- Infectious Disease
Senior Fellow, Stanford Center for Inovation in Global Health (CIGH) (2015 - Present)
HIV Specialist, AAHIVS, American Academy of HIV Medicine, HIV (2016)
Board Certification: Infectious Disease, American Board of Internal Medicine (2014)
Board Certification: Internal Medicine, American Board of Internal Medicine (2011)
Fellowship: Stanford University (2015) CA
Residency: New York - Presbyterial Hospital / Weill Cornell Medical College (2011) NY
Medical Education: Weill Cornell Medical College (2008) NY
Masters of Science, Stanford University, Epidemiology and clinical research (2015)
Community and International Work
Simplifying Hepatitis C Antiviral therapy in Rwanda for Elsewhere in the Developing world (SHARED), Rwanda
Hepatitis C clinical research
Partners in Health, Rwanda Biomedical Center, Rwanda Military Hospital
Opportunities for Student Involvement
Switch From Nevirapine-based Regimen to Once a Day Rilpivirine/Emtricitabine/Tenofovir, Kigali, Rwanda
HIV Clinical Research
Rwanda Biomedical Center, Rwanda Military Hospital
Opportunities for Student Involvement
Switch From Nevirapine-based Regimen to Once a Day Rilpivirine/Emtricitabine/Tenofovir
The study will be an open-label, pilot study in virologically suppressed patients comparing the efficacy, safety and tolerability of two Antiretroviral regimen strategies: Arm A: "Immediate switch" Rilpivirine/Emtricitabine/Tenofovir (single tablet formulation (STF))at randomization Arm B: "Delayed switch" Continue Nevirapine/Lamivudine/other Nucleoside reverse transcriptase inhibitor (NRTI)through 24 weeks then switch to STF of Rilpivirine/emtrictabine/tenofovir and followed through 48 weeks.
Stanford is currently not accepting patients for this trial.
Lack of an association between clinical INSTI-related body weight gain and direct interference with MC4 receptor (MC4R), a key central regulator of body weight
2020; 15 (2): e0229617
An increasing prevalence of overweight and obesity in people living with HIV has been associated with initiation of antiretroviral therapy with integrase strand transfer inhibitors (INSTIs). An off-target inhibition of the endogenous ligand binding to the human melanocortin 4 receptor (MC4R) has been suggested as a potential mechanism for clinical body weight gain following initiation of dolutegravir, an INSTI. In this study, we interrogated several INSTIs for their capacity for antagonism or agonism of MC4R in an in vitro cell-based assays including at concentrations far exceeding plasma concentrations reached at the recommended dosages. Our results indicate that while INSTIs do exhibit the capacity to antagonize MC4R, this occurs at concentrations well above predicted clinical exposure and is thus an implausible explanation for INSTI-associated weight gain.
View details for DOI 10.1371/journal.pone.0229617
View details for Web of Science ID 000535239800019
View details for PubMedID 32109250
View details for PubMedCentralID PMC7048285
Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir-containing regimens for initial treatment of HIV-1 infection: week 144 results from two randomised, double-blind, multicentre, phase 3, non-inferiority trials.
The lancet. HIV
2020; 7 (6): e389–e400
In the primary week-48 analyses of two phase 3 studies, coformulated bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to a dolutegravir-containing regimen in treatment-naive people with HIV. We report week-144 efficacy and safety results from these studies.We did two double-blind, active-controlled studies (now in open-label extension phase). Study 1 randomly assigned (1:1) HLA-B*5701-negative adults without hepatitis B virus co-infection to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg, or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg once daily. Study 2 randomly assigned (1:1) adults to bictegravir, emtricitabine, and tenofovir alafenamide, or dolutegravir 50 mg given with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg. We previously reported non-inferiority at the primary endpoint. Here, we report the week-144 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 144, by US Food and Drug Administration Snapshot algorithm, analysed in the same manner. These studies were registered with ClinicalTrials.gov, NCT02607930 and NCT02607956.629 participants were randomly assigned and treated in study 1 (314 to bictegravir, emtricitabine, and tenofovir alafenamide, and 315 to dolutegravir, abacavir, and lamivudine) and 645 in study 2 (327 to bictegravir, emtricitabine, and tenofovir alafenamide, 325 to dolutegravir, emtricitabine, tenofovir alafenamide). At week 144, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to both dolutegravir-containing regimens for efficacy. In study 1, 256 (82%) of 314 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 265 (84%) of 315 in the dolutegravir, abacavir, and lamivudine group (difference -2·6%, 95% CI -8·5 to 3·4). In study 2, 262 (82%) of 320 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 273 (84%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (difference -1·9%, -7·8 to 3·9). In both studies, no participant had treatment-emergent resistance to study drugs up to week 144. All treatment regimens were well tolerated with additional exposure. Adverse events that led to study drug discontinuation were reported for no participants in the bictegravir, emtricitabine, and tenofovir alafenamide group versus five (2%) of 315 in the dolutegravir, abacavir, and lamivudine group (study 1), and six (2%) of 320 in the bictegravir, emtricitabine, and tenofovir alafenamide versus six (2%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (study 2). In study 1, statistically significant differences were observed in median changes from baseline in fasting total cholesterol (14 mg/dL vs 10 mg/dL; p=0·034), direct LDL (21 mg/dL vs 14 mg/dL; p=0·004), and total cholesterol to HDL ratio (-0·1 vs -0·3; p=0·007) at week 144; no differences were observed between groups in study 2. Weight gain was seen across all treatment groups in both studies, with no differences in median changes from baseline in weight at week 144 for either study.These long-term data support the use of bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people with HIV, with no emergent resistance.Gilead Sciences.
