

  View details for DOI 10.1371/journal.pone.0014764

  View details for PubMedID 21483491

• Integrating Tobacco Cessation Into Mental Health Care for Posttraumatic Stress Disorder A Randomized Controlled Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION McFall, M., Saxon, A. J., Malte, C. A., Chow, B., Bailey, S., Baker, D. G., Beckham, J. C., Boardman, K. D., Carmody, T. P., Joseph, A. M., Smith, M. W., Shih, M., Lu, Y., Holodniy, M., Lavori, P. W. 2010; 304 (22): 2485-2493

  Abstract

  Most smokers with mental illness do not receive tobacco cessation treatment.To determine whether integrating smoking cessation treatment into mental health care for veterans with posttraumatic stress disorder (PTSD) improves long-term smoking abstinence rates.A randomized controlled trial of 943 smokers with military-related PTSD who were recruited from outpatient PTSD clinics at 10 Veterans Affairs medical centers and followed up for 18 to 48 months between November 2004 and July 2009.Smoking cessation treatment integrated within mental health care for PTSD delivered by mental health clinicians (integrated care [IC]) vs referral to Veterans Affairs smoking cessation clinics (SCC). Patients received smoking cessation treatment within 3 months of study enrollment.Smoking outcomes included 12-month bioverified prolonged abstinence (primary outcome) and 7- and 30-day point prevalence abstinence assessed at 3-month intervals. Amount of smoking cessation medications and counseling sessions delivered were tested as mediators of outcome. Posttraumatic stress disorder and depression were repeatedly assessed using the PTSD Checklist and Patient Health Questionnaire 9, respectively, to determine if IC participation or quitting smoking worsened psychiatric status.Integrated care was better than SCC on prolonged abstinence (8.9% vs 4.5%; adjusted odds ratio, 2.26; 95% confidence interval [CI], 1.30-3.91; P = .004). Differences between IC vs SCC were largest at 6 months for 7-day point prevalence abstinence (78/472 [16.5%] vs 34/471 [7.2%], P < .001) and remained significant at 18 months (86/472 [18.2%] vs 51/471 [10.8%], P < .001). Number of counseling sessions received and days of cessation medication used explained 39.1% of the treatment effect. Between baseline and 18 months, psychiatric status did not differ between treatment conditions. Posttraumatic stress disorder symptoms for quitters and nonquitters improved. Nonquitters worsened slightly on the Patient Health Questionnaire 9 relative to quitters (differences ranged between 0.4 and 2.1, P = .03), whose scores did not change over time.Among smokers with military-related PTSD, integrating smoking cessation treatment into mental health care compared with referral to specialized cessation treatment resulted in greater prolonged abstinence.clinicaltrials.gov Identifier: NCT00118534.

  View details for Web of Science ID 000285053300022

  View details for PubMedID 21139110

• Comparative effectiveness of dried plasma HIV-1 viral load testing in Brazil using ViveST for sample collection JOURNAL OF CLINICAL VIROLOGY Zanoni, M., Cortes, R., Diaz, R. S., Sucupira, M. C., Ferreira, D., Inocencio, L. A., Vilhena, C., Loveday, C., Lloyd, R. M., Holodniy, M. 2010; 49 (4): 245-248

  Abstract

  Utilization of dried plasma for HIV-1 viral load testing would significantly decrease sample shipping costs.To describe the precision and reproducibility of ViveST(®) (ST) as a transportation method for shipping specimens for HIV-1 viral load (VL) testing.Thirty clinical plasma samples were used to generate replicate samples with HIV VL values of 4 log(10), 3 log(10) and 2 log(10) copies/mL for reproducibility testing and an additional 299 samples with HIV VL <50 copies/mL (99); 1.7 log(10) to 3.99 log(10) (100); and 4 log(10) to 5.99 log(10)/mL (100) were used to compare ViveST to frozen plasma samples using the VERSANT(®) HIV-1 RNA 3.0 Assay. Results were compared using Student t-test, Pearson correlation and Bland-Altman analyses.Mean intra-assay variance among frozen and dried plasma triplicates was 0.15 log(10) and 0.09 log(10) copies/mL respectively (n=10, P=NS). Compared to frozen plasma, there was a mean reduction of 0.3 log(10), 0.27 log(10), and 0.35 log(10) copies/mL at the 4 log(10), 3 log(10), and 2 log(10) copy/mL samples respectively (n=30, all comparisons, P<0.01). Overall correlation between 299 frozen and ViveST samples was r=0.97, where 12 of 99 undetectable frozen VL were positive with ST, and 12 of 200 frozen detectable VL were undetectable with ViveST (mean VL 2.1, 1.9 log(10) copies/mL respectively).HIV-1 viral load results using ViveST were reproducible, correlated well with frozen plasma, though yielding minimally lower values. Our data suggest that dried plasma for HIV-1 VL testing using ViveST has promise for use in HIV clinical practice.

  View details for DOI 10.1016/j.jcv.2010.08.017

  View details for Web of Science ID 000284105300004

  View details for PubMedID 20880740

• Effect of Home Testing of International Normalized Ratio on Clinical Events. NEW ENGLAND JOURNAL OF MEDICINE Matchar, D. B., Jacobson, A., Dolor, R., Edson, R., Uyeda, L., Phibbs, C. S., Vertrees, J. E., Shih, M., Holodniy, M., Lavori, P. 2010; 363 (17): 1608-1620

  Abstract

  Warfarin anticoagulation reduces thromboembolic complications in patients with atrial fibrillation or mechanical heart valves, but effective management is complex, and the international normalized ratio (INR) is often outside the target range. As compared with venous plasma testing, point-of-care INR measuring devices allow greater testing frequency and patient involvement and may improve clinical outcomes.We randomly assigned 2922 patients who were taking warfarin because of mechanical heart valves or atrial fibrillation and who were competent in the use of point-of-care INR devices to either weekly self-testing at home or monthly high-quality testing in a clinic. The primary end point was the time to a first major event (stroke, major bleeding episode, or death).The patients were followed for 2.0 to 4.75 years, for a total of 8730 patient-years of follow-up. The time to the first primary event was not significantly longer in the self-testing group than in the clinic-testing group (hazard ratio, 0.88; 95% confidence interval, 0.75 to 1.04; P=0.14). The two groups had similar rates of clinical outcomes except that the self-testing group reported more minor bleeding episodes. Over the entire follow-up period, the self-testing group had a small but significant improvement in the percentage of time during which the INR was within the target range (absolute difference between groups, 3.8 percentage points; P<0.001). At 2 years of follow-up, the self-testing group also had a small but significant improvement in patient satisfaction with anticoagulation therapy (P=0.002) and quality of life (P<0.001).As compared with monthly high-quality clinic testing, weekly self-testing did not delay the time to a first stroke, major bleeding episode, or death to the extent suggested by prior studies. These results do not support the superiority of self-testing over clinic testing in reducing the risk of stroke, major bleeding episode, and death among patients taking warfarin therapy. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT00032591.).

  View details for Web of Science ID 000283242700005

  View details for PubMedID 20961244

• An evaluation of patient self-testing competency of prothrombin time for managing anticoagulation: pre-randomization results of VA Cooperative Study #481-The Home INR Study (THINRS) JOURNAL OF THROMBOSIS AND THROMBOLYSIS Dolor, R. J., Ruybalid, R. L., Uyeda, L., Edson, R. G., Phibbs, C., Vertrees, J. E., Shih, M., Jacobson, A. K., Matchar, D. B. 2010; 30 (3): 263-275

  Abstract

  Prior studies suggest patient self-testing (PST) of prothrombin time (PT) can improve the quality of anticoagulation (AC) and reduce complications (e.g., bleeding and thromboembolic events). "The Home INR Study" (THINRS) compared AC management with frequent PST using a home monitoring device to high-quality AC management (HQACM) with clinic-based monitoring on major health outcomes. A key clinical and policy question is whether and which patients can successfully use such devices. We report the results of Part 1 of THINRS in which patients and caregivers were evaluated for their ability to perform PST. Study-eligible patients (n = 3643) were trained to use the home monitoring device and evaluated after 2-4 weeks for PST competency. Information about demographics, medical history, warfarin use, medications, plus measures of numeracy, literacy, cognition, dexterity, and satisfaction with AC were collected. Approximately 80% (2931 of 3643) of patients trained on PST demonstrated competency; of these, 8% (238) required caregiver assistance. Testers who were not competent to perform PST had higher numbers of practice attempts, higher cuvette wastage, and were less able to perform a fingerstick or obtain blood for the cuvette in a timely fashion. Factors associated with failure to pass PST training included increased age, previous stroke history, poor cognition, and poor manual dexterity. A majority of patients were able to perform PST. Successful home monitoring of PT with a PST device required adequate levels of cognition and manual dexterity. Training a caregiver modestly increased the proportion of patients who can perform PST.

  View details for DOI 10.1007/s11239-010-0499-8

  View details for Web of Science ID 000282215300002

  View details for PubMedID 20628787

• Maternal-Fetal Pharmacokinetics and Dynamics of a Single Intrapartum Dose of Maraviroc in Rhesus Macaques ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Winters, M. A., Van Rompay, K. K., Kashuba, A. D., Shulman, N. S., Holodniy, M. 2010; 54 (10): 4059-4063

  Abstract

  Single-dose nevirapine (NVP) is effective in reducing mother-to-child transmission (MTCT) of HIV; however, the subsequent development of drug resistance is problematic. The pharmacokinetic profile of the HIV entry inhibitor maraviroc after a single intrapartum dose in rhesus macaques was studied to determine whether maraviroc could serve as an alternative to NVP in a single-dose strategy. Four pregnant macaques received an oral dose of maraviroc 2 h before delivery, and both infant and maternal plasma maraviroc concentrations and CCR5 receptor occupancy on CD4(+) lymphocytes were measured over time. Maximum plasma maraviroc concentrations were found at delivery (2-h-postintrapartum dose) in both the mothers and infants, with median concentrations of 974 ng/ml (range, 86 to 2,830 ng/ml) and 22 ng/ml (range, 4 to 99 ng/ml), respectively. Maraviroc was detected in the plasma of mothers up to 48 h after dosing but only as long as 3.5 h in the infants. The median fetal-maternal area under the concentration-time curve (AUC) ratio was 0.009 (range, 0.000 to 0.015). Maraviroc receptor occupancy data showed evidence of unprotected CCR5 receptors on CD4(+) cells in the mothers 24 to 48 h after dosing. Extremely low CCR5 expression on CD4(+) cells of newborn macaques prevented determination of receptor occupancy in the infants. In rhesus macaques, maraviroc was poorly transferred across the placenta and was quickly cleared from the infants' blood. The low concentrations of fetal maraviroc and short pharmacokinetic profile in infants suggest that a single maternal intrapartum dose of maraviroc would not be effective in reducing the risk of MTCT of HIV.

  View details for DOI 10.1128/AAC.00747-10

  View details for Web of Science ID 000281907200002

  View details for PubMedID 20696881

  View details for PubMedCentralID PMC2944591

• Impact of Interferon-Ribavirin Treatment on Hepatitis C Virus (HCV) Protease Quasispecies Diversity in HIV- and HCV-Coinfected Patients JOURNAL OF INFECTIOUS DISEASES Chary, A., Winters, M. A., Kottilil, S., Murphy, A. A., Polis, M. A., Holodniy, M. 2010; 202 (6): 889-893

  Abstract

  Patients with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) coinfection for whom prior treatment of HCV with interferon-ribavirin has failed may require subsequent treatment with new HCV protease inhibitors (PIs). We evaluated the diversity of HCV nonstructural protein 3 (NS3) in 26 HCV- and HIV-coinfected patients receiving stable antiretroviral therapy (ART) who were treated with interferon-ribavirin. Plasma HCV RNA clonal analysis was performed. There was greater baseline NS3 diversity in patients with nonresponse or relapse than in those with sustained virologic response. Interferon-ribavirin treatment did not result in significant changes in HCV protease gene diversity or significant HCV PI resistance mutations. The effect of prior interferon-ribavirin treatment on HCV NS3 will likely not impact HCV PI efficacy in HIV-coinfected patients receiving ART.

  View details for DOI 10.1086/655784

  View details for Web of Science ID 000281091200010

  View details for PubMedID 20677940

  View details for PubMedCentralID PMC2924472

• Effect of a Zoster Vaccine on Herpes Zoster-Related Interference with Functional Status and Health-Related Quality-of-Life Measures in Older Adults JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Schmader, K. E., Johnson, G. R., Saddier, P., Ciarleglio, M., Wang, W. W., Zhang, J. H., Chan, I. S., Yeh, S., Levin, M. J., Harbecke, R. M., Oxman, M. N. 2010; 58 (9): 1634-1641

  Abstract

  To determine the efficacy of a zoster vaccine on herpes zoster (HR)-related interference with activities of daily living (ADLs) and health-related quality of life (HRQL).Randomized double-blind placebo controlled trial.Twenty-two U.S. sites.Thirty eight thousand five hundred forty-six women and men aged 60 and olcer.HZ burden of interference with ADLs and HRQL using ratings from the Zoster Brief Pain Inventory (ZBPI) and Medical Outcomes Study 12-item Short Form Survey (SF-12) mental component summary (MCS) and physical component summary (PCS) scores. Vaccine efficacy was calculated for the modified-intention-to-treat trial population and solely in participants who developed HZ.For the modified-intention-to-treat population, the overall zoster vaccine efficacy was 66% (95% confidence interval (CI)=55-74%) for ZBPI ADL burden of interference score and 55% (95% CI=48-61%) for both the SF-12 MCS and PCS scores. Of participants who developed HZ, zoster vaccine reduced the ZBPI ADL burden of interference score by 31% (95% CI=12-51%) and did not significantly reduce the effect on HRQL.Zoster vaccine reduced the burden of HZ-related interference with ADLs in the population of vaccinees and in vaccinees who developed HZ. Zoster vaccine reduced the effect of HZ on HRQL in the population of vaccinees but not in vaccinees who developed HZ.

  View details for DOI 10.1111/j.1532-5415.2010.03021.x

  View details for Web of Science ID 000281549000002

  View details for PubMedID 20863322

  View details for PubMedCentralID PMC2946120

• Recent advances in hepatitis C virus treatment: review of HCV protease inhibitor clinical trials. Reviews on recent clinical trials Chary, A., Holodniy, M. 2010; 5 (3): 158-173

  Abstract

  Hepatitis C virus (HCV) infection affects millions of people world-wide, and chronic infection can result in end-stage liver disease and hepatocellular carcinoma. Conventional therapy to date has involved combination antiviral therapy including alpha-interferon and ribavirin; response rates with these drugs are variable based on both viral and host factors, such as HCV viral load, HCV genotype, HIV co-infection, host genetic polymorphisms (such as those in the IL28B region), and other factors. Recent advances in HCV treatment have included pegylated forms of alpha-interferon and, more recently, the development of specifically targeted antiviral therapy for HCV (STAT-C) with novel HCV protease inhibitors (PIs) for genotype 1 HCV. Although unlikely to be administered as monotherapy due to the potential for development of HCV PI drug resistance mutations, results of phase II trials of two PIs in development have recently been reported, demonstrating promising therapeutic efficacy of HCV PIs in combination with established conventional treatment. This review outlines the advances and the challenges in the development of these HCV PIs as effective HCV antiviral agents and their role in clinical practice.

  View details for PubMedID 20482493

• Is spinal tuberculosis contagious? INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES Schirmer, P., Renault, C. A., Holodniy, M. 2010; 14 (8): E659-E666

  Abstract

  While pulmonary Mycobacterium tuberculosis infections are recognized for their public health implications, less is known about the infectiousness of extrapulmonary tuberculosis, specifically, spinal tuberculosis or Pott's disease. We present a case of spinal tuberculosis with concomitant active pulmonary tuberculosis in the absence of chest radiographic abnormalities or symptoms, and review the literature regarding infectiousness of concomitant spinal and pulmonary tuberculosis.

  View details for DOI 10.1016/j.ijid.2009.11.009

  View details for Web of Science ID 000282662100003

  View details for PubMedID 20181507

• Connection Domain Mutations in Treatment-Experienced Patients in the OPTIMA Trial JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Dau, B., Ayers, D., Singer, J., Harrigan, P. R., Brown, S., Kyriakides, T., Cameron, D. W., Angus, B., Holodniy, M. 2010; 54 (2): 160-166

  Abstract

  To determine the frequency of mutations in the connection domain (CD) of HIV reverse transcriptase in treatment-experienced patients in the Options in Management with Antiretrovirals trial, their impact on susceptibility to antiretroviral (ARV) drugs, and their impact on virologic outcomes.Baseline plasma ARV genotypes and inferred resistance phenotypes were obtained. Frequencies of E312Q, Y318F, G333D, G333E, G335C, G335D, N348I, A360I, A360V, V365I, A371V, A376S, and E399G were compared with a treatment-naive population. The association of CD mutations with inferred IC50 fold changes to nucleos(t)ide reverse transcriptase inhibitors was evaluated. Univariate and multivariate analyses examined the association of CD mutations with a >1 log10 per milliliter decrease in HIV viral load after 24 weeks on a new ARV regimen.Higher CD mutation rates were seen in Options in Management with Antiretrovirals patients (n = 345) compared with a treatment-naive population. CD mutations were associated with increased inferred IC50 fold changes to abacavir, stavudine, tenofovir, and zidovudine. On univariate analysis, A371V was associated with lack of virologic response, as was having any CD mutation on multivariate analysis.CD mutations are frequent in treatment-experienced populations. They are associated with reduced susceptibility to some nucleos(t)ide reverse transcriptase inhibitors and with a diminished response to ARV therapy.

  View details for DOI 10.1097/QAI.0b013e3181cbd235

  View details for Web of Science ID 000278100600008

  View details for PubMedID 20130473

• Impact of Highly Active Antiretroviral Therapy on Hepatitis C Virus Protease Quasispecies Diversity in HIV Co-Infected Patients JOURNAL OF MEDICAL VIROLOGY Winters, M. A., Chary, A., Eison, R., Asmuth, D., Holodniy, M. 2010; 82 (5): 791-798

  Abstract

  Many hepatitis C virus (HCV)-infected patients are also infected with HIV, and undergo antiretroviral (ARV) treatment for their human immunodeficiency virus (HIV) infection. Due to changes in HIV burden and immunologic status, HIV ARV treatment may have indirect effects on the HCV population, which could impact the effectiveness of subsequent HCV protease inhibitor (PI) treatment. The genetic variability of the protease-encoding HCV NS3 gene was evaluated in 10 co-infected patients initiating ARVs (both before and after ARV initiation), and compared to the genetic variability in 10 patients on stable ARV therapy. After RT-PCR of plasma-derived HCV RNA, a mean of 20 clones per patient time-point were sequenced and analyzed for changes in the HCV quasispecies population. No significant differences in sequence diversity or complexity at the nucleic acid or amino acid levels were seen at baseline between groups or between the two time points in either group. HCV protease diversity in the pre- and post-ARV treatment samples was not significantly different than samples from patients on stable ARV therapy. There was no significant development of amino acid substitutions known to confer HCV PI resistance in either group. Initiation of ARV for HIV infection does not significantly alter the genetic diversity or complexity of the HCV NS3 gene or result in increased number of HCV PI-associated amino acid changes. These results suggest ARV treatment for HIV would not affect the efficacy of HCV PI treatment.

  View details for DOI 10.1002/jmv.21679

  View details for Web of Science ID 000276324100009

  View details for PubMedID 20336744

• A simple solid matrix transport device SampleTanker (R) for economic collection, storage and transport of patient plasma between clinical sites for HIV-1 molecular and antibody testing Loveday, C., Lloyd, R. M., MacRae, E., Grossman, Z., Mathis, R., Burns, D., Cooper, J., Holodniy, M. WILEY-BLACKWELL. 2010: 37-38

  View details for Web of Science ID 000277084400103

• Effective Detection of the 2009 H1N1 Influenza Pandemic in US Veterans Affairs Medical Centers Using a National Electronic Biosurveillance System PLOS ONE Schirmer, P., Lucero, C., Oda, G., Lopez, J., Holodniy, M. 2010; 5 (3)

  Abstract

  The 2008-09 influenza season was the time in which the Department of Veterans Affairs (VA) utilized an electronic biosurveillance system for tracking and monitoring of influenza trends. The system, known as ESSENCE or Electronic Surveillance System for the Early Notification of Community-based Epidemics, was monitored for the influenza season as well as for a rise in influenza cases at the start of the H1N1 2009 influenza pandemic. We also describe trends noted in influenza-like illness (ILI) outpatient encounter data in VA medical centers during the 2008-09 influenza season, before and after the recognition of pandemic H1N1 2009 influenza virus.We determined prevalence of ILI coded visits using VA's ESSENCE for 2008-09 seasonal influenza (Sept. 28, 2008-April 25, 2009 corresponding to CDC 2008-2009 flu season weeks 40-16) and the early period of pandemic H1N1 2009 (April 26, 2009-July 31, 2009 corresponding to CDC 2008-2009 flu season weeks 17-30). Differences in diagnostic ICD-9-CM code frequencies were analyzed using Chi-square and odds ratios. There were 649,574 ILI encounters captured representing 633,893 patients. The prevalence of VA ILI visits mirrored the CDC's Outpatient ILI Surveillance Network (ILINet) data with peaks in late December, early February, and late April/early May, mirroring the ILINet data; however, the peaks seen in the VA were smaller. Of 31 ILI codes, 6 decreased and 11 increased significantly during the early period of pandemic H1N1 2009. The ILI codes that significantly increased were more likely to be symptom codes. Although influenza with respiratory manifestation (487.1) was the most common code used among 150 confirmed pandemic H1N1 2009 cases, overall it significantly decreased since the start of the pandemic.VA ESSENCE effectively detected and tracked changing ILI trends during pandemic H1N1 2009 and represents an important temporal alerting system for monitoring health events in VA facilities.

  View details for DOI 10.1371/journal.pone.0009533

  View details for Web of Science ID 000275197100015

  View details for PubMedID 20209055

  View details for PubMedCentralID PMC2832014

• Structured interruptions of highly active antiretroviral therapy in cycles of 4 weeks off/12 weeks on therapy in children having a chronically undetectable viral load cause progressively smaller viral rebounds INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES Palacios, G. C., Sanchez, L. M., Briones, E., Ramirez, T. J., Castillo, H., Rivera, L. G., Vazquez, C. A., Rodriguez-Padilla, C., Holodniy, M. 2010; 14 (1): E34-E40

  Abstract

  To evaluate the viral, immune and clinical impact of a structured treatment interruption (STI) program of highly active antiretroviral therapy (HAART) in three cycles of 4 weeks off/12 weeks on therapy in a cohort of children with HIV infection under chronic viral control.Using a single-group time series experimentation design and following informed consent, the HAART of children with HIV and a chronically undetectable viral load (VL) was discontinued for 4 weeks and then restarted and continued for 12 weeks for a total of three cycles. The VL, CD4+/CD8+ lymphocytes, and clinical status were evaluated at the end of each STI and at 6 and 12 weeks after HAART was resumed.Four children with a median age of 10.3 years (range 6.5-11.2 years) were included in the study. Their clinical immune categories were: A1 (n=2), A2 (n=1), and B3 (n=1). Treatment of all four patients was with zidovudine (AZT)+lamivudine (3TC)+ritonavir (RTV). At the end of the first STI, VL was a median 214000 copies/ml (range 27400-616000), corresponding to 5.3 log(10) (range 4.4-5.8). At the end of the second STI, VL was a median 72400 copies/ml (range 17800-126000) or 4.7 log(10) (range 4.2-5.1), which corresponds to a rebound 0.6 log(10) lower than the first. At the end of the third STI, VL was a median 28200 copies/ml (range 5370-140000) or 4.45 log(10) (range 3.7-5.1), a rebound 0.85 log(10) lower than the first. All rebounds were followed by a decrease in the VL to undetectable levels during the treatment periods. CD8+ T lymphocyte counts increased during viral rebounds and an initial decrease in CD4+ T lymphocyte counts was followed by a tendency to increase even exceeding CD8+ T cell counts. Only one event of transitory severe immunosuppression occurred. There were no symptoms related to the HIV infection.The STI of HAART in cycles of 4 weeks off/12 weeks on therapy in children with chronically undetectable VL can cause progressively lower viral rebounds followed by a decrease to undetectable levels, with a low risk of severe immunosuppression and without the occurrence of symptoms related to HIV.

  View details for DOI 10.1016/j.ijid.2009.03.003

  View details for Web of Science ID 000273987200006

  View details for PubMedID 19467895

• DETECTION OF MIXTURES OF HEPATITIS C VIRUS (HCV) TYPES Holodniy, M., Diaz, R. S., Mathis, R. L., Feorino, P. M., Loveday, C., Grossman, Z., Kantor, R., Tang, Y. W., Lloyd, R. M. ELSEVIER SCIENCE BV. 2010: S464

  View details for DOI 10.1016/S0168-8278(10)61195-6

  View details for Web of Science ID 000277018002394

• A colinear assay for detection of HIV drug resistance to approved and investigational drugs Lloyd, R. M., Holodniy, M., Burns, D., Diaz, R. S., Loveday, C., Janini, L. R., Grossman, Z. SAGE PUBLICATIONS LTD. 2010: A93

  View details for Web of Science ID 000287431300080

• Sudden sensorineural hearing loss associated with vardenafil. Pharmacotherapy Snodgrass, A. J., Campbell, H. M., Mace, D. L., Faria, V. L., Swanson, K. M., Holodniy, M. 2010; 30 (1): 112-?

