Philip Grant

All Publications

• Sex differences and immune correlates of Long COVID development, persistence, and resolution. bioRxiv : the preprint server for biology Hamlin, R. E., Pienkos, S. M., Chan, L., Stabile, M. A., Pinedo, K., Rao, M., Grant, P., Bonilla, H., Holubar, M., Singh, U., Jacobson, K. B., Jagannathan, P., Maldonado, Y., Holmes, S. P., Subramanian, A., Blish, C. A. 2024

  Abstract

  Sex differences have been observed in acute COVID-19 and Long COVID (LC) outcomes, with greater disease severity and mortality during acute infection in males and a greater proportion of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to the pathogenesis of LC. To investigate the immunologic underpinnings of LC development and persistence, we used single-cell transcriptomics, single-cell proteomics, and plasma proteomics on blood samples obtained during acute SARS-CoV-2 infection and at 3 and 12 months post-infection in a cohort of 45 patients who either developed LC or recovered. Several sex-specific immune pathways were associated with LC. Specifically, males who would develop LC at 3 months had widespread increases in TGF-β signaling during acute infection in proliferating NK cells. Females who would develop LC demonstrated increased expression of XIST, an RNA gene implicated in autoimmunity, and increased IL1 signaling in monocytes at 12 months post infection. Several immune features of LC were also conserved across sexes. Both males and females with LC had reduced co-stimulatory signaling from monocytes and broad upregulation of NF-κB transcription factors. In both sexes, those with persistent LC demonstrated increased LAG3, a marker of T cell exhaustion, reduced ETS1 transcription factor expression across lymphocyte subsets, and elevated intracellular IL-4 levels in T cell subsets, suggesting that ETS1 alterations may drive an aberrantly elevated Th2-like response in LC. Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics.

  View details for DOI 10.1101/2024.06.18.599612

  View details for PubMedID 38948732

  View details for PubMedCentralID PMC11212991

• Prevalence of Emergent Dolutegravir Resistance Mutations in People Living with HIV: A Rapid Scoping Review. Viruses Chu, C., Tao, K., Kouamou, V., Avalos, A., Scott, J., Grant, P. M., Rhee, S. Y., McCluskey, S. M., Jordan, M. R., Morgan, R. L., Shafer, R. W. 2024; 16 (3)

  Abstract

  Dolutegravir (DTG) is a cornerstone of global antiretroviral (ARV) therapy (ART) due to its high efficacy and favorable tolerability. However, limited data exist regarding the risk of emergent integrase strand transfer inhibitor (INSTI) drug-resistance mutations (DRMs) in individuals receiving DTG-containing ART.We performed a PubMed search using the term "Dolutegravir", last updated 18 December 2023, to estimate the prevalence of VF with emergent INSTI DRMs in people living with HIV (PLWH) without previous VF on an INSTI who received DTG-containing ART.Of 2131 retrieved records, 43 clinical trials, 39 cohorts, and 6 cross-sectional studies provided data across 6 clinical scenarios based on ART history, virological status, and co-administered ARVs: (1) ART-naïve PLWH receiving DTG plus two NRTIs; (2) ART-naïve PLWH receiving DTG plus lamivudine; (3) ART-experienced PLWH with VF on a previous regimen receiving DTG plus two NRTIs; (4) ART-experienced PLWH with virological suppression receiving DTG plus two NRTIs; (5) ART-experienced PLWH with virological suppression receiving DTG and a second ARV; and (6) ART-experienced PLWH with virological suppression receiving DTG monotherapy. The median proportion of PLWH in clinical trials with emergent INSTI DRMs was 1.5% for scenario 3 and 3.4% for scenario 6. In the remaining four trial scenarios, VF prevalence with emergent INSTI DRMs was ≤0.1%. Data from cohort studies minimally influenced prevalence estimates from clinical trials, whereas cross-sectional studies yielded prevalence data lacking denominator details.In clinical trials, the prevalence of VF with emergent INSTI DRMs in PLWH receiving DTG-containing regimens has been low. Novel approaches are required to assess VF prevalence with emergent INSTI DRMs in PLWH receiving DTG in real-world settings.

  View details for DOI 10.3390/v16030399

  View details for PubMedID 38543764

  View details for PubMedCentralID PMC10975848

• Associations between county-level public health expenditures and community health planning activities with COVID-19 incidence and mortality. Preventive medicine reports Liang, R., Kiang, M. V., Grant, P., Jackson, C., Rehkopf, D. H. 2023; 36: 102410

  Abstract

  The COVID-19 pandemic has revealed consequences of past defunding of the U.S. public health system, but the extent to which public health infrastructure is associated with COVID-19 burden is unknown. We aimed to determine whether previous county-level public health expenditures and community health planning activities are associated with COVID-19 cases and deaths. We examined 3050 of 3143 U.S. counties and county equivalents from March 1, 2020 to February 28, 2022. Multivariable-adjusted linear regression and generalized additive models were used to estimate associations between county-level public health expenditures and completion of community health planning activities by a county health department with outcomes of county-level COVID-19 cases and deaths per 100,000 population. After adjusting for county-level covariates, counties in the highest tertile of public health expenditures per capita had on average 542 fewer COVID-19 cases per 100,000 population (95% CI, -1004 to -81) and 21 fewer deaths per 100,000 population (95% CI, -32 to -10) than counties in the lowest tertile. For analyses of community health planning activities, adjusted estimates of association remained negative for COVID-19 deaths, but confidence intervals included negative and positive values. In conclusion, higher levels of local public health expenditures and community health planning activities were associated with fewer county-level COVID-19 deaths, and to a lesser extent, cases. Future public health funding should be aligned with evidence for the value of county health departments programs and explore further which types of spending are most cost effective.

  View details for DOI 10.1016/j.pmedr.2023.102410

  View details for PubMedID 37732021

  View details for PubMedCentralID PMC10507150

• Safety and efficacy of sofosbuvir-velpatasvir to treat chronic hepatitis C virus infection in treatment-naive patients in Rwanda (SHARED-3): a single-arm trial. The lancet. Gastroenterology & hepatology Kateera, F., Shumbusho, F., Manirambona, L., Kabihizi, J., Murangwa, A., Serumondo, J., Makuza, J. D., Nsanzimana, S., Muvunyi, C. M., Kabakambira, J. D., Sylvain, H., Camus, G., Grant, P. M., Gupta, N. 2022

  Abstract

  BACKGROUND: Hepatitis C virus (HCV) genotype 4 is the predominant type of HCV found in sub-Saharan Africa. Various genotype 4 subtypes, such as 4r, frequently have resistance-associated substitutions that can increase rates of treatment failure with common direct-acting antiviral regimens. In-vitro studies suggest that the NS5A inhibitor velpatasvir is effective against viral isolates containing such resistance-associated substitutions, but its clinical efficacy against genotype 4 non-a/d subtypes in sub-Saharan Africa remains to be confirmed. We aimed to evaluate the safety and efficacy of sofosbuvir-velpatasvir among adults chronically infected with HCV and naive to direct-acting antiviral treatment in Rwanda, where genotype 4 non-a/d subtypes predominate.METHODS: In this single-arm prospective trial, we enrolled adults (age ≥18 years) in Rwanda who had chronic HCV infection and a plasma HCV RNA titre of at least 1000 IU/mL. Patients were referred from hospitals with HCV treatment programmes throughout Rwanda and were sequentially enrolled and assessed for eligibility at a single study site. Individuals with decompensated liver disease or hepatitis B virus co-infection were excluded. Participants were given an oral fixed-dose combination tablet of sofosbuvir (400 mg) and velpatasvir (100 mg) once-daily for 12 weeks. The primary endpoint was the proportion of participants with a sustained virological response 12 weeks after completion of treatment (SVR12) in the intention-to-treat population. Viral sequencing of the NS5A and NS5B genes was done at baseline for all participants and end of follow-up (week 24) for participants who did not have SVR12. This study is registered with ClinicalTrials.gov (NCT03888729) and is completed.FINDINGS: Between Sept 23, 2019, and Jan 10, 2020, 73 individuals were screened for eligibility, of whom 12 (16%) were excluded and 61 (84%) were enrolled. 40 (66%) participants were female, 21 (34%) were male, median age was 64 years (IQR 51-74), and median baseline HCV viral load was 5·7 log10 IU/mL (5·2-6·2). The genotypes identified among the participants were 4k (28 [46%] participants), 4r (11 [18%]), 4v (eight [13%]), 4q (five [8%]), 4l (three [5%]), 4b (one [2%]), 4c (one [2%]), and one undetermined genotype 4 subtype. Three isolates could not be sequenced and were of indeterminate genotype. Of the 55 HCV isolates that were successfully sequenced, all had at least two NS5A resistance-associated substitutions. 59 (97% [95% CI 89-99]) participants had SVR12. 18 (30%) participants had grade 3 adverse events (including 12 [20%] with hypertension), and none had grade 4 adverse events. Four (7%) participants had serious adverse events, including one asthma exacerbation, one abscess, one uterine myoma, and one pelvic fracture related to a motor vehicle accident. No serious adverse events were attributed to the study drug and no adverse event resulted in discontinuation of the study drug.INTERPRETATION: A 12-week regimen of sofosbuvir-velpatasvir is safe and efficacious in treating chronic HCV genotype 4 infection in patients in Rwanda. This regimen could be an effective treatment option in regions known to have a high prevalence of HCV genotype 4 of diverse non-a/d subtypes.FUNDING: Gilead Sciences.

  View details for DOI 10.1016/S2468-1253(21)00398-8

  View details for PubMedID 35248213

• Safety and efficacy of sofosbuvir-velpatasvir-voxilaprevir for re-treatment of chronic hepatitis C virus infection in patients with previous direct-acting antiviral treatment failure in Rwanda (SHARED-3): a single-arm trial. The lancet. Gastroenterology & hepatology Gupta, N., Manirambona, L., Shumbusho, F., Kabihizi, J., Murangwa, A., Serumondo, J., Makuza, J. D., Nsanzimana, S., Muvunyi, C. M., Mukabatsinda, C., Musabeyezu, E., Camus, G., Grant, P. M., Kateera, F. 2022

  Abstract

  BACKGROUND: Hepatitis C virus (HCV) genotype 4 non-a/d subtypes, which frequently have NS5A resistance-associated substitutions, are highly prevalent in sub-Saharan Africa. These subtypes, particularly genotype 4r, have been associated with higher rates of failure of treatment regimens containing the NS5A inhibitors ledipasvir or daclatasvir, which are the most accessible direct-acting antivirals in low-income countries. Clinical evidence regarding the efficacy of re-treatment options for these subtypes is limited. We aimed to evaluate the safety and efficacy of sofosbuvir-velpatasvir-voxilaprevir for the treatment of adults in Rwanda with chronic HCV infection, predominantly of genotype 4, and a history of direct-acting antiviral treatment failure.METHODS: In this single-arm prospective trial, we enrolled adults (aged ≥18 years) with a HCV RNA titre of at least 1000 IU/mL, and a documented history of direct-acting antiviral failure. Patients were assessed for eligibility at a single study site after referral from hospitals with HCV treatment programmes throughout Rwanda, and participants for whom sofosbuvir-ledipasvir treatment had failed in the previous SHARED trial were also included. Participants with decompensated liver disease or hepatitis B virus co-infection were excluded. Participants were treated once daily with an oral fixed-dose combination tablet containing sofosbuvir (400 mg), velpatasvir (100 mg), and voxilaprevir (100 mg) for 12 weeks. The primary endpoint was the proportion of participants with a sustained virological response 12 weeks after completion of treatment (SVR12) in the intention-to-treat population. Viral sequencing of NS3, NS5A, and NS5B genes was done at baseline in all participants and at end of follow-up (week 24) in participants with treatment failure. The study is registered with ClinicalTrials.gov (NCT03888729) and is completed.FINDINGS: Between Sept 23, 2019, and Jan 10, 2020, 49 individuals were screened and 40 participants were enrolled. 20 (50%) were female, 20 (50%) were male, median age was 63 years (IQR 56-68), and median HCV viral load was 6·2 log10 IU/mL (5·8-6·5) at baseline. The genotype subtypes identified were 4r (18 [45%] participants), 4k (six [15%]), 4b (five [13%]), 4q (four [10%]), 4l (two [5%]), 4a (one [3%]), 4m (one [3%]), and 3h (one [3%]). One (3%) genotype 4 isolate could not be subtyped, and one (3%) isolate was of unknown genotype. All successfully sequenced isolates (33 [83%]) had at least two NS5A resistance-associated substitutions and 25 (63%) had three or more. 39 (98% [95% CI 87-100]) participants had SVR12. Seven (18%) participants had a total of ten grade 3, 4, or 5 adverse events, including three (8%) cases of hypertension, and one (3%) case each of cataract, diabetes, gastrointestinal bleeding, joint pain, low back pain, vaginal cancer, and sudden death. Four of these events were categorised as serious adverse events resulting in hospitalisation. The one sudden death occurred at home from an unknown cause 4 weeks after the completion of treatment. No serious adverse event was determined to be related to the study drug or resulted in treatment discontinuation.INTERPRETATION: A 12 week course of sofosbuvir-velpatasvir-voxilaprevir is safe and efficacious for the re-treatment of individuals infected with HCV genotype 4 non-a/d subtypes with frequent baseline NS5A resistance-associated substitutions, following failure of previous direct-acting antiviral treatment. Improved affordability and access to sofosbuvir-velpatasvir-voxilaprevir in regions with these subtypes is crucial.FUNDING: Gilead Sciences.