  Abstract

  The phosphodiesterase type 5 (PDE-5) inhibitors-sildenafil, vardenafil, and tadalafil-are used primarily in erectile dysfunction, but sildenafil is also indicated for pulmonary hypertension. Common adverse effects of vardenafil include headache, flushing, nasal congestion, dyspepsia, and nausea. Recently, PDE-5 inhibitors have been associated with adverse vision effects, and emerging evidence now indicates that they may also be responsible for hearing changes and hearing loss. We describe a patient who developed unilateral sudden sensorineural hearing loss possibly related to the use of vardenafil for erectile dysfunction. To our knowledge, only one other case of hearing loss related to this drug class has been published. Our patient was a 57-year-old man who came to the emergency department with right-sided mild-to-moderate hearing loss in the 500-3000-Hz range, confirmed by audiogram, that occurred after ingestion of vardenafil. The patient was hospitalized 2 days later for administration of intravenous dexamethasone, followed by oral prednisone. He reported that his hearing had improved on the fourth hospital day and was discharged 3 days later, continuing to taper the prednisone on an outpatient basis. A repeat audiogram after 10 days of corticosteroid therapy confirmed that his hearing in the 500-3000-Hz range was within normal limits. Use of the Naranjo adverse drug reaction probability scale indicated a possible (score of 3) adverse reaction of sudden sensorineural hearing loss associated with vardenafil consumption. We also performed an analysis of hearing loss cases related to PDE-5 inhibitors in the United States Food and Drug Administration's Adverse Event Reporting System database to compare the characteristics of our patient with those of other reported adverse event cases. Based on the temporal relation of the sudden sensorineural hearing loss to this patient's drug consumption, we propose that the vardenafil is a likely cause of the hearing loss. This case provides further evidence that PDE-5 inhibitor consumption should be considered as a possible cause in patients presenting with sudden sensorineural hearing loss.

  View details for DOI 10.1592/phco.30.1.112

  View details for PubMedID 20030481

• Varicella-Zoster Virus-Specific Immune Responses to Herpes Zoster in Elderly Participants in a Trial of a Clinically Effective Zoster Vaccine JOURNAL OF INFECTIOUS DISEASES Weinberg, A., Zhang, J. H., Oxman, M. N., Johnson, G. R., Hayward, A. R., Caulfield, M. J., Irwin, M. R., Clair, J., Smith, J. G., Stanley, H., Marchese, R. D., Harbecke, R., Williams, H. M., Chan, I. S., Arbeit, R. D., Gershon, A. A., Schoedel, F., Morrison, V. A., Kauffman, C. A., Straus, S. E., Schmader, K. E., Davis, L. E., Levin, M. J. 2009; 200 (7): 1068-1077

  Abstract

  The objectives of this study were to evaluate the association between varicella-zoster virus (VZV)-specific humoral and cell-mediated immunity (CMI) to herpes zoster (HZ) and protection against HZ morbidity and to compare immune responses to HZ and zoster vaccine.In 981 elderly persons who developed HZ during a zoster vaccine efficacy trial (321 vaccinees and 660 placebo recipients) and 1362 without HZ (682 vaccinees and 680 placebo recipients), CMI was measured by VZV responder cell frequency and interferon-gamma enzyme-linked immunospot, and antibodies were measured by VZV enzyme-linked immunosorbent assay against affinity-purified VZV glycoproteins (gpELISA).Robust VZV CMI at HZ onset correlated with reduced HZ morbidity, whereas VZV gpELISA titers did not. Three weeks after HZ onset, gpELISA titers were highest in those with more severe HZ and were slightly increased in placebo recipients (compared with zoster vaccine recipients) and in older individuals. VZV CMI responses to HZ were similar in zoster vaccine and placebo recipients and were not affected by demographic characteristics or antiviral therapy, except for responder cell frequency at HZ onset, which decreased with age. When responses to zoster vaccine and HZ could be compared, VZV CMI values were similar, but antibody titers were lower.Higher VZV CMI at HZ onset was associated with reduced HZ severity and less postherpetic neuralgia. Higher antibody titers were associated with increased HZ severity and occurrence of postherpetic neuralgia. HZ and zoster vaccine generated comparable VZV CMI.

  View details for DOI 10.1086/605611

  View details for Web of Science ID 000269475000009

  View details for PubMedID 19712037

• The concurrent validity and responsiveness of the health utilities index (HUI 3) among patients with advanced HIV/AIDS QUALITY OF LIFE RESEARCH Nosyk, B., Sun, H., Bansback, N., Guh, D. P., Li, X., Barnett, P., Bayoumi, A., Griffin, S., Joyce, V., Holodniy, M., Owens, D. K., Anis, A. H. 2009; 18 (7): 815-824

  Abstract

  To assess the concurrent validity and responsiveness of the Health Utility Index 3 (HUI3) in patients with advanced HIV/AIDS, and to determine the responsiveness of this measure, the MOS-HIV and EQ-5D to HIV-related clinical events.Data from the OPTIMA (OPTions In Management with Antiretrovirals) trial was analyzed. Two aspects of the validity of the HUI3 were considered: concurrent validity was evaluated using Spearman correlations with MOS-HIV component and summary scores. Responsiveness to AIDS-defining events (ADE) and all adverse events (our external change criterion) was assessed using area under the receiver operating characteristic (AUROC) curves.The study enrolled 368 patients (mean follow-up: 3.66 years); 82% had at least one severe adverse event and 27% had at least one ADE. The HUI3 scale and items showed good concurrent validity, with 85% of the expected relationships with the MOS-HIV subscales verified. The HUI3 was responsive to both adverse events (AUROC [95%CI]: 0.68 [0.57, 0.80]) and ADEs (0.62 [0.51, 0.74]). The EQ-5D was responsive to ADEs (0.66 [0.56, 0.76]), but not responsive to adverse events (0.56 [0.46, 0.68]).The HUI3 is a valid and responsive measure of the change in HRQoL associated with clinical events in an advanced HIV/AIDS population.

  View details for DOI 10.1007/s11136-009-9504-0

  View details for Web of Science ID 000268881000003

  View details for PubMedID 19562514

• Quality of Life of Patients With Advanced HIV/AIDS: Measuring the Impact of Both AIDS-Defining Events and Non-AIDS Serious Adverse Events 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Annual Meeting of the Infectious-Diseases-Society-of-America Anis, A. H., Nosyk, B., Sun, H., Guh, D. P., Bansback, N., Li, X., Barnett, P. G., Joyce, V., Swanson, K. M., Kyriakides, T. C., Holodniy, M., Cameron, D. W., Brown, S. T. LIPPINCOTT WILLIAMS & WILKINS. 2009: 631–39

  Abstract

  To investigate the relative magnitude and duration of impact of AIDS-defining events (ADEs) and non-AIDS serious adverse events (SAEs) on health-related quality of life (HRQoL) among patients with advanced HIV/AIDS.We use data from OPTIMA (OPTions In Management with Antiretrovirals), a multinational, randomized, open, control, clinical management trial of treatment strategies for patients with multidrug-resistant HIV and advanced immune disease. Longitudinal models were used to determine the effects of ADEs and SAEs on HRQoL across periods before, during, and after event onset. The Medical Outcomes Study HIV Health Survey (MOS-HIV) physical and mental health summary scores (MOS-PHS and MOS-MHS), EQ-5D, and the Health Utilities Index Mark 3 HRQoL measures were all assessed at regular follow-up intervals during the trial.ADEs occurred much less frequently than SAEs (n = 147 vs. n = 821) in the study sample population of 368 patients, during median follow-up of 3.96 years. Although both ADEs and SAEs had significant negative impacts on HRQoL, SAEs had at least as large an impact upon HRQoL as ADEs when both were included in a multivariate linear regression model, controlling for other covariates. However, the effect of ADEs on HRQoL was more persistent, with larger magnitude of effect across all instruments in time intervals further from the onset of the event.Non-AIDS SAEs occurring in patients with late-stage HIV/AIDS seem to have at least as important an immediate impact on patient HRQoL as ADEs; however, the impact of ADEs seems to be more persistent. Our findings call for a greater emphasis on the detection and active prevention of non-AIDS SAEs in patients with late-stage HIV/AIDS.

  View details for Web of Science ID 000268346600018

  View details for PubMedID 19430303

• Thrombocytopenia from Combination Treatment with Oseltamivir and Probenecid: Case Report, MedWatch Data Summary, and Review of the Literature PHARMACOTHERAPY Raisch, D. W., Straight, T. M., Holodniy, M. 2009; 29 (8): 988-992

  Abstract

  The possibility of an avian flu pandemic has spurred interest in preventive treatments with antivirals such as oseltamivir. Combining treatment with probenecid to delay excretion may extend limited supplies of oseltamivir. We previously conducted a pharmacokinetic study of oseltamivir plus probenecid among healthy volunteers. In this article, we describe a 68-year-old woman who, during the pharmacokinetic study, developed severe thrombocytopenia 2 weeks after starting oseltamivir plus probenecid. She was receiving no other drug therapy at the time. Her platelet count decreased from 200 to 15 x 10(3)/mm(3), although no clinically evident bleeding abnormalities were noted. The two drugs were discontinued. One week later, without any therapeutic intervention, her platelet count returned to normal. By using the Naranjo adverse drug reaction probability scale to assess the strength of the association between the drugs and the adverse event, a score of 7 was derived for both drugs, indicating that the association was probable. We found no previous literature reports of thrombocytopenia associated with either drug. However, a review of the United States Food and Drug Administration's Adverse Event Reporting System database found 93 cases of thrombocytopenia and/or decreased platelet counts associated with oseltamivir and 24 cases associated with probenecid administration. Signal detection analyses were significant for oseltamivir (p=0.001), but not probenecid. The underlying mechanism of thrombocytopenia with these drugs is unknown. Clinicians should be aware that the use of oseltamivir and probenecid has been reported to be associated with thrombocytopenia.

  View details for Web of Science ID 000268563800012

  View details for PubMedID 19637952

• A Real-Time PCR Assay to Identify and Discriminate Among Wild-Type and Vaccine Strains of Varicella-Zoster Virus and Herpes Simplex Virus in Clinical Specimens, and Comparison With the Clinical Diagnoses JOURNAL OF MEDICAL VIROLOGY Harbecke, R., Oxman, M. N., Arnold, B. A., Ip, C., Johnson, G. R., Levin, M. J., Gelb, L. D., Schmader, K. E., Straus, S. E., Wang, H., Wright, P. F., Pachucki, C. T., Gershon, A. A., Arbeit, R. D., Davis, L. E., Simberkoff, M. S., Weinberg, A., Williams, H. M., Cheney, C., Petrukhin, L., Abraham, K. G., Shaw, A., Manoff, S., Antonello, J. M., Green, T., Wang, Y., Tan, C., Keller, P. M. 2009; 81 (7): 1310-1322

  Abstract

  A real-time PCR assay was developed to identify varicella-zoster virus (VZV) and herpes simplex virus (HSV) DNA in clinical specimens from subjects with suspected herpes zoster (HZ; shingles). Three sets of primers and probes were used in separate PCR reactions to detect and discriminate among wild-type VZV (VZV-WT), Oka vaccine strain VZV (VZV-Oka), and HSV DNA, and the reaction for each virus DNA was multiplexed with primers and probe specific for the human beta-globin gene to assess specimen adequacy. Discrimination of all VZV-WT strains, including Japanese isolates and the Oka parent strain, from VZV-Oka was based upon a single nucleotide polymorphism at position 106262 in ORF 62, resulting in preferential amplification by the homologous primer pair. The assay was highly sensitive and specific for the target virus DNA, and no cross-reactions were detected with any other infectious agent. With the PCR assay as the gold standard, the sensitivity of virus culture was 53% for VZV and 77% for HSV. There was 92% agreement between the clinical diagnosis of HZ by the Clinical Evaluation Committee and the PCR assay results.

  View details for DOI 10.1002/jmv.21506

  View details for Web of Science ID 000266613900024

  View details for PubMedID 19475609

• Effect of the MTHFR C677T and A1298C Polymorphisms on Survival in Patients With Advanced CKD and ESRD: A Prospective Study AMERICAN JOURNAL OF KIDNEY DISEASES Jamison, R. L., Shih, M., Humphries, D. E., Guarino, P. D., Kaufman, J. S., Goldfarb, D. S., Warren, S. R., Gaziano, J. M., Lavori, P. 2009; 53 (5): 779-789

  Abstract

  Abnormalities in the gene regulating methylenetetrahydrofolate reductase (MTHFR) are associated with increased homocysteine levels and increased mortality in normal and chronic kidney disease (CKD) populations.Gene association study.This was a substudy of 677 patients from 21 Veterans Affairs medical centers participating in a randomized clinical trial (Homocysteinemia in Kidney and End-Stage Renal Disease [HOST]) of the effect on all-cause mortality of vitamin-induced lowering of plasma homocysteine levels. Of 677 patients, 213 (31%) were treated by using dialysis (end-stage renal disease [ESRD]) and 464 (69%) had a Cockcroft-Gault estimated creatinine clearance less than 30 mL/min (advanced CKD).Polymorphisms C677T (rs1801133) and A1298C (rs1801131) of the MTHFR gene.Unadjusted and adjusted all-cause mortality.DNA was extracted from blood samples and amplified by means of polymerase chain reaction.The adjusted hazard ratio in a recessive model of the relationship between the C677T polymorphism and all-cause mortality in all patients was 1.47 (95% confidence interval, 1.00 to 2.16; P = 0.05). In patients with ESRD with the mutant TT genotype, the adjusted hazard ratio for mortality in all patients was 2.27 (95% confidence interval, 1.07 to 4.84; P = 0.03); patients with advanced CKD showed a similar, although not significant, trend. The risk of myocardial infarction (P = 0.05) and composite risk of myocardial infarction, stroke, lower-extremity amputation, and mortality (P = 0.02) were greater in patients with ESRD with the mutant T allele at nucleotide 677. The overall relationship between the A1298C polymorphism and mortality was not significant (P = 0.6).Participants were 98% men; DNA samples were not obtained at enrollment in HOST; linkage disequilibrium with another causal polymorphism is a potential confounding factor; and power was reduced by the limited number of participants.These findings provide additional support for the hypothesis that the mutant TT genotype at nucleotide 677 of the gene regulating MTHFR activity may increase the mortality risk in patients with ESRD.

  View details for DOI 10.1053/j.ajkd.2008.12.023

  View details for Web of Science ID 000265923500010

  View details for PubMedID 19272686

• Oseltamivir for treatment and prophylaxis of influenza infection EXPERT OPINION ON DRUG SAFETY Schirmer, P., Holodniy, M. 2009; 8 (3): 357-371

  Abstract

  Influenza infection is a global problem affecting millions of people worldwide, despite efficacious vaccines. Treatment and prophylaxis against influenza have been successful using antiviral medications such as adamantanes and neuraminidase inhibitors.To review the antiviral agents and specifically the neuraminidase inhibitor, oseltamivir, for use in treatment and prophylaxis of influenza infection.This review focuses on published literature regarding the clinical use of oseltamivir, as well as discussing emerging threats such as avian influenza, antiviral resistance, and strategies such as combination antiviral treatment to mitigate these threats.Oseltamivir is effective in reducing symptom burden in those with influenza A or B infection, and is preventative against developing infection after exposure. Emergence of naturally occurring or post-treatment oseltamivir-resistant influenza as well as an avian influenza pandemic may limit its future use as a monotherapeutic antiviral treatment agent.

  View details for DOI 10.1517/14740330902840519

  View details for Web of Science ID 000266768700011

  View details for PubMedID 19355841

• Dried-Plasma Transport Using a Novel Matrix and Collection System for Human Immunodeficiency Virus and Hepatitis C Virus Virologic Testing JOURNAL OF CLINICAL MICROBIOLOGY Lloyd, R. M., Burns, D. A., Huong, J. T., Mathis, R. L., Winters, M. A., Tanner, M., De la Rosa, A., Yen-Lieberman, B., Armstrong, W., Taege, A., McClernon, D. R., Wetshtein, J. L., Friedrich, B. M., Ferguson, M. R., O'Brien, W., Feorino, P. M., Holodniy, M. 2009; 47 (5): 1491-1496

  Abstract

  A novel method for the collection and transportation of dried-blood-plasma samples, SampleTanker (ST), was developed and compared to standard shipping protocols for frozen-plasma specimens containing human immunodeficiency virus type 1 (HIV-1) and/or hepatitis C virus (HCV). Matched frozen and dried 1-ml EDTA-containing plasma samples were collected and analyzed by several molecular-based virologic assays. After addition of 1.175 ml of reconstitution buffer, 1.035 ml of dried plasma was recovered. Mean intra-assay variances were 0.05, 0.05, and 0.06 log(10) copies/ml for the Versant, Amplicor, and NucliSens QT HIV-1 load assays, respectively (P, not significant). However, mean HIV-1 viral load was consistently reduced in dried samples by 0.32 to 0.51 log(10) copies/ml, depending on assay type (P < 0.05). Infectious HIV-1 was not recovered from dried ST plasma. There was no significant difference in HIV-1 viral load results obtained using ST after 8 weeks of storage at ambient temperature. Compared to frozen plasma, HIV-1 genotypic results were >99% concordant at the nucleotide and amino acid levels, as well as for resistance-associated mutations. We further demonstrated successful detection of multiple analytes, including HIV-1 viral load, HIV-1 antiretroviral resistance genotype, and HCV genotype, from a single ST unit. Dried plasma collected with ST yielded comparable results to frozen samples for multiple-analyte clinical testing. As such, ST could be a useful alternative for virologic tests and clinical trials worldwide by significantly diminishing transportation cost and the sample volume restrictions associated with dried-blood-spot technology.

  View details for DOI 10.1128/JCM.02354-08

  View details for Web of Science ID 000265641000031

  View details for PubMedID 19321732

  View details for PubMedCentralID PMC2681841

• Health-Related Quality of Life in a Randomized Trial of Antiretroviral Therapy for Advanced HIV Disease Journal of Acquired Immune Deficiency Syndromes Joyce, V., Barnett PG, Bayoumi A, Griffin SC, Kyriakides TC, Yu W, Sundaram V, Holodniy M, Brown ST, Cameron W 2009; 50 (1): 27-36
• Evaluation of SampleTanker (R) for collection, storage and transport of dried plasma from a resource-limited setting (R-LS) to a resource-rich setting (R-RS) for HIV-1 genotypic analysis Loveday, C., MaCrae, E., Holodniy, M., Mathis, R., Burns, D., Cooper, J., Grossman, Z., Lloyd, R. M. INT MEDICAL PRESS LTD. 2009: A197

  View details for Web of Science ID 000268039900191

• Health-Related Quality of Life in a Randomized Trial of Antiretroviral Therapy for Advanced HIV Disease 26th Annual Meeting of the Society-for-Medical-Decision-Making Joyce, V. R., Barnett, P. G., Bayoumi, A. M., Griffin, S. C., Kyriakides, T. C., Yu, W., Sundaram, V., Holodniy, M., Brown, S. T., Cameron, W., Youle, M., Sculpher, M., Anis, A. H., Owens, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2009: 27–36

  Abstract

  To assess and compare alternative approaches of measuring preference-based health-related quality of life (HRQoL) in treatment-experienced HIV patients and evaluate their association with health status and clinical variables.Cross-sectional study.Twenty-eight Veterans Affairs hospitals in the United States, 13 hospitals in Canada, and 8 hospitals in the United Kingdom.Three hundred sixty-eight treatment-experienced HIV-infected patients enrolled in the Options in Management with Antiretrovirals randomized trial.Baseline sociodemographic and clinical indicators and baseline HRQoL using the Medical Outcome Study HIV Health Survey (MOS-HIV), the EQ-5D, the EQ-5D visual analog scale (EQ-5D VAS), the Health Utilities Index Mark 3 (HUI3), and standard gamble (SG) and time trade-off (TTO) techniques.The mean (SD) baseline HRQoL scores were as follows: MOS-HIV physical health summary score 41.70 (11.16), MOS-HIV mental health summary score 44.76 (11.38), EQ-5D 0.77 (0.19), HUI3 0.59 (0.32), EQ-5D VAS 65.94 (21.71), SG 0.75 (0.29), and TTO 0.80 (0.31). Correlations between MOS-HIV summary scores and EQ-5D, EQ-5D VAS, and HUI3 ranged from 0.60 to 0.70; the correlation between EQ-5D and HUI3 was 0.73; and the correlation between SG and TTO was 0.43. Preference-based HRQoL scores were related to physical, mental, social, and overall health as measured by MOS-HIV. Concomitant medication use, CD4 cell count, and HIV viral load were related to some instruments' scores.On average, preference-based HRQoL for treatment-experienced HIV patients was decreased relative to national norms but also highly variable. Health status and clinical variables were related to HRQoL.

  View details for Web of Science ID 000262019100004

  View details for PubMedID 19295332

• Infectious complications in OIF/OEF veterans with traumatic brain injury JOURNAL OF REHABILITATION RESEARCH AND DEVELOPMENT Dau, B., Oda, G., Holodniy, M. 2009; 46 (6): 673-684

  Abstract

  Of veterans from the U.S. Global War on Terrorism who have sought care in the Department of Veterans Affairs, approximately 12% have an infectious disease diagnosis. Infections in those veterans with traumatic brain injury (TBI) include infections associated with blast injuries and burns, such as skin and soft tissue infections; infections as a result of retained bullet or shrapnel fragments; pulmonary infections resulting from lung injury, intubation, or resultant tracheostomy; hospital-acquired infections, such as those associated with methicillin-resistant Staphylococcus aureus and other antimicrobial resistant organisms such as Acinetobacter baumannii; and infections from implanted prosthetic devices, such as metal hardware or skull flaps. Longer-term cognitive impairment may result in behaviors that place veterans with TBI at risk for human immunodeficiency virus or hepatitis C virus infections. Finally, chronic infections acquired abroad, such as cutaneous leishmaniasis or Q-fever, may be diagnosed after veterans return to the United States. These infections present challenges in terms of added morbidity and costs associated with complex antimicrobial management; isolation requirements; and surgical procedures, such as those to remove infected retained fragments or prosthetic devices. In this review, providers will become more familiar with the scope and complexity of infectious disease management in veterans with TBI.

  View details for DOI 10.1682/JRRD.2008.09.0113

  View details for Web of Science ID 000272638100005

  View details for PubMedID 20104397

• Novel Targets for Antiretroviral Therapy Clinical Progress to Date DRUGS Dau, B., Holodniy, M. 2009; 69 (1): 31-50

  Abstract

  The advent of HIV-1 resistance to antiretroviral medications, the need for lifelong antiretroviral therapy (ART) for HIV-infected individuals, and the goal of minimizing ART-related adverse effects and toxicity all drive the need for new antiretroviral drugs. Two new classes of antiretroviral medications for HIV treatment, the CCR5 and integrase inhibitors, have recently been approved for use in patients in whom previous HIV treatment regimens have failed. These new agent classes are a welcome addition to other antiretroviral classes, which include nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors. Maraviroc is a CCR5 co-receptor antagonist that blocks HIV binding to the CCR5 receptor, which is a CD4 co-receptor necessary for cell entry. It is approved for use in ART-experienced patients with CCR5-tropic HIV, and was found to significantly reduce HIV viral load and increase CD4+ cell count when combined with an optimized background ART regimen (OBR). Treatment failure with maraviroc has been described and is primarily associated with the presence of CXCR4-tropic virus. Vicriviroc is another CCR5 co-receptor antagonist that is in late clinical trials. Raltegravir is the first US FDA-approved HIV-1 integrase inhibitor. It is approved for use in ART-experienced patients and was found to significantly reduce HIV viral load and increase CD4+ cell counts compared with placebo in combination with an OBR. Raltegravir has also been studied in treatment-naive patients and was found to be non-inferior to an efavirenz-based regimen. Elvitegravir is another HIV-1 integrase inhibitor in clinical development. Other new antiretroviral agents in clinical development include PRO140, a monoclonal antibody against CCR5, and bevirimat, a maturation inhibitor that prevents late-stage gag polyprotein processing. A number of other drug targets, such as CCR5 co-receptor agonists, CXCR4 co-receptor antagonists, novel fusion inhibitors, and alternative antiretroviral strategies, such as immune stimulation and gene therapy, are under investigation.

  View details for Web of Science ID 000264204600003

  View details for PubMedID 19192935

• Pharmacokinetics and tolerability of oseltamivir combined with probenecid ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Holodniy, M., Penzak, S. R., Straight, T. M., Davey, R. T., Lee, K. K., Goetz, M. B., Raisch, D. W., Cunningham, F., Lin, E. T., Olivo, N., Deyton, L. R. 2008; 52 (9): 3013-3021

  Abstract

  Oseltamivir is an inhibitor of influenza virus neuraminidase, which is approved for use for the treatment and prophylaxis of influenza A and B virus infections. In the event of an influenza pandemic, oseltamivir supplies may be limited; thus, alternative dosing strategies for oseltamivir prophylaxis should be explored. Healthy volunteers were randomized to a three-arm, open-label study and given 75 mg oral oseltamivir every 24 h (group 1), 75 mg oseltamivir every 48 h (q48h) combined with 500 mg probenecid four times a day (group 2), or 75 mg oseltamivir q48h combined with 500 mg probenecid twice a day (group 3) for 15 days. Pharmacokinetic data, obtained by noncompartmental methods, and safety data are reported. Forty-eight subjects completed the pharmacokinetic analysis. The study drugs were generally well tolerated, except for one case of reversible grade 4 thrombocytopenia in a subject in group 2. The calculated 90% confidence intervals (CIs) for the geometric mean ratios between groups 2 and 3 and group 1 were outside the bioequivalence criteria boundary (0.80 to 1.25) at 0.63 to 0.89 for group 2 versus group 1 and 0.57 to 0.90 for group 3 versus group 1. The steady-state apparent oral clearance of oseltamivir carboxylate was significantly less in groups 2 (7.4 liters/h; 90% CI, 6.08 to 8.71) and 3 (7.19 liters/h; 90% CI, 6.41 to 7.98) than in group 1 (9.75 liters/h; 90% CI, 6.91 to 12.60) (P < 0.05 for both comparisons by analysis of variance). The (arithmetic) mean concentration at 48 h for group 2 was not significantly different from the mean concentration at 24 h for group 1 (42 +/- 76 and 81 +/- 54 ng/ml, respectively; P = 0.194), but the mean concentration at 48 h for group 3 was significantly less than the mean concentration at 24 h for group 1 (23 +/- 26 and 81 +/- 54 ng/ml, respectively; P = 0.012). Alternate-day dosing of oseltamivir plus dosing with probenecid four times daily achieved trough oseltamivir carboxylate concentrations adequate for neuraminidase inhibition in vitro, and this combination should be studied further.

  View details for DOI 10.1128/AAC.00047-08

  View details for Web of Science ID 000258667300003

  View details for PubMedID 18559644

  View details for PubMedCentralID PMC2533494

• The Relationship Between HIV Infection and Cardiovascular Disease. Current cardiology reviews Dau, B., Holodniy, M. 2008; 4 (3): 203-218

  Abstract

  Over 30 million people are currently living with human immunodeficiency virus (HIV) infection, and over 2 million new infections occur per year. HIV has been found to directly affect vascular biology resulting in an increased risk of cardiovascular disease compared to uninfected persons. Although HIV infection can now be treated effectively with combination antiretroviral medications, significant toxicities such as hyperlipidemia, diabetes, and excess cardiovascular co-morbidity; as well as the potential for significant drug-drug interactions between HIV and cardiovascular medications, present new challenges for the management of persons infected with HIV. We first review basic principles of HIV pathogenesis and treatment and then discuss relevant clinical management strategies that will be useful for cardiologists who might be involved in the care of HIV infected patients.

  View details for DOI 10.2174/157340308785160589

  View details for PubMedID 19936197

  View details for PubMedCentralID PMC2780822

• Cost-effectiveness of HIV screening in patients older than 55 years of age ANNALS OF INTERNAL MEDICINE Sanders, G. D., Bayoumi, A. M., Holodnly, M., Owens, D. K. 2008; 148 (12): 889-?

  Abstract

  Although HIV infection is more prevalent in people younger than age 45 years, a substantial number of infections occur in older persons. Recent guidelines recommend HIV screening in patients age 13 to 64 years. The cost-effectiveness of HIV screening in patients age 55 to 75 years is uncertain.To examine the costs and benefits of HIV screening in patients age 55 to 75 years.Markov model.Derived from the literature.Patients age 55 to 75 years with unknown HIV status.Lifetime.Societal.HIV screening program for patients age 55 to 75 years compared with current practice.Life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness.For a 65-year-old patient, HIV screening using traditional counseling costs $55,440 per QALY compared with current practice when the prevalence of HIV was 0.5% and the patient did not have a sexual partner at risk. In sexually active patients, the incremental cost-effectiveness ratio was $30,020 per QALY. At a prevalence of 0.1%, HIV screening cost less than $60,000 per QALY for patients younger than age 75 years with a partner at risk if less costly streamlined counseling is used.Cost-effectiveness of HIV screening depended on HIV prevalence, age of the patient, counseling costs, and whether the patient was sexually active. Sensitivity analyses with other variables did not change the results substantially.The effects of age on the toxicity and efficacy of highly active antiretroviral therapy and death from AIDS were uncertain. Sensitivity analyses exploring these variables did not qualitatively affect the results.If the tested population has an HIV prevalence of 0.1% or greater, HIV screening in persons from age 55 to 75 years reaches conventional levels of cost-effectiveness when counseling is streamlined and if the screened patient has a partner at risk. Screening patients with advanced age for HIV is economically attractive in many circumstances.

  View details for Web of Science ID 000257425000001

  View details for PubMedID 18559840

  View details for PubMedCentralID PMC3428219

• Frequency of HIV screening in the Veterans Health Administration: Implications for early diagnosis of HIV infection AIDS EDUCATION AND PREVENTION Valdiserri, R. O., Rodriguez, F., Holodruy, M. 2008; 20 (3): 258-264

  Abstract

  We evaluated the frequency of HIV testing across the Department of Veterans Affairs (VA), the largest provider of HIV care in the United States. An electronic survey was used to determine the volume and location of HIV screening, confirmatory testing, rapid testing and laboratory consent policies in VA medical centers between October 1, 2005, and September 30, 2006. One hundred thirty-five VA laboratories reported that 112,033 HIV screening tests were performed (81% outpatients vs. 19% inpatients, p<.0001). Overall HIV prevalence was 1.49% (1.62% in inpatients vs. 1.46% in outpatients, p=N.S., range=0.2-3.8%). Rapid testing was available in 67% of facilities, 60% of which took place in the clinical laboratory. Sixty-four percent of labs required a copy of the informed consent in order to perform testing. We estimate that fewer than 10% of VA inpatients and fewer than 5% of VA outpatients were tested for HIV during the survey period. Substantial opportunities for increasing routine HIV testing exist in this population.

  View details for Web of Science ID 000256717600005

  View details for PubMedID 18558822

• Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine 44th Annual Meeting of the Infectious-Diseases-Society-of-America Levin, M. J., Oxman, M. N., Zhang, J. H., Johnson, G. R., Stanley, H., Hayward, A. R., Caulfield, M. J., Irwin, M. R., Smith, J. G., Clair, J., Chan, I. S., Williams, H., Harbecke, R., Marchese, R., Straus, S. E., Gershon, A., Weinberg, A. UNIV CHICAGO PRESS. 2008: 825–35

  Abstract

  A double-blind, placebo-controlled trial that involved 38,546 subjects > or =60 years old demonstrated efficacy of a high-potency live-attenuated Oka/Merck varicella-zoster virus (VZV) vaccine. The trial included an immunology substudy to determine the relationship of VZV-specific immune responses to vaccination and clinical outcome.The immunology substudy enrolled 1395 subjects at 2 sites where blood samples obtained prior to vaccination, at 6 weeks after vaccination, and at 1, 2, and 3 years thereafter were tested for VZV-specific cell-mediated immunity (VZV-CMI) by gamma-interferon ELISPOT and responder cell frequency assays and for VZV antibody by glycoprotein ELISA.VZV-CMI and VZV antibodies were significantly increased in vaccine recipients at 6 weeks after vaccination. The vaccine-induced increases in VZV-CMI persisted during the 3 years of follow-up, although their magnitude decreased over time. The magnitude of these VZV-specific immune responses was greater in subjects 60-69 years old than in subjects > or =70 years old.The zoster vaccine induced a significant increase in VZV-CMI and VZV antibody. The magnitude and duration of the boost in VZV-CMI in vaccine recipients and the relationship of this boost to age paralleled the clinical effects of the vaccine observed during the efficacy trial. These findings support the hypothesis that boosting VZV-CMI protects older adults against herpes zoster and postherpetic neuralgia.

  View details for DOI 10.1086/528696

  View details for Web of Science ID 000253773900008

  View details for PubMedID 18419349

• Vaccination against herpes zoster and postherpetic neuralgia JOURNAL OF INFECTIOUS DISEASES Oxman, M. N., Levin, M. J., Shingles Prevention Study Grp 2008; 197: S228-S236

  Abstract

  Herpes zoster (HZ) and postherpetic neuralgia (PHN) cause significant morbidity in older adults. The incidence and severity of HZ and PHN increase with age in association with an age-related decline in varicella-zoster virus (VZV)-specific cell-mediated immunity (VZV-CMI). VZV vaccines can boost VZV-CMI. Therefore, we tested the hypothesis that VZV vaccination would protect older adults against HZ and PHN.We enrolled 38,546 adults > or =60 years of age in a randomized, double-blind, placebo-controlled trial of an investigational HZ vaccine and actively followed subjects for the development of HZ. The primary end point was the burden of illness due to HZ (HZ BOI), a composite measure of the incidence, severity, and duration of pain and discomfort caused by HZ. The secondary end point was the incidence of PHN.Subject retention was >95%. HZ vaccine reduced the HZ BOI by 61.1% (95% confidence interval [CI], 51.1%-69.1%; P<.001) and reduced the incidence of PHN by 66.5% (95% CI, 47.5%-79.2%; P<.001). The incidence of HZ was also reduced by 51.3% (95% CI, 44.2%-57.6%; P<.001). HZ vaccine was well tolerated; injection site reactions were generally mild. HZ vaccine neither caused nor induced HZ.The Shingles Prevention Study demonstrated that HZ vaccine significantly reduced the morbidity due to HZ and PHN in older adults.

  View details for DOI 10.1086/522159

  View details for Web of Science ID 000253773600035

  View details for PubMedID 18419402

  View details for PubMedCentralID PMC4017882

• Safety, tolerability, pharmacokinetics, and efficacy of an interleukin-2 agonist among HIV-infected patients receiving highly active antiretroviral therapy JOURNAL OF INTERFERON AND CYTOKINE RESEARCH Davey, R. T., Pertel, P. E., Benson, A., Cassell, D. J., Gazzard, B. G., Holodniy, M., Lalezari, J. P., Levy, Y., Mitsuyasu, R. T., Palella, F. J., Pollard, R. B., Rajagopalan, P., Sagg, M. S., Salata, R. A., Sha, B. E., Choudhri, S. 2008; 28 (2): 89-100

  Abstract

  We sought to determine the safety, maximum tolerated dose, optimal dose, and preliminary dose efficacy of intermittent subcutaneously (s.c.) administered BAY 50-4798 among patients with HIV infection receiving highly active antiretroviral therapy (HAART) compared with patients receiving HAART alone. A phase I/II randomized, double-blind, dose-escalation study was conducted of the safety, tolerability, pharmacokinetics, and efficacy of s.c. BAY 50-4798 administered to HIV-infected patients already receiving stable HAART. There were no unexpected safety findings in a population of HIV-infected patients receiving HAART plus SC BAY 50-4798 as adjunctive therapy. BAY 50-4798 exhibited nearly dose-proportional pharmacokinetics, and accumulation was minimal during multiple-dose treatment. Limited efficacy data indicated that treatment with BAY 50-4798 caused at least a transient increase in CD4(+) T cell counts in some recipients, particularly at the early time points. In general, this effect appeared to increase with increasing dose. Bay 50-4798 was generally well tolerated across the dose range tested, but a lack of potent, sustained immunologic activity suggests that further optimization of dose and schedule will be necessary.

  View details for DOI 10.1089/jir.2007.0064

  View details for Web of Science ID 000253629900004

  View details for PubMedID 18279104

• Severe pneumonia due to adenovirus serotype 14: A new respiratory threat? CLINICAL INFECTIOUS DISEASES Louie, J. K., Kajon, A. E., Holodniy, M., Guardia-LaBar, L., Lee, B., Petru, A. M., Hacker, J. K., Schnurr, D. P. 2008; 46 (3): 421-425

  Abstract

  Adenoviruses are associated with sporadic infection and community and institutional outbreaks; they can cause especially severe disease in infants, young children, immunocompromised persons, and transplant recipients. Fifty-two adenovirus serotypes have been recognized and classified within 7 subgroups or species (A-G), with limited data available on associated clinical syndromes and disease severity in more than one-half of the known serotypes.We describe the clinical presentation and virologic characterization of 1 adult and 2 pediatric patients admitted to 2 separate hospitals during April-May 2006 with severe acute respiratory tract infection. All patients had underlying chronic pulmonary disease; none were severely immunocompromised. All 3 experienced serious chronic sequelae or died.Adenovirus was isolated from all 3 case patients. Adenovirus serotype 14, a subspecies B2 serotype not previously associated with severe clinical illness, was confirmed by neutralization assay and sequencing of the hexon gene. Restriction enzyme analysis with BamHI, BglII, HindIII, and SmaI showed all 3 viruses to be identical and to belong to a new genome type that we have designated "Ad14a."Our identification of severe respiratory illness due to a previously rarely reported adenovirus serotype may signify the emergence in the United States of a new genomic variant that has the potential to spread globally and cause epidemics. These case reports highlight the need for rapid diagnosis and improved surveillance, with serotyping and molecular characterization, to identify emerging variants of adenovirus, which may assist with targeted development of antiviral agents or type-specific vaccines.

  View details for DOI 10.1086/525261

  View details for Web of Science ID 000252221200010

  View details for PubMedID 18173356

• HIV infection in the elderly Clinical Interventions in Aging Nguyen N, Holodniy M 2008; 3 (4): 1-20
• Detection of mixtures of hepatitis C virus genotypes Lloyd, R. M., Holodniy, M., Mathis, R. L., Feorino, P. M., O'Brien, W. INT MEDICAL PRESS LTD. 2008: A124

  View details for Web of Science ID 000257428100132

• HIV infection in the elderly CLINICAL INTERVENTIONS IN AGING Nguyen, N., Holodniy, M. 2008; 3 (3): 453-472

  Abstract

  In the US, an estimated 1 million people are infected with HIV, although one-third of this population are unaware of their diagnosis. While HIV infection is commonly thought to affect younger adults, there are an increasing number of patients over 50 years of age living with the condition. UNAIDS and WHO estimate that of the 40 million people living with HIV/AIDS in the world, approximately 2.8 million are 50 years and older. With the introduction of highly active antiretroviral therapy (HAART) in the mid-1990s, survival following HIV diagnosis has risen dramatically and HIV infection has evolved from an acute disease process to being managed as a chronic medical condition. As treated HIV-infected patients live longer and the number of new HIV diagnoses in older patients rise, clinicians need to be aware of these trends and become familiar with the management of HIV infection in the older patient. This article is intended for the general clinician, including geriatricians, and will review epidemiologic data and HIV treatment as well as provide a discussion on medical management issues affecting the older HIV-infected patient.

  View details for Web of Science ID 000208238800006

  View details for PubMedID 18982916

  View details for PubMedCentralID PMC2682378

• Prevalence of HIV infection among inpatients and outpatients in department of veterans affairs health care systems: Implications for screening programs for HIV AMERICAN JOURNAL OF PUBLIC HEALTH Owens, D. K., Sundaram, V., Lazzeroni, L. C., Douglass, L. R., Sanders, G. D., Taylor, K., VanGroningen, R., Shadle, V. M., McWhorter, V. C., Agoncillo, T., Haren, N., Nyland, J., Tempio, P., Khayr, W., Dietzen, D. J., Jensen, P., Simberkoff, M. S., Bozzette, S. A., Holodniy, M. 2007; 97 (12): 2173-2178

  Abstract

  We sought to determine the prevalence of HIV in both inpatient and outpatient settings in 6 Department of Veterans Affairs (VA) health care sites.We collected demographic data and data on comorbid conditions and then conducted blinded, anonymous HIV testing. We conducted a multivariate analysis to determine predictors of HIV infection.We tested 4500 outpatient blood specimens and 4205 inpatient blood specimens; 326 (3.7%) patients tested positive for HIV. Inpatient HIV prevalence ranged from 1.2% to 6.9%; outpatient HIV prevalence ranged from 0.9% to 8.9%. Having a history of hepatitis B or C infection, a sexually transmitted disease, or pneumonia also predicted HIV infection. The prevalence of previously undocumented HIV infection varied from 0.1% to 2.8% among outpatients and from 0.0% to 1.7% among inpatients.The prevalence of undocumented HIV infection was sufficiently high for routine voluntary screening to be cost effective in each of the 6 sites we evaluated. Many VA health care systems should consider expanded routine voluntary HIV screening.

  View details for DOI 10.2105/AJPH.2007.110700

  View details for PubMedID 17971545

• A systematic review of cost-utility analyses in HIV/AIDS: Implications for public policy MEDICAL DECISION MAKING Hornberger, J., Holodniy, M., Robertus, K., Winnike, M., Gibson, E., Verhulst, E. 2007; 27 (6): 789-821

  Abstract

  To determine whether gaps exist in published cost-utility analyses as measured by their coverage of topics addressed in current HIV guidelines from the Department of Health and Human Services (DHHS).A systematic review of US-based cost-effectiveness analyses of HIV/AIDS prevention and management strategies, based on original, published research.Predefined criteria were used to identify all analyses pertaining to prevention and management of HIV/AIDS; information was collected on type of strategy, patient demographics, study perspective, quality of the study, effectiveness measures, costs, and cost-effectiveness ratios.One hundred and six studies were identified; 62 described strategies for averting new HIV infections, and 44 dealt with managing persons who are HIV positive. The quality of studies was generally high, but gaps were found in all studies. Especially common were omissions in reporting data abstraction methodology and discussions of direction and magnitude of potential biases. Among the 22 most highly rated papers (score of 90 or higher), only 1 was cited in the guidelines, and 3 papers reported on interventions that were superseded by newer approaches. Using a USD 100,000 threshold, the guidelines usually endorsed interventions found to be cost-effective. Exceptions included recommending postexposure prophylaxis (PEP) for populations in which PEP is unlikely to be cost-effective and not recommending primary resistance testing in treatment-naive persons, although the intervention was reported to have a cost-effectiveness ratio of less than USD 50,000.Despite an abundant literature on the cost-utility of HIV/AIDS-targeted strategies, guidelines cite relatively few of these papers, and gaps exist regarding assessments of some strategies and special populations.

  View details for DOI 10.1177/0272989X07306112

  View details for Web of Science ID 000251318600008

  View details for PubMedID 18057191

• Evolution of genotypic resistance algorithms and their impact on the interpretation of clinical trials: An OPTIMA trial substudy HIV CLINICAL TRIALS Desai, S., Kyriakides, T., Holodniy, M., Al-Salman, J., Griffith, B., Kozal, M. 2007; 8 (5): 293-302

  Abstract

  The outdated rules of older HIV genotypic resistance algorithms can affect virologic responses. This study was designed to determine how often these incorrect resistance interpretations affect analyses of long-term clinical trials, antiretroviral (ARV) choices, and HIV disease progression rates.Baseline VIRCO virtual phenotypes (VVP) from patients screened in 2001-2002 for OPTIMA were compared to 2005 Stanford HIV resistance database algorithm (HIVDB-10/05, version 4.1.4) interpretations of the HIV-1 pol sequences. Drugs were called discordant if resistant by one algorithm and sensitive by the other.Of 2,341 drug comparisons, 501 (21.4%) were discordant, affecting 140 (86.4%) of 162 screened patients. NRTI/NtRTIs were more discordant than NNRTIs and PIs (38.6% vs. 4.3% vs. 12.8%; p < .0001). Sixty-nine (53%) patients were placed on 2 drugs reported as sensitive by VVP but resistant by HIVDB-10/05; they had higher than expected rates of disease progression and a similar time to first event or death as patients on ARVs classified as resistant by both algorithms (p = .61).Underestimation of drug resistance by older genotypic algorithms resulted in using ARVs incorrectly thought to be sensitive and in higher than expected rates of HIV disease progression. The use of older genotypes to interpret long-term clinical trials should account for this underestimation, because results may be different if viral sequences are interpreted with newer algorithms.

  View details for DOI 10.1310/hct0805-293

  View details for Web of Science ID 000250560300004

  View details for PubMedID 17956830

• Role of environmental surveillance in determining the risk of hospital-acquired legionellosis: A national surveillance study with clinical correlations INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY Stout, J. E., Muder, R. R., Mietzner, S., Wagener, M. M., Perri, M. B., DeRoos, K., Goodrich, D., Arnold, W., Williamson, T., Ruark, O., Treadway, C., Eckstein, E. C., Marshall, D., Rafferty, M. E., Sarro, K., Page, J., Jenkins, R., Oda, G., Shimoda, K. J., Zervos, M. J., Bittner, M., Camhi, S. L., Panwalker, A. P., Donskey, C. J., Nguyen, M., Holodniy, M., Yu, V. L. 2007; 28 (7): 818-824

  Abstract

  Hospital-acquired Legionella pneumonia has a fatality rate of 28%, and the source is the water distribution system. Two prevention strategies have been advocated. One approach to prevention is clinical surveillance for disease without routine environmental monitoring. Another approach recommends environmental monitoring even in the absence of known cases of Legionella pneumonia. We determined the Legionella colonization status of water systems in hospitals to establish whether the results of environmental surveillance correlated with discovery of disease. None of these hospitals had previously experienced endemic hospital-acquired Legionella pneumonia.Cohort study.Twenty US hospitals in 13 states.Hospitals performed clinical and environmental surveillance for Legionella from 2000 through 2002. All specimens were shipped to the Special Pathogens Laboratory at the Veterans Affairs Pittsburgh Medical Center.Legionella pneumophila and Legionella anisa were isolated from 14 (70%) of 20 hospital water systems. Of 676 environmental samples, 198 (29%) were positive for Legionella species. High-level colonization of the water system (30% or more of the distal outlets were positive for L. pneumophila) was demonstrated for 6 (43%) of the 14 hospitals with positive findings. L. pneumophila serogroup 1 was detected in 5 of these 6 hospitals, whereas 1 hospital was colonized with L. pneumophila serogroup 5. A total of 633 patients were evaluated for Legionella pneumonia from 12 (60%) of the 20 hospitals: 377 by urinary antigen testing and 577 by sputum culture. Hospital-acquired Legionella pneumonia was identified in 4 hospitals, all of which were hospitals with L. pneumophila serogroup 1 found in 30% or more of the distal outlets. No cases of disease due to other serogroups or species (L. anisa) were identified.Environmental monitoring followed by clinical surveillance was successful in uncovering previously unrecognized cases of hospital-acquired Legionella pneumonia.

  View details for DOI 10.1086/518754

  View details for Web of Science ID 000249121400008

  View details for PubMedID 17564984

• Representational fluency in HIV clinical practice: A model of instructor discourse JOURNAL OF CONTINUING EDUCATION IN THE HEALTH PROFESSIONS Banach, M. A., Gifford, B. R., Holodniy, M. 2007; 27 (3): 149-156

  Abstract

  Clinicians treating human immunodeficiency virus (HIV) patients are expected to stay up-to-date with rapidly changing knowledge and practice. Continuing medical education (CME) programs are one source of new knowledge about HIV clinical management. Little is known about instructor-participant discourse in HIV CME programs and whether or how instructors model their decision-making strategies.Discussions about clinical cases between instructors and participants in attendance at a HIV CME program were videotaped, transcribed, segmented, and coded, focusing on the participants' questions and the instructor's responses.Twenty-four case studies involving four instructors and 45 participants (54% infectious disease clinicians and 46% general practitioners) were analyzed. Five case studies are presented herein to illustrate how the instructors use the participants' questions and case studies to model cognitive processing and decision making in HIV treatment practice.This article provides a model of interactive and practice-based teaching discourse in the context of an HIV CME activity. Throughout this discourse the instructors model the fluent use of representations for the CME learners and provide a safe environment where participants can share their misunderstandings.

  View details for DOI 10.1002/chp.118

  View details for Web of Science ID 000250064300003

  View details for PubMedID 17876845

• HIV testing of at risk patients in a large integrated health care system JOURNAL OF GENERAL INTERNAL MEDICINE Owens, D. K., Sundaram, V., Lazzeroni, L. C., Douglass, L. R., Tempio, P., Holodniy, M., Sanders, G. D., Shadle, V. M., McWhorter, V. C., Agoncillo, T., Haren, N., Chavis, D., Borowsky, L. H., Yano, E. M., Jensen, P., Simberkoff, M. S., Bozzette, S. A. 2007; 22 (3): 315-320

  Abstract

  Early identification of HIV infection is critical for patients to receive life-prolonging treatment and risk-reduction counseling. Understanding HIV screening practices and barriers to HIV testing is an important prelude to designing successful HIV screening programs. Our objective was to evaluate current practice patterns for identification of HIV.We used a retrospective cohort analysis of 13,991 at-risk patients seen at 4 large Department of Veterans Affairs (VA) health-care systems. We also reviewed 1,100 medical records of tested patients. We assessed HIV testing rates among at-risk patients, the rationale for HIV testing, and predictors of HIV testing and of HIV infection.Of the 13,991 patients at risk for HIV, only 36% had been HIV-tested. The prevalence of HIV ranged from 1% to 20% among tested patients at the 4 sites. Approximately 90% of patients who were tested had a documented reason for testing.One-half to two-thirds of patients at risk for HIV had not been tested within our selected VA sites. Among tested patients, the rationale for HIV testing was well documented. Further testing of at-risk patients could clearly benefit patients who have unidentified HIV infection by providing earlier access to life-prolonging therapy.