  View details for DOI 10.1016/S2468-1253(21)00399-X

  View details for PubMedID 35248212

• Fostemsavir: a first-in-class HIV-1 attachment inhibitor. Current opinion in HIV and AIDS Grant, P. M., Kozal, M. J. 2022; 17 (1): 32-35

  Abstract

  PURPOSE OF REVIEW: Fostemsavir is a recently Food and Drug Administration-approved HIV-1 attachment inhibitor that binds to HIV-1 gp120 and prevents viral attachment to the cellular CD4 receptor. Here, we review the pharmacology, efficacy, tolerability, and resistance profile of fostemsavir.RECENT FINDINGS: Fostemsavir is well tolerated and maintains virologic activity in individuals harboring multidrug-resistant HIV-1. In conjunction with optimal background therapy, a majority of heavily treatment-experienced clinical trial participants treated with fostemsavir achieved virologic suppression.SUMMARY: The approval of fostemsavir represents an important advance for individuals harboring multidrug resistant HIV-1 due to its novel mechanism of action and lack of cross-resistance to other antiretrovirals. Further study will better define the role of resistance testing for fostemsavir and fostemsavir's potential role outside of salvage therapy in heavily treatment-experienced individuals.

  View details for DOI 10.1097/COH.0000000000000712

  View details for PubMedID 34871189

• Survivors of SARS-CoV-2 Infection Show Neuropsychiatric Sequelae Measured by Surveys, Neurocognitive Testing, and Magnetic Resonance Imaging: Preliminary Results Hack, L., Brawer, J., Zhang, X., Wintermark, M., Jiang, B., Stetz, P., Yesavage, J., Grant, P., Bonilla, H., Subramanian, A., Williams, L. SPRINGERNATURE. 2021: 205-206

  View details for Web of Science ID 000725511400390

• Factors Associated with Resilience Among Older People Living with HIV. AIDS and behavior Berko, J., Mazonson, P., Loo, T., Grant, P., Zolopa, A., Spinelli, F., Short, D. 2021

  Abstract

  Resilience, a measure of stress coping ability, may be important in helping older people (age 50+) living with HIV (PLWH) age successfully, but limited data exist regarding factors that contribute to resilience for this group. This study uses the Connor-Davidson Resilience Scale 2 (CD-RISC2) to assess resilience, based on a cross-sectional analysis of 1047 older PLWH. Bivariate linear regression models were used to identify predictor variables that had a relationship with resilience. Those variables were then included in a multivariable linear regression model, which was pared using backward selection. In the multivariable model, higher income and greater interpersonal support were associated with greater resilience, whereas depression and anxiety were associated with lower resilience. Relevant interventions that address these issues, such as increasing opportunities for social support and increasing screening for and treatment of depression and anxiety, are identified as potential pathways to increase resilience among older PLWH.

  View details for DOI 10.1007/s10461-021-03499-z

  View details for PubMedID 34698952

• Patients with uncomplicated COVID-19 have long-term persistent symptoms and functional impairment similar to patients with severe COVID-19: a cautionary tale during a global pandemic. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Jacobson, K. B., Rao, M., Bonilla, H., Subramanian, A., Hack, I., Madrigal, M., Singh, U., Jagannathan, P., Grant, P. 2021

  Abstract

  To assess the prevalence of persistent functional impairment after COVID-19, we assessed 118 individuals 3-4 months after their initial COVID-19 diagnosis with a symptom survey, work productivity and activity index questionnaire, and 6-minute walk test. We found significant persistent symptoms and functional impairment, even in non-hospitalized patients with COVID-19.

  View details for DOI 10.1093/cid/ciab103

  View details for PubMedID 33624010

• SARS-CoV-2 Neutralization Resistance Mutations in Patient with HIV/AIDS, California, USA. Emerging infectious diseases Hoffman, S. A., Costales, C., Sahoo, M. K., Palanisamy, S., Yamamoto, F., Huang, C., Verghese, M., Solis, D. C., Sibai, M., Subramanian, A., Tompkins, L. S., Grant, P., Shafer, R. W., Pinsky, B. A. 2021; 27 (10)

  Abstract

  We report persistent severe acute respiratory syndrome coronavirus 2 infection in a patient with HIV/AIDS; the virus developed spike N terminal domain and receptor binding domain neutralization resistance mutations. Our findings suggest that immunocompromised patients can harbor emerging variants of severe acute respiratory syndrome coronavirus 2.

  View details for DOI 10.3201/eid2710.211461

  View details for PubMedID 34296992

• Signatures of immune dysfunction in HIV and HCV infection share features with chronic inflammation in aging and persist after viral reduction or elimination. Proceedings of the National Academy of Sciences of the United States of America Lopez Angel, C. J., Pham, E. A., Du, H. n., Vallania, F. n., Fram, B. J., Perez, K. n., Nguyen, T. n., Rosenberg-Hasson, Y. n., Ahmed, A. n., Dekker, C. L., Grant, P. M., Khatri, P. n., Maecker, H. T., Glenn, J. S., Davis, M. M., Furman, D. n. 2021; 118 (14)

  Abstract

  Chronic inflammation is thought to be a major cause of morbidity and mortality in aging, but whether similar mechanisms underlie dysfunction in infection-associated chronic inflammation is unclear. Here, we profiled the immune proteome, and cellular composition and signaling states in a cohort of aging individuals versus a set of HIV patients on long-term antiretroviral therapy therapy or hepatitis C virus (HCV) patients before and after sofosbuvir treatment. We found shared alterations in aging-associated and infection-associated chronic inflammation including T cell memory inflation, up-regulation of intracellular signaling pathways of inflammation, and diminished sensitivity to cytokines in lymphocytes and myeloid cells. In the HIV cohort, these dysregulations were evident despite viral suppression for over 10 y. Viral clearance in the HCV cohort partially restored cellular sensitivity to interferon-α, but many immune system alterations persisted for at least 1 y posttreatment. Our findings indicate that in the HIV and HCV cohorts, a broad remodeling and degradation of the immune system can persist for a year or more, even after the removal or drastic reduction of the pathogen load and that this shares some features of chronic inflammation in aging.

  View details for DOI 10.1073/pnas.2022928118

  View details for PubMedID 33811141

• Risk factors for difficult-to-treat Hepatitis C Virus genotype 4r in Rwanda and implications for elimination in sub-Saharan africa. Journal of viral hepatitis Shumbusho, F. n., Liu, A. F., Kateera, F. n., Kabahizi, J. n., Nsanzaimana, S. n., Serumondo, J. n., Damascene Makuza, J. n., Grant, P. M., Musabeyezu, E. n., Muvunyi, C. n., Gupta, N. n. 2021

  Abstract

  In sub-Saharan Africa there exist distinct HCV genotype (GT) subtypes harboring resistance-associated substitutions to commonly used non-structural protein 5A (NS5A) inhibitor-based direct-acting antiviral (DAA) regimens. In particular, GT4r subtype has demonstrated high rates of treatment failure. In the absence of routine viral sequencing in sub-Saharan Africa, it is important to identify sociodemographic, epidemiologic, and clinical characteristics that may be associated with GT4r infection. Methods: A secondary analysis was performed on data from 300 adults with HCV GT4 enrolled in a prospective trial assessing the safety and efficacy of sofosbuvir-ledipasvir in Rwanda in 2017. Association between characteristics at enrolment and GT subtype were assessed by chi-squared analysis and logistic regression. In multivariate analysis, there was a higher proportion of participants with GT4r subtype with age < 40 years (OR 3.6, 95% CI 1.3-10.5, p=0.02), previous hospitalization (OR 2.5, 95% CI 1.3-5.0, p=0.006), previous surgery (OR 2.2, 95% CI 1.1-4.2, p=0.03), cirrhosis (OR 3.2, 95% CI 1.3-7.5, p=0.008), and baseline HCV RNA > 1 million IU/mL (OR 3.4, 95% CI 1.6-6.9, p=0.001). Rwandan adults with GT4r are more likely to be younger, have a history of hospital admissions and surgeries, and have more active or advanced liver disease compared to those with other GT4 subtypes. In the absence of advanced diagnostics to assess GT subtype, patients with these characteristics may warrant closer monitoring for treatment failure or alternative DAA regimens. More treatment experience with diverse DAA regimens is urgently needed for GT subtypes particular to this region.

  View details for DOI 10.1111/jvh.13467

  View details for PubMedID 33421247

• Use of Remdesivir for Pregnant Patients with Severe Novel 2019 Coronavirus Disease. American journal of obstetrics and gynecology Igbinosa, I., Miller, S., Bianco, K., Nelson, J., Kappagoda, S., Blackburn, B. G., Grant, P., Subramanian, A., Lyell, D., El-Sayed, Y., Aziz, N. 2020

  View details for DOI 10.1016/j.ajog.2020.08.001

  View details for PubMedID 32771381

• Cytokine profile in plasma of severe COVID-19 does not differ from ARDS and sepsis. JCI insight Wilson, J. G., Simpson, L. J., Ferreira, A., Rustagi, A., Roque, J. A., Asuni, A., Ranganath, T., Grant, P. M., Subramanian, A. K., Rosenberg-Hasson, Y., Maecker, H., Holmes, S., Levitt, J. E., Blish, C., Rogers, A. J. 2020

  Abstract

  BACKGROUND: Elevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare to those observed in critically ill patients with ARDS or sepsis due to other causes.METHODS: We used a luminex assay to determine expression of 76 cytokines from plasma of hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients. Our analysis focused on detecting statistical differences in levels of 6 cytokines associated with cytokine storm (IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNFalpha) between patients with moderate COVID-19, severe COVID-19, and ARDS or sepsis.RESULTS: 15 hospitalized COVID-19 patients, 9 of whom were critically ill, were compared to critically ill patients with ARDS (n = 12) or sepsis (n = 16). There were no statistically significant differences in baseline levels of IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNFalpha between patients with COVID-19 and critically ill controls with ARDS or sepsis.CONCLUSIONS: Levels of inflammatory cytokines were not higher in severe COVID-19 patients than in moderate COVID-19 or critically ill patients with ARDS or sepsis in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 may be unwarranted.FUNDING: A.J.R.: Stanford ICU Biobank NHLBI K23 HL125663. C.A.B.: Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases #1016687; NIH/NIAID U19AI057229-16 (PI MM Davis); Stanford Maternal Child Health Research Institute; Chan Zuckerberg Biohub.

  View details for DOI 10.1172/jci.insight.140289

  View details for PubMedID 32706339

• A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nature medicine Wilk, A. J., Rustagi, A., Zhao, N. Q., Roque, J., Martinez-Colon, G. J., McKechnie, J. L., Ivison, G. T., Ranganath, T., Vergara, R., Hollis, T., Simpson, L. J., Grant, P., Subramanian, A., Rogers, A. J., Blish, C. A. 2020

  Abstract

  There is an urgent need to better understand the pathophysiology of Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, which has infected more than three million people worldwide1. Approximately 20% of patients with COVID-19 develop severe disease and 5% of patients require intensive care2. Severe disease has been associated with changes in peripheral immune activity, including increased levels of pro-inflammatory cytokines3,4 that may be produced by a subset of inflammatory monocytes5,6, lymphopenia7,8 and T cell exhaustion9,10. To elucidate pathways in peripheral immune cells that might lead to immunopathology or protective immunity in severe COVID-19, we applied single-cell RNA sequencing (scRNA-seq) to profile peripheral blood mononuclear cells (PBMCs) from seven patients hospitalized for COVID-19, four of whom had acute respiratory distress syndrome, and six healthy controls. We identify reconfiguration of peripheral immune cell phenotype in COVID-19, including a heterogeneous interferon-stimulated gene signature, HLA class II downregulation and a developing neutrophil population that appears closely related to plasmablasts appearing in patients with acute respiratory failure requiring mechanical ventilation. Importantly, we found that peripheral monocytes and lymphocytes do not express substantial amounts of pro-inflammatory cytokines. Collectively, we provide a cell atlas of the peripheral immune response to severe COVID-19.

  View details for DOI 10.1038/s41591-020-0944-y

  View details for PubMedID 32514174

• A single-cell atlas of the peripheral immune response to severe COVID-19. medRxiv : the preprint server for health sciences Wilk, A. J., Rustagi, A., Zhao, N. Q., Roque, J., Martinez-Colon, G. J., McKechnie, J. L., Ivison, G. T., Ranganath, T., Vergara, R., Hollis, T., Simpson, L. J., Grant, P., Subramanian, A., Rogers, A. J., Blish, C. A. 2020

  Abstract

  There is an urgent need to better understand the pathophysiology of Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2. Here, we apply single-cell RNA sequencing (scRNA-seq) to peripheral blood mononuclear cells (PBMCs) of 7 patients hospitalized with confirmed COVID-19 and 6 healthy controls. We identify substantial reconfiguration of peripheral immune cell phenotype in COVID-19, including a heterogeneous interferon-stimulated gene (ISG) signature, HLA class II downregulation, and a novel B cell-derived granulocyte population appearing in patients with acute respiratory failure requiring mechanical ventilation. Importantly, peripheral monocytes and lymphocytes do not express substantial amounts of pro-inflammatory cytokines, suggesting that circulating leukocytes do not significantly contribute to the potential COVID-19 cytokine storm. Collectively, we provide the most thorough cell atlas to date of the peripheral immune response to severe COVID-19.