  View details for DOI 10.1007/s11606-006-0028-9

  View details for PubMedID 17356961

• Relationship between antiretroviral prescribing patterns and treatment guidelines in treatment-naive HIV-1-infected US veterans (1992-2004) JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Holodniy, M., Hornberger, J., Rapoport, D., Robertus, K., MaCurdy, T. E., Lopez, J., Volberding, P., Deyton, L. 2007; 44 (1): 20-29

  Abstract

  To analyze temporal patterns of antiretroviral (ARV) prescribing practices relative to nationally defined guidelines in treatment-naive patients with HIV-1 infection.Retrospective cohort study.We evaluated ARV prescribing patterns among ARV treatment-naive veterans who were receiving care within the US Department of Veterans Affairs (VA) from 1992 through 2004 in comparison to evolving adult HIV-1 treatment guidelines.A total of 15,934 patients initiated ARV treatment. Since 1999, >94% of patients initiated at least a 3-ARV medication combination, although the percentage of patients who initiated a guideline "preferred" or "alternative" regimen never rose to greater than 72% and was significantly associated with being black and with region of care. After 1999, 20% of patients started 4 or more active ARV agents in combination, which was significantly associated with lower baseline CD4 cell count, higher viral load, and receiving care in the western United States. The proportion of patients receiving guideline "not recommended" regimens (virologically undesirable or overlapping toxicities) was <1% after 1997. VA prescribing trends generally predated guideline recommendations by 6 to 12 months.VA prescribing patterns for ARV initiation adhere to treatment guidelines that maximize safety. Guidelines designed to maximize efficacy were not followed as stringently. Evaluating clinical practice patterns against contemporary treatment guidelines can inform guideline development.

  View details for Web of Science ID 000243189400004

  View details for PubMedID 17091020

• Darunavir in the treatment of HIV-1 infection - Viewpoint DRUGS Holodniy, M. 2007; 67 (18): 2803-2803

  View details for Web of Science ID 000252178500011

  View details for PubMedID 18062725

• siRNA delivery into human T cells and primary cells with carbon-nanotube transporters ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Liu, Z., Winters, M., Holodniy, M., Dai, H. 2007; 46 (12): 2023-2027

  View details for DOI 10.1002/anie.200604295

  View details for Web of Science ID 000245071000016

  View details for PubMedID 17290476

• HIV-1 load quantitation: A 17-year perspective Symposium on Bridging Generations Toward an Understanding of Infectious Disease Pathogenesis Holodniy, M. UNIV CHICAGO PRESS. 2006: S38–S44

  Abstract

  During the past decade and a half, quantitation of plasma-associated human immunodeficiency virus type 1 (HIV-1) RNA level, or HIV-1 load, has been validated in clinical practice and clinical trials as an important surrogate marker of HIV-1 disease progression and of the potency and durability of antiretroviral regimens. This review highlights some of the history, accomplishments, and impact of Tom Merigan's laboratory on the use of HIV-1 load as a marker, as well as on updating technologies for determining HIV-1 load, their performance, interpretation of the results, and their use in clinical practice.

  View details for Web of Science ID 000240317800007

  View details for PubMedID 16921471

• Bridging generations: Understanding pathogenesis leads to new infectious diseases therapies and diagnostics - Introduction and dedication JOURNAL OF INFECTIOUS DISEASES Holodniy, M., Katzenstein, D. 2006; 194: S1-S2

  View details for DOI 10.1086/505354

  View details for Web of Science ID 000240317800001

• Prevention of shingles by varicella zoster virus vaccination EXPERT REVIEW OF VACCINES Holodniy, M. 2006; 5 (4): 431-443

  Abstract

  Herpes zoster is caused by reactivation from previous varicella zoster virus (VZV) infection, and affects millions of people worldwide. It primarily affects older adults and those with immune system dysfunction, most likely as a result of reduced or lost VZV-specific cell-mediated immunity. Complications include post-herpetic neuralgia, a potentially debilitating and chronic pain syndrome. Current treatment of herpes zoster and post-herpetic neuralgia involves antiviral agents and analgesics, and is associated with significant economic cost. Results from several clinical trials have determined that a live, attenuated VZV vaccine using the Oka/Merck strain (Zostavax) is safe, elevates VZV-specific cell-mediated immunity, and significantly reduces the incidence of herpes zoster and post-herpetic neuralgia in people over 60 years of age. Regulatory approval has recently been obtained and once launched, it is expected that this vaccine will significantly reduce the morbidity and financial costs associated with herpes zoster. Durability of vaccine response and possible booster vaccination will still need to be determined.

  View details for DOI 10.1586/14760584.5.4.431

  View details for Web of Science ID 000243482800012

  View details for PubMedID 16989624

• Hepatitis C virus protease gene diversity in patients coinfected with human immunodeficiency virus JOURNAL OF VIROLOGY Winters, M. A., Welles, S. L., Holodniy, M. 2006; 80 (8): 4196-4199

  Abstract

  The clonal variability of the hepatitis C virus (HCV) protease gene in 24 individuals with HCV genotypes 1a, 1b, 2b, and 3a who were coinfected with the human immunodeficiency virus was evaluated. Within-genotype variability at the nucleotide and amino acid levels ranged from 6.5 to 8.6% and 2.2 to 3.8%, respectively. After adjustments were made for correlation of intrapatient clonal variation, mixed-model analysis indicated that nucleotide and amino acid variability among patients with different genotypes did not differ significantly. However, within individual patients, clonal variability differed by up to 5.3% and 5.8% at the nucleotide and amino acid levels, respectively, and genotype 1a had significantly greater nucleotide variability than other genotypes (P = 0.01). Significant variability exists within HCV protease gene variants at the patient level and could affect the effectiveness of HCV protease inhibitors.

  View details for DOI 10.1128/JVI.80.8.4196-4199.2006

  View details for Web of Science ID 000236685600053

  View details for PubMedID 16571838

  View details for PubMedCentralID PMC1440459

• The effect of diagnosis with HIV infection on health-related quality of life QUALITY OF LIFE RESEARCH Honiden, S., Sundaram, V., Nease, R. F., Holodniy, M., Lazzeroni, L. C., Zolopa, A., Owens, D. K. 2006; 15 (1): 69-82

  Abstract

  We sought to understand how diagnosis with HIV affects health-related quality of life. We assessed health-related quality of life using utility-based measures in a Department of Veterans Affairs (VA) clinic and a University-based clinic. Respondents assessed health-related quality of life regarding their current health, and retrospectively assessed their health 1 month prior to and 2 months after diagnosis with HIV infection. Sixty-six patients completed the study. The overall mean utilities for health 1 month before and 2 months after diagnosis were 0.87 (standard error 0.037), and 0.80 (0.043) (p<0.005 by rank sign test), but the effect of diagnosis differed between the two clinics, with a substantial decrease in the university clinic and a small non-significant decrease in the VA clinic. The overall mean utility for current health was 0.85 (0.034), assessed on average 7.5 years after diagnosis. When asked directly whether diagnosis of HIV decreased health-related quality of life, 47% agreed, but 35% stated that HIV diagnosis positively affected health-related quality of life. Diagnosis with HIV decreased health-related quality of life at 2 months on average, but this effect diminished over time, and differed among patient populations. Years after diagnosis, although half of the patients believed that diagnosis reduced health-related quality of life, one-third reported improved health-related quality of life.

  View details for DOI 10.1007/s11136-005-8485-x

  View details for PubMedID 16411032

• Case files from Stanford University Medical Center: the initial presentation of HIV-1 infection--where public and personal health meet. MedGenMed : Medscape general medicine Liu, M., Holodniy, M., Zolopa, A. R., Shafer, R. W. 2006; 8 (1): 24-?

  View details for PubMedID 16915154

• The safety and tolerability of Z-100 in patients infected with HIV-1 ANTIVIRAL THERAPY Borucki, M., Holodniy, M., Pierone, G., Ruane, P., Steinhart, C., Williams, S., Slom, T., Palella, F., Hare, C. B., Yoshida, Y., Li, X., Pollard, R. B. 2006; 11 (3): 297-303

  Abstract

  Z-100 is an extract of the Mycobacterium tuberculosis strain Aoyama B, which contains various polysaccharides. Aoyama B has previously been shown to induce a T helper 1-type cytokine response in various murine oncological models and has also demonstrated inhibitory activity against HIV-1 in vitro. This multicentre study primarily determined the safety of Z-100 in early HIV-1-infected patients who were treatment naive; were treatment experienced, but had elected to discontinue highly active antiretroviral therapy (HAART) 8 weeks or longer before the study; or were stable on their first or second HAART regimen for at least 12 weeks before the study. Thirty-two individuals participated in this study and self-injected either placebo, 20 microg or 40 microg Z-100 twice a week for 8 weeks. Z-100 was well tolerated and the safety profiles of the Z-100 treatment groups were not meaningfully different compared with the placebo group. Plasma levels of HIV-1 RNA were not statistically significantly different in any treatment group at the end of the treatment period. There were no statistically significant differences among the treatment groups in the change from baseline to week 8 for any of the biological endpoints including plasma levels of HIV-1 RNA; CD4+ and CD8+ T-cell counts; levels of macrophage inflammatory protein 1; soluble tumour necrosis factor receptor 1; C-reactive protein; interleukin-6; and granulocyte colony stimulating factor. Consequently, this trial demonstrates the safety of Z-100 in HIV-1 infected patients without evidence of any activity at the doses administered.

  View details for Web of Science ID 000237963400003

  View details for PubMedID 16759045

• Evolution of genotypic resistance algorithms and their impact on the interpretation of clinical trials: an OPTIMA trial substudy 15th International HIV Drug Resistance Workshop Desai, S. S., Kyriakides, T. C., Holodniy, M., Al-Salman, J., Griffith, B. P., Kozal, M. J. INT MEDICAL PRESS LTD. 2006: S184–S184

  View details for Web of Science ID 000239984700184

• Utilization and access to Antiretroviral genotypic resistance testing and results within the US department of veterans affairs JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Goetz, M. B., Holodniy, M., Poulton, J. S., Rodriguez, F. H., Rigsby, M. O. 2006; 41 (1): 59-62

  Abstract

  We sought to characterize variation in the use of HIV genotypic resistance tests and how results were reported.Clinicians and laboratory managers at all Veterans Affairs (VA) medical centers were asked to complete a survey in March 2003 regarding HIV resistance testing practices.Surveys from 131 of 150 sites were returned. Forty-eight percent of HIV clinicians indicated that US Department of Health and Human Services guidelines were the usual basis for ordering tests. Although between 12% and 31% of respondents indicated that they always, sometimes, seldom, or never ordered resistance tests in patients with acute or chronic HIV infection, >70% ordered tests in adherent patients with treatment failure. Among the 32 centers with >200 patients in care, 13 +/- 8 (mean +/- standard deviation) tests were performed per 100 patients in care during 2002. Forty-nine percent of clinicians said that tests were helpful, but only 33% expressed confidence in using test results. Only 40% of sites entered results in the VA electronic medical record.Ordering patterns for HIV resistance tests differed significantly among VA sites. A minority of clinicians indicated confidence in the use of test results. A consistent system to capture and present complete results was absent.

  View details for Web of Science ID 000234438500009

  View details for PubMedID 16340474

• Laboratory-acquired brucellosis Uhde, K. B., Chang, M. A., Oda, G., Rosen, J. I., Holodniy, M., Cody, S., Ari, M., Bragg, S. L., Fischer, M., Clark, T. A. AMER SOC TROP MED & HYGIENE. 2005: 54-55

  View details for Web of Science ID 000202990000164

• Clinical utility of viral load measurements in individuals with chronic hepatitis C infection on antiviral therapy JOURNAL OF VIRAL HEPATITIS Terrault, N. A., Pawlotsky, J. M., McHutchison, J., Anderson, F., Krajden, M., GORDON, S., Zitron, I., Perrillo, R., Gish, R., Holodniy, M., Friesenhahn, M. 2005; 12 (5): 465-472

  Abstract

  Both absolute viral load and log decline in viral load from baseline were found clinically useful in predicting sustained virological response and lack of sustained virological response (non-sustained virological response, NSVR) to treatment. We assessed the clinical utility of hepatitis C virus (HCV) RNA quantitation and changes in viral load using the VERSANT HCV RNA 3.0 Assay (bDNA) in 351 HCV-infected individuals treated with interferon plus ribavirin. We show that viral load decision thresholds provided negative predictive values (NPVs) of >95% at week 4 using a 100 000 IU/mL cut-off and at weeks 8 and 12 using 10 000 IU/mL cut-offs. A 2-log decline from baseline provided NPVs >95% at weeks 8 and 12. Combinations of absolute viral loads and changes in viral load from baseline did not enhance the performance of the decision rules for predicting NSVR. The positive predictive values (PPVs) at weeks 8 and 12 were 59.1 and 67.3%. This study highlights the critical importance of viral quantitation in gauging therapeutic response in patients with chronic HCV infection on antiviral therapy. Early changes in viral load, measured as absolute viral loads or change in viral load from baseline, are highly predictive of NSVR at 8 and 12 weeks. PPVs are modest but these data may provide encouragement to patients who are in the early phases of treatment when side effects are frequent. Additionally, we demonstrated the need for cautious interpretation of stopping rules when the values are at or near the decision thresholds.

  View details for DOI 10.1111/j.1365-2893.2005.00615.x

  View details for Web of Science ID 000231223400003

  View details for PubMedID 16108760

• Accuracy, precision, and consistency of expert HIV type 1 genotype interpretation: An international comparison (The GUESS Study) CLINICAL INFECTIOUS DISEASES Zolopa, A. R., Lazzeroni, L. C., Rinehart, A., Vezinet, F. B., Clavel, F., Collier, A., Conway, B., Gulick, R. M., Holodniy, M., Perno, C. F., Shafer, R. W., Richman, D. D., Wainberg, M. A., Kuritzkes, D. R. 2005; 41 (1): 92-99

  Abstract

  Resistance testing is considered standard of care in HIV medicine, but there is no standard interpretation system for genotype tests. We sought to determine how much agreement exists within a group of experts in the interpretation of complex genotypes.Genotypes from clinical specimens were sent to an international panel of 12 resistance experts. Phenotypic susceptibility testing of these clinical isolates was performed with antivirogram. Experts predicted phenotype fold change category (<2.5-fold change, 2.5-4.0-fold change, >4.0- to 7.0-fold change, >7.0- to 10-fold change, >10- to 20-fold change, or >20-fold change) and predicted expected drug activity for each of 16 antiretroviral drugs. Experts were also asked to make treatment recommendations on the basis of the genotype.The experts predicted the exact phenotype fold change category correctly 44% of the time, but they varied widely by antiretroviral drug (range, 25%-74%). The highest accuracy was observed for lamivudine (74%) and the nonnucleoside reverse transcriptase inhibitors (66%-69%). Experts generally predicted higher levels of resistance to the remaining nucleoside reverse transcriptase inhibitors than what was found by phenotypic testing. Agreement among experts in predicting phenotype fold change category ranged widely depending on the drug (median agreement, 42% [range, 28%-74%]); the same pattern was observed in predicting expected drug activity (median agreement, 45% [range, 32%-87%]). Experts agreed on treatment recommendations in a median of 79% of instances, and recommendations were consistent over time, with blinded retesting.Although their ability to predict phenotype from a genotype varied for individual antiretroviral drugs, this expert panel had a high degree of agreement in deriving treatment recommendations from the genotype.

  View details for Web of Science ID 000229530400015

  View details for PubMedID 15937768

• A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults NEW ENGLAND JOURNAL OF MEDICINE Oxman, M. N., Levin, M. J., Johnson, G. R., Schmader, K. E., Straus, S. E., Gelb, L. D., Arbeit, R. D., Simberkoff, M. S., Gershon, A. A., Davis, L. E., Weinberg, A., Boardman, K. D., Williams, H. M., Zhang, J. H., Peduzzi, P. N., Beisel, C. E., Morrison, V. A., Guatelli, J. C., Brooks, P. A., Kauffman, C. A., Pachucki, C. T., Neuzil, K. M., Betts, R. F., Wright, P. F., Griffin, M. R., Brunell, P., Soto, N. E., Marques, A. R., Keay, S. K., Goodman, R. P., Cotton, D. J., Gnann, J. W., Loutit, J., Holodniy, M., Keitel, W. A., Crawford, G. E., Yeh, S. S., Lobo, Z., Toney, J. F., Greenberg, R. N., Keller, P. M., Harbecke, R., Hayward, A. R., Irwin, M. R., Kyriakides, T. C., Chan, C. Y., Chan, I. S., Wang, W. W., Annunziato, P. W., Silber, J. L. 2005; 352 (22): 2271-2284

  Abstract

  The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults.We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia.More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild.The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

  View details for Web of Science ID 000229446400004

  View details for PubMedID 15930418

• Proteomic analysis of serum cytokine levels in response to highly active antiretroviral therapy (HAART) JOURNAL OF PROTEOME RESEARCH Relucio, K. I., Beernink, H. T., Chen, D., Israelski, D. M., Kim, R., Holodniy, M. 2005; 4 (2): 227-231

  Abstract

  A 30-cytokine protein microarray was used to screen for cytokine profile changes in HIV-infected patients in response to highly active antiretroviral therapy (HAART). Serum cytokines showing significant changes were confirmed by enzyme immunoassay. Monokine induced by gamma-interferon (MIG) and interferon-inducible protein-10 (IP-10) levels significantly decreased after 24 weeks of HAART. Protein microarrays are useful for initial screening of novel cytokine expression. Further studies are needed to elucidate the role of MIG and IP-10 in response to HAART.

  View details for DOI 10.1021/pr049930y

  View details for Web of Science ID 000228421900004

  View details for PubMedID 15822897

• Cost-effectiveness of screening for HIV in the era of highly active antiretroviral therapy NEW ENGLAND JOURNAL OF MEDICINE Sanders, G. D., Bayoumi, A. M., Sundaram, V., Bilir, S. P., Neukermans, C. P., Rydzak, C. E., Douglass, L. R., Lazzeroni, L. C., Holodniy, M., Owens, D. K. 2005; 352 (6): 570-585

  Abstract

  The costs, benefits, and cost-effectiveness of screening for human immunodeficiency virus (HIV) in health care settings during the era of highly active antiretroviral therapy (HAART) have not been determined.We developed a Markov model of costs, quality of life, and survival associated with an HIV-screening program as compared with current practice. In both strategies, symptomatic patients were identified through symptom-based case finding. Identified patients started treatment when their CD4 count dropped to 350 cells per cubic millimeter. Disease progression was defined on the basis of CD4 levels and viral load. The likelihood of sexual transmission was based on viral load, knowledge of HIV status, and efficacy of counseling.Given a 1 percent prevalence of unidentified HIV infection, screening increased life expectancy by 5.48 days, or 4.70 quality-adjusted days, at an estimated cost of 194 dollars per screened patient, for a cost-effectiveness ratio of 15,078 dollars per quality-adjusted life-year. Screening cost less than 50,000 dollars per quality-adjusted life-year if the prevalence of unidentified HIV infection exceeded 0.05 percent. Excluding HIV transmission, the cost-effectiveness of screening was 41,736 dollars per quality-adjusted life-year. Screening every five years, as compared with a one-time screening program, cost 57,138 dollars per quality-adjusted life-year, but was more attractive in settings with a high incidence of infection. Our results were sensitive to the efficacy of behavior modification, the benefit of early identification and therapy, and the prevalence and incidence of HIV infection.The cost-effectiveness of routine HIV screening in health care settings, even in relatively low-prevalence populations, is similar to that of commonly accepted interventions, and such programs should be expanded.

  View details for Web of Science ID 000226862100007

  View details for PubMedID 15703422

• Clinical utility of viral load measurements in individuals with chronic hepatitis C infection on antiviral therapy. Journal of Viral Hepatitis Terrault, N., Pawlotsky JM, McHutchison J, Anderson F, Krajden M, Gordon S, Zitron I, Perrillo R, Gish R, Holodniy M, Friesenhahn M. 2005; 12 (5): 465-472
• Comparison of whole blood, plasma, and PBMC HIV-1 resistance genotyping and matched dried samples using SampleTanker (TM) a novel dried transportation matrix Lloyd, R. M., Burns, D. A., Huong, J. T., Kirkpatrick, B. D., Mathis, R. L., Holodniy, M., Tanner, M. L., Feorino, P. M. INT MEDICAL PRESS LTD. 2005: S50

  View details for Web of Science ID 000232470800048

• Resistance genotyping using a novel long range amplicon system, HIV-1 LR-GeneTanker (TM) complete Huong, J. T., Burns, D. A., Kirkpatrick, B. D., Prince, R. T., Holodniy, M., Lloyd, R. M. INT MEDICAL PRESS LTD. 2005: S47

  View details for Web of Science ID 000231963100058

• Cost-effectiveness of screening for HIV in the era of highly active antiretroviral therapy New England Journal of Medicine Sanders GD, Bayoumi AM, Sundaram V, Bilir SP, Neukermans CP, Rydzak CE, Douglass LR, Lazzeroni LC, Holodniy M, Owens DK 2005; 352 (6): 570-585
• Prevalence of antiretroviral drug resistance in the HIV-1-infected urban indigent population in San Francisco: a representative study INTERNATIONAL JOURNAL OF STD & AIDS Holodniy, M., Charlebois, E. D., Bangsberg, D. R., Zolopa, A. R., Schulte, M., Moss, A. R. 2004; 15 (8): 543-551

  Abstract

  We determined the prevalence of antiretroviral (ARV) resistance in HIV-1 infected indigent persons in San Francisco, California. Three hundred and twenty-seven subjects (159 (49%) ARV naïve, and 168 (51%) ARV-experienced), were recruited during 1996-97 and 1999-2000. Plasma HIV-1 viral load quantification and genotypic resistance testing were performed. Twice as many subjects received nucleoside reverse transcriptase inhibitors (NRTIs) as non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs); resistance mutation prevalences were 30%, 14% and 16% respectively. Risk of any resistance mutations was strongly and independently associated with prior ARV exposure (OR = 1.3 per year of exposure, P < 0.0001) and with ARV exposure prior to HAART (OR = 2.5, P = 0.015). Prevalences of primary ARV resistance mutations among both treatment-naive and treatment-experienced subjects in this indigent urban population are low compared to other observational cohorts, are directly related to length and type of prior ARV exposure, and did not increase significantly between recruitment periods.

  View details for Web of Science ID 000223453900010

  View details for PubMedID 15307966

• Comparison of HIV-1 viral load and resistance genotyping between frozen plasma and a novel dried plasma transportation matrix Lloyd, R. M., Burns, D. A., Thompson, A. M., Mathis, R. L., Holodniy, M., Huong, J. T., De La Rosa, A., Yen-Lieberman, B., Armstrong, W., Taege, A., McClernon, D. R., Feorino, P. M. INT MEDICAL PRESS LTD. 2004: U96

  View details for Web of Science ID 000231615600145

• Multicenter evaluation of the performance characteristics of the Bayer VERSANT HCV RNA 3.0 assay (bDNA) JOURNAL OF CLINICAL MICROBIOLOGY Elbeik, T., Surtihadi, J., Destree, M., Gorlin, J., Holodniy, M., Jortani, S. A., Kuramoto, K., Ng, V., Valdes, R., Valsamakis, A., Terrault, N. A. 2004; 42 (2): 563-569

  Abstract

  In this multicenter evaluation, the VERSANT HCV RNA 3.0 Assay (bDNA) (Bayer Diagnostics, Tarrytown, N.Y.) was shown to have excellent reproducibility, linearity, and analytical sensitivity across specimen collection matrices (serum, EDTA, ACD-A), and hepatitis C virus (HCV) genotypes 1 to 6. The VERSANT HCV bDNA Assay has a reportable range of 615 to 7690000 (7.69 x 10(6)) IU/ml. The total coefficient of variation (CV) ranged from 32.4% at 615 IU/ml to 17% at 6.8 x 10(6) IU/ml. The assay was linear across the reportable range. Analytical specificity of 98.8% was determined by testing 999 specimens from volunteer blood donors. Evaluation of HCV genotypes using RNA transcripts of representative clones of 1a, 1b, 2a, 2b, 2c, 3a, 4a, 5a, and 6a and patient specimens showed that the largest difference between genotype 1, upon which the assay is standardized, and non-1 genotypes was within 1.5-fold. Testing of potentially interfering endogenous substances and exogenous substances and conditions found no interference in HCV-positive or HCV-negative specimens except for unconjugated bilirubin at concentrations of >or=20 mg/dl and protein at concentrations of >or=9 g/dl. Biological variability was estimated from 29 clinically stable individuals not on HCV therapy who were tested weekly over an 8-week period. The combined estimate of total (biologic plus assay) variability was 0.15 log(10) standard deviation (CV, 36.1%), a fold change of 2.6. Thus, the observed fold change between any two consecutive HCV RNA measures is expected to be less than 2.6-fold (equivalent to 0.41 log(10) IU/ml) 95% of the time in clinically stable individuals.