  View details for DOI 10.1101/2020.04.17.20069930

  View details for PubMedID 32511639

• Enhancing natural killer cell function with gp41-targeting bispecific antibodies to combat HIV infection. AIDS (London, England) Ramadoss, N. S., Zhao, N. Q., Richardson, B. A., Grant, P. M., Kim, P. S., Blish, C. A. 2020

  Abstract

  OBJECTIVE(S): To develop and evaluate the activity of bispecific antibodies (bsAbs) to enhance NK cell antibody-dependent cellular cytotoxicity (ADCC) against HIV-infected cells.DESIGN: These bsAbs are based on patient-derived antibodies targeting the conserved gp41 stump of HIV Env, and also incorporate a high affinity single chain variable fragment (scFv) targeting the activating receptor CD16 on NK cells. Overall, we expect the bsAbs to provide increased affinity and avidity over their corresponding monoclonal antibodies, allowing for improved ADCC activity against Env-expressing target cells.METHODS: bsAbs and their corresponding mAbs were expressed in 293T cells and purified. The binding of bsAbs and mAbs to their intended targets was determined using Bio-Layer Interferometry, as well as flow cytometry-based binding assays on in vitro infected cells. The ability of these bsAbs to improve NK cell activity against HIV-infected cells was tested using in vitro co-culture assays, using flow cytometry and calcein release to analyze NK cell degranulation and target cell killing, respectively.RESULTS: The bsAbs bound gp41 with similar affinity to their corresponding mAbs, and had increased affinity for CD16. The bsAbs also bound to primary CD4 T cells infected in vitro with two different strains of HIV. In addition, the bsAbs induce increased NK cell degranulation and killing of autologous HIV-infected CD4 T cells.CONCLUSIONS: Based on their in vitro killing efficacy, bsAbs may provide a promising strategy to improve NK-mediated immune targeting of infected cells during HIV infection.

  View details for DOI 10.1097/QAD.0000000000002543

  View details for PubMedID 32287071

• Safety and Efficacy of Limited Laboratory Monitoring for Hepatitis C Treatment: A Blinded Clinical Trial in Rwanda. Hepatology communications Grant, P., Shumbusho, F., Van Nuil, J. I., Kateera, F., Mukherjee, J., Kabahizi, J., Ntaganda, F., Nsanzimana, S., Mbituyumuremyi, A., Damascene, M. J., Muvunyi, C. M., Mukabatsinda, C., Musabeyezu, E., Ntirenganya, C., Gupta, N. 2020; 4 (4): 569-576

  Abstract

  Direct-acting antivirals for hepatitis C virus (HCV) are highly effective and well-tolerated. However, only a small percentage of HCV-infected individuals globally have received therapy. Reducing the complexity of monitoring during HCV therapy, if shown to be safe, could facilitate greater access to HCV services, particularly in resource-limited settings such as sub-Saharan Africa. We enrolled a total of 300 patients who were chronically infected with genotype 4 HCV in Rwanda and treated them with fixed-dose ledispasvir/sofosbuvir for 12 weeks. For 60 consecutive participants enrolled, we blinded the study clinician to on-treatment laboratory results. We compared the efficacy, safety, and tolerability in those with blinded laboratory results to those with standard laboratory monitoring. Baseline characteristics among those with blinded laboratory values were comparable to those with standard monitoring. Among both groups, the median age was 63 years, and the median HCV viral load was 5.9 log (versus 64 years and 6.0 log, respectively). Sustained virologic response rates at 12 weeks after treatment completion were similar in those with blinded laboratories (87%) compared to those with standard laboratory monitoring (87%). There was no increase in adverse events in those with blinded laboratory results, and no participants discontinued the study medication because of an adverse event. Conclusion: On-treatment laboratory monitoring did not improve patient outcomes in those treated with ledispasvir/sofosbuvir. Eliminating this monitoring in treatment programs in resource-limited settings may facilitate and accelerate scale-up of HCV therapy.

  View details for DOI 10.1002/hep4.1482

  View details for PubMedID 32258951

  View details for PubMedCentralID PMC7109339

• Safety and Efficacy of Limited Laboratory Monitoring for Hepatitis C Treatment: A Blinded Clinical Trial in Rwanda HEPATOLOGY COMMUNICATIONS Grant, P., Shumbusho, F., Van Nuil, J., Kateera, F., Mukherjee, J., Kabahizi, J., Ntaganda, F., Nsanzimana, S., Mbituyumuremyi, A., Damascene, M., Muvunyi, C., Mukabatsinda, C., Musabeyezu, E., Ntirenganya, C., Gupta, N. 2020

  View details for DOI 10.1002/hep4.1482

  View details for Web of Science ID 000511122000001

• Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. The New England journal of medicine Goldman, J. D., Lye, D. C., Hui, D. S., Marks, K. M., Bruno, R. n., Montejano, R. n., Spinner, C. D., Galli, M. n., Ahn, M. Y., Nahass, R. G., Chen, Y. S., SenGupta, D. n., Hyland, R. H., Osinusi, A. O., Cao, H. n., Blair, C. n., Wei, X. n., Gaggar, A. n., Brainard, D. M., Towner, W. J., Muñoz, J. n., Mullane, K. M., Marty, F. M., Tashima, K. T., Diaz, G. n., Subramanian, A. n. 2020

  Abstract

  Remdesivir is an RNA polymerase inhibitor with potent antiviral activity in vitro and efficacy in animal models of coronavirus disease 2019 (Covid-19).We conducted a randomized, open-label, phase 3 trial involving hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation of 94% or less while they were breathing ambient air, and radiologic evidence of pneumonia. Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received 200 mg of remdesivir on day 1 and 100 mg once daily on subsequent days. The primary end point was clinical status on day 14, assessed on a 7-point ordinal scale.In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). The median duration of treatment was 5 days (interquartile range, 5 to 5) in the 5-day group and 9 days (interquartile range, 5 to 10) in the 10-day group. At baseline, patients randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P = 0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P = 0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%).In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined. (Funded by Gilead Sciences; GS-US-540-5773 ClinicalTrials.gov number, NCT04292899.).

  View details for DOI 10.1056/NEJMoa2015301

  View details for PubMedID 32459919

• Improved quality of life following direct-acting antiviral treatment for chronic hepatitis C infection in Rwanda: Results from a clinical trial in sub-Saharan Africa (the SHARED study). Journal of viral hepatitis Van Nuil, J. I., Umutesi, G. n., Shumbusho, F. n., Kateera, F. n., Dushimimana, J. d., Muvunyi, C. M., Musabeyezu, E. n., Mukabatsinda, C. n., Ntirenganya, C. n., Kabahizi, J. n., Serumondo, J. n., Makuza, J. D., Nsanzimana, S. n., Grant, P. n., Gupta, N. n. 2020

  Abstract

  Around 71 million people are living with chronic hepatitis C virus (HCV) infection, with approximately 14% residing in Sub-Saharan Africa. Direct acting anti-viral (DAA) therapies offer clear benefits for liver-related morbidity and mortality, and data from high-income settings suggest that DAA treatments also provide significant benefits in terms of health-related quality of life (HRQL). In this study, we assessed the effect of DAA treatment on HRQL for individuals treated for HCV in a clinical trial in Rwanda. We assessed the HRQL of participants using an 83-question composite survey at Day 0 ('baseline') and Week 24 ('endpoint'). Data were analyzed in R. 296 participants were included in this analysis. Their ages ranged from 19-90 and 184 (62.2%) were female. There were significant improvements from baseline to endpoint median scores for all physical and mental quality of life sub-scales. Additionally, a reduction - before and after treatment - in the proportion of those classified as depressed and needing social support was statistically significant (both p<0.001). Economic productivity increased after treatment (p<0.001) and households classified as food secure increased from baseline to endpoint (p<0.001). These results demonstrate that Rwandans with chronic HCV infection experience both clinical and HRQL benefits, including household level benefits like substantial gains in workforce stability, economic productivity, and poverty alleviation, from DAA treatment. A stronger demonstration of accurate and broader household level benefits achieved through treatment of HCV with DAAs will help financing and investment for HCV in resource-constrained settings become an urgent priority.

  View details for DOI 10.1111/jvh.13386

  View details for PubMedID 32858774

• Treated HIV Infection Alters Phenotype but Not HIV-Specific Function of Peripheral Blood Natural Killer Cells. Frontiers in immunology Zhao, N. Q., Ferreira, A., Grant, P. M., Holmes, S., Blish, C. A. 2020; 11: 829

  Abstract

  Natural killer (NK) cells are the predominant antiviral cells of the innate immune system, and may play an important role in acquisition and disease progression of HIV. While untreated HIV infection is associated with distinct alterations in the peripheral blood NK cell repertoire, less is known about how NK phenotype is altered in the setting of long-term viral suppression with antiretroviral therapy (ART), as well as how NK memory can impact functional responses. As such, we sought to identify changes in NK cell phenotype and function using high-dimensional mass cytometry to simultaneously analyze both surface and functional marker expression of peripheral blood NK cells in a cohort of ART-suppressed, HIV+ patients and HIV- healthy controls. We found that the NK cell repertoire following IL-2 treatment was altered in individuals with treated HIV infection compared to healthy controls, with increased expression of markers including NKG2C and CD2, and decreased expression of CD244 and NKp30. Using co-culture assays with autologous, in vitro HIV-infected CD4 T cells, we identified a subset of NK cells with enhanced responsiveness to HIV-1-infected cells, but no differences in the magnitude of anti-HIV NK cell responses between the HIV+ and HIV- groups. In addition, by profiling of NK cell receptors on responding cells, we found similar phenotypes of HIV-responsive NK cell subsets in both groups. Lastly, we identified clusters of NK cells that are altered in individuals with treated HIV infection compared to healthy controls, but found that these clusters are distinct from those that respond to HIV in vitro. As such, we conclude that while chronic, treated HIV infection induces a reshaping of the IL-2-stimulated peripheral blood NK cell repertoire, it does so in a way that does not make the repertoire more HIV-specific.

  View details for DOI 10.3389/fimmu.2020.00829

  View details for PubMedID 32477342

• A systematic review of the genetic mechanisms of dolutegravir resistance. The Journal of antimicrobial chemotherapy Rhee, S. Y., Grant, P. M., Tzou, P. L., Barrow, G. n., Harrigan, P. R., Ioannidis, J. P., Shafer, R. W. 2019

  Abstract

  Characterizing the mutations selected by the integrase strand transfer inhibitor (INSTI) dolutegravir and their effects on susceptibility is essential for identifying viruses less likely to respond to dolutegravir therapy and for monitoring persons with virological failure (VF) on dolutegravir therapy.We systematically reviewed dolutegravir resistance studies to identify mutations emerging under dolutegravir selection pressure, the effect of INSTI resistance mutations on in vitro dolutegravir susceptibility, and the virological efficacy of dolutegravir in antiretroviral-experienced persons.We analysed 14 studies describing 84 in vitro passage experiments, 26 studies describing 63 persons developing VF plus INSTI resistance mutations on a dolutegravir-containing regimen, 41 studies describing dolutegravir susceptibility results, and 22 clinical trials and 16 cohort studies of dolutegravir-containing regimens. The most common INSTI resistance mutations in persons with VF on a dolutegravir-containing regimen were R263K, G118R, N155H and Q148H/R, with R263K and G118R predominating in previously INSTI-naive persons. R263K reduced dolutegravir susceptibility ∼2-fold. G118R generally reduced dolutegravir susceptibility >5-fold. The highest levels of reduced susceptibility occurred in viruses containing Q148 mutations in combination with G140 and/or E138 mutations. Dolutegravir two-drug regimens were highly effective for first-line therapy and for virologically suppressed persons provided dolutegravir's companion drug was fully active. Dolutegravir three-drug regimens were highly effective for salvage therapy in INSTI-naive persons provided one or more of dolutegravir's companion drugs was fully active. However, dolutegravir monotherapy in virologically suppressed persons and functional dolutegravir monotherapy in persons with active viral replication were associated with a non-trivial risk of VF plus INSTI resistance mutations.

  View details for DOI 10.1093/jac/dkz256

  View details for PubMedID 31280314

• Treatment of chronic hepatitis C virus infection in Rwanda with ledipasvir-sofosbuvir (SHARED): a single-arm trial. The lancet. Gastroenterology & hepatology Gupta, N., Mbituyumuremyi, A., Kabahizi, J., Ntaganda, F., Muvunyi, C. M., Shumbusho, F., Musabeyezu, E., Mukabatsinda, C., Ntirenganya, C., Van Nuil, J. I., Kateera, F., Camus, G., Damascene, M. J., Nsanzimana, S., Mukherjee, J., Grant, P. M. 2018

  Abstract

  BACKGROUND: Limited treatment data are available for hepatitis C virus (HCV) in sub-Saharan Africa, especially for genotype 4. Our objective was to establish the safety and efficacy of ledipasvir-sofosbuvir for chronic HCV genotype 1 or 4 infection in adults in Rwanda.METHODS: We did a single-arm trial to evaluate the safety and efficacy of ledipasvir-sofosbuvir in Rwandan adults with chronic HCV infection at a single study site (Rwanda Military Hospital, Kigali, Rwanda). We enrolled individuals aged 18 years or older with HCV genotype 1 or 4 infection and a plasma HCV RNA concentration of more than 1000 IU/mL at screening. All participants were given ledipasvir (90 mg) and sofosbuvir (400 mg) in a single combination tablet once daily for 12 weeks. We established HCV genotype using an Abbott platform, and HCV subtype with PCR amplification. The primary endpoint was the proportion of participants with a sustained virological response 12 weeks after therapy (SVR12). All patients enrolled in the study were included in the primary endpoint analyses. This study is registered with ClinicalTrials.gov, number NCT02964091.FINDINGS: 300 participants were enrolled between Feb 6, 2017, and Sept 18, 2017, and the follow-up period was completed on March 1, 2018. On genotyping, 248 (83%) participants were reported as having genotype 4, four (1%) genotype 1, and 48 (16%) both genotype 1 and genotype 4. Subsequent viral sequencing showed all participants actually had genotype 4 infection with subtype 4k (134 [45%]), subtype 4r (48 [16%]), subtype 4q (42 [14%]), and subtype 4v (24 [8%]) predominating. Overall, 261 (87%, 95% CI 83-91) participants achieved SVR12. In participants with genotype 4r, SVR12 was observed in 27 (56%, 95% CI 41-71) participants versus 234 (93%, 90-96) individuals with other subtypes. There were no drug-related treatment discontinuations due to ledipasvir-sofosbuvir. The most common adverse events were hypertension (97 [32%]), headache (78 [26%]), dizziness (61 [20%]), and fatigue (56 [19%]). There were six serious adverse events; none were assessed to be due to the study drug. 296 participants had data for pill counts at week 4 and 8; 271 (92%) had 100% adherence and only one (<1%) had an adherence of less than 90%.INTERPRETATION: This is the first large-scale prospective study reporting direct-acting antiviral outcomes in sub-Saharan Africa. The high adherence and treatment success without intensive support measures or highly specialised clinical providers, and lack of treatment discontinuations due to adverse events support the feasibility of HCV treatment decentralisation and scale-up in sub-Saharan Africa. Genotype 4r is uniquely expressed in this region and associated with high rates of treatment failure, suggesting a need for rigorous test-of-cure in clinical practice and consideration of the use of newer pangenotypic direct-acting antiviral regimens in this region.FUNDING: Gilead Sciences.