  View details for DOI 10.1128/JCM.42.2.563-569.2004

  View details for Web of Science ID 000189379000012

  View details for PubMedID 14766817

  View details for PubMedCentralID PMC344448

• Inhibition of HIV infectivity by a natural human isolate of Lactobacillus jensenii engineered to express functional two-domain CD4 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Chang, T. L., Chang, C. H., Simpson, D. A., Xu, Q., Martin, P. K., Lagenaur, L. A., SCHOOLNIK, G. K., Ho, D. D., Hillier, S. L., Holodniy, M., Lewicki, J. A., Lee, P. P. 2003; 100 (20): 11672-11677

  Abstract

  The predominant mode of HIV transmission worldwide is via heterosexual contact, with the cervico-vaginal mucosa being the main portal of entry in women. The cervico-vaginal mucosa is naturally colonized with commensal bacteria, primarily lactobacilli. To address the urgent need for female-controlled approaches to block the heterosexual transmission of HIV, we have engineered natural human vaginal isolates of Lactobacillus jensenii to secrete two-domain CD4 (2D CD4) proteins. The secreted 2D CD4 recognized a conformation-dependent anti-CD4 antibody and bound HIV type 1 (HIV-1) gp120, suggesting that the expressed proteins adopted a native conformation. Single-cycle infection assays using HIV-1HxB2 carrying a luciferase reporter gene demonstrated that Lactobacillus-derived 2D CD4 inhibited HIV-1 entry into target cells in a dose-dependent manner. Importantly, coincubation of the engineered bacteria with recombinant HIV-1HxB2 reporter virus led to a significant decrease in virus infectivity of HeLa cells expressing CD4-CXCR4-CCR5. Engineered lactobacilli also caused a modest, but statistically significant, decrease in infectivity of a primary isolate, HIV-1JR-FL. This represents an important first step toward the development of engineered commensal bacteria within the vaginal microflora to inhibit heterosexual transmission of HIV.

  View details for DOI 10.1073/pnas.1934747100

  View details for Web of Science ID 000185685700089

  View details for PubMedID 12972635

  View details for PubMedCentralID PMC208816

• High levels of adherence do not prevent accumulation of HIV drug resistance mutations AIDS Bangsberg, D. R., Charlebois, E. D., Grant, R. M., Holodniy, M., Deeks, S. G., Perry, S., Conroy, K. N., Clark, R., Guzman, D., Zolopa, A., Moss, A. 2003; 17 (13): 1925-1932

  Abstract

  To assess the relationship between development of antiretroviral drug resistance and adherence by measured treatment duration, virologic suppression, and the rate of accumulating new drug resistance mutations at different levels of adherence.Adherence was measured with unannounced pill counts performed at the participant's usual place of residence in a prospective cohort of HIV-positive urban poor individuals. Two genotypic resistance tests separated by 6 months (G1 and G2) were obtained in individuals on a stable regimen and with detectable viremia (> 50 copies/ml). The primary resistance outcome was the number of new HIV antiretroviral drug resistance mutations occurring over the 6 months between G1 and G2.High levels of adherence were closely associated with greater time on treatment (P < 0.0001) and viral suppression (P < 0.0001) in 148 individuals. In a subset of 57 patients with a plasma viral load > 50 copies/ml on stable therapy, the accumulation of new drug resistance mutations was positively associated with the duration of prior treatment (P = 0.03) and pill count adherence (P = 0.002). Assuming fully suppressed individuals (< 50 copies/ml) do not develop resistance, it was estimated that 23% of all drug resistance occurs in the top quintile of adherence (92-100%), and over 50% of all drug resistance mutations occur in the top two quintiles of adherence (79-100%).Increasing rates of viral suppression at high levels of adherence is balanced by increasing rates of drug resistance among viremic patients. Exceptionally high levels of adherence will not prevent population levels of drug resistance.

  View details for DOI 10.1097/01.aids.0000076320.42412.fd

  View details for Web of Science ID 000185067700008

  View details for PubMedID 12960825

• An open-label randomized clinical trial of novel therapeutic strategies for HIV-infected patients in whom antiretroviral therapy has failed: rationale and design of the OPTIMA Trial CONTROLLED CLINICAL TRIALS Kyriakides, T. C., Babiker, A., Singer, J., Cameron, W., Schechter, M. T., Holodniy, M., Brown, S. T., Youle, M., Gazzard, B. 2003; 24 (4): 481-500

  Abstract

  OPTIMA (OPTions In Management with Antiretrovirals) is a clinical trial with a factorial randomization to evaluate the hypotheses that mega-antiretroviral therapy (ART) consisting of five or more anti-HIV drugs compared to standard-ART consisting of four or fewer anti-HIV drugs and a 3-month antiretroviral drug-free period (ARDFP) compared to no ARDFP will delay the occurrence of new or recurrent acquired immunodeficiency syndrome events or death, and prove to be more cost-effective in treating human immunodeficiency virus-infected individuals previously exposed to ART drugs from the current three main classes. The aim is to randomize 1,700 participants to four treatment strategy arms: (1) ARDFP+standard-ART; (2) ARDFP+mega-ART; (3) no ARDFP+standard-ART; (4) no ARDFP+mega-ART. The planned study duration is 3.5 years with 2.5 years of intake and a minimum 1 year of follow-up. The OPTIMA Trial was initiated in June 2001 at 30 U.S. Department of Veterans' Affairs hospitals, 22 hospitals in Canada, and 25 hospitals in the United Kingdom. This is the first large-scale, multicenter, randomized controlled trial to compare the relative efficacy of these different therapeutic strategies. We discuss the rationale behind the OPTIMA Trial design as well as the issues arising from the conduct of a trial that involves three national clinical trial agencies.

  View details for DOI 10.1016/S0197-2456(03)00029-1

  View details for Web of Science ID 000184355000010

  View details for PubMedID 12865041

• Successful management of disseminated Nocardia transvalensis infection in a heart transplant recipient after development of sulfonamide resistance: Case report and review JOURNAL OF HEART AND LUNG TRANSPLANTATION Lopez, F. A., Johnson, F., Novosad, D. M., Beaman, B. L., Holodniy, M. 2003; 22 (4): 492-497

  Abstract

  Nocardia transvalensis is a rarely reported cause of clinically significant disease, and, to our knowledge, has not been reported previously as a cause of infection in the cardiac transplant population. We report a case of N transvalensis new taxon-2 pulmonary infection that disseminated to the brain and skin in a cardiac transplant recipient despite adequate sulfonamide serum levels. Subsequent isolates were resistant to sulfonamides, and molecular ribotyping of the primary and subsequent isolates confirmed that these were the same N transvalensis new taxon-2 strain. The taxonomic and diagnostic considerations, as well as the clinical significance of anti-microbial-resistant nocardia, are reviewed and discussed herein.

  View details for DOI 10.1016/S1053-2498(02)00663-0

  View details for Web of Science ID 000182020300017

  View details for PubMedID 12681430

• Accuracy of the TRUGENE HIV-1 genotyping kit JOURNAL OF CLINICAL MICROBIOLOGY Grant, R. M., Kuritzkes, D. R., JOHNSON, V. A., Mellors, J. W., Sullivan, J. L., Swanstrom, R., D'Aquila, R. T., van Gorder, M., Holodniy, M., Lloyd, R. M., Reid, C., Morgan, G. F., Winslow, D. L. 2003; 41 (4): 1586-1593

  Abstract

  Drug resistance and poor virological responses are associated with well-characterized mutations in the viral reading frames that encode the proteins that are targeted by currently available antiretroviral drugs. An integrated system was developed that includes target gene amplification, DNA sequencing chemistry (TRUGENE HIV-1 Genotyping Kit), and hardware and interpretative software (the OpenGene DNA Sequencing System) for detection of mutations in the human immunodeficiency virus type 1 (HIV-1) protease and reverse transcriptase sequences. The integrated system incorporates reverse transcription-PCR from extracted HIV-1 RNA, a coupled amplification and sequencing step (CLIP), polyacrylamide gel electrophoresis, semiautomated analysis of data, and generation of an interpretative report. To assess the accuracy and robustness of the assay system, 270 coded plasma specimens derived from nine patients were sent to six laboratories for blinded analysis. All specimens contained HIV-1 subtype B viruses. Results of 270 independent assays were compared to "gold standard" consensus sequences of the virus populations determined by sequence analysis of 16 to 20 clones of viral DNA amplicons derived from two independent PCRs using primers not used in the kit. The accuracy of the integrated system for nucleotide base identification was 98.7%, and the accuracy for codon identification at 54 sites associated with drug resistance was 97.6%. In a separate analysis of plasma spiked with infectious molecular clones, the assay reproducibly detected all 72 different drug resistance mutations that were evaluated. There were no significant differences in accuracy between laboratories, between technologists, between kit lots, or between days. This integrated assay system for the detection of HIV-1 drug resistance mutations has a high degree of accuracy and reproducibility in several laboratories.

  View details for DOI 10.1128/JCM.41.4.1586-1593.2003

  View details for Web of Science ID 000182179900037

  View details for PubMedID 12682149

  View details for PubMedCentralID PMC153856

• Impact of highly active antiretroviral therapy and immunologic status on hepatitis C virus quasispecies diversity in human immunodeficiency virus/hepatitis C virus-coinfected patients JOURNAL OF VIROLOGY Babik, J. M., Holodniy, M. 2003; 77 (3): 1940-1950

  Abstract

  This study analyzes the effect of highly active antiretroviral therapy (HAART), and thus immunologic status, on hepatitis C virus (HCV) load and quasispecies diversity in patients coinfected with the human immunodeficiency virus (HIV) and HCV. Three cohorts of coinfected patients were analyzed retrospectively over a period of 7 to 10 months: group A was antiretroviral drug naïve at baseline and then on HAART for the remainder of the study, group B did not receive antiretroviral therapy at any point, and group C was on HAART for the entire study. HCV quasispecies diversity was analyzed by sequencing hypervariable region 1. In a longitudinal analysis, there was no significant change from baseline in any immunologic, virologic, or quasispecies parameter in any of the three groups. However, in comparison to groups A and B, group C had significantly higher CD4+- and CD8+-cell counts, a trend toward a higher HCV load, and significantly increased number of HCV clones, entropy, genetic distance, and ratio of nonsynonymous substitutions per nonsynonymous site to synonymous substitutions per synonymous site (Ka/Ks). In addition, CD4+-cell count was positively correlated with HCV load, genetic distance, and Ka. Interestingly, patients infected with HCV genotype 2 or 3 had a significantly higher CD4+-cell count, HCV load, genetic distance, and Ka/Ks than those infected with genotype 1. These results suggest that there is no immediate effect of HAART on HCV but that, with prolonged HAART, immune restoration results in an increase in HCV load and quasispecies diversity.

  View details for DOI 10.1128/JVI.77.3.1940-1950.2003

  View details for Web of Science ID 000180488700030

  View details for PubMedID 12525628

  View details for PubMedCentralID PMC140862

• Role of Deoxyribonucleoside Kinases and Deoxyribonucleotide Pool Alterations in Nucleoside Reverse Transcriptase Inhibitor Induced Mitochondrial Toxicity Curr. Med. Chem. - Anti-Infective Agents Relucio K, Holodniy M 2003; 2: 241-262
• HIV-1 RNA and viral load CLINICS IN LABORATORY MEDICINE Relucio, K., Holodniy, M. 2002; 22 (3): 593-?

  Abstract

  Viral load monitoring has become the standard of care in clinical practice to assess risk for disease progression and to monitor treatment response. Furthermore, viral load monitoring has contributed greatly to the understanding of HIV disease pathogenesis and response to various antiretroviral regimens, and has broadened its applications to include blood bank screening. The assays that are currently available are more sensitive, precise, and robust. There is now a better understanding of their limitations and the clinical scenarios and assay performance issues that result in variations of viral load results.

  View details for Web of Science ID 000178324900003

  View details for PubMedID 12244588

• Modelling the relationship between adherence and accumulation of protease inhibitor drug-resistance mutations based on objectively measured adherence and empirically derived relationships Bangsberg, D. R., Kagay, C. R., Porco, T., Grant, R., Holodniy, M., Charlebois, E. D., Zolopa, A. R., Conroy, K. N., Guzman, D., Moss, A. R. INT MEDICAL PRESS LTD. 2002: S174

  View details for Web of Science ID 000177401300161

• A pilot trial of indinavir, ritonavir, didanosine, and lamivudine in a once-daily four-drug regimen for HIV infection JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Mole, L., Schmidgall, D., Holodniy, Y. 2001; 27 (3): 260-265

  Abstract

  To evaluate the tolerance, pharmacokinetics, and virologic and immunologic outcomes of once-daily indinavir, ritonavir, didanosine, and lamivudine in HIV-seropositive individuals.Open-label 24-week pilot study.Ten HIV-seropositive subjects who were either antiretroviral-naive or minimally experienced with short-term single-or dual-nucleoside therapy provided informed consent and were enrolled. All subjects received didanosine (400 mg) 30 to 60 minutes before a meal followed by indinavir (1200 mg), ritonavir (400 mg), and lamivudine (300 mg) concurrent with the aforementioned meal.Safety laboratory tests, including a complete blood cell count and amylase, lipase, liver transaminase, and nonfasting lipid monitoring as well as plasma HIV viral load and CD4+ lymphocyte count, were carried out at monthly intervals. Genotyping was performed at baseline. Pharmacokinetic studies for indinavir and ritonavir were performed at week 8.Nine of 10 subjects completed 24 weeks of therapy. No subject demonstrated primary protease inhibitor mutations at baseline. Toxicities experienced by subjects were typically mild and consistent with those commonly reported for each of the medications, including two cases of hematuria. By week 24, median nonfasting cholesterol and triglyceride levels increased by 49% and 108%, respectively. Median baseline plasma HIV viral load and CD4+ lymphocyte count were 29,292 (4.47 log10) copies/ml and 224 cells/mm3, respectively. Eight of 10 subjects had a plasma HIV viral load of <50 copies/ml by week 12. The 2 subjects with a detectable HIV viral load reached <50 copies/ml by week 28. Median CD4+ lymphocyte counts increased by 193 cells/mm3 at week 24. Indinavir and ritonavir plasma concentrations remained above respective inhibitory and effective concentrations (IC95 and EC50) (uncorrected for protein binding) throughout the 24-hour dosing interval for 6 of 10 and 8 of 10 subjects, respectively.Our pilot study demonstrates excellent virologic suppression despite low minimum protease inhibitor concentrations during a dosing interval in some patients and is supportive of further study.

  View details for Web of Science ID 000169840800007

  View details for PubMedID 11464145

• Multinodular polymyositis in a patient with human immunodeficiency and hepatitis C virus coinfection MUSCLE & NERVE Richardson, S. J., LOPEZ, F., Rojas, S., Cho, S. H., Holodniy, M., Herndier, B., Katz, J. 2001; 24 (3): 433-437

  Abstract

  We report a patient who developed multiple inflammatory muscle masses and generalized polymyositis in the setting of combined human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection. Magnetic resonance imaging (MRI) of muscles showed patchy edema which was particularly intense within the nodular masses. Polymerase chain reaction (PCR) showed no evidence of either virus within muscle. This report reviews earlier literature on muscle nodules associated with myositis and discusses the differential diagnosis of muscle masses in HIV infection.

  View details for Web of Science ID 000167117100020

  View details for PubMedID 11353433

• HIV resistance testing--has it come of age? AIDS reader Holodniy, M. 2000; 10 (8): 474-475

  View details for PubMedID 10967807

• Assessment of developmental toxicity of antiretroviral drugs using a rat whole embryo culture system TERATOLOGY Fujinaga, M., Schulte, M., Holodniy, M. 2000; 62 (2): 108-114

  Abstract

  Previous guidelines for HIV-infected pregnant women have recommended zidovudine (ZDV) monotherapy during the second and third trimesters of pregnancy to prevent fetal HIV infection. New guidelines suggest that women should continue or be offered combination antiretroviral therapy (including protease inhibitors) during pregnancy. Nevertheless, little animal or human toxicity data underlie these recommendations.We used an in vitro rat whole embryo culture system to assess the embryo toxicity of various nucleoside analogues, namely, ZDV, dideoxyinosine (ddI), and 2', 3'-dideoxycytidine (ddC), and the HIV-1 protease inhibitor, indinavir, both alone and in combination.Although human fetal concentrations of these compounds are unknown, no gross abnormalities were detected after incubation with these agents, either alone or in combination at concentrations that would be expected to be achievable in human maternal serum (1-50 microM). ZDV in combination with ddC at >100 microM, resulted in severe growth retardation and morphologic abnormalities not seen with either agent singly.We conclude that the combination of ZDV/ddC results in severe concentration-dependent embryo toxicity. No growth retardation or gross morphologic abnormalities were found for any of the agents, either singly or in combination, at clinically relevant concentrations.

  View details for Web of Science ID 000088528900007

  View details for PubMedID 10931508

• Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population AIDS Bangsberg, D. R., Hecht, F. M., Charlebois, E. D., Zolopa, A. R., Holodniy, M., Sheiner, L., Bamberger, J. D., Chesney, M. A., Moss, A. 2000; 14 (4): 357-366

  Abstract

  To examine the relationship between adherence, viral suppression and antiretroviral resistance in HIV-infected homeless and marginally housed people on protease inhibitor (PI) therapy.A cross-sectional analysis of subjects in an observational prospective cohort systematically sampled from free meal lines, homeless shelters and low-income, single-room occupancy (SRO) hotels.Thirty-four HIV-infected people with a median of 12 months of PI therapy.Adherence measured by periodic unannounced pill counts, electronic medication monitoring, and self-report; HIV RNA viral load; and HIV-1 genotypic changes associated with drug resistance.Median adherence was 89, 73, and 67% by self-report, pill count, and electronic medication monitor, respectively. Thirty-eight per cent of the population had over 90% adherence by pill count. Depending on the measure, adherence explained 36-65% of the variation in concurrent HIV RNA levels. The three adherence measures were closely related. Of 20 genotyped patients who received a new reverse transcriptase inhibitor (RTI) when starting a PI, three had primary protease gene substitutions. Of 12 genotyped patients who received a PI without a new RTI, six had primary protease gene substitutions (P < 0.03).A substantial proportion of homeless and marginally housed individuals had good adherence to PI therapy. A strong relationship was found between independent methods of measuring adherence and concurrent viral suppression. PI resistance was more closely related to the failure to change RTI when starting a PI than to the level of adherence.

  View details for Web of Science ID 000086155800008

  View details for PubMedID 10770537

• Stability of plasma human immunodeficiency virus load in VACUTAINER PPT plasma preparation tubes during overnight shipment JOURNAL OF CLINICAL MICROBIOLOGY Holodniy, M., Rainen, L., Herman, S., Yen-Lieberman, B. 2000; 38 (1): 323-326

  Abstract

  VACUTAINER PPT plasma preparation tubes were evaluated to determine the effects of various handling and shipping conditions on plasma human immunodeficiency virus (HIV) load determinations. Plasmas obtained from PPT tubes stored and shipped under nine different conditions were compared to conventional EDTA tube plasmas stored at -70 degrees C within 2 h after phlebotomy. Compared to viral loads in frozen EDTA plasma, those in PPT tube plasma that was frozen immediately and either separated or shipped in situ were not significantly different. Viral loads in PPT tube plasma after storage for 6 h at either room temperature or 4 degrees C, followed by shipment at ambient temperature or on wet or dry ice, were not significantly different from baseline viral loads in EDTA or PPT plasma. The results of this study indicate that the HIV load in PPT tube plasma is equivalent to that in standard EDTA plasma. Plasma viral load is not affected by storage or shipment temperature when plasma is collected in PPT tubes. Furthermore, plasmas can be shipped in spun PPT tubes, and the tubes provide a safer and more convenient method for sample collection and transport than regular EDTA tubes.

  View details for Web of Science ID 000084689800057

  View details for PubMedID 10618109

  View details for PubMedCentralID PMC88717

• Viral Load Monitoring in HIV Infection. Current infectious disease reports Holodniy, M. 1999; 1 (5): 497-503

  Abstract

  Measurement of HIV-1 viral load is now an accepted part of clinical practice for the determination of clinical prognosis and antiretroviral effectiveness in HIV infection. Consensus guidelines have been published on the appropriate use of this testing. Furthermore, recent advances in molecular technology have improved the sensitivity and reproducibility of viral load assays, and these improved assays have provided new insight into the pathogenesis of HIV disease. This article reviews new issues affecting viral load quantification, including viral subtypes, sex, compartmental differences, and other covariables.

  View details for PubMedID 11095829

• A double blind, randomized, placebo-controlled phase II study to assess the safety and efficacy of orally administered SP-303 for the symptomatic treatment of diarrhea in patients with AIDS AMERICAN JOURNAL OF GASTROENTEROLOGY Holodniy, M., KOCH, J., Mistal, M., Schmidt, J. M., Khandwala, A., Pennington, J. E., Porter, S. B. 1999; 94 (11): 3267-3273

  Abstract

  The aim of this study was to investigate the safety and effectiveness of orally administered SP-303 in patients with AIDS and diarrhea.This is a multicenter, phase II, randomized, double blind, placebo-controlled study. HIV-positive subjects with a history of a CD4 count <200 or an AIDS-defining illness were admitted to an inpatient study unit and screened for diarrhea defined as at least three abnormal (i.e., soft or watery) stools and >200 g of abnormal stool weight over a 24-h period. Subjects discontinued all antidiarrheal agents >24 h before enrollment. Stool samples were studied for routine pathogens. Subjects received 500 mg p.o. of SP-303 or placebo every 6 h for 96 h (4 days). Stool frequency and weights were recorded. Subjects were monitored for symptoms and side effects and were seen 1 wk later in follow-up.A total of 26 subjects received SP-303, and 25 received placebo. There were no significant demographic differences between treatment arms. A total of 41 subjects (80%) were receiving antiretroviral therapy and 39 subjects (77%) were receiving at least one protease inhibitor. Stool studies revealed no pathogens in 48 of 51 patients (94%). There were no serious adverse events or laboratory abnormalities. The SP-303 treatment group demonstrated a mean reduction from baseline stool weight of 451 g/24 h versus 150 g/24 h with placebo on day 4 of treatment (p = 0.14), and a mean reduction in abnormal stool frequency of three abnormal stools in 24 h versus two in 24 h in the placebo group (p = 0.30). Daily measures analysis over 4 days of treatment demonstrated that SP-303 subjects had a significant reduction in stool weight (p = 0.008) and abnormal stool frequency (p = 0.04) when compared to placebo-treated subjects.SP-303 is safe and well tolerated. These results suggest that SP-303 may be effective in reducing stool weight and frequency in patients with AIDS and diarrhea.

  View details for Web of Science ID 000083596500033

  View details for PubMedID 10566728

• Decreased medical expenditures for care of HIV-seropositive patients - The impact of highly active antiretroviral therapy at a US Veterans Affairs Medical Center PHARMACOECONOMICS Mole, L., Ockrim, K., Holodniy, M. 1999; 16 (3): 307-315

  Abstract

  To identify any changes in expenditures and in morbidity and mortality with the progression of treatment of the HIV-seropositive population from monotherapy with a nucleoside reverse transcriptase inhibitor (NRTI) [1993] through dual NRTI therapy (1995) to highly active antiretroviral therapy (HAART) [1997].This study retrospectively compared 3 separate years of the total expenditures encountered in the management of HIV-seropositive individuals seen at a US Veterans Affairs Medical Center.Utilising a computerised hospital database, we identified those patients with HIV-related International Classification of Diseases, version 9 (ICD-9) codes and collected all healthcare-related expenditure data. The 3 eras selected for comparison were controlled for similar utilisation of prophylaxis against opportunistic infections, access to investigational antivirals, consistency between primary care providers and distribution of new anti-HIV therapies relative to that era. Cost data for inpatient and outpatient activities (visits and admissions) were derived from actual expenditures. Major categories were then compared, including total inpatient/outpatient expenditures and utilisation, laboratory and prescription costs, and morbidity and mortality rates.The 3 periods had similar patient populations, with 86, 86 and 82% of patients in 1993, 1995 and 1997, respectively, having some degree of immunosuppression (defined as CD4+ lymphocyte counts < 500 cells/mm3). Morbidity and mortality were not changed by the addition of dual NRTI therapy. HAART therapy produced 60 and 70% declines in relative mortality when compared with the single and dual NRTI eras. Dual NRTI or HAART therapy decreased overall expenditures as compared with NRTI monotherapy. HIV-related outpatient resource utilisation other than pharmacy and laboratory costs fell by 25 and 59% in 1997 as compared with 1993 and 1995, respectively. The greatest fall in resource utilisation was for inpatient bed-days of care, where the average cost per patient fell by $US2782 between 1993 and 1997. Pharmacy and laboratory expenditures increased by $US1825 and $US231 per patient from 1993 to 1997, respectively. Overall, the impact of HAART was a decrease of $US1193 in the average total cost per patient from 1993 to 1997.The introduction of HAART provided a positive outcome on patient morbidity and mortality and on medical centre expenditures. The end result was a cost shift of expenditures from inpatient utilisation to outpatient pharmacy and laboratory costs. This information is important for patients and providers, who need to make clinical decisions on lifelong therapies, and for healthcare financial planners, who need to predict inpatient and outpatient healthcare utilisation during an era of limited healthcare dollars.