  View details for PubMedID 30552056

• Effect of Testosterone Use on Bone Mineral Density in HIV-Infected Men AIDS RESEARCH AND HUMAN RETROVIRUSES Grant, P. M., Li, X., Jacobson, L. P., Palella, F. J., Kingsley, L. A., Margolick, J. B., Dobs, A. S., Lake, J. E., Althoff, K. N., Brown, T. T. 2019; 35 (1): 75–80

  View details for DOI 10.1089/aid.2018.0150

  View details for Web of Science ID 000448918700001

• Effect of Testosterone Use on Bone Mineral Density in HIV-infected Men. AIDS research and human retroviruses Grant, P. M., Li, X., Jacobson, L., Palella, F. J., Kingsley, L., Margolick, J. B., Dobs, A. S., Lake, J. E., Althoff, K. N., Brown, T. 2018

  Abstract

  BACKGROUND HIV-infected men have increased rates of osteoporosis and fracture compared to HIV-uninfected men. Testosterone use among HIV-infected men is common. In HIV-uninfected men, testosterone increases bone mineral density (BMD), but its effects have not been evaluated in HIV-infected men. METHODS In a substudy of Multicenter AIDS Cohort Study (MACS), the Bone Strength Substudy (BOSS) enrolled 202 HIV-infected and 201 HIV-uninfected men age 50 and 69 years. Study participants underwent dual-energy x-ray absorptiometry (DXA) at the lumbar spine (LS), total hip (TH), and femoral neck (FN), and detailed assessment of osteoporosis risk factors. We used multivariable linear regression to determine associations and 95% confidence intervals (CI) between self-reported testosterone use and T-scores at the LS, TH, and FN after adjustment for demographics, behavioral covariates, comorbidities, and other traditional osteoporosis risk factors. RESULTS HIV-infected men reported more frequent testosterone use (22% vs. 4%; p<0.001) and had lower median BMD T-score at TH than HIV-uninfected men (0.0 vs. 0.3; p=0.045) but similar T-scores at LS and FN. In the overall study population, testosterone use was associated with significantly greater BMD T-score at LS (0.68; 95% CI:.0.22,1.13). In HIV-infected men with virologic suppression, testosterone was significantly associated with higher BMD T-score at LS (0.95; 95% CI: 0.36, 1.54) and TH (0.45; 95% CI: 0.04, 0.86). CONCLUSIONS Current testosterone use is common in HIV-infected men and was associated with higher BMD, compared to those not taking testosterone. Testosterone's role in reducing fracture risk in HIV-infected men should be investigated.

  View details for PubMedID 30280921

• Safety and Efficacy of Ledipasvir/Sofosbuvir without on-Treatment Laboratory Monitoring in HCV-Infected Rwandans: The Shared 2 Study Grant, P., Kabahizi, J., Mbituyumuremyi, A., Van Nuil, J., Mukabatsinda, C., Damascene, M., Shumbusho, F., Ntirenganya, C., Nsanzimana, S., Gupta, N. WILEY. 2018: 36A

  View details for Web of Science ID 000446020500055

• A Comparison of the Liver Fat Score and CT Liver-to-Spleen Ratio as Predictors of Fatty Liver Disease by HIV Serostatus. Journal of clinical gastroenterology and hepatology Mellor-Crummey, L. E., Lake, J. E., Wilhalme, H., Tseng, C., Grant, P. M., Erlandson, K. M., Price, J. C., Palella, F. J., Kingsley, L. A., Budoff, M., Post, W. S., Brown, T. T. 2018; 2 (3)

  Abstract

  Background and Aim: Non-alcoholic fatty liver disease (NAFLD) is common among HIV-infected (HIV+) adults. The Liver Fat Score (LFS) is a non-invasive, rapid, inexpensive diagnostic tool that uses routine clinical data and is validated against biopsy in HIV-uninfected (HIV-) persons. CT liver-to-spleen (L/S) attenuation ratio is another validated method to diagnose NAFLD. We compared NAFLD prevalence using the LFS versus L/S ratio among Multicenter AIDS Cohort Study participants to assess the LFS's performance in HIV+vs. HIV-men.Methods: In a cross-sectional analysis of men reporting<3 alcoholic drinks daily (308 HIV+, 218 HIV-), Spearman correlations determined relationships between LFS and L/S ratio by HIV serostatus. Multivariable regression determined factors associated with discordance in LFS- and L/S ratio-defined NAFLD prevalence.Results: NAFLD prevalence by LFS and L/S ratio were 28%/15% for HIV+men and 20%/19% for HIV-men, respectively. Correlations between LFS and L/S ratio were weaker among HIV+than HIV-men, but improved with increasing BMI and exclusion of HCV-infected men. LFS and L/S ratio discordance occurred more frequently and across BMI strata among HIV+men, but predominantly at BMI<30 kg/m2 among HIV-men. In multivariate analysis, only lower total testosterone levels were significantly associated with discordance.Conclusion: NAFLD prevalence was similar by LFS and L/S ratio identification among HIV-men, but dissimilar and with frequent discordance between the two tests among HIV+men. As discordance may be multifactorial, biopsy data are needed to determine the best non-invasive diagnostic test for NAFLD in HIV+persons.

  View details for PubMedID 30511049

• High Rates of Rapid Virologic Response for Chronic Hepatitis C Infection Treated with Ledipasvir/Sofosbuvir in Rwanda: Preliminary Results from the SHARED Study Gupta, N., Kabahizi, J., Muvunyi, C., Mbituyumuremyi, A., Van Nuil, J. I., Grant, P. M. WILEY. 2017: 615A

  View details for Web of Science ID 000412089801285

• Collaborative update of a rule-based expert system for HIV-1 genotypic resistance test interpretation. PloS one Paredes, R. n., Tzou, P. L., van Zyl, G. n., Barrow, G. n., Camacho, R. n., Carmona, S. n., Grant, P. M., Gupta, R. K., Hamers, R. L., Harrigan, P. R., Jordan, M. R., Kantor, R. n., Katzenstein, D. A., Kuritzkes, D. R., Maldarelli, F. n., Otelea, D. n., Wallis, C. L., Schapiro, J. M., Shafer, R. W. 2017; 12 (7): e0181357

  Abstract

  HIV-1 genotypic resistance test (GRT) interpretation systems (IS) require updates as new studies on HIV-1 drug resistance are published and as treatment guidelines evolve.An expert panel was created to provide recommendations for the update of the Stanford HIV Drug Resistance Database (HIVDB) GRT-IS. The panel was polled on the ARVs to be included in a GRT report, and the drug-resistance interpretations associated with 160 drug-resistance mutation (DRM) pattern-ARV combinations. The DRM pattern-ARV combinations included 52 nucleoside RT inhibitor (NRTI) DRM pattern-ARV combinations (13 patterns x 4 NRTIs), 27 nonnucleoside RT inhibitor (NNRTI) DRM pattern-ARV combinations (9 patterns x 3 NNRTIs), 39 protease inhibitor (PI) DRM pattern-ARV combinations (13 patterns x 3 PIs) and 42 integrase strand transfer inhibitor (INSTI) DRM pattern-ARV combinations (14 patterns x 3 INSTIs).There was universal agreement that a GRT report should include the NRTIs lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir disoproxil fumarate; the NNRTIs efavirenz, etravirine, nevirapine, and rilpivirine; the PIs atazanavir/r, darunavir/r, and lopinavir/r (with "/r" indicating pharmacological boosting with ritonavir or cobicistat); and the INSTIs dolutegravir, elvitegravir, and raltegravir. There was a range of opinion as to whether the NRTIs stavudine and didanosine and the PIs nelfinavir, indinavir/r, saquinavir/r, fosamprenavir/r, and tipranavir/r should be included. The expert panel members provided highly concordant DRM pattern-ARV interpretations with only 6% of NRTI, 6% of NNRTI, 5% of PI, and 3% of INSTI individual expert interpretations differing from the expert panel median by more than one resistance level. The expert panel median differed from the HIVDB 7.0 GRT-IS for 20 (12.5%) of the 160 DRM pattern-ARV combinations including 12 NRTI, two NNRTI, and six INSTI pattern-ARV combinations. Eighteen of these differences were updated in HIVDB 8.1 GRT-IS to reflect the expert panel median. Additionally, HIVDB users are now provided with the option to exclude those ARVs not considered to be universally required.The HIVDB GRT-IS was updated through a collaborative process to reflect changes in HIV drug resistance knowledge, treatment guidelines, and expert opinion. Such a process broadens consensus among experts and identifies areas requiring further study.

  View details for PubMedID 28753637

• Long-term body composition changes in antiretroviral-treated HIV-infected individuals AIDS Grant, P. M., Kitch, D., McComsey, G. A., Collier, A. C., Bartali, B., Koletar, S. L., Erlandson, K. M., Lake, J. E., Yin, M. T., Melbourne, K., Ha, B., Brown, T. T. 2016; 30 (18): 2805-2813

  Abstract

  Body composition impacts physical function and mortality. We compared long-term body composition changes after antiretroviral therapy (ART) initiation in HIV-infected individuals to that in HIV-uninfected controls.Prospective observational study.We performed dual-energy x-ray absorptiometry (DXA) approximately 7.5 years after initial DXA in available HIV-infected individuals who received DXAs during the randomized treatment trial AIDS Clinical Trials Group A5202. For controls, we used DXA results from HIV-uninfected participants in the Boston Area Community Health/Bone and Women's Interagency HIV Study cohorts. Repeated measures analyses compared adjusted body composition changes between HIV-infected and HIV-uninfected individuals. Multivariable analyses evaluated factors associated with body composition change in HIV-infected individuals.We obtained DXA results in 97 HIV-infected and 614 HIV-uninfected participants. Compared with controls, HIV-infected individuals had greater adjusted lean mass and total, trunk, and limb fat gain during the first 96 weeks of ART. Subsequently, HIV-infected individuals lost lean mass compared with controls. Total, trunk, and limb fat gains after 96 weeks of ART slowed in HIV-infected individuals but remained greater than in controls. Lower CD4 T-cell count was associated with lean mass and fat gain during the initial 96 weeks of ART, but subsequently no HIV-related characteristic was associated with body composition change.Consistent with a 'return to health effect', HIV-infected individuals, especially those with lower baseline CD4 T-cell counts, gained more lean mass and fat during the first 96 weeks of ART than HIV-uninfected individuals. Continued fat gain and lean mass loss after 96 weeks may predispose HIV-infected individuals to obesity-related diseases and physical function impairment.

  View details for DOI 10.1097/QAD.0000000000001248

  View details for Web of Science ID 000387206900008

  View details for PubMedID 27662545

• A Randomized Switch From Nevirapine-Based Antiretroviral Therapy to Single Tablet Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate in Virologically Suppressed Human Immunodeficiency Virus-1-Infected Rwandans. Open forum infectious diseases Collins, S. E., Grant, P. M., Uwinkindi, F., Talbot, A., Seruyange, E., Slamowitz, D., Mugeni, A., Remera, E., Niyonsenga, S. P., Nyirimigabo, J., Uwizihiwe, J. P., Dongier, P., Muhayimpundu, R., Mazarati, J., Zolopa, A., Nsanzimana, S. 2016; 3 (3): ofw141-?

  Abstract

  Background.  Many human immunodeficiency virus (HIV)-infected patients remain on nevirapine-based antiretroviral therapy (ART) despite safety and efficacy concerns. Switching to a rilpivirine-based regimen is an alternative, but there is little experience with rilpivirine in sub-Saharan Africa where induction of rilpivirine metabolism by nevirapine, HIV subtype, and dietary differences could potentially impact efficacy. Methods.  We conducted an open-label noninferiority study of virologically suppressed (HIV-1 ribonucleic acid [RNA] < 50 copies/mL) HIV-1-infected Rwandan adults taking nevirapine plus 2 nucleos(t)ide reverse-transcriptase inhibitors. One hundred fifty participants were randomized 2:1 to switch to coformulated rilpivirine-emtricitabine-tenofovir disoproxil fumarate (referenced as the Switch Arm) or continue current therapy. The primary efficacy endpoint was HIV-1 RNA < 200 copies/mL at week 24 assessed by the US Food and Drug Administration Snapshot algorithm with a noninferiority margin of 12%. Results.  Between April and September 2014, 184 patients were screened, and 150 patients were enrolled; 99 patients switched to rilpivirine-emtricitabine-tenofovir, and 51 patients continued their nevirapine-based ART. The mean age was 42 years and 43% of participants were women. At week 24, virologic suppression (HIV-1 RNA level <200 copies/mL) was maintained in 93% and 92% in the Switch Arm versus the continuation arm, respectively. The Switch Arm was noninferior to continued nevirapine-based ART (efficacy difference 0.8%; 95% confidence interval, -7.5% to +12.0%). Both regimens were generally safe and well tolerated, although 2 deaths, neither attributed to study medications, occurred in participants in the Switch Arm. Conclusions.  A switch from nevirapine-based ART to rilpivirine-emtricitabine-tenofovir disoproxil fumarate had similar virologic efficacy to continued nevirapine-based ART after 24 weeks with few adverse events.

  View details for PubMedID 27704000

• Long-term Bone Mineral Density Changes in Antiretroviral-Treated HIV-Infected Individuals JOURNAL OF INFECTIOUS DISEASES Grant, P. M., Kitch, D., McComsey, G. A., Collier, A. C., Koletar, S. L., Erlandson, K. M., Yin, M. T., Bartali, B., Ha, B., Melbourne, K., Brown, T. T. 2016; 214 (4): 607-611

  Abstract

  We compared adjusted bone mineral density (BMD) changes between human immunodeficiency virus (HIV)-infected individuals during the first approximately 7.5 years after antiretroviral therapy (ART) initiation and HIV-uninfected controls. HIV-infected individuals (n = 97) had significantly greater adjusted BMD decline than controls (n = 614) during the first 96 weeks of ART. Subsequently, the rate of BMD decline slowed in HIV-infected individuals but remained greater than the rate of decline in HIV-uninfected individuals at the lumbar spine but not at the hip. In HIV-infected individuals after 96 weeks, no HIV- or treatment-related characteristic was associated with BMD loss, but lower lean body mass was associated with greater BMD loss at both lumbar spine and hip.

  View details for DOI 10.1093/infdis/jiw204

  View details for Web of Science ID 000384849600014

  View details for PubMedID 27330053

  View details for PubMedCentralID PMC4957444

• Tenofovir and bone health CURRENT OPINION IN HIV AND AIDS Grant, P. M., Cotter, A. G. 2016; 11 (3): 326-332

  Abstract

  With continued improvements to the antiviral efficacy and tolerability of antiretroviral therapy, long-term safety of antiretroviral therapy has become paramount. Low bone mineral density and fragility fractures are more common in HIV-infected individuals than in the general population. The aims of this review are to describe potential mechanisms underlying the adverse effects of tenofovir on bone, clinical studies of tenofovir disoproxil fumarate (TDF) and bone, and more recent bone data on tenofovir alafenamide.Several studies have demonstrated an approximately 1-3% greater bone mineral density loss with TDF compared with other agents. Recent studies with tenofovir alafenamide have shown improved bone (and renal) safety with similar virologic efficacy when compared to TDF.Given these findings, TDF-containing regimens may be gradually replaced with non-TDF containing regimens for the treatment of HIV infection, especially in those at higher risk for fragility fracture.

  View details for DOI 10.1097/COH.0000000000000248

  View details for Web of Science ID 000374766200010

  View details for PubMedID 26859637

  View details for PubMedCentralID PMC4844450

• Modifying Antiretroviral Therapy in Virologically Suppressed HIV-1-Infected Patients DRUGS Collins, S. E., Grant, P. M., Shafer, R. W. 2016; 76 (1): 75-98

  Abstract

  HIV-1-infected patients with suppressed plasma viral loads often require changes to their antiretroviral (ARV) therapy to manage drug toxicity and intolerance, to improve adherence, and to avoid drug interactions. In patients who have never experienced virologic failure while receiving ARV therapy and who have no evidence of drug resistance, switching to any of the acceptable US Department of Health and Human Services first-line therapies is expected to maintain virologic suppression. However, in virologically suppressed patients with a history of virologic failure or drug resistance, it can be more challenging to change therapy while still maintaining virologic suppression. In these patients, it may be difficult to know whether the discontinuation of one of the ARVs in a suppressive regimen constitutes the removal of a key regimen component that will not be adequately supplanted by one or more substituted ARVs. In this article, we review many of the clinical scenarios requiring ARV therapy modification in patients with stable virologic suppression and outline the strategies for modifying therapy while maintaining long-term virologic suppression.

  View details for DOI 10.1007/s40265-015-0515-6

  View details for Web of Science ID 000367608600005

  View details for PubMedCentralID PMC4700066

• Modifying Antiretroviral Therapy in Virologically Suppressed HIV-1-Infected Patients. Drugs Collins, S. E., Grant, P. M., Shafer, R. W. 2016; 76 (1): 75-98

  Abstract

  HIV-1-infected patients with suppressed plasma viral loads often require changes to their antiretroviral (ARV) therapy to manage drug toxicity and intolerance, to improve adherence, and to avoid drug interactions. In patients who have never experienced virologic failure while receiving ARV therapy and who have no evidence of drug resistance, switching to any of the acceptable US Department of Health and Human Services first-line therapies is expected to maintain virologic suppression. However, in virologically suppressed patients with a history of virologic failure or drug resistance, it can be more challenging to change therapy while still maintaining virologic suppression. In these patients, it may be difficult to know whether the discontinuation of one of the ARVs in a suppressive regimen constitutes the removal of a key regimen component that will not be adequately supplanted by one or more substituted ARVs. In this article, we review many of the clinical scenarios requiring ARV therapy modification in patients with stable virologic suppression and outline the strategies for modifying therapy while maintaining long-term virologic suppression.

  View details for DOI 10.1007/s40265-015-0515-6

  View details for PubMedID 26677129

  View details for PubMedCentralID PMC4700066

• Molecular Detection of Leptospira in Two Returned Travelers: Higher Bacterial Load in Cerebrospinal Fluid Versus Serum or Plasma. American journal of tropical medicine and hygiene Waggoner, J. J., Soda, E. A., Seibert, R., Grant, P., Pinsky, B. A. 2015; 93 (2): 238-240

  Abstract

  Leptospirosis is a potentially severe illness in returned travelers. Patients often present with fever, headache, and neck pain, which may lead to a workup for meningitis including the acquisition of cerebrospinal fluid (CSF). Although Leptospira DNA has been detected in CSF by polymerase chain reaction (PCR), little data exist regarding the utility of testing CSF in addition to serum or plasma obtained on presentation. In this report, we present two cases of leptospirosis in returned travelers presenting with fever and headache. Our first patient had neutrophilic meningitis, and Leptospira was detectable only in CSF obtained on admission. The second patient had a normal CSF profile, but Leptospira was detected in CSF at a bacterial load 5- to 10-fold higher than that in plasma. CSF is an important specimen for the diagnosis of Leptospira by molecular methods and may yield an actionable diagnosis in the absence of leptospiremia.

  View details for DOI 10.4269/ajtmh.15-0174

  View details for PubMedID 26033024

  View details for PubMedCentralID PMC4530740

• Case Report: Molecular Detection of Leptospira in Two Returned Travelers: Higher Bacterial Load in Cerebrospinal Fluid versus Serum or Plasma AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE Waggoner, J. J., Soda, E. A., Seibert, R., Grant, P., Pinsky, B. A. 2015; 93 (2): 238-240

  Abstract

  Leptospirosis is a potentially severe illness in returned travelers. Patients often present with fever, headache, and neck pain, which may lead to a workup for meningitis including the acquisition of cerebrospinal fluid (CSF). Although Leptospira DNA has been detected in CSF by polymerase chain reaction (PCR), little data exist regarding the utility of testing CSF in addition to serum or plasma obtained on presentation. In this report, we present two cases of leptospirosis in returned travelers presenting with fever and headache. Our first patient had neutrophilic meningitis, and Leptospira was detectable only in CSF obtained on admission. The second patient had a normal CSF profile, but Leptospira was detected in CSF at a bacterial load 5- to 10-fold higher than that in plasma. CSF is an important specimen for the diagnosis of Leptospira by molecular methods and may yield an actionable diagnosis in the absence of leptospiremia.

  View details for DOI 10.4269/ajtmh.15-0174

  View details for Web of Science ID 000359327400009

  View details for PubMedCentralID PMC4530740

• Clinically Indicated Corticosteroids Do Not Affect Bone Turnover During Immune Restoration of Severely Lymphopenic HIV-Infected Patients AIDS RESEARCH AND HUMAN RETROVIRUSES Grant, P. M., Sheikh, V., DerSimonian, R., Rupert, A., Roby, G., Pau, A., Sneller, M. C., Rico, S., Brown, T. T., Sereti, I. 2015; 31 (7): 739-744

  Abstract

  Lymphopenia, corticosteroids, antiretroviral therapy (ART), and inflammation negatively impact bone turnover and decrease bone mineral density, but their combined effect has not been evaluated. We examined the association between corticosteroids on bone turnover markers in severely lymphopenic HIV-infected patients initiating ART. Levels of osteocalcin (bone formation marker) and C-terminal telopeptide (CTX; bone resorption marker) were measured at baseline, weeks 4, 12, and 48 of ART in individuals with severe lymphopenia and opportunistic infection (OI) who received (n=28) or did not receive corticosteroids (n=30) during the first year of ART, and in a control group with CD4 >200 (n=15). Wilcoxon tests were used to compare median values of variables between groups. Correlations between plasma interleukin (IL)-6 and tumor necrosis factor (TNF) levels with bone turnover marker levels were performed using Spearman's coefficient. Individuals given corticosteroids received a median of 21 days at a 35 mg prednisone-equivalent daily dose. Individuals with severe lymphopenia had lower osteocalcin levels at baseline and week 4 and higher CTX levels at ART initiation vs.Bone turnover markers did not differ in severely lymphopenic persons according to corticosteroid receipt. In those with severe lymphopenia, higher IL-6 was associated with higher CTX levels at ART initiation only. HIV-infected patients with severe lymphopenia and OI had lower levels of bone formation and higher levels of bone resorption than those initiating ART at higher CD4. Corticosteroid use, as prescribed during OI, was not associated with bone turnover. In contrast, higher markers of systemic inflammation prior to ART were associated with greater bone resorption.

  View details for DOI 10.1089/aid.2015.0028

  View details for Web of Science ID 000369885400012

  View details for PubMedID 25919454

  View details for PubMedCentralID PMC4505768

• Patterns of peripheral neuropathy in ART-na < ve patients initiating modern ART regimen JOURNAL OF NEUROVIROLOGY Lee, A. J., Bosch, R. J., Evans, S. R., Wu, K., Harrison, T., Grant, P., Clifford, D. B. 2015; 21 (2): 210-218

  Abstract

  The purpose of this study was to evaluate associations of pre-ART CD4 with peripheral neuropathy (PN) and estimate the prevalence of PN in HIV-positive patients starting modern combination antiretroviral therapy (cART) regimens. ART-naïve subjects initiating cART were followed longitudinally and screened for signs/symptoms of PN. Lower pre-ART CD4 count was associated with post-ART PN. After 7 years (n = 117), the prevalence (95 % CI) of PN and SPN were 31 % (23, 40 %) and 5 % (2, 11 %) with pre-ART CD4 count >250 copies/μL. PN continues to be identified in HIV-infected individuals on modern cART by targeted assessment but is generally without symptoms.

  View details for DOI 10.1007/s13365-015-0327-1

  View details for Web of Science ID 000351671300010

  View details for PubMedID 25678143

• Differential skeletal impact of tenofovir disoproxil fumarate in young versus old HIV-infected adults HIV CLINICAL TRIALS Grant, P. M., Kitch, D., McComsey, G. A., Tierney, C., Ha, B., Brown, T. T. 2015; 16 (2): 66-71

  Abstract

  Lower peak bone mass in early adulthood predicts subsequent fragility fractures. Antiretroviral toxicity could contribute to young HIV-infected individuals not achieving adequate peak bone mass.To determine if tenofovir disoproxil fumarate's (TDF) effect on bone mineral density (BMD) differs by age.We examined BMD data at the lumbar spine and hip from AIDS Clinical Trials Group (ACTG) A5224s and ASSERT and randomized treatment-naive studies comparing TDF/emtricitabine versus abacavir/lamivudine (with efavirenz or atazanavir/ritonavir). In this post hoc analysis, we defined the TDF effect as the difference between mean 48-week BMD per cent changes for lumbar spine and hip in individuals randomized to TDF versus abacavir. We used multivariable linear regression to compare the TDF effect in individuals younger and older than 30 years. If TDF effect by age did not differ significantly between studies, we pooled study populations. Otherwise, analyses were conducted separately within each study population.Among 652 subjects, 21% were below age 30 years. The relationship between age and TDF effect significantly differed between A5224s and ASSERT (P = 0.008 for lumbar spine; P = 0.007 for hip). In A5224s, there was more bone loss with TDF at lumbar spine and hip in subjects under 30 years old versus in older subjects ( - 4.5% vs - 1.4%; P = 0.045; - 4.3% vs - 1.6%; P = 0.026, respectively). There was no significant evidence for this age-associated TDF effect in ASSERT.There was heterogeneity in the observed effect of TDF on bone density in young adults compared to older adults, suggesting that further investigation is required to understand the impact of age on BMD decline with TDF.