  View details for Web of Science ID 000082728900007

  View details for PubMedID 10558042

• Editorial response: What is antiretroviral failure? CLINICAL INFECTIOUS DISEASES Holodniy, N. 1999; 29 (1): 82-84

  View details for Web of Science ID 000081685300014

• Effects of collection, processing, and storage on RNA detection and quantification. Methods in molecular medicine Holodniy, M. 1999; 26: 43-59

  Abstract

  Historically, clinicians and researchers have relied upon the development of clinical endpoints or the use of surrogate markers in the evaluation of disease pathogenesis and in response to various therapeutic agents. In addition, microbiologic methods of detecting various pathogens have usually required the culture of an agent. The majority of bacterial pathogen culture methods have been standardized and identification has become relatively straightforward. Nonetheless, a wide variety of unculturable pathogens have been identified. Recent advances in molecular diagnostics have provided clinicians with the ability to measure directly infectious agents. Certain viral pathogens such as human immunodeficiency virus (HIV) are detectable by standard culture techniques whereas others such as hepatitis C virus (HCV) are not.

  View details for DOI 10.1385/0-89603-518-2:43

  View details for PubMedID 21340869

• Reduced nucleoside analogue susceptibility patterns and correlation with proportion of mutant virus detected by differential hybridization in patients receiving AZT and ddI. Skowron, G., Petropoulos, C., Holodniy, M., Wesley, M., Ferrigno, L., Frost, K., Amer Fdn AIDS Res Community Based Clin Trials N LIPPINCOTT WILLIAMS & WILKINS. 1998: S19

  View details for Web of Science ID 000077311300070

• Nucleoside analogue associated mutations correlate with viral load response to lamivudine (3TC) in 150 nucleoside analogue-experienced individuals. Skowron, G., Holodniy, M., Wesley, M., Ferrigno, L., Frost, K., Amer Fdn AIDS Res Community Based Clin Trials N LIPPINCOTT WILLIAMS & WILKINS. 1998: S18

  View details for Web of Science ID 000077311300068

• Controversies in AIDS treatment. Proceedings from CME conference sponsored by Cornell University Medical College and the American Foundation for AIDS Research (AmFAR). November 8, 1997. Faculty roundtable discussion. AIDS patient care and STDs Frost, K. R., Bellman, P., Cohen, C. J., Currier, J., Dobkin, J., El-Sadr, W., Holodniy, M., Leonard, A., Merrick, S., Pinsky, L., Rubin, D. S., Saag, M., Vaughn, A. 1998; 12 (7): 543-555

  View details for PubMedID 15462006

• Controversies in AIDS treatment. Proceedings from CME conference sponsored by Cornell University Medical College and the American Foundation for AIDS Research (AmFAR). November 8, 1997. Question and answer session. AIDS patient care and STDs Frost, K. R., Bellman, P., Cohen, C. J., Currier, J., Dobkin, J., El-Sadr, W., Holodniy, M., Leonard, A., Merrick, S., Pinsky, L., Rubin, D., Vaughn, A., Saag, M. 1998; 12 (7): 557-566

  View details for PubMedID 15462007

• Phenotypic and genotypic testing in clinical practice AIDS PATIENT CARE AND STDS Holodniy, M. 1998; 12 (7): 527-531

  View details for Web of Science ID 000075346700004

  View details for PubMedID 15462003

• Zidovudine treatment in patients with primary (Acute) human immunodeficiency virus type 1 infection: A randomized, double-blind, placebo-controlled trial XIth International Conference on AIDS Niu, M. T., Bethel, J., Holodniy, M., Standiford, H. C., Schnittman, S. M. OXFORD UNIV PRESS INC. 1998: 80–91

  Abstract

  A multicenter, double-blind, placebo-controlled trial randomized 28 patients with primary (acute) human immunodeficiency virus (HIV)-1 infection (PHI) to receive zidovudine, 1000 mg daily, or placebo for 24 weeks. At week 48, compared with placebo patients, zidovudine-treated patients had significantly higher CD4 cell counts (zidovudine, 666 cells/mm3; placebo, 362; P = .004) and lower peripheral blood mononuclear cell (PBMC) culture titers (zidovudine, 0.58 log infectious units per million cells; placebo, 1.68; P = .02) but no difference in plasma RNA (zidovudine, 3.93 log copies/mL; placebo, 4.00; P = .83). Serious adverse events and minor clinical events were infrequent and comparable in both arms. There were two deaths: 1 patient died of sepsis and renal disease (zidovudine arm), and 1 patient died of sepsis and tension pneumothorax (placebo arm). Six months of high-dose zidovudine initiated during PHI results in higher CD4 cell counts and lower PBMC culture titers but no difference in plasma HIV-1 RNA. Further studies with more potent antiretroviral combination therapies are warranted.

  View details for Web of Science ID 000074357900011

  View details for PubMedID 9652426

• HIV quantitation in spiked vaginocervical secretions: lack of non-specific inhibitory factors JOURNAL OF VIROLOGICAL METHODS Holodniy, M., Anderson, D., Wright, D., Sharma, O., Cohn, J., Alexander, N., Stratton, P., Reichelderferd, P. 1998; 72 (2): 185-195

  Abstract

  The objective of this study was to assess the effect of menstrual phase on the ability to quantitate HIV-1 in vaginocervical secretions (VCS) through reconstruction experiments with HIV seronegative VCS collected throughout the menstrual cycle. Measurement of HIV-1 inoculated into both fresh and frozen VCS was undertaken by quantitative micro co-culture, p24 antigen assay and polymerase chain reaction (PCR) for both HIV-1 RNA and pro-viral DNA. Two laboratories carried out these assays over a range of viral concentrations. The study involved a randomized factorial design and the factors were: (1) diluents (phases of the menstrual cycle and controls); (2) laboratories; (3) stock concentrations; and (4) frozen versus fresh VCS samples. Each assay was assessed independently using a random effects analysis of variance (ANOVA) model. No statistical differences due to menstrual cycle were seen in the assay results of p24 antigen (P = 0.08), PBMC culture (P = 0.74), plasma culture (P = 0.13), cell-free RNA (P = 0.44), cell-associated RNA (P = 0.58) and cell-associated DNA (P = 0.43). Inter-laboratory differences were statistically significant for cell-free RNA (P < 0.001), cell-associated DNA (P < 0.001) and p24 (P < 0.001). It is concluded that VCS obtained throughout the menstrual cycle from HIV-uninfected women lacks intrinsic inhibitory factors which could limit detection and quantification by antigen, culture or nucleic acid-based technologies for HIV-1 in VCS throughout the menstrual cycle. Using a standardized collection procedure, we suggest that variation in HIV quantity over time, when reported in VCS of infected women, should be attributed to HIV-associated biologic factors, rather than non-specific or other technical factors.

  View details for Web of Science ID 000074790000007

  View details for PubMedID 9694326

• Simultaneous genotyping and species identification using hybridization pattern recognition analysis of generic Mycobacterium DNA arrays GENOME RESEARCH Gingeras, T. R., Ghandour, G., Wang, E. G., Berno, A., Small, P. M., Drobniewski, F., Alland, D., Desmond, E., Holodniy, M., Drenkow, J. 1998; 8 (5): 435-448

  Abstract

  High-density oligonucleotide arrays can be used to rapidly examine large amounts of DNA sequence in a high throughput manner. An array designed to determine the specific nucleotide sequence of 705 bp of the rpoB gene of Mycobacterium tuberculosis accurately detected rifampin resistance associated with mutations of 44 clinical isolates of M. tuberculosis. The nucleotide sequence diversity in 121 Mycobacterial isolates (comprised of 10 species) was examined by both conventional dideoxynucleotide sequencing of the rpoB and 16S genes and by analysis of the rpoB oligonucleotide array hybridization patterns. Species identification for each of the isolates was similar irrespective of whether 16S sequence, rpoB sequence, or the pattern of rpoB hybridization was used. However, for several species, the number of alleles in the 16S and rpoB gene sequences provided discordant estimates of the genetic diversity within a species. In addition to confirming the array's intended utility for sequencing the region of M. tuberculosis that confers rifampin resistance, this work demonstrates that this array can identify the species of nontuberculous Mycobacteria. This demonstrates the general point that DNA microarrays that sequence important genomic regions (such as drug resistance or pathogenicity islands) can simultaneously identify species and provide some insight into the organism's population structure.

  View details for Web of Science ID 000073748300007

  View details for PubMedID 9582189

• Human immunodeficiency virus type 1 populations in blood and semen JOURNAL OF VIROLOGY Delwart, E. L., Mullins, J. I., Gupta, P., Learn, G. H., Holodniy, M., KATZENSTEIN, D., Walker, B. D., Singh, M. K. 1998; 72 (1): 617-623

  Abstract

  Transmission of human immunodeficiency virus type 1 (HIV-1) usually results in outgrowth of viruses with macrophage-tropic phenotype and consensus non-syncytium-inducing (NSI) V3 loop sequences, despite the presence of virus with broader host range and the syncytium-inducing (SI) phenotype in the blood of many donors. We examined proviruses in contemporaneous peripheral blood mononuclear cells (PBMC) and non-spermatozoal semen mononuclear cells (NSMC) of five HIV-1-infected individuals to determine if this preferential outgrowth could be due to compartmentalization and thus preferential transmission of viruses of the NSI phenotype from the male genital tract. Phylogenetic reconstructions of approximately 700-bp sequences covering the second constant region through the fifth variable region (C2 to V5) of the viral envelope gene revealed distinct variant populations in the blood versus the semen in two patients with AIDS and in one asymptomatic individual (patient 613), whereas similar variant populations were found in both compartments in two other asymptomatic individuals. Variants with amino acids in the V3 loop that predict the SI phenotype were found in both AIDS patients and in patient 613; however, the distribution of these variants between the two compartments was not consistent. SI variants were found only in the PBMC of one AIDS patient but only in the NSMC of the other, while they were found in both compartments in patient 613. It is therefore unlikely that restriction of SI variants from the male genital tract accounts for the observed NSI transmission bias. Furthermore, no evidence for a semen-specific signature amino acid sequence was detected.

  View details for Web of Science ID A1998YL01000073

  View details for PubMedID 9420266

  View details for PubMedCentralID PMC109415

• The impact of active herpes simplex virus infection on human immunodeficiency virus load Antibody Workshop - The Role of Humoral Immunity in the Treatment and Prevention of Emerging and Extant Infectious Diseases Mole, L., RIPICH, S., Margolis, D., Holodniy, M. OXFORD UNIV PRESS INC. 1997: 766–70

  Abstract

  The effect of a concurrent herpes simplex virus (HSV) infection on human immunodeficiency virus type 1 (HIV-1) load was evaluated. Sixteen subjects were identified with an active HSV infection and had pre-outbreak, acute-phase, and post-outbreak plasma (n = 16) and peripheral blood mononuclear cell (PBMC) (n = 8) samples for evaluation. All subjects were treated for an acute HSV outbreak with acyclovir for 10 days, followed by chronic prophylaxis. HIV-1 plasma RNA levels were determined by branched DNA, and intracellular HIV gag mRNA copy numbers were determined by quantitative reverse transcriptase-polymerase chain reaction ELISA. Plasma virus load increased a median of 3.4-fold during the acute outbreak (range, 0- to 10-fold; P = .002), while post-outbreak levels (30-45 days after the appearance of lesions) remained above pre-outbreak, baseline levels in some subjects. Intracellular HIV gag mRNA increased during the outbreak as well. Thus, an acute HSV episode can result in increased HIV transcription and plasma virus load.

  View details for Web of Science ID A1997XT81900032

  View details for PubMedID 9291329

• Polymerase chain reaction for diagnosis of HIV infection - Response ANNALS OF INTERNAL MEDICINE Owens, D. K., Holodniy, M., Garber, A. M. 1997; 126 (9): 740-740

  View details for Web of Science ID A1997WW14700016

• HIV-1 protease inhibitors - A review for clinicians JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Deeks, S. G., Smith, M., Holodniy, M., Kahn, J. O. 1997; 277 (2): 145-153

  Abstract

  The clinical care of people infected with human immunodeficiency virus (HIV) has been substantially affected by the introduction of HIV-specific protease inhibitors (PIs). The 4 PIs available are saquinavir mesylate, ritonavir, indinavir sulfate, and nelfinavir mesylate. Comparison studies have not been reported; therefore, an assessment of the available data to aid clinicians and patients in choosing appropriate treatment will be presented.A systematic review of peer-reviewed publications, abstracts from national and international conferences, and product registration information through September 1996.Criteria used to select studies include their relevance to PIs, having been published in the English language, and pertinence for clinicians. Data quality and validity included the venue of the publication and relevance to clinical care.Oral adminstration of ritonavir, indinavir, or nelfinavir generates sustainable drug serum levels to effectively inhibit the protease enzyme; however, saquinavir may not generate sustained levels necessary to inhibit the protease enzyme. Patients treated with ritonavir, indinavir, or nelfinavir experience similar reductions in viral load and increases in CD4+ lymphocytes; smaller effects occur among those treated with saquinavir. Two randomized placebo-controlled studies conducted among patients with severe immune system suppression and substantial zidovudine treatment experience demonstrated reduced HIV disease progression and reduced mortality with PI treatment. Genotypic resistance to PIs occurs; the clinical relevance of resistance is unclear. The costs of these agents including required monitoring impose new and substantial costs.The PIs have emerged as critical drugs for people with HIV infection. Optimal use involves combination with reverse transcriptase inhibitors. Resistance develops to each agent, and cross-resistance is likely. These agents must be used at full doses with attention to ensuring patient compliance. The expense of these agents may be offset by forestalling disease progression and death and returning people to productive life. Selecting the initial PI must be individualized, and factors to consider include proven activity, possible toxicities, dosing regimens, drug interactions, and costs.

  View details for Web of Science ID A1997WA65000036

  View details for PubMedID 8990341

• Prescribing practice and cost of antibacterial prophylaxis for surgery at a US Veterans Affairs Hospital PHARMACOECONOMICS Ryono, R. A., Jones, K. S., Coleman, R. W., Holodniy, M. 1996; 10 (6): 630-643

  Abstract

  This study retrospectively compared the actual drug-related cost of antibacterial prophylaxis for specific operative procedures with the theoretical costs based on recommendations published in Medical Letter on Drugs and Therapeutics, the Surgical Infection Society, and those of the chiefs of each surgical subspecialty at our institution. We identified all patients who received in intravenous bacterial for prophylaxis before a clean or clean-contaminated operation between 1st January and 30th September 1993, using the medical centre's computerised information system. The information included comprehensive surgical case histories, and pharmacy and microbiology records. Only those operations in which recommendations for surgical prophylaxis were present in all 3 guidelines were included. The outcome measures were antibacterial-related costs (drug acquisition and administration costs), the number of antibacterial doses dispensed, and choice of antibacterial agents. During the study period, 3,322 operations were performed, 2,993 of which were excluded. Thus, 329 patients undergoing operations in 6 subspecialties were included in the analysis. The actual mean cost per patient significantly exceeded the projected costs using Medical Letter Consultants' and Surgical Infection Society guidelines for all 6 subspecialties [mean excess cost per patient: $US49.04 and $US34.95, respectively (1994 values)] and institutional guidelines for 4 of the 6 subspecialties (mean excess cost per patient: $US24.36). The actual mean number of doses per patient significantly exceeded those projected using Medical Letter Consultants' and Surgical Infection Society guidelines for all 6 subspecialties (mean excess number of doses per patient: 6.0 and 4.0, respectively) and institutional guidelines for 4 of the 6 subspecialties (mean excess number of doses per patient: 2.9). The choice of antibacterial was appropriate in approximately 90% of cases. We conclude that the practice of antibacterial prophylaxis for specific operative procedures performed by 6 subspecialties is not in accordance with institutional or published guidelines, and the excess cost is primarily a result of prolonged duration of antibacterial prophylaxis.

  View details for Web of Science ID A1996VX12000009

  View details for PubMedID 10164063

• Evaluation of Chiron HIV-1/HIV-2 recombinant immunoblot assay JOURNAL OF CLINICAL MICROBIOLOGY Kline, R. L., McNairn, D., Holodniy, M., Mole, L., Margolis, D., Blattner, W., Quinn, T. C. 1996; 34 (11): 2650-2653

  Abstract

  In a study to determine the reliability, sensitivity, and specificity of the Chiron RIBA HIV-1/HIV-2 Strip Immunoblot Assay (RIBA HIV-1/2 SIA) for confirmation of human immunodeficiency virus type 1 (HIV-1) and HIV-2 antibodies, 1,263 serum samples from various populations in the United States, Caribbean, Africa, India, and Thailand were evaluated by RIBA HIV-1/2 SIA, and the results were compared with those obtained by an HIV-1 Western blot (immunoblot) assay. All sera were tested by HIV enzyme immunoassay, RIBA HIV-1/2 SIA, and Western blotting. Samples with discrepant results were further tested by an HIV-1 and/or HIV-2 immunofluorescent-antibody assay and HIV-1 p24 antigen assay. The RIBA HIV-1/2 SIA detected all 17 HIV-1 and HIV-2 dually reactive serum samples, all 215 HIV-2-positive serum samples, and 480 of 481 HIV-1-positive serum samples for a sensitivity of 99.8%. Of 548 negative samples, 523 were RIBA HIV-1/2 SIA negative, for a specificity of 95.4%, with 22 (4%) samples interpreted as indeterminate and 3 (0.6%) interpreted as falsely positive. Western blotting detected 391 of 548 negative samples (specificity, 71.4%), with 152 (27.7%) samples interpreted as indeterminate and 5 (0.9%) interpreted as falsely positive. In conclusion, the RIBA HIV-1/2 SIA had a sensitivity comparable to that of Western blotting and could discriminate HIV-1 from HIV-2 in one blot, providing a cost advantage. Because of its high degree of specificity, the RIBA HIV-1/2 SIA further reduced the number of indeterminate results found by Western blotting, providing a more accurate means of assessing seronegative individuals.

  View details for Web of Science ID A1996VM55600003

  View details for PubMedID 8897158

  View details for PubMedCentralID PMC229379

• Human immunodeficiency virus reverse transcriptase codon 215 mutations diminish virologic response to didanosine-zidovudine therapy in subjects with non-syncytium-inducing phenotype JOURNAL OF INFECTIOUS DISEASES Holodniy, M., KATZENSTEIN, D., Mole, L., Winters, M., Merigan, T. 1996; 174 (4): 854-857

  Abstract

  Eight zidovudine-experienced subjects received zidovudine and didanosine for 30 weeks followed by 30 weeks of didanosine monotherapy. At study entry, plasma from 4 subjects had human immunodeficiency virus RNA pol T215Y/F mutant and 4 had codon 215 wild type. All 8 subjects had non-syncytium-inducing virus phenotype. Sustained 10-fold decreases in plasma RNA levels were seen only in subjects who initially had 215 wild type RNA, despite the development of a T215Y/F mutation during combination therapy. Virologic and immunologic benefits were maintained in this group with didanosine monotherapy. No subject developed a pol L74V codon mutation. Significant differences in plasma virus load and CD4 cell responses were seen in this zidovudine-didanosine combination pilot study relative to codon 215 genotype.

  View details for Web of Science ID A1996VK04500027

  View details for PubMedID 8843229

• HIV viral load markers in clinical practice NATURE MEDICINE Saag, M. S., Holodniy, M., Kuritzkes, D. R., OBRIEN, W. A., COOMBS, R., POSCHER, M. E., Jacobsen, D. M., Shaw, G. M., Richman, D. D., Volberding, P. A. 1996; 2 (6): 625-629

  Abstract

  Plasma HIV RNA determinations are an important prognostic marker of disease progression and, when used appropriately, provide a valuable tool for the management of individual patients. But what constitutes appropriate use?

  View details for Web of Science ID A1996UN69100022

  View details for PubMedID 8640545

• A meta-analytic evaluation of the polymerase chain reaction for the diagnosis of HIV infection in infants JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Owens, D. K., Holodniy, M., McDonald, T. W., Scott, J., Sonnad, S. 1996; 275 (17): 1342-1348

  Abstract

  To evaluate the sensitivity and specificity of the polymerase chain reaction (PCR) for the diagnosis of infection with human immunodeficiency virus (HIV) in infants.We used studies published between 1988 and 1994 identified in a literature search of 17 databases, including MEDLINE.Studies were included if DNA amplification by PCR was performed on peripheral blood mononuclear cells from infants or children.Two investigators independently extracted data. The study design was assessed independently by 2 investigators who were blinded to study results.Thirty-two studies met the inclusion criteria and were analyzed. The median reported sensitivity was 91.6% (range, 31%-100%), and the median specificity was 100% (range, 50%-100%). A summary receiver operating characteristic curve based on all 32 studies indicated that PCR has a maximum joint sensitivity and specificity between 93.2% and 94.9%. Subgroup analysis indicated that the joint sensitivity and specificity was significantly (P = .04) higher in older infants (98.2%) than in neonates (aged < or = 30 days; 93.3%). For infants at low risk of perinatal transmission (probability of transmission, 8.3%), the positive predictive value for PCR is 55.8% in neonates and 83.2% in older infants. A negative PCR result reduces the probability of HIV infection to less than 3%. No studies met all criteria for study design.Although PCR is one of the best available tests for diagnosis of HIV infection in neonates and infants, it is not definitive. Therefore, PCR should be interpreted with the aid of careful clinical follow-up examinations. The sensitivity and specificity of PCR in neonates is lower than in older infants, which results in a low positive predictive value; however, negative tests are informative. Delaying the use of PCR until after the neonatal period or repeating PCR on independent samples obtained 30 to 60 days later will reduce test errors.

  View details for PubMedID 8614121

• Polymerase chain reaction for the diagnosis of HIV infection in adults - A meta-analysis with recommendations for clinical practice and study design ANNALS OF INTERNAL MEDICINE Owens, D. K., Holodniy, M., Garber, A. M., Scott, J., Sonnad, S., Moses, L., Kinosian, B., Schwartz, J. S. 1996; 124 (9): 803-?

  Abstract

  To do a meta-analysis of studies that have evaluated the sensitivity and specificity of polymerase chain reaction (PCR) assay for the diagnosis of human immunodeficiency virus (HIV) infection in adults. Evaluating the performance of PCR is difficult because in certain clinical situations, the sensitivity or specificity of PCR may exceed those of the current reference standard tests (enzyme immunoassay followed by confirmatory Western blot analysis). Therefore, an additional goal was to develop recommendations for 1) the design of future evaluative studies of PCR and 2) the use of PCR in persons with suspected HIV infection.Studies published between 1988 and 1994 that were identified in a search of 17 computer databases, including MEDLINE, and abstracts identified from conference proceedings.Studies were included if DNA amplification by PCR was done on peripheral blood mononuclear cells from adults. Ninety-six studies met the inclusion criteria.Data were extracted independently by two reviewers. Study design was assessed independently by two investigators blinded to study results.Reported sensitivities for PCR range from 10% to 100%, and specificities range from 40% to 100%. A summary receiver-operating characteristic curve based on all 96 studies has a maximum joint sensitivity and specificity (upper left point on the curve, where sensitivity equals specificity) of 97.0% to 98.1%. If the threshold value that defines a positive PCR result is chosen so that sensitivity is higher than 98.1%, specificity will decrease to less than 98.1%. Conversely, if the threshold value that defines a positive PCR result is chosen so that specificity is greater than 98.1%, sensitivity will decrease to less than 98.1%. If sensitivity and specificity are chosen to be equal, the corresponding false-positive rate is 1.9% to 3.0%. At the maximum joint sensitivity and specificity, the positive predictive value of PCR ranges from 34% to 85% as the prevalence of HIV increases from 1.0% to 10%. We identified seven areas in which study design could be modified to 1) reduce susceptibility to bias in estimates of the sensitivity and specificity of PCR and 2) to increase the generalizability of the study results. These modifications will also help to overcome methodologic problems created by the lack of a reference standard test.The PCR assay is not sufficiently accurate to be used for the diagnosis of HIV infection without confirmation. Use of PCR for the diagnosis of HIV in adults should be limited to situations in which antibody tests are known to be insufficient. Future studies of PCR performance should be sufficiently large and should use adequate reference standard tests and standardized methods for the performance of PCR. Specimens should be evaluated by persons blinded to clinical status and to the results of other diagnostic tests for HIV infection.