  View details for DOI 10.1179/1528433614Z.0000000010

  View details for Web of Science ID 000355915500003

  View details for PubMedID 25872972

• Encephalitis caused by chikungunya virus in a traveler from the kingdom of tonga. Journal of clinical microbiology Nelson, J., Waggoner, J. J., Sahoo, M. K., Grant, P. M., Pinsky, B. A. 2014; 52 (9): 3459-3461

  Abstract

  Febrile travelers from countries with unique endemic pathogens pose a significant diagnostic challenge. In this report, we describe the case of a Tongan man presenting with fever, rash, and altered mental status. The diagnosis of Chikungunya encephalitis was made using a laboratory-developed real-time RT-PCR and serologic testing.

  View details for DOI 10.1128/JCM.01288-14

  View details for PubMedID 24958800

• Association between Latent Proviral Characteristics and Immune Activation in Antiretrovirus-Treated Human Immunodeficiency Virus Type 1-Infected Adults. Journal of virology Liang, E. C., Sceats, L., Bayless, N. L., Strauss-Albee, D. M., Kubo, J., Grant, P. M., Furman, D., Desai, M., Katzenstein, D. A., Davis, M. M., Zolopa, A. R., Blish, C. A. 2014; 88 (15): 8629-8639

  Abstract

  Generalized immune activation during HIV infection is associated with an increased risk of cardiovascular disease, neurocognitive disease, osteoporosis, metabolic disorders, and physical frailty. The mechanisms driving this immune activation are poorly understood, particularly for individuals effectively treated with antiretroviral medications. We hypothesized that viral characteristics such as sequence diversity may play a role in driving HIV-associated immune activation. We therefore sequenced proviral DNA isolated from peripheral blood mononuclear cells from HIV-infected individuals on fully suppressive antiretroviral therapy. We performed phylogenetic analyses, calculated viral diversity and divergence in the env and pol genes, and determined coreceptor tropism and the frequency of drug resistance mutations. Comprehensive immune profiling included quantification of immune cell subsets, plasma cytokine levels, and intracellular signaling responses in T cells, B cells, and monocytes. These antiretroviral therapy-treated HIV-infected individuals exhibited a wide range of diversity and divergence in both env and pol genes. However, proviral diversity and divergence in env and pol, coreceptor tropism, and the level of drug resistance did not significantly correlate with markers of immune activation. A clinical history of virologic failure was also not significantly associated with levels of immune activation, indicating that a history of virologic failure does not inexorably lead to increased immune activation as long as suppressive antiretroviral medications are provided. Overall, this study demonstrates that latent viral diversity is unlikely to be a major driver of persistent HIV-associated immune activation.Chronic immune activation, which is associated with cardiovascular disease, neurologic disease, and early aging, is likely to be a major driver of morbidity and mortality in HIV-infected individuals. Although treatment of HIV with antiretroviral medications decreases the level of immune activation, levels do not return to normal. The factors driving this persistent immune activation, particularly during effective treatment, are poorly understood. In this study, we investigated whether characteristics of the latent, integrated HIV provirus that persists during treatment are associated with immune activation. We found no relationship between latent viral characteristics and immune activation in treated individuals, indicating that qualities of the provirus are unlikely to be a major driver of persistent inflammation. We also found that individuals who had previously failed treatment but were currently effectively treated did not have significantly increased levels of immune activation, providing hope that past treatment failures do not have a lifelong "legacy" impact.

  View details for DOI 10.1128/JVI.01257-14

  View details for PubMedID 24850730

  View details for PubMedCentralID PMC4135944

• Clinical and Immunologic Predictors of Death After an Acute Opportunistic Infection: Results from ACTG A5164 HIV CLINICAL TRIALS Grant, P. M., Komarow, L., Sanchez, A., Sattler, F. R., Asmuth, D. M., Pollard, R. B., Zolopal, A. R. 2014; 15 (4): 133-139

  Abstract

  In the pre-antiretroviral therapy (ART) era, markers of increased disease severity during an acute opportunistic infection (OI) were associated with mortality. Even with ART, mortality remains high during the first year after an OI in persons with advanced HIV infection, but it is unclear whether previous predictors of mortality remain valid in the current era.To determine clinical and immunological predictors of death after an OI.We used clinical data and stored plasma from ACTG A5164, a multicenter study evaluating the optimal timing of ART during a nontuberculous OI. We developed Cox models evaluating associations between clinical parameters and plasma marker levels at entry and time to death over the first 48 weeks after the diagnosis of OI. We developed multivariable models incorporating only clinical parameters, only plasma marker levels, or both.The median CD4+ T-cell count in study participants at baseline was 29 cells/µL. Sixty-four percent of subjects had Pneumocystis jirovecii pneumonia (PCP). Twenty-three of 282 (8.2%) subjects died. In univariate analyses, entry mycobacterial infection, OI number, hospitalization, low albumin, low hemoglobin, lower CD4, and higher IL-8 and sTNFrII levels and lower IL-17 levels were associated with mortality. In the combined model using both clinical and immunologic parameters, the presence of an entry mycobacterial infection and higher sTNFrII levels were significantly associated with death.In the ART era, clinical risk factors for death previously identified in the pre-ART era remain predictive. Additionally, activation of the innate immune system is associated with an increased risk of death following an acute OI.

  View details for DOI 10.1310/hct1504-133

  View details for Web of Science ID 000339857200001

  View details for PubMedID 25143022

  View details for PubMedCentralID PMC4167015

• Evolution of HIV treatment guidelines in high- and low-income countries: Converging recommendations ANTIVIRAL RESEARCH Richardson, E. T., Grant, P. M., Zolopa, A. R. 2014; 103: 88-93

  Abstract

  Over the past 15 years, antiretroviral treatment guidelines for HIV infection have evolved significantly, reflecting the major advances in this therapeutic area. Evidenced-based recommendations have largely replaced expert opinion, while diagnostic monitoring and therapeutic interventions have become more sophisticated and effective. Just 10 years ago, there was a marked difference in access to antiretroviral therapy for patients in wealthy and impoverished countries. The increasing availability of therapy across the globe, however, has made it possible for international guidelines to resemble more closely those in high-income countries. This article compares the evolution of antiretroviral therapy treatment guidelines from the United States Department of Health and Human Services and the World Health Organization, focusing on when to initiate ART in asymptomatic patients and in those with an opportunistic infection; initial regimens in the general population and in special populations; when to change and what to change; and laboratory monitoring.

  View details for DOI 10.1016/j.antiviral.2013.12.007

  View details for Web of Science ID 000332821000011

  View details for PubMedID 24374148

• Comparative effectiveness and cost-effectiveness of antiretroviral therapy and pre-exposure prophylaxis for HIV prevention in South Africa. BMC medicine Alistar, S. S., Grant, P. M., Bendavid, E. 2014; 12: 46-?

  Abstract

  Antiretroviral therapy (ART) and oral pre-exposure prophylaxis (PrEP) are effective in reducing HIV transmission in heterosexual adults. The epidemiologic impact and cost-effectiveness of combined prevention approaches in resource-limited settings remain unclear.We develop a dynamic mathematical model of the HIV epidemic in South Africa's adult population. We assume ART reduces HIV transmission by 95% and PrEP by 60%. We model two ART strategies: scaling up access for those with CD4 counts ≤ 350 cells/μL (Guidelines) and for all identified HIV-infected individuals (Universal). PrEP strategies include use in the general population (General) and in high-risk individuals (Focused). We consider strategies where ART, PrEP, or both are scaled up to 100% of remaining eligible individuals yearly. We measure infections averted, quality-adjusted life-years (QALYs) gained and incremental cost-effectiveness ratios over 20 years.Scaling up ART to 50% of eligible individuals averts 1,513,000 infections over 20 years (Guidelines) and 3,591,000 infections (Universal). Universal ART is the most cost-effective strategy at any scale ($160-$220/QALY versus comparable scale Guidelines ART expansion). General PrEP is costly and provides limited benefits beyond ART scale-up ($7,680/QALY to add 100% PrEP to 50% Universal ART). Cost-effectiveness of General PrEP becomes less favorable when ART is widely given ($12,640/QALY gained when added to 100% Universal ART). If feasible, Focused PrEP is cost saving or highly cost effective versus status quo and when added to ART strategies.Expanded ART coverage to individuals in early disease stages may be more cost-effective than current guidelines. PrEP can be cost-saving if delivered to individuals at increased risk of infection.

  View details for DOI 10.1186/1741-7015-12-46

  View details for PubMedID 24629217

• Comparative effectiveness and cost-effectiveness of antiretroviral therapy and pre-exposure prophylaxis for HIV prevention in South Africa. BMC medicine Alistar, S. S., Grant, P. M., Bendavid, E. 2014; 12: 46-?

  Abstract

  Antiretroviral therapy (ART) and oral pre-exposure prophylaxis (PrEP) are effective in reducing HIV transmission in heterosexual adults. The epidemiologic impact and cost-effectiveness of combined prevention approaches in resource-limited settings remain unclear.We develop a dynamic mathematical model of the HIV epidemic in South Africa's adult population. We assume ART reduces HIV transmission by 95% and PrEP by 60%. We model two ART strategies: scaling up access for those with CD4 counts ≤ 350 cells/μL (Guidelines) and for all identified HIV-infected individuals (Universal). PrEP strategies include use in the general population (General) and in high-risk individuals (Focused). We consider strategies where ART, PrEP, or both are scaled up to 100% of remaining eligible individuals yearly. We measure infections averted, quality-adjusted life-years (QALYs) gained and incremental cost-effectiveness ratios over 20 years.Scaling up ART to 50% of eligible individuals averts 1,513,000 infections over 20 years (Guidelines) and 3,591,000 infections (Universal). Universal ART is the most cost-effective strategy at any scale ($160-$220/QALY versus comparable scale Guidelines ART expansion). General PrEP is costly and provides limited benefits beyond ART scale-up ($7,680/QALY to add 100% PrEP to 50% Universal ART). Cost-effectiveness of General PrEP becomes less favorable when ART is widely given ($12,640/QALY gained when added to 100% Universal ART). If feasible, Focused PrEP is cost saving or highly cost effective versus status quo and when added to ART strategies.Expanded ART coverage to individuals in early disease stages may be more cost-effective than current guidelines. PrEP can be cost-saving if delivered to individuals at increased risk of infection.

  View details for DOI 10.1186/1741-7015-12-46

  View details for PubMedID 24629217

• TREATING PSYCHOLOGICAL TRAUMA AMONG RWANDAN ORPHANS IS ASSOCIATED WITH A REDUCTION IN HIV RISK-TAKING BEHAVIORS: A PILOT STUDY AIDS EDUCATION AND PREVENTION Talbot, A., Uwihoreye, C., Kamen, C., Grant, P., McGlynn, L., Mugabe, I., Nshimyumukiza, M., Dongier, P., Slamowitz, D., Padilla, C., Uvamahoro, J., Musayidire, I., Mukarubuga, A., Zolopa, A. 2013; 25 (6): 468-479

  Abstract

  The nongovernmental organization, Uyisenga N'Manzi (UNM), provides Rwandan orphans of genocide and HIV/AIDS with education, social, and mental health services. Many orphans in UNM report symptoms of psychological trauma. The primary study objective was to evaluate a multidisciplinary program integrating HIV prevention with an existing package of mental health services. We randomly selected 120 orphans between ages 15-25 years served by UNM and evaluated sexually-transmitted infections, HIV risk-taking behaviors and knowledge, and mental health at baseline, 5, 9, and 12 months. Increased trauma symptoms at baseline were associated with poorer coping skills and social functioning, and increased psychological distress and HIV risk-taking behavior. Following the 12-month intervention, trauma symptoms declined significantly, with those accessing counseling services showing greatest improvement. Orphans with the highest trauma scores benefited most from the intervention. In this at-risk population, addressing mental health issues in the context of HIV prevention is critical.

  View details for Web of Science ID 000327416100002

  View details for PubMedID 24245594

• Low Baseline CD4+ Count Is Associated With Greater Bone Mineral Density Loss After Antiretroviral Therapy Initiation. Clinical infectious diseases Grant, P. M., Kitch, D., McComsey, G. A., Dube, M. P., Haubrich, R., Huang, J., Riddler, S., Tebas, P., Zolopa, A. R., Collier, A. C., Brown, T. T. 2013; 57 (10): 1483-1488

  Abstract

  Background. Bone mineral density (BMD) decreases 2%-6% in the 2 years after antiretroviral therapy (ART) initiation. Pre-ART immune deficiency and early immune recovery may contribute to this loss. Methods. We pooled data from 3 studies of ART initiation in treatment-naive patients in which serial whole-body dual-energy X-ray absorptiometry scans were performed. We used linear regression to evaluate effects of baseline CD4(+) and 16-week CD4(+) change (both absolute and relative) on 96-week total BMD change from baseline. We performed multivariable linear regression to assess associations between baseline variables of age, sex, race/ethnicity, body mass index (BMI), hepatitis C status, parent study, human immunodeficiency virus type 1 (HIV-1) RNA level, and assignment to a protease inhibitor (PI)- or tenofovir-containing regimen on 96-week total BMD change. Results. The included 796 subjects had mean 96-week total BMD loss of 2.0%. In multivariable analysis, baseline CD4(+) cell count was significantly associated with 96-week BMD loss; individuals with baseline CD4(+) <50 cells/µL lost significantly more BMD compared to those with CD4(+) ≥500 cells/µL. A greater relative, but not absolute, 16-week increase in CD4(+) count was significantly associated with greater declines in BMD, but not after controlling for baseline CD4(+) count. In multivariable analysis, older age, female sex, lower BMI, higher HIV-1 RNA levels, and PI and tenofovir assignment were also associated with greater BMD decline. Conclusions. Low pretreatment CD4(+) count, but not greater CD4(+) count increase, is a strong and independent risk factor for bone loss after ART initiation. ART initiation at higher CD4(+) counts may reduce the burden of osteoporosis and fragility fractures.

  View details for DOI 10.1093/cid/cit538

  View details for PubMedID 23943825

  View details for PubMedCentralID PMC3805172

• Early Virologic Response to Abacavir/Lamivudine and Tenofovir/Emtricitabine During ACTG A5202 HIV CLINICAL TRIALS Grant, P. M., Tierney, C., Budhathoki, C., Daar, E. S., Sax, P. E., Collier, A. C., Fischl, M. A., Zolopa, A. R., Balamane, M., Katzenstein, D. 2013; 14 (6): 284-291

  Abstract

  ACTG A5202 randomized treatment-naïve individuals to tenofovir-emtricitabine (TDF/FTC) or abacavir-lamivudine (ABC/3TC) combined with efavirenz (EFV) or atazanavir/ritonavir (ATV/r). Individuals in the high screening viral load (VL) stratum (≥100,000 copies/mL) had increased rates of virologic failure with ABC/3TC.To compare regimen-specific early virologic response.Using Wilcoxon rank-sum tests, we compared regimen-specific VL changes from entry to week 4 in A5202 subjects (N = 1,813) and from entry to week 1, 2, and 4 in substudy subjects (n = 179). We evaluated associations between week 4 VL change and time to virologic failure with Cox proportional hazards models.TDF/FTC and ABC/3TC produced similar week 4 VL declines in the entire study population and in the high VL stratum. EFV produced greater VL declines from baseline at week 4 than ATV/r (median -2.1 vs -1.9 log10 copies/mL; P < .001). In the substudy of subjects with week 1, 2, and 4 VL data, there was no difference in VL decline in individuals randomized to TDF/FTC versus ABC/3TC, but EFV resulted in greater VL decline from entry at each of these timepoints than ATV/r. Smaller week 4 VL decline was associated with increased risk of virologic failure.Within all treatment arms, a less robust week 4 virologic response was associated with higher risk for subsequent virologic failure. However, between-regimen differences in week 4 VL declines did not parallel the previously reported differences in longer term virologic efficacy in A5202, suggesting that between-regimen differences in responses were not due to intrinsic differences in antiviral activity.

  View details for DOI 10.1310/hct1408-284

  View details for Web of Science ID 000328443500003

  View details for PubMedID 24334181

• Elevated Interleukin 8 and T-Helper 1 and T-Helper 17 Cytokine Levels Prior to Antiretroviral Therapy in Participants Who Developed Immune Reconstitution Inflammatory Syndrome During ACTG A5164 JOURNAL OF INFECTIOUS DISEASES Grant, P. M., Komarow, L., Lederman, M. M., Pahwa, S., Zolopa, A. R., Andersen, J., Asmuth, D. M., Devaraj, S., Pollard, R. B., Richterman, A., Kanthikeel, S., Sereti, I. 2012; 206 (11): 1715-1723

  Abstract

  Immune reconstitution inflammatory syndrome (IRIS) reflects an aberrant immune response that can develop in human immunodeficiency virus-infected patients initiating antiretroviral therapy (ART). Its pathogenesis remains unclear.We performed a nested case-control study using specimens from ACTG A5164. We compared plasma biomarkers and T-cell subsets in 19 IRIS and 39 control participants at study entry, ART initiation, and IRIS and used conditional logistic regression to develop IRIS predictive models. We evaluated the effect of corticosteroids on biomarker levels.Eleven and 8 participants developed paradoxical and unmasking IRIS, respectively, none while still receiving corticosteroids. Compared to controls, cases displayed elevations at study entry in interleukin (IL) 8, T-helper (Th) 1 (IL-2, interferon [IFN]-γ, tumor necrosis factor [TNF]) and Th17 (IL-17) cytokine levels that persisted through ART initiation and IRIS. In logistic regression, baseline higher IFN-γ and TNF were strong predictors of IRIS. Participants who received corticosteroids and later developed IRIS had marked increases in IL-6, IL-8, and IFN-γ at the time of IRIS. T-cell activation markers did not differ in cases and controls prior to ART but were increased in cases at the time of IRIS.Increased IL-8, Th1, and Th17 cytokine levels in IRIS patients precede ART initiation and could help identify patient populations at higher risk for IRIS.

  View details for DOI 10.1093/infdis/jis604

  View details for Web of Science ID 000310968700013

  View details for PubMedID 23002445

  View details for PubMedCentralID PMC3488199

• When to start ART in the setting of acute AIDS-related opportunistic infections: the time is now! Current HIV/AIDS reports Grant, P. M., Zolopa, A. R. 2012; 9 (3): 251-258

  Abstract

  Despite the substantial benefits of combination antiretroviral therapy (ART), a significant proportion of HIV-infected individuals still present with advanced disease and active AIDS-related opportunistic infections (OIs). The weight of evidence from recent studies supports the early initiation of ART (ie, within 2 weeks of initiating treatment for the acute OIs). Initiating ART early in acutely ill patients can reduce AIDS-related progression and death. Early ART has not been associated with increased rates of immune reconstitution inflammatory syndrome in prospective studies of non-tuberculosis OIs, although this concern is frequently cited as a reason to delay ART. Nor has early ART been associated with increased adverse outcomes. Nonetheless, initiating ART early in acute care settings can be challenging to implement and requires a well-coordinated multidisciplinary team with expertise in ART management.

  View details for DOI 10.1007/s11904-012-0126-8

  View details for PubMedID 22733609

• When to Start ART in the Setting of Acute AIDS-Related Opportunistic Infections: The Time Is Now! CURRENT HIV/AIDS REPORTS Grant, P. M., Zolopa, A. R. 2012; 9 (3): 251-258

  View details for DOI 10.1007/s11904-012-0126-8

  View details for Web of Science ID 000208974300008

• Blood (1 -> 3)-beta-D-Glucan as a Diagnostic Test for HIV-Related Pneumocystis jirovecii Pneumonia CLINICAL INFECTIOUS DISEASES Sax, P. E., Komarow, L., Finkelman, M. A., Grant, P. M., Andersen, J., Scully, E., Powderly, W. G., Zolopa, A. R. 2011; 53 (2): 197-202

  Abstract

  (See the editorial commentary by Morris and Masur, on pages 203-204.)Improved noninvasive diagnostic tests for Pneumocystis jirovecii pneumonia (PCP) are needed. We evaluated the test characteristics of plasma (1 → 3)-β-D-glucan (β-glucan) for HIV-related PCP among a large group of patients presenting with diverse opportunistic infections (OIs).The study population included all 282 participants in AIDS Clinical Trials Group A5164, a study of early versus deferred antiretroviral therapy in conjunction with initial therapy of acute OIs. Baseline plasma samples were assayed for β-glucan, with standard assay reference values defining ≥ 80 pg/mL as positive. Before this analysis, diagnosis of PCP was independently adjudicated by 2 study investigators after reviewing reports from study sites.A total of 252 persons had a β-glucan result that could be analyzed, 173 (69%) of whom had received a diagnosis of PCP. Median β-glucan with PCP was 408 pg/mL (interquartile range [IQR], 209-500 pg/mL), compared with 37 pg/mL (IQR, 31-235 pg/mL) without PCP (P < .001). The sensitivity of β-glucan dichotomized at 80 pg/mL for the diagnosis of PCP was 92% (95% confidence interval [CI], 87%-96%), and the specificity was 65% (95% CI, 53%-75%); positive and negative predictive values were 85% (95% CI, 79%-90%) and 80% (95% CI, 68%-89%) respectively, based on the study prevalence of 69% of patients with PCP. Rates of abnormal lactate dehyrogenase levels did not differ significantly between those with and without PCP.Blood (1 → 3)-β-D-glucan is strongly correlated with HIV-related PCP. In some clinical centers, this may be a more sensitive test than the induced sputum examination and could reduce the need for both bronchoscopy and empirical therapy of PCP.

  View details for DOI 10.1093/cid/cir335

  View details for Web of Science ID 000293024000014

  View details for PubMedID 21690628

• Cost-effectiveness of antiretroviral regimens in the World Health Organization's treatment guidelines: a South African analysis AIDS Bendavid, E., Grant, P., Talbot, A., Owens, D. K., Zolopa, A. 2011; 25 (2): 211-220

  Abstract

  the World Health Organization (WHO) recently changed its first-line antiretroviral treatment guidelines in resource-limited settings. The cost-effectiveness of the new guidelines is unknown.comparative effectiveness and cost-effectiveness analysis using a model of HIV disease progression and treatment.using a simulation of HIV disease and treatment in South Africa, we compared the life expectancy, quality-adjusted life expectancy, lifetime costs, and cost-effectiveness of five initial regimens. Four are currently recommended by the WHO: tenofovir/lamivudine/efavirenz; tenofovir/lamivudine/nevirapine; zidovudine/lamivudine/efavirenz; and zidovudine/lamivudine/nevirapine. The fifth is the most common regimen in current use: stavudine/lamivudine/nevirapine. Virologic suppression and toxicities determine regimen effectiveness and cost-effectiveness.choice of first-line regimen is associated with a difference of nearly 12 months of quality-adjusted life expectancy, from 135.2 months (tenofovir/lamivudine/efavirenz) to 123.7 months (stavudine/lamivudine/nevirapine). Stavudine/lamivudine/nevirapine is more costly and less effective than zidovudine/lamivudine/nevirapine. Initiating treatment with a regimen containing tenofovir/lamivudine/nevirapine is associated with an incremental cost-effectiveness ratio of $1045 per quality-adjusted life year compared with zidovudine/lamivudine/nevirapine. Using tenofovir/lamivudine/efavirenz was associated with the highest survival, fewest opportunistic diseases, lowest rate of regimen substitution, and an incremental cost-effectiveness ratio of $5949 per quality-adjusted life year gained compared with tenofovir/lamivudine/nevirapine. Zidovudine/lamivudine/efavirenz was more costly and less effective than tenofovir/lamivudine/nevirapine. Results were sensitive to the rates of toxicities and the disutility associated with each toxicity.among the options recommended by WHO, we estimate only three should be considered under normal circumstances. Choice among those depends on available resources and willingness to pay. Stavudine/lamivudine/nevirapine is associated with the poorest quality-adjusted survival and higher costs than zidovudine/lamivudine/nevirapine.

  View details for DOI 10.1097/QAD.0b013e328340fdf8

  View details for PubMedID 21124202

• Concerns Regarding a Randomized Study of the Timing of Antiretroviral Therapy in Zimbabweans with AIDS and Acute Cryptococcal Meningitis CLINICAL INFECTIOUS DISEASES Grant, P. M., Aberg, J. A., Zolopa, A. R. 2010; 51 (8): 984-985

  View details for DOI 10.1086/656435

  View details for Web of Science ID 000282036700018

  View details for PubMedID 20858075

• Early Antiretroviral Therapy for Patients With Acute AIDS-Related Opportunistic Infections: A Cost-Effectiveness Analysis of ACTG A5164 HIV CLINICAL TRIALS Sax, P. E., Sloan, C. E., Schackman, B. R., Grant, P. M., Rong, J., Zolopa, A. R., Powderly, W., Losina, E., Freedberg, K. A. 2010; 11 (5): 248-259

  Abstract

  ACTG A5164 demonstrated that early antiretroviral therapy (ART) in HIV-infected patients with acute opportunistic infections (OIs) reduced death and AIDS progression compared to ART initiation 1 month later. We project the life expectancies, costs, and incremental cost-effectiveness ratios (ICERs) of these strategies.using an HIV simulation model, we compared 2 strategies for patients with acute OIs: (1) an intervention to deliver early ART, and (2) deferred ART. Parameters from ACTG A5164 included initial mean CD4 count (47/microL), linkage to outpatient care (87%), and immune reconstitution inflammatory syndrome 1 month after ART initiation (7%). The estimated intervention cost was $1,650/patient.early ART lowered projected 1-year mortality from 10.4% to 8.2% and increased life expectancy from 10.07 to 10.39 quality-adjusted life-years (QALYs). Lifetime costs increased from $385,220 with deferred ART to $397,500 with early ART, primarily because life expectancy increased, producing an ICER of $38,600/QALY. Results were most sensitive to increased intervention cost and decreased virologic efficacy in the early ART strategy.an intervention to initiate ART early in patients with acute OIs improves survival and meets US cost-effectiveness thresholds. Programs should be developed to implement this strategy at sites where HIV-infected patients present with OIs.

  View details for DOI 10.1310/hct1105-248

  View details for Web of Science ID 000284681400002

  View details for PubMedID 21126955

• Optimal antiretroviral therapy: HIV-1 treatment strategies to avoid and overcome drug resistance CURRENT OPINION IN INVESTIGATIONAL DRUGS Grant, P. M., Zolopa, A. R. 2010; 11 (8): 901-910

  Abstract

  Potent antiretroviral therapy (ART) has transformed HIV infection into a chronic manageable disease, but drug resistance remains a common problem that limits the effectiveness and clinical benefits of treatment. With increasing experience with ART, the understanding of viral dynamics of HIV improved, and researchers learned how challenging HIV can be to control. With new-class and new-generation drugs, it is hoped that the lessons learned will be useful for limiting drug resistance and optimizing the use of ART for long-term management of HIV infection.