  View details for Web of Science ID A1996UG25400004

  View details for PubMedID 8610949

• Antiretroviral monotherapy in early stage human immunodeficiency virus disease has no detectable effect on virus load in peripheral blood and lymph nodes JOURNAL OF INFECTIOUS DISEASES Cohen, O. J., Pantaleo, G., Holodniy, M., Fox, C. H., Orenstein, J. M., Schnittman, S., Niu, M., Graziosi, C., Pavlakis, G. N., Lalezari, J., Bartlett, J. A., Steigbigel, R. T., Cohn, J., Novak, R., McMahon, D., Bilello, J., Fauci, A. S. 1996; 173 (4): 849-856

  Abstract

  Initiation of antiretroviral monotherapy early in the course of infection with human immunodeficiency virus may result in a temporary slowing in the rate of disease progression; however, little is known about the virologic effects of early therapy. Virus load was measured in peripheral blood and lymph nodes from 16 antiretroviral-naive patients with a mean CD4 T lymphocyte count of 659 cells/microliter at baseline and after 8 weeks of either no treatment or zidovudine therapy. CD4 T lymphocyte counts and all virologic parameters examined remained unchanged regardless of zidovudine treatment status. Histopathology and virus distribution within lymph nodes remained constant between baseline and week 8 in each patient, indicating that the virologic and histologic parameters examined in a single lymph node are representative of a systemic process. Early antiretroviral monotherapy with zidovudine had no effect on virologic parameters in this group of patients with relatively high CD4 T lymphocyte counts and low measures of virus load at baseline.

  View details for Web of Science ID A1996UB27400009

  View details for PubMedID 8603962

• Quantitative relationship between platelet count and plasma virion HIV RNA AIDS Holodniy, M., Margolis, D., Carroll, R., Todd, J., Mole, L. 1996; 10 (2): 232-233

  View details for Web of Science ID A1996TW20500018

  View details for PubMedID 8838716

• SAFETY, PHARMACOKINETICS, AND ANTIVIRAL RESPONSE OF CD4-IMMUNOGLOBULIN-G BY INTRAVENOUS BOLUS IN AIDS AND AIDS-RELATED COMPLEX JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Collier, A. C., COOMBS, R. W., KATZENSTEIN, D., Holodniy, M., Gibson, J., Mordenti, J., Izu, A. E., Duliege, A. M., Ammann, A. J., Merigan, T., Corey, L. 1995; 10 (2): 150-156

  Abstract

  To assess the safety, pharmacokinetics, and antiviral effects of intravenous recombinant CD4 immunoglobulin G (CD4-IgG), a 12-week Phase One study with an optional maintenance phase was performed. Twenty-two subjects with advanced human immunodeficiency virus (HIV) infection were enrolled; 15 subjects completed the initial 12 weeks. CD4-IgG doses were 30, 100, or 300 micrograms/kg weekly; 1,000 micrograms/kg once, twice, or three times per week; or 3,000 micrograms/kg twice weekly. Serum concentrations of CD4-IgG increased linearly with dose, with average peak serum concentrations of 22 micrograms/ml with 1,000 micrograms/kg. CD4-IgG was well tolerated; one patient had self-limited tachycardia and flushing associated with CD4-IgG therapy. No changes were seen in CD4 cell counts, hematologic or coagulation studies, serum chemistries, HIV p24 antigen titers, or plasma HIV titers. No subject developed anti-CD4 antibodies. HIV isolates from five patients had IC90 values that were higher than the peak concentrations of CD4-IgG achieved in those patients. Additional studies that achieve higher CD4-IgG concentrations are necessary to evaluate the antiviral activity of this compound.

  View details for Web of Science ID A1995RW33000006

  View details for PubMedID 7552478

• NONISOTOPIC HYBRIDIZATION ASSAY FOR DETERMINATION OF RELATIVE AMOUNTS OF GENOTYPIC HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ZIDOVUDINE RESISTANCE JOURNAL OF CLINICAL MICROBIOLOGY Eastman, P. S., Boyer, E., Mole, L., Kolberg, J., Urdea, M., Holodniy, M. 1995; 33 (10): 2777-2780

  Abstract

  A nonisotopic hybridization assay for human immunodeficiency virus genotypic zidovudine resistance determination is described. Biotinylated PCR product was hybridized with enzyme-labeled probes for wild-type or resistant mutant sequences and detected colorimetrically or chemiluminescently in a microplate format. Changes in mutant-to-wild-type ratios allow for the monitoring of longitudinal patient samples.

  View details for Web of Science ID A1995RV56500050

  View details for PubMedID 8567926

  View details for PubMedCentralID PMC228576

• DECREASED HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PLASMA VIREMIA DURING ANTIRETROVIRAL THERAPY REFLECTS DOWN-REGULATION OF VIRAL REPLICATION IN LYMPHOID-TISSUE PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Cohen, O. J., Pantaleo, G., Holodniy, M., SCHNITMAN, S., Niu, M., Graziosi, C., Pavlakis, G. N., Lalezari, J., Bartlett, J. A., Steigbigel, R. T., Cohn, J., Novak, R., McMahon, D., Fauci, A. S. 1995; 92 (13): 6017-6021

  Abstract

  Although several immunologic and virologic markers measured in peripheral blood are useful for predicting accelerated progression of human immunodeficiency virus (HIV) disease, their validity for evaluating the response to antiretroviral therapy and their ability to accurately reflect changes in lymphoid organs remain unclear. In the present study, changes in certain virologic markers have been analyzed in peripheral blood and lymphoid tissue during antiretroviral therapy. Sixteen HIV-infected individuals who were receiving antiretroviral therapy with zidovudine for > or = 6 months were randomly assigned either to continue on zidovudine alone or to add didanosine for 8 weeks. Lymph node biopsies were performed at baseline and after 8 weeks. Viral burden (i.e., HIV DNA copies per 10(6) mononuclear cells) and virus replication in mononuclear cells isolated from peripheral blood and lymph node and plasma viremia were determined by semiquantitative polymerase chain reaction assays. Virologic and immunologic markers remained unchanged in peripheral blood and lymph node of patients who continued on zidovudine alone. In contrast, a decrease in virus replication in lymph nodes was observed in four of six patients who added didanosine to their regimen, and this was associated with a decrease in plasma viremia. These results indicate that decreases in plasma viremia detected during antiretroviral therapy reflect downregulation of virus replication in lymphoid tissue.

  View details for Web of Science ID A1995RF05000054

  View details for PubMedID 7597072

  View details for PubMedCentralID PMC41633

• DETERMINATION OF HUMAN-IMMUNODEFICIENCY-VIRUS RNA IN PLASMA AND CELLULAR VIRAL-DNA GENOTYPIC ZIDOVUDINE RESISTANCE AND VIRAL LOAD DURING ZIDOVUDINE-DIDANOSINE COMBINATION THERAPY JOURNAL OF VIROLOGY Holodniy, M., Mole, L., Margolis, D., Moss, J., Dong, H. L., Boyer, E., Urdea, M., Kolberg, J., Eastman, S. 1995; 69 (6): 3510-3516

  Abstract

  Eleven human immunodeficiency virus (HIV)-infected subjects on long-term zidovudine (ZDV) therapy had didanosine (ddI) added to their antiretroviral regimen. HIV RNA in plasma was quantitated by branched-DNA signal amplification assay. Peripheral blood mononuclear cell (PBMC) HIV viral DNA was quantitated by PCR. The relative amounts of wild-type (WT) sequence, ddI resistance-associated codon changes (reverse transcriptase [RT] gene codon 65 K-->R [RT K65R], RT 174V, RT I135K/T/V, and RT M184I/V), and ZDV resistance-associated codon change (RT T215Y/F) from HIV RNA in plasma and RT T215Y/F from PBMC viral DNA were determined by differential hybridization of PCR products from 10 of 11 subjects. All subjects had evidence of RT T215Y/F mutation in both RNA in plasma and PBMC DNA at baseline. Subjects with a mixture of WT and RT T215Y/F HIV RNA in plasma at baseline demonstrated a decline in RNA levels in plasma after the addition of ddI. However, after 6 months of ZDV-ddI therapy, WT HIV RNA in plasma was undetectable in all subjects who had demonstrated a mixture at baseline. Subjects with only RT T215Y/F RNA present in plasma at baseline remained so and demonstrated no decline in RNA levels in plasma. In all subjects, no significant changes in PBMC DNA viral load and RT T215Y/F or WT levels were seen. HIV RNA in plasma demonstrated a significantly higher RT T215Y/F mutant/WT ratio than that of PBMC viral DNA, both at baseline and after ZDV-ddI combination therapy in all subjects. No subjects developed mutations associated with ddI resistance at codons 65, 74, 135, and 184 during this study. This study suggests that determination of relative amounts of RT T215Y/F and WT species from HIV RNA in plasma at baseline may be predictive of virologic response during ZDV-ddI combination therapy.

  View details for Web of Science ID A1995QX93100030

  View details for PubMedID 7745698

  View details for PubMedCentralID PMC189064

• COMPARATIVE STABILITIES OF QUANTITATIVE HUMAN-IMMUNODEFICIENCY-VIRUS RNA IN PLASMA FROM SAMPLES COLLECTED IN VACUTAINER CPT, VACUTAINER PPT, AND STANDARD VACUTAINER TUBES JOURNAL OF CLINICAL MICROBIOLOGY Holodniy, M., Mole, L., YENLIEBERMAN, B., Margolis, D., Starkey, C., Carroll, R., Spahlinger, T., Todd, J., Jackson, J. B. 1995; 33 (6): 1562-1566

  Abstract

  This study compared the levels of human immunodeficiency virus (HIV) virion RNA in plasma from whole blood collected in VACUTAINER CPT (cell preparation tube), VACUTAINER PPT (plasma preparation tube), VACUTAINER SST (serum separation tube), and standard VACUTAINER tubes with sodium heparin, acid citrate dextrose, sodium citrate, and potassium EDTA used as anticoagulants. Quantitative plasma HIV RNA levels were measured by branched-DNA signal amplification. Blood from all tubes was either processed within 1 to 3 h after collection or stored at room temperature or at 4 degrees C for analysis at 6 to 8 and 30 h postdraw. Immediately separated plasma from sodium citrate CPT tubes held at 4 degrees C maintained better stability of HIV RNA equivalents than whole blood held at room temperature or 4 degrees C. The highest number of HIV RNA equivalents was seen with EDTA VACUTAINER tubes. HIV RNA equivalents in all types of plasma were significantly higher than in SST tubes. Although a decline in HIV RNA equivalents was seen in all collection devices after 30 h, a significantly greater decline in plasma HIV RNA equivalents occurred in acid citrate dextrose VACUTAINER tubes than in citrate CPT, PPT, and standard EDTA VACUTAINER tubes. In order to minimize the variability of quantitative HIV RNA test results, our data suggest that samples collected for a particular assay should be processed at the same time postdraw using a particular tube type throughout a given study.

  View details for Web of Science ID A1995QZ72300026

  View details for PubMedID 7650187

  View details for PubMedCentralID PMC228216

• PERFORMANCE-CHARACTERISTICS FOR THE QUANTITATION OF PLASMA HIV-1 RNA USING BRANCHED DNA SIGNAL AMPLIFICATION TECHNOLOGY 1st Annual Symposium on Surrogate Markers of HIV - Strategies and Issues for Selection and Use Todd, J., PACHL, C., White, R., Yeghiazarian, T., Johnson, P., Taylor, B., Holodniy, M., Kern, D., Hamren, S., Chernoff, D., Urdea, M. LIPPINCOTT WILLIAMS & WILKINS. 1995: S35–S44

  Abstract

  Highly sensitive assays that quantitate human immunodeficiency virus type 1 (HIV-1) RNA may be valuable for clinical research and the treatment of HIV-1-infected patients. In this study we evaluated the reproducibility and accuracy of the first-generation branched DNA (bDNA-1.0) signal amplification assay under conditions that are relevant to routine use in a clinical context. We show that the bDNA-1.0 assay was able to discern two- to three-fold changes in plasma HIV-1 RNA levels as significant. Reverse transcription coupled to polymerase chain reaction (RT-PCR) was less reproducible and required a 3.7- to 5.8-fold change in plasma HIV-1 RNA levels to be statistically significant. The accuracy of the bDNA-1.0 assay in RNA quantitation was not affected by HIV-1 genotypic variation or by the presence of hemoglobin, bilirubin, lipemia, or any of a dozen therapeutic drugs. Using the bDNA-1.0 assay, we show that HIV-1 RNA levels in plasma specimens were stable when stored at -80 degrees C and were able to withstand at least three freeze-thaw cycles without significant loss. We also examined the performance of an ultrasensitive bDNA assay with improvements to the signal amplification technology. The ultrasensitive bDNA assay displayed a quantitation limit of approximately 500 RNA Eq/ml, yet maintained a dynamic quantitation range up to 1.6 x 10(6) RNA Eq/ml. Like the bDNA-1.0 assay, the ultrasensitive bDNA assay was not affected by HIV-1 genotype variability.

  View details for Web of Science ID A1995TD18600006

  View details for PubMedID 7552511

• HIV viral load quantification, HIV resistance, and antiretroviral therapy. AIDS clinical review Katzenstein, D. A., Holodniy, M. 1995: 277-303

  Abstract

  We are moving rapidly beyond a "black box" understanding of the pathogenesis of HIV. The sites of virus replication, the molecular regulation of virus production in the host, and the dynamics between productive virus infection and immunological and clinical events are areas of intense study using powerful new tools. The quantitation of virus load and genetic characterization of replicating virus has important implications for the development and evaluation of drugs and treatment strategies for HIV. As new compounds are introduced, their ability to reduce virus load in vivo has become a primary consideration in the decision to initiate large efficacy trials and may soon be used, in combination with other markers, in the licensing of new agents. In parallel, rapid molecular evaluation of virus from patients, targeting those who break through drug-induced suppression, provides an explanation for the failure of drugs to sustain an effect on virus load. This approach has compressed the process of drug evaluation and set the stage for the evaluation of complex combinations and sequences of drugs to maintain suppression of virus and prevent the development of drug resistance. The most controversial question for the next few years is whether the measurement of virus load or detection of drug resistance can be incorporated into the practice of medicine and the management of individual patients. There is evidence that changes in virus load are the most proximate markers of drug response and that detection of resistance mutations can predict clinical and immunological decline. However, the window of time between a change in load or the development of drug resistance and a decline in CD4 cells is relatively short. With dideoxynucleoside therapies, a CD4 cell decline follows a rise in virus load or development of resistance within 3-6 months. In early studies with protease inhibitors and nonnucleoside reverse transcriptase inhibitors, the development of resistance and a return to baseline of virus load may occur within 2-3 months, mirrored by a fall in CD4 cells. The challenge to investigators is how to best use these new tools to determine whether changes or additions in therapy, initiated on the basis of virological measurements, result in more effective management of disease.

  View details for PubMedID 7488557

• DEFICIENCY IN ANTIBODY-RESPONSE TO HUMAN CYTOMEGALOVIRUS GLYCOPROTEIN GH IN HUMAN IMMUNODEFICIENCY VIRUS-TREATED PATIENTS AT RISK FOR CYTOMEGALOVIRUS RETINITIS JOURNAL OF INFECTIOUS DISEASES Rasmussen, L., Morris, S., Wolitz, R., Dowling, A., Fessell, J., Holodniy, M., Merigan, T. C. 1994; 170 (3): 673-677

  Abstract

  Human immunodeficiency virus (HIV)-infected patients at risk for symptomatic human cytomegalovirus (CMV) infection were studied for serum antibody to CMV glycoproteins gH and gB. Antibody titers to gB in HIV-seropositive patients, irrespective of CD4 cell counts or presence of CMV retinitis, were significantly higher than titers in HIV-seronegative, CMV-seropositive patients but were comparable to titers detected in HIV-seronegative patients with CMV mononucleosis. In contrast, antibody to gH was rarely detected in HIV-seropositive patients with CD4 cell counts > 100/mm3 compared with patients with counts > 100/mm3. The inability to detect gH antibody at a time of high risk for symptomatic CMV retinitis suggests that immune intervention with either gH-specific vaccine or passive immunotherapy may benefit HIV-infected persons at risk for symptomatic CMV disease.

  View details for Web of Science ID A1994PE26500026

  View details for PubMedID 7915750

• STABILITIES OF QUANTITATIVE PLASMA CULTURE FOR HUMAN-IMMUNODEFICIENCY-VIRUS, RNA, AND P24 ANTIGEN FROM SAMPLES COLLECTED IN VACUTAINER CPT AND STANDARD VACUTAINER TUBES JOURNAL OF CLINICAL MICROBIOLOGY Mole, L., Margolis, D., Carroll, R., Todd, J., Holodniy, M. 1994; 32 (9): 2212-2215

  Abstract

  We evaluated the stability of human immunodeficiency virus (HIV) load markers from blood samples collected in VACUTAINER CPT or standard VACUTAINER brand tubes using sodium heparin or sodium citrate as anticoagulants. Quantitative plasma culture and p24 antigen concentrations were determined, and HIV RNA levels in plasma were measured by both reverse transcription-PCR-enzyme-linked immunosorbent assay (RT-PCR-ELISA) and branched DNA methods. All tubes were stored at room temperature for analysis at 2, 24, 48, and 72 h after the blood samples were drawn. No difference was seen between tube types with respect to the HIV titer in plasma or the positivity rate for all samples that demonstrated a fall in titer over time. Unbound p24 antigen levels in plasma decreased during the initial 48-h period in both tube types. Immune complex-dissociated p24 antigen levels decreased in CPT tubes but not in standard VACUTAINER tubes. The HIV RNA copy number in plasma measured by RT-PCR-ELISA was stable in most subjects and was significantly higher in CPT tubes than in standard VACUTAINER tubes at 24 and 72 h after the blood samples were drawn. The branched DNA probe assay detected a significant decline in HIV RNA equivalent in plasma over 72 h in both collection tubes, the decline being more dramatic in the standard VACUTAINER tube than the CPT tube. Overall, interday variability suggests that samples collected for a particular assay should be processed at the same time after blood is drawn and that a particular tube type be used throughout a given study.

  View details for Web of Science ID A1994PB54100032

  View details for PubMedID 7814549

  View details for PubMedCentralID PMC263969

• CLINICAL-APPLICATION OF REVERSE TRANSCRIPTION-POLYMERASE CHAIN-REACTION FOR HIV-INFECTION CLINICS IN LABORATORY MEDICINE Holodniy, M. 1994; 14 (2): 335-349

  Abstract

  This article describes the current knowledge of the various RT-PCR assays and their clinical application in HIV disease. The importance of assay precision and sample handling is emphasized. A review of quantification techniques is also presented. Finally, the relevant literature describing the application of RT-PCR for both virion RNA in plasma and cellular mRNA is reviewed.

  View details for Web of Science ID A1994PD13100009

  View details for PubMedID 7523019

• ANTIBIOTIC-ASSOCIATED PSEUDOMEMBRANOUS ENTERITIS DUE TO CLOSTRIDIUM-DIFFICILE CLINICAL INFECTIOUS DISEASES TSUTAOKA, B., Hansen, J., Johnson, D., Holodniy, M. 1994; 18 (6): 982-984

  Abstract

  Although pseudomembranous colitis is relatively common following antibiotic exposure, there have been few reported cases of pseudomembrane formation involving the small intestine. Herein we report a case of pseudomembranous enteritis of the small and large intestine that occurred after antibiotic exposure. The etiologic organism appears to be Clostridium difficile, as evidenced by the characteristic pseudomembranous lesions and a positive ELISA for toxin A in an ileal tissue specimen.

  View details for Web of Science ID A1994NQ82600023

  View details for PubMedID 8086563

• THE USE OF PENTOXIFYLLINE ALONE IN HIV-INFECTED PATIENTS JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY Mole, L., Margolis, D., Ghotbi, L., Holodniy, M. 1994; 7 (5): 519-521

  View details for Web of Science ID A1994NG41300016

  View details for PubMedID 7908984

• DIURNAL AND SHORT-TERM STABILITY OF HIV VIRUS LOAD AS MEASURED BY GENE AMPLIFICATION JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Holodniy, M., Mole, L., Winters, M., Merigan, T. C. 1994; 7 (4): 363-368

  Abstract

  To determine whether human immunodeficiency virus (HIV) viral load has short term stability, eight clinically stable subjects infected with HIV and having CD4 counts ranging between 10-600/mm3, had blood samples taken at 0800 and 1700 on 3 consecutive days and then weekly at 0800 for 1 month (8-10 observations/subject). Plasma HIV RNA, peripheral blood mononuclear cell (PBMC) proviral DNA, serum p24 antigen levels, and mononuclear cell subsets were measured at each time point. Mean plasma HIV RNA, PBMC HIV DNA, and p24 antigen [both regular and immune complex dissociated (ICD)] levels did not change significantly between mornings and afternoons or on successive days or weeks. CD4+, CD8+, and CD56+ number demonstrated a diurnal variation in those subjects with > 200 CD4 cells/mm3. We conclude that HIV viral load demonstrates short-term stability in clinically stable subjects. This stability has important implications for monitoring HIV disease progression or antiretroviral therapy.

  View details for Web of Science ID A1994NC77500007

  View details for PubMedID 7907661

• PERIPHERAL-BLOOD MONONUCLEAR CELL HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROVIRAL DNA QUANTIFICATION BY POLYMERASE CHAIN-REACTION - RELATIONSHIP TO IMMUNODEFICIENCY AND DRUG EFFECT JOURNAL OF CLINICAL MICROBIOLOGY Montoya, J. G., Wood, R., KATZENSTEIN, D., HOLODNY, M., Merigan, T. C. 1993; 31 (10): 2692-2696

  Abstract

  Human immunodeficiency virus type 1 (HIV-1) proviral DNA from peripheral blood mononuclear cells (PBMCs) was quantitated in 61 HIV-1-seropositive individuals by a nonisotopic polymerase chain reaction assay. Primers from the gag region (SK38, SK39) were used to determine the log10 HIV-1 proviral copy number per 10(6) CD4+ T lymphocytes (peripheral blood proviral load). A standard curve was generated for each assay by using ACH-2 cell DNA. The peripheral blood proviral load was followed in 15 individuals in a longitudinal study and was measured in 45 individuals in a cross-sectional analysis. Three of four untreated patients who were followed for 14 months had stable PBMC proviral loads and CD4+ T lymphocyte counts; one untreated patient had a sustained increase in PBMC proviral load followed 5 months later by a significant decline in the CD4+ T lymphocyte count. Eleven previously untreated individuals were monitored for 1 year following initiation of zidovudine and/or 2',3'-dideoxyinosine therapy. The mean log10 number of proviral HIV-1 copies per 10(6) CD4+ T cells decreased from 4.3 +/- 0.4 at the baseline to 3.5 +/- 0.6 after 2 to 4 months of therapy (P < 0.01). This initial 0.8 log10 fall in the PBMC proviral load after the initiation of therapy was followed by a rise in the PBMC proviral load by the sixth month of therapy. The PBMC proviral load in 45 subjects, both treated (n = 25) and untreated (n = 20), correlated inversely with the CD4+ T lymphocyte count (P < 0.01, R = 0.49). PBMC proviral DNA quantification by a nonisotopic polymerase chain reaction assay correlates with HIV-1 disease progression and could be used to monitor the effect of antiretroviral therapy.

  View details for PubMedID 7902845

• HCV INFECTION AMONG VETERANS - CLINICAL CORRELATION WITH VIREMIA AND ANTIBODY-RESPONSE CHEUNG, R., CARLSON, T., HSU, H., HOLODNIY, M., SALEM, P., GREENBERG, H. W B SAUNDERS CO. 1993: A84

  View details for DOI 10.1016/0270-9139(93)91864-O

  View details for Web of Science ID A1993LY99500111

• DETECTION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 IN SEMEN - EFFECTS OF DISEASE STAGE AND NUCLEOSIDE THERAPY JOURNAL OF INFECTIOUS DISEASES Hamed, K. A., Winters, M. A., Holodniy, M., Katzenstein, D. A., Merigan, T. C. 1993; 167 (4): 798-802

  Abstract

  The effects of clinical stage of infection and antiviral therapy on the detection of human immunodeficiency virus type 1 (HIV-1) nucleic acids in semen were investigated by the polymerase chain reaction. HIV-1 was detected in 45 (87%) of 52 semen specimens from 29 (81%) of 36 men. Seventeen (77%) of 22 stage II or III subjects and 12 (86%) of 14 stage IV subjects had positive specimens. The CD4+ lymphocyte count was not significantly different comparing subjects with positive and negative semen. Moreover, 6 (67%) of 9 untreated men had positive specimens compared with 23 (85%) of 27 men treated with zidovudine, 2',3'-dideoxyinosine, or both for a mean of 20 months. Thus, the detection of HIV-1 in semen was independent of both stage of infection and long-term treatment. In a semiquantitative analysis of 6 men followed for 8 weeks after the start of nucleoside therapy, a decrease in HIV-1 RNA in seminal plasma was demonstrated in 2.

  View details for Web of Science ID A1993KU08600002

  View details for PubMedID 8450243

• MEASUREMENT OF HIV VIRUS LOAD AND GENOTYPIC RESISTANCE BY GENE AMPLIFICATION IN ASYMPTOMATIC SUBJECTS TREATED WITH COMBINATION THERAPY JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Holodniy, M., KATZENSTEIN, D., Winters, M., Montoya, J., Shafer, R., Kozal, M., Ragni, M., Merigan, T. C. 1993; 6 (4): 366-369

  Abstract

  Quantification of viral load in HIV disease has become increasingly important as a marker of antiviral efficacy. We applied gene amplification techniques in vivo to asses antiretroviral activity of combination therapy. Five HIV-infected subjects, four of whom were drug naive, were administered combination therapy with zidovudine (ZDV) and didanosine (ddI). Plasma and peripheral blood mononuclear cells (PBMC) were obtained twice at baseline and then at 1, 3, 6, 9, and 12 months after the initiation of therapy. Results show that plasma HIV RNA copy number fell from 2,170 +/- 660/ml to undetectable at 1 month, with continued suppression at 12 months. HIV proviral DNA copy number decreased from 3.9 to 3.0 log10/10(6) CD4+ T cells at 12 months. Cell dilution cultures were positive in 4 of 5 subjects at baseline and in only 1 of 5 after 12 months. CD4+ T-cell count increased from 390 +/- 30/mm3 pretherapy, to 505 +/- 66/mm3 after 6 months of therapy, but returned to baseline levels after 12 months of therapy. No mutations were detected from PBMC DNA for codon 215 and 74 in the HIV pol gene from the drug-naive subjects. These findings suggest that gene amplification techniques can be used to study changes in viral load or genotype and can be applied in real time to samples from patients involved in clinical trials.

  View details for Web of Science ID A1993KU22100007

  View details for PubMedID 8095981

• EFFECT OF ANTIVIRAL TREATMENT AND DISEASE STATE ON HIV VIRUS LOAD HOLODNIY, M. WILEY-LISS. 1993: 3

  View details for Web of Science ID A1993KX96500006

• Peripheral blood mononuclear cell human immunodeficiency virus type 1 proviral DNA quantification by polymerase chain reaction: relationship to immunodeficiency and drug effect Journal of Clinical Microbiology Montoya, J., Wood R, Katzenstein D, Holodny M, Merigan TC 1993; 31 (10): 2692-96
• Quantitative RNA and DNA gene amplification can rapidly monitor HIV infection and antiviral activity in cell cultures. PCR methods and applications Winters, M. A., Holodniy, M., Katzenstein, D. A., Merigan, T. C. 1992; 1 (4): 257-262

  Abstract

  We have developed a quantitative gene amplification procedure to assess the replication of human immunodeficiency virus (HIV) in cell cultures and evaluate the effect of drugs on viral replication. Increases in HIV gag RNA and DNA in phytohemagglutinin-stimulated normal peri-pheral blood mononuclear cells (PBMC) infected with HIV at very low multiplicity of infection paralleled the production of HIV p24 antigen in culture supernatants. Quantitative gene amplification was able to monitor the accumulation of viral nucleic acids in control cultures and demonstrate the effect of various concentrations of azidothymidine (AZT) on the replication of both AZT-sensitive and -resistant strains of HIV. The sensitivity of patient-derived virus strains to AZT could also be successfully measured by these procedures. The results of our studies suggest that quantitative measurement of HIV gag RNA and DNA can be used to monitor the kinetics of viral replication, antiviral activity, viral drug resistance, and mechanism of drug action.

  View details for PubMedID 1477661

• USE OF THE POLYMERASE CHAIN-REACTION FOR THE DIAGNOSIS OF HIV-INFECTION IN ADULTS - A META-ANALYTIC EVALUATION OF TEST-PERFORMANCE OWENS, D. K., HOLODNIY, M., GARBER, A. M., SONNAD, S., SCOTT, J., KINOSIAN, B., SCHWARTZ, J. S. SLACK INC. 1992: A588

  View details for Web of Science ID A1992HN74102608

• THE SULFONE SYNDROME IN A PATIENT RECEIVING DAPSONE PROPHYLAXIS FOR PNEUMOCYSTIS-CARINII PNEUMONIA WESTERN JOURNAL OF MEDICINE MOHLEBOETANI, J., AKULA, S. K., Holodniy, M., KATZENSTEIN, D., Garcia, G. 1992; 156 (3): 303-306

  View details for Web of Science ID A1992HJ56900020

  View details for PubMedID 1595261

  View details for PubMedCentralID PMC1003252

• CORRELATION OF MORPHOLOGICAL DIAGNOSIS OF PNEUMOCYSTIS-CARINII WITH THE PRESENCE OF PNEUMOCYSTIS DNA AMPLIFIED BY THE POLYMERASE CHAIN-REACTION MODERN PATHOLOGY Blumenfeld, W., McCook, O., Holodniy, M., Katzenstein, D. A. 1992; 5 (2): 103-106

  Abstract

  We compared the presence of P. carinii in clinical specimens as detected by standard cytomorphologic techniques with amplification of P. carinii-specific DNA by the polymerase chain reaction (PCR). Results correlated in 33 of 37 instances (89%): nine specimens were positive by both PCR and morphology; 24 specimens were negative by both techniques. Two specimens from one patient were obtained 3 days apart. The first specimen was both cytologically and PCR negative, while the second specimen was both cytologically and PCR positive for P. carinii. At least in some instances, therefore, PCR is no more sensitive than morphology, and other factors such as specimen adequacy are more important. Twelve of the 24 negative specimens were from patients with prior histories of P. carinii pneumonia, suggesting that recurrent disease may be from reacquisition of organisms in previously exposed individuals, rather than reactivation of latent organisms. Discrepant results included three morphologically negative specimens that were positive by PCR. It remains to be determined whether the increased sensitivity of PCR in these cases is real or artifactual. One morphologically positive specimen was negative by PCR. Polymerase chain reaction correlates well with cytomorphologic diagnosis of P. carinii pneumonia and may be a valuable diagnostic and epidemiologic tool.

  View details for Web of Science ID A1992HJ85500003

  View details for PubMedID 1374186

• PLASMA VIREMIA IN HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION - RELATIONSHIP TO STAGE OF DISEASE AND ANTIVIRAL TREATMENT JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY Katzenstein, D. A., Holodniy, M., Israelski, D. M., Sengupta, S., Mole, L. A., BUBP, J. L., Merigan, T. C. 1992; 5 (2): 107-112

  Abstract

  Quantitative culture of human immunodeficiency virus (HIV) was performed on 121 plasma samples from 76 HIV-infected individuals to determine the sensitivity of the assay at different stages of disease and to measure the effect of antiviral therapy on plasma viremia. Plasma virus was detected in 49 of 76 (64%) of patients, primarily those with AIDS and AIDS-related complex (36 of 38) versus asymptomatic subjects (13 of 38) (p less than 0.001, chi 2). Similarly, plasma cultures were more often positive in patients with less than 250 CD4+ T cells per microliter (38 of 40) than in those with greater than 250 CD4+ T cells per microliter (11 of 36) (p less than 0.001, chi 2). Plasma virus cultures were also more likely to be positive in patients with detectable serum p24 antigen (24 of 26) than in those without detectable p24 antigen (25 of 50) (p = 0.0023, chi 2). An effect of zidovudine (ZDV) treatment on plasma viremia was seen in a comparison of treated and untreated patients with less than 250 CD4+ T cells per microliter. Geometric mean titers of plasma viremia from 16 patients treated with ZDV for more than 3 months were significantly lower than titers from 24 untreated patients (10(1.3) versus 10(2.1), p less than 0.05, Student's t test. A comparison of pre- and posttherapy titers in 33 patients receiving antiviral treatment showed that plasma virus was not detectable at either time in 17 patients; there was a fall in plasma virus titer in 12; and titers were unchanged or increased in 4. In patients with advanced disease, plasma viremia is a potential marker of antiviral drug activity.

  View details for Web of Science ID A1992GZ90200001

  View details for PubMedID 1732501

• DETECTION AND QUANTIFICATION OF GENE AMPLIFICATION PRODUCTS BY A NONISOTOPIC AUTOMATED-SYSTEM BIOTECHNIQUES Holodniy, M., Winters, M. A., Merigan, T. C. 1992; 12 (1): 36-?

  Abstract

  We describe in this report the ability to determine human immunodeficiency virus proviral copy number by an automated nonisotopic method. Our system utilizes a FACStarPLUS cell sorter, the GeneAmp PCR System 9600 and a Biomek 1000 robotic workstation. Linking these three machines allows cell populations to be sorted and the DNA amplified and quantitated with minimal technical effort. We have developed this system to quantitate proviral DNA copy number in sorted subpopulations of peripheral blood cells in one day.

  View details for Web of Science ID A1992GZ18400006

  View details for PubMedID 1531177

• DECREASE IN HIV PROVIRUS IN PERIPHERAL-BLOOD MONONUCLEAR-CELLS DURING ZIDOVUDINE AND HUMAN RIL-2 ADMINISTRATION JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY Clark, A. G., Holodniy, M., Schwartz, D. H., Katzenstein, D. A., Merigan, T. C. 1992; 5 (1): 52-59

  Abstract

  Quantification of human immunodeficiency virus (HIV) proviral DNA in peripheral blood mononuclear cells (PBMC) was performed in 13 HIV-seropositive asymptomatic individuals during 10-24 months by polymerase chain reaction amplification of multiple half-log dilutions of cellular DNA. At enrollment, subjects had a geometric mean titer of 100 copies of HIV provirus per 10(6) PBMC (mean +/- SD, 2 +/- 0.9 log10). In four untreated individuals there was no significant change in provirus levels during a mean period of 13.3 months. In eight patients treated with zidovudine (ZDV) and human recombinant interleukin 2 (rIL-2), HIV provirus copies declined to 13 per 10(6) cells (1.1 +/- 0.8 log10) at the end of the first course of ZDV and rIL-2 at week 20 (p less than 0.01), and to 40 per 10(6) cells (1.6 +/- 0.9 log10) after 12 months of treatment (p less than 0.04). Subsequent courses, which included 12 weeks of ZDV alone or 4 weeks of IL-2 alone, did not significantly change the already depressed provirus copy numbers. Proviral copy number also remained depressed during drug-free "washout periods" between courses. Finally, we observed a return to a geometric mean of 400 copies per 10(6) cells (2.6 +/- 0.3 log10) a mean of 7.9 months after discontinuation of therapy. Measurement of changes in HIV provirus should provide a direct marker for defining antiviral activity of drugs, biologics, and combination therapy.

  View details for Web of Science ID A1992GW91300009

  View details for PubMedID 1738087

• Quantitative virological measures of antiretroviral therapy. AIDS clinical review Katzenstein, D. A., Holodniy, M. 1992: 41-67

  View details for PubMedID 1376615

• REDUCTION IN PLASMA HUMAN-IMMUNODEFICIENCY-VIRUS RIBONUCLEIC-ACID AFTER DIDEOXYNUCLEOSIDE THERAPY AS DETERMINED BY THE POLYMERASE CHAIN-REACTION JOURNAL OF CLINICAL INVESTIGATION Holodniy, M., Katzenstein, D. A., Israelski, D. M., Merigan, T. C. 1991; 88 (5): 1755-1759

  Abstract

  Cell-free HIV RNA in plasma was detected and quantitated after antiviral therapy by the polymerase chain reaction. RNA was extracted from plasma, reverse transcribed to cDNA, amplified by polymerase chain reaction, and quantitated by absorbance based on an enzyme-linked affinity assay. 72 HIV antibody-positive subjects had one plasma sample taken. 39 who were not receiving antiretroviral therapy at the time had a mean plasma HIV RNA copy number of 690 +/- 360 (mean +/- SEM) per 200 microliters of plasma, while 33 subjects who had been receiving zidovudine therapy for a minimum of 3 mo had a mean copy number of 134 +/- 219 (P less than 0.05). 27 additional HIV antibody-positive patients had two plasma samples taken before and 1 mo after initiating dideoxynucleoside therapy. Plasma HIV RNA copy number fell from 540 +/- 175 to 77 +/- 35 (P less than 0.05). Finally, nine of these subjects had two baseline samples obtained before initiating therapy and two posttreatment samples 1 and 2 mo after therapy was begun. Mean plasma RNA copy number declined from 794 +/- 274 to less than 40 (below the lower limit of sensitivity) after 1 mo of therapy, with suppression maintained after 2 mo of therapy. These results suggest that gene amplification can be used to detect and quantitate changes in plasma HIV RNA after dideoxynucleoside therapy. Plasma HIV polymerase chain reaction may be a more sensitive marker to monitor antiviral therapy, particularly in asymptomatic patients where measurement of p24 antigen or quantitative plasma cultures are negative.

  View details for Web of Science ID A1991GN72700044

  View details for PubMedID 1682345

  View details for PubMedCentralID PMC295721

• DETECTION OF HUMAN-IMMUNODEFICIENCY-VIRUS DNA AND RNA IN SEMEN BY THE POLYMERASE CHAIN-REACTION JOURNAL OF INFECTIOUS DISEASES Mermin, J. H., Holodniy, M., Katzenstein, D. A., Merigan, T. C. 1991; 164 (4): 769-772

  Abstract

  Peripheral blood mononuclear cells (PBMC) and semen of 23 men infected with human immunodeficiency virus (HIV) were examined for the presence of HIV DNA and RNA using the polymerase chain reaction (PCR) and a nonisotopic detection assay. None of the men was receiving antiretroviral therapy at the time of collection. Semen samples were separated into cell-free seminal fluid, nonspermatozoal mononuclear cells (NSMC), and spermatozoa. All of the PBMC samples, 17 (74%) of 23 NSMC samples, and none of the spermatozoal samples were positive for HIV gag gene DNA. Of 23 cell-free seminal fluid samples, 15 (65%) were positive for HIV gag gene RNA by PCR. Cell-free HIV RNA was more likely to be present in the semen of men with less than 400 than in those with greater than or equal to 400 cells/mm3 (P less than .04) and was present in all patient with p24 antigen in serum. The presence of HIV DNA in NSMC samples was not related to CD4 cell count, disease status, or the presence of p24 antigen in the serum. This study shows that HIV nucleic acid can be detected by PCR in either the cell-free seminal fluid or NSMC of 87% of semen samples but not in the DNA of spermatozoa from HIV-infected men.

  View details for Web of Science ID A1991GF80500022

  View details for PubMedID 1680138

• INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS GENE AMPLIFICATION BY HEPARIN JOURNAL OF CLINICAL MICROBIOLOGY Holodniy, M., Kim, S., KATZENSTEIN, D., Konrad, M., Groves, E., Merigan, T. C. 1991; 29 (4): 676-679

  Abstract

  Gene amplification of virus-specific sequences is widely used as a method to detect or confirm human immunodeficiency virus (HIV) infection. In this study we used an enzyme-linked affinity assay to quantify polymerase chain reaction products from whole blood, plasma, and separated mononuclear cells collected in the presence of four common anticoagulants: acid citrate dextrose, sodium EDTA, potassium oxalate, and sodium heparin. Attenuation of the product signal was observed after amplification of nucleic acid extraction from whole blood, washed mononuclear cells, and plasma from specimens collected in sodium heparin. These inhibitory effects on gene amplification could be reversed with heparinase. The addition of as little as 0.05 U of heparin completely inhibited amplification of an HLA-DQa sequence from placental DNA. We conclude that heparin can cause attenuation or inhibition of gene amplification. Acid citrate dextrose and EDTA, which lack inhibitory activity, are the most appropriate anticoagulants for clinical blood samples when polymerase chain reaction amplification is anticipated.

  View details for PubMedID 1909709

• DETECTION AND QUANTIFICATION OF HUMAN-IMMUNODEFICIENCY-VIRUS RNA IN PATIENT SERUM BY USE OF THE POLYMERASE CHAIN-REACTION JOURNAL OF INFECTIOUS DISEASES Holodniy, M., Katzenstein, D. A., Sengupta, S., Wang, A. M., CASIPIT, C., Schwartz, D. H., Konrad, M., Groves, E., Merigan, T. C. 1991; 163 (4): 862-866

  Abstract

  Human immunodeficiency virus (HIV) RNA was detected and quantified in the serum of HIV-seropositive individuals using the polymerase chain reaction (PCR) and a nonisotopic enzyme-linked affinity assay. Of 55 HIV-infected patients who were not receiving therapy, serum HIV RNA was detected in 9 of 19 who were asymptomatic, 11 of 16 with AIDS-related complex (ARC), and 18 of 20 with AIDS, with copy numbers ranging from 10(2) to greater than or equal to 5 x 10(4) 200 microliters of serum based on a relationship between absorbance and known copy number of gag gene RNA. Linear regression analysis demonstrated a correlation between infectious titer in 42 patient sera cocultured with donor peripheral blood mononuclear cells (PBMC) and PCR product absorbance (r = .70, P less than .01). Serum HIV RNA detected by PCR also correlated with serum p24 antigen positivity, CD4 counts less than 400/mm3, and the presence of HIV-related symptoms or disease. Quantification of infectious HIV RNA in cell-free serum by PCR may be useful as a marker for for disease progression or in monitoring antiviral therapy.

  View details for Web of Science ID A1991FD93900031

  View details for PubMedID 2010639

• CEREBRAL SPARGANOSIS - CASE-REPORT AND REVIEW REVIEWS OF INFECTIOUS DISEASES Holodniy, M., ALMENOFF, J., Loutit, J., Steinberg, G. K. 1991; 13 (1): 155-159

  Abstract

  Sparganosis is a rare infection caused by a tapeworm larva from the genus Spirometra. A 21-year-old Indian man presented with an 18-month history of episodic confusion followed by a grand mal seizure. Computed tomography and magnetic resonance imaging of the brain confirmed the presence of a lesion of the left occipital lobe. Subsequent stereotactic biopsy revealed a plerocercoid larva or sparganum. Surgical resection resulted in cure. This case prompted a review of the literature on central nervous system sparganosis. Altogether, 17 other cases of primary cerebral sparganosis have been reported previously. Seizures, headache, and focal neurologic signs are common at presentation. Neuroradiologic imaging is sensitive but not specific for the identification of lesions. Enzyme-linked immunosorbent assay of cerebrospinal fluid or serum may be diagnostically helpful. However, the diagnosis is generally made after surgical resection, which is usually curative.

  View details for Web of Science ID A1991EU52000025

  View details for PubMedID 2017616

• CORRELATION BETWEEN HUMAN-IMMUNODEFICIENCY-VIRUS (HIV) LOAD, STAGE OF DISEASE AND DIDEOXY DRUG ADMINISTRATION USING QUANTITATIVE RNA AND DNA-POLYMERASE CHAIN-REACTION (PCR) AND VIREMIA MEASUREMENTS WORKSHOP ON VIRAL QUANTITATION IN HIV INFECTION Merigan, T. C., Clark, G., KATZENSTEIN, D., Holodniy, M. INSERM / JOHN LIBBEY EUROTEXT. 1991: 147–152

  View details for Web of Science ID A1991BV41D00017

• Recombinant soluble CD4 therapy in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. A phase I-II escalating dosage trial. Annals of internal medicine Schooley, R. T., Merigan, T. C., Gaut, P., Hirsch, M. S., Holodniy, M., Flynn, T., Liu, S., BYINGTON, R. E., Henochowicz, S., Gubish, E. 1990; 112 (4): 247-253

  Abstract

  To study the safety and pharmacokinetics and to derive preliminary evidence on surrogate indicators of efficacy of recombinant soluble CD4 (rsCD4) in patients with the acquired immunodeficiency syndrome (AIDS) and advanced AIDS-related complex.Open label, escalating dosage, phase I-II tolerance trial.Massachusetts General Hospital, Cedars-Sinai Medical Center, and Stanford University Medical School, three tertiary care institutions and members of the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. INSTRUCTIONS: Cohorts of 3 to 11 patients received rsCD4 by intravenous infusion or intramuscular injection in dosages of up to 30 mg per day for 28 days. MEASUREMENTS andRecombinant soluble CD4 was tolerated by these patients with no significant clinical or immunologic toxicities. Serum levels of rsCD4 in patients receiving doses of 9 or 30 mg per day administered intramuscularly were in the range of rsCD4 concentrations required to inhibit replication of human immunodeficiency virus 1 (HIV-1) in vitro. A decline in serum HIV-1 p24 antigen was seen in patients receiving 30 mg of rsCD4 daily, but no such changes were noted at lower dosages.Recombinant soluble CD4 is well tolerated by patients with AIDS or advanced AIDS-related complex. Our study has also provided preliminary evidence of antiviral activity of rsCD4 in vivo. Our data suggest that further trials of receptor-based therapies against HIV-1 are warranted.

  View details for PubMedID 2297203

• RECOMBINANT SOLUBLE CD4 THERAPY IN PATIENTS WITH THE ACQUIRED-IMMUNODEFICIENCY-SYNDROME (AIDS) AND AIDS-RELATED COMPLEX - A PHASE-I PHASE-II ESCALATING DOSAGE TRIAL ANNALS OF INTERNAL MEDICINE Schooley, R. T., Merigan, T. C., Gaut, P., Hirsch, M. S., Holodniy, M., Flynn, T., Liu, S., BYINGTON, R. E., Henochowicz, S., Gubish, E., Spriggs, D., Kufe, D., Schindler, J., Dawson, A., Thomas, D., Hanson, D. G., Letwin, B., Liu, T., GULINELLO, J., Kennedy, S., Fisher, R., Ho, D. D. 1990; 112 (4): 247-253

  Abstract

  To study the safety and pharmacokinetics and to derive preliminary evidence on surrogate indicators of efficacy of recombinant soluble CD4 (rsCD4) in patients with the acquired immunodeficiency syndrome (AIDS) and advanced AIDS-related complex.Open label, escalating dosage, phase I-II tolerance trial.Massachusetts General Hospital, Cedars-Sinai Medical Center, and Stanford University Medical School, three tertiary care institutions and members of the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. INSTRUCTIONS: Cohorts of 3 to 11 patients received rsCD4 by intravenous infusion or intramuscular injection in dosages of up to 30 mg per day for 28 days. MEASUREMENTS andRecombinant soluble CD4 was tolerated by these patients with no significant clinical or immunologic toxicities. Serum levels of rsCD4 in patients receiving doses of 9 or 30 mg per day administered intramuscularly were in the range of rsCD4 concentrations required to inhibit replication of human immunodeficiency virus 1 (HIV-1) in vitro. A decline in serum HIV-1 p24 antigen was seen in patients receiving 30 mg of rsCD4 daily, but no such changes were noted at lower dosages.Recombinant soluble CD4 is well tolerated by patients with AIDS or advanced AIDS-related complex. Our study has also provided preliminary evidence of antiviral activity of rsCD4 in vivo. Our data suggest that further trials of receptor-based therapies against HIV-1 are warranted.

  View details for Web of Science ID A1990CN55400004

• FULMINANT KAPOSIS-SARCOMA COMPLICATING LONG-TERM CORTICOSTEROID-THERAPY AMERICAN JOURNAL OF MEDICINE KOOP, H. O., Holodniy, M., List, A. F. 1987; 83 (4): 787-789

  Abstract

  Cutaneous Kaposi's sarcoma occurs rarely in patients receiving long-term corticosteroid therapy. The case of a rapidly progressive form of Kaposi's sarcoma occurring in a 29-year-old Palestinian woman with steroid-dependent Crohn's disease and familial Mediterranean fever is reported. Despite an extensive transfusion history, serologic and virologic studies failed to demonstrate exposure to the human immunodeficiency virus. Serologic and virologic evidence of concomitant cytomegalovirus infection, however, suggests possible pathogenic features similar to the acquired immunodeficiency syndrome-related form of Kaposi's sarcoma.

  View details for Web of Science ID A1987K590600029

  View details for PubMedID 2823601

• Enhanced Influenza Surveillance Using Telephone Triage and Electronic Syndromic Surveillance in the Department of Veterans Affairs, 2011-2015. Public health reports (Washington, D.C. : 1974) Lucero-Obusan, C. n., Winston, C. A., Schirmer, P. L., Oda, G. n., Holodniy, M. n. ; 132 (1_suppl): 16S–22S

  Abstract

  Telephone triage (TT) is a method whereby medical professionals speak by telephone to patients to assess their symptoms or health concerns and offer advice. These services are often administered through an electronic TT system, which guides TT professionals during the encounter through the use of structured protocols and algorithms to help determine the severity of the patients' health issue and refer them to appropriate care. TT is also an emerging data source for public health surveillance of infectious and noninfectious diseases, including influenza. We calculated Spearman correlation coefficients to compare the weekly number of US Department of Veterans Affairs (VA) TT calls with other conventional influenza measures for the 2011-2012 through 2014-2015 influenza seasons, for which there were a total of 35 666 influenza-coded TT encounters. Influenza-coded calls were strongly correlated with weekly VA influenza-coded hospitalizations (0.85), emergency department visits (0.90), influenza-like illness outpatient visits (0.92), influenza tests performed (0.86), positive influenza tests (0.82), and influenza antiviral prescriptions (0.89). The correlation between VA-TT and Centers for Disease Control and Prevention (CDC) national data for weekly influenza hospitalizations, influenza tests performed, and positive influenza tests was also strong. TT correlates well with VA health care use and CDC data and is a timely data source for monitoring influenza activity.

  View details for PubMedID 28692402