  View details for Web of Science ID 000280192200005

  View details for PubMedID 20721832

• Risk Factor Analyses for Immune Reconstitution Inflammatory Syndrome in a Randomized Study of Early vs. Deferred ART during an Opportunistic Infection PLOS ONE Grant, P. M., Komarow, L., Andersen, J., Sereti, I., Pahwa, S., Lederman, M. M., Eron, J., Sanne, I., Powderly, W., Hogg, E., Suckow, C., Zolopa, A. 2010; 5 (7)

  Abstract

  Immune reconstitution inflammatory syndrome (IRIS) is reported widely in patients initiating antiretroviral therapy (ART). However, few studies are prospective, and no study has evaluated the impact of the timing of ART when allocated randomly during an acute opportunistic infection (OI).A5164 randomized 282 subjects with AIDS-related OIs (tuberculosis excluded), to early or deferred ART. IRIS was identified prospectively using pre-defined criteria. We evaluated associations between IRIS and baseline variables in subjects with follow-up on ART using Wilcoxon and Fisher's exact tests, logistic regression, and Cox models with time-varying covariates. Twenty of 262 (7.6%) subjects developed IRIS after a median of 33 days on ART. Subjects with fungal infections (other than pneumocystis) developed IRIS somewhat more frequently (OR = 2.7; 95% CI: 1.02, 7.2; p-value = 0.06 (using Fisher's exact test)). In Cox models, lower baseline and higher on-treatment CD4+ T-cell counts and percentage were associated with IRIS. Additionally, higher baseline and lower on-treatment HIV RNA levels were associated with IRIS. Corticosteroids during OI management and the timing of ART were not associated with the development of IRIS.In patients with advanced immunosuppression and non-tuberculous OIs, the presence of a fungal infection, lower CD4+ T-cell counts and higher HIV RNA levels at baseline, and higher CD4+ T-cell counts and lower HIV RNA levels on treatment are associated with IRIS. Early initiation of ART does not increase the incidence of IRIS, and concern about IRIS should not prompt deferral of ART.ClinicalTrials.gov NCT00055120.

  View details for DOI 10.1371/journal.pone.0011416

  View details for Web of Science ID 000279465500005

  View details for PubMedID 20617176

  View details for PubMedCentralID PMC2895658

• Predicting Tipranavir and Darunavir Resistance Using Genotypic, Phenotypic, and Virtual Phenotypic Resistance Patterns: an Independent Cohort Analysis of Clinical Isolates Highly Resistant to All Other Protease Inhibitors ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Talbot, A., Grant, P., Taylor, J., Baril, J., Liu, T. F., Charest, H., Brenner, B., Roger, M., Shafer, R., Cantin, R., Zolopa, A. 2010; 54 (6): 2473-2479

  Abstract

  Genotypic interpretation systems (GISs) for darunavir and tipranavir susceptibility are rarely tested by the use of independent data sets. The virtual phenotype (the phenotype determined by Virco [the "Vircotype"]) was used to interpret all genotypes in Québec, Canada, and phenotypes were determined for isolates predicted to be resistant to all protease inhibitors other than darunavir and tipranavir. We used multivariate analyses to predict relative phenotypic susceptibility to darunavir and tipranavir. We compared the performance characteristics of the Agence Nationale de Recherche sur le Sida scoring algorithm, the Stanford HIV database scoring algorithm (with separate analyses of the discrete and numerical scores), the Vircotype, and the darunavir and tipranavir manufacturers' scores for prediction of the phenotype. Of the 100 isolates whose phenotypes were determined, 89 and 72 were susceptible to darunavir and tipranavir, respectively. In multivariate analyses, the presence of I84V and V82T and the lack of L10F predicted that the isolates would be more susceptible to darunavir than tipranavir. The presence of I54L, V32I, and I47V predicted that the isolates would be more susceptible to tipranavir. All GISs except the system that provided the Stanford HIV database discrete score performed well in predicting the darunavir resistance phenotype (R(2) = 0.61 to 0.69); the R(2) value for the Stanford HIV database discrete scoring system was 0.38. Other than the system that provided the Vircotype (R(2) = 0.80), all GISs performed poorly in predicting the tipranavir resistance phenotype (R(2) = 0.00 to 0.31). In this independent cohort harboring highly protease inhibitor-resistant HIV isolates, reduced phenotypic susceptibility to darunavir and tipranavir was rare. Generally, GISs predict susceptibility to darunavir substantially better than they predict susceptibility to tipranavir.

  View details for DOI 10.1128/AAC.00096-10

  View details for Web of Science ID 000277756000025

  View details for PubMedID 20368406

  View details for PubMedCentralID PMC2876425

• International Cohort Analysis of the Antiviral Activities of Zidovudine and Tenofovir in the Presence of the K65R Mutation in Reverse Transcriptase ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Grant, P. M., Taylor, J., Nevins, A. B., Calvez, V., Marcelin, A., Wirden, M., Zolopa, A. R. 2010; 54 (4): 1520-1525

  Abstract

  A K65R mutation in HIV-1 reverse transcriptase can occur with the failure of tenofovir-, didanosine-, abacavir-, and, in some cases, stavudine-containing regimens and leads to reduced phenotypic susceptibility to these drugs and hypersusceptibility to zidovudine, but its clinical impact is poorly described. We identified isolates with the K65R mutation within the Stanford Resistance Database and a French cohort for which subsequent treatment and virological response data were available. The partial genotypic susceptibility score (pGSS) was defined as the genotypic susceptibility score (GSS) excluding the salvage regimen's nucleoside reverse transcriptase inhibitor (NRTI) component. A three-part virologic response variable was defined (e.g., complete virologic response, partial virologic response, and no virologic response). Univariate, multivariate, and bootstrap analyses evaluated factors associated with the virologic response, focusing on the contributions of zidovudine and tenofovir. Seventy-one of 130 patients (55%) achieved a complete virologic response (defined as an HIV RNA level of <200 copies/ml). In univariate analyses, pGSS and zidovudine use in the salvage regimen were predictors of the virologic response. In a multivariate analysis, pGSS and zidovudine and tenofovir use were associated with the virologic response. Bootstrap analyses showed similar reductions in HIV RNA levels with zidovudine or tenofovir use (0.5 to 0.9 log(10)). In the presence of K65R, zidovudine and tenofovir are associated with similar reductions in HIV RNA levels. Given its tolerability, tenofovir may be the preferred agent over zidovudine even in the presence of the K65R mutation.

  View details for DOI 10.1128/AAC.01380-09

  View details for Web of Science ID 000275662700017

  View details for PubMedID 20124005

  View details for PubMedCentralID PMC2849386

• Switch from enfuvirtide to raltegravir in virologically suppressed HIV-1 infected patients: Effects on level of residual viremia and quality of life JOURNAL OF CLINICAL VIROLOGY Grant, P. M., Palmer, S., Bendavid, E., Talbot, A., Slamowitz, D. C., Cain, P., Kobayashi, S. S., Balamane, M., Zolopa, A. R. 2009; 46 (4): 305-308

  Abstract

  Raltegravir is a potential treatment option for virologically suppressed HIV-1 infected patients on enfuvirtide with injection site reactions.To characterize safety and efficacy of an enfuvirtide to raltegravir switch including changes in T-cells, quality of life, and residual viremia.In patients with viral load <50 copies/mL and injection site reactions, enfuvirtide was switched to raltegravir without additional changes to the antiretroviral regimen. Virologic failure was defined as a viral load >1000 copies/mL or two consecutive viral load measurements between 50 and 1000 copies/mL (low-level viremia). Over the 24 week study, we compared changes in T-cells, injection site reactions, quality of life, and residual viremia, as measured through the single-copy assay which can detect plasma virus down to a single copy, using paired t-tests.Fourteen patients with a median CD4+ T-cell count of 420 cells/microL were enrolled. After the switch, two patients experienced virologic failure due to confirmed low-level viremia. However, both patients subsequently were re-suppressed, one without any changes to his regimen. There was no change in CD4+ T-cell count. Injection site reactions resolved. However, there was little reported change in quality of life. The baseline median level of residual viremia was 6 copies/mL and did not change after the switch to raltegravir.A switch to raltegravir in virologically suppressed patients on enfuvirtide is effective in maintaining immunologic and virologic control at 24 weeks but did not result in a change in residual viremia.

  View details for DOI 10.1016/j.jcv.2009.09.025

  View details for Web of Science ID 000272460900002

  View details for PubMedID 19819183

• The use of resistance testing in the management of HIV-1-infected patients CURRENT OPINION IN HIV AND AIDS Grant, P. M., Zolopa, A. R. 2009; 4 (6): 474-480

  Abstract

  Resistance testing has become an important component of the recommended care for treatment-naive and treatment-experienced HIV-infected patients in the developed world, and their use has been shown to improve clinical outcomes. Despite the widespread use of resistance testing, the clinician faces a number of challenges in optimally applying these technologies to antiretroviral management.Even with the aid of a genotypic interpretation system, the interpretation of a genotype is complex and benefits from expert input. Phenotypic resistance testing is limited by cost and availability for many patients. Standard resistance testing (both genotypes and phenotypes) is unable to detect minority species. The presence of resistant minority populations has been associated with virologic failure. However, the current techniques available to detect their presence are cumbersome and not soon likely to become part of routine clinical care. The development of the chemokine (C-C motif) receptor 5 antagonists has provided new challenges in quantifying antiretroviral resistance.Resistance testing plays a central role in the management of treatment-experienced patients. Further progress in the interpretation of resistance testing, especially as new agents are developed, will continue to add value to the care of HIV-infected patients.

  View details for DOI 10.1097/COH.0b013e328331c14f

  View details for Web of Science ID 000208083400003

  View details for PubMedID 20048713

• Initiation of antiretroviral therapy in the hospitalized patient with an acute AIDS-related opportunistic infection and other conditions: no time to lose. Current HIV/AIDS reports Grant, P., Zolopa, A. 2009; 6 (2): 63-67

  Abstract

  Treatment guidelines have recently become more definitive regarding the optimal timing for initiation of combination antiretroviral therapy (ART) in the setting of an acute AIDS-related opportunistic infection (OI). These recent changes reflect new data from a prospective, randomized study and several retrospective studies, all of which support earlier initiation of ART during an OI. These studies focus on OIs for which effective antimicrobial therapy exists. For AIDS-related conditions that lack effective antimicrobial therapy, there are few studies to help inform the optimal timing to initiate ART, but most clinicians initiate ART early, as little else can be offered to these patients. For patients with HIV admitted for non-AIDS-related conditions, there are few data that directly address the optimal timing for ART. Initiating ART in the hospitalized patient can be challenging and requires a well-coordinated multidisciplinary team with expertise in ART management.

  View details for PubMedID 19358776

• Maintaining Reduced Viral Fitness and CD4 Response in HIV-Infected Patients with Viremia Receiving a Boosted Protease Inhibitor CLINICAL INFECTIOUS DISEASES Grant, P., Taylor, J., Cain, P., Short, W., Gallant, J., Farthing, C., Thal, G., Coakley, E., Zolopa, A. 2009; 48 (5): 680-682

  Abstract

  When fully suppressive regimens are not available, incompletely suppressive regimens also provide immunologic benefits. In this study, with stable background therapy, human immunodeficiency virus (HIV)-infected patients who were randomized to receive atazanavir or boosted atazanavir, compared with those who continued boosted protease inhibitor therapy, maintained similar virologic and immunologic control, resistance-mutation patterns, and replication capacities with reduced use of lipid-lowering medication.

  View details for DOI 10.1086/597008

  View details for Web of Science ID 000263061700026

  View details for PubMedID 19191657

• Virologic Response to Lopinavir-Ritonavir-Based Antiretroviral Regimens in a Multicenter International Clinical Cohort: Comparison of Genotypic Interpretation Scores ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Grant, P., Wong, E. C., Rode, R., Shafer, R., De Luca, A., Nadler, J., Hawkins, T., Cohen, C., Harrington, R., Kempf, D., Zolopa, A. 2008; 52 (11): 4050-4056

  Abstract

  Several genotypic interpretation scores have been proposed for the evaluation of susceptibility to lopinavir/ritonavir (LPV/r) but have not been compared using an independent data set. This study was a retrospective multicenter cohort of patients initiating LPV/r-based therapy. The virologic response (VR) was defined as a viral load of <500 copies/ml at week 24. The genotypic interpretation scores surveyed were the LPV mutation score, the ViroLogic score, the ATU score, the Stanford database score, and the International AIDS Society-USA mutation list. Of the 103 patients included in the analysis, 76% achieved VR at 24 weeks. For scores with clinical breakpoints defined (LPV mutation, ATU, ViroLogic, and Stanford), over 80% of the patients below the breakpoints achieved VR, while 50% or less above the breakpoints responded. Protease mutations at positions 10, 54, and 82 and at positions 54, 84, and 90 were associated with a lack of VR in the univariate and multivariate analyses, respectively. The area under the receiver-operator characteristic curves for the five genotypic interpretation scores studied ranged from 0.73 to 0.76. The study confirms that the currently available genotypic interpretation scores which are widely used by clinicians performed similarly well and can be effectively used to predict the virologic activity of LPV/r in treatment-experienced patients.

  View details for DOI 10.1128/AAC.00605-08

  View details for PubMedID 18710915

• Integrase inhibitors: a clinical review of raltegravir and elvitegravir. Journal of HIV therapy Grant, P., Zolopa, A. 2008; 13 (2): 36-39

  View details for PubMedID 18953272