View details for DOI 10.1016/S2352-3018(20)30099-0
View details for PubMedID 32504574
Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial
2019; 6 (6): E364–E372
The single-tablet regimen consisting of bictegravir, emtricitabine, and tenofovir alafenamide is recommended for treatment of HIV-1 infection on the basis of data from 48 weeks of treatment. Here, we examine the longer-term efficacy, safety, and tolerability of bictegravir, emtricitabine, and tenofovir alafenamide compared with dolutegravir plus co-formulated emtricitabine and tenofovir alafenamide at week 96.This ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial was done at 126 outpatient centres in ten countries. We enrolled treatment-naive adults (aged ≥18 years) with HIV-1 infection who had an estimated glomerular filtration rate of at least 30 mL/min and sensitivity to emtricitabine and tenofovir. People with chronic hepatitis B or C infection, or both, and those who had used antivirals previously for prophylaxis were allowed. We randomly assigned participants (1:1) to receive treatment with either co-formulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg (the bictegravir group) or dolutegravir 50 mg with co-formulated emtricitabine 200 mg and tenofovir alafenamide 25 mg (the dolutegravir group), each with matching placebo, once daily for 144 weeks. Treatment allocation was masked to all participants and investigators. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. We previously reported the primary endpoint. Here, we report the week 96 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 96 by US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. This study was registered with ClinicalTrials.gov, number NCT02607956.Between Nov 13, 2015, and July 14, 2016, we screened 742 individuals, of whom 657 were enrolled. 327 participants were assigned to the bictegravir group and 330 to the dolutegravir group. Of these, 320 in the bictegravir group and 325 in the dolutegravir group received at least one dose of study drug. At week 96, HIV-1 RNA less than 50 copies per mL was achieved by 269 (84%) of 320 participants in the bictegravir group and 281 (86%) of 325 in the dolutegravir group (difference -2·3%, 95% CI -7·9 to 3·2), demonstrating non-inferiority of the bictegravir regimen compared with the dolutegravir regimen. Both treatments continued to be well tolerated through 96 weeks; 283 (88%) of 320 participants in the bictegravir group and 288 (89%) of 325 in the dolutegravir group had any adverse event and 55 (17%), and 33 (10%) had any serious adverse event. The most common adverse events were diarrhoea (57 [18%] of 320 in the bictegravir group vs 51 [16%] of 325 in the dolutegravir group) and headache (51 [16%] of 320 vs 48 [15%] of 325). Deaths were reported for three (1%) individuals in each group (one cardiac arrest, one gastric adenocarcinoma, and one hypertensive heart disease and congestive cardiac failure in the bictegravir group and one unknown causes, one pulmonary embolism, and one lymphoma in the dolutegravir group); none were considered to be treatment related. Adverse events led to discontinuation in six (2%) participants in the bictegravir group and five (2%) in the dolutegravir group; one of these events in the bictegravir group versus four in the dolutegravir group occurred between weeks 48 and 96. Study drug-related adverse events were reported for 64 (20%) participants in the bictegravir group and 92 (28%) in the dolutegravir group.These week 96 data support bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people living with chronic HIV.Gilead Sciences, Inc.
View details for DOI 10.1016/S2352-3018(19)30080-3
View details for Web of Science ID 000469200000011
View details for PubMedID 31068272
Bictegravir combined with emtricitabine and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial.
The lancet. HIV
Bictegravir co-formulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination is recommended for treatment of HIV-1-infection and might be better tolerated than other integrase inhibitor-based single-tablet regimens, but long-term outcomes data are not available. We assessed the efficacy, safety and tolerability of bictegravir, emtricitabine, and tenofovir alafenamide compared with co-formulated dolutegravir, abacavir, and lamivudine at week 96.This ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial was done at 122 outpatient centres in nine countries. We enrolled adults (aged ≥18 years) living with HIV who were treatment naive and HLA-B*5701 negative, did not have hepatitis B virus infection, and had an estimated glomerular filtration rate of at least 50 mL/min. We randomly assigned participants (1:1) to receive co-formulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg (the bictegravir group) or co-formulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (the dolutegravir group), each with matching placebo, once daily for 144 weeks. Treatment allocation was masked to all participants and investigators. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. We previously reported the primary endpoint. Here, we report the week 96 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 96 by US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. This study was registered with ClinicalTrials.gov, number NCT02607930.Between Nov 13, 2015, and July 14, 2016, we screened 739 participants, of whom 108 were excluded and 631 enrolled and randomly assigned to bictegravir, emtricitabine, and tenofovir alafenamide (n=316) or dolutegravir, abacavir, and lamivudine (n=315). Two participants in the bictegravir group did not receive at least one dose of their assigned drug and were excluded from analyses. At week 96, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to dolutegravir, abacavir, and lamivudine, with 276 (88%) of 314 participants in the bictegravir group versus 283 (90%) of 315 participants in the dolutegravir group achieving HIV-1 RNA less than 50 copies per mL (difference -1·9%; 95% CI -6·9 to 3·1). The most common adverse events were nausea (36 [11%] of 314 for the bictegravir group vs 76 [24%] of 315 for the dolutegravir group), diarrhoea (48 [15%] vs 50 [16%]), and headache (41 [13%] vs 51 [16%]). 36 (11%) participants in the bictegravir group versus 39 (12%) participants in the dolutegravir group had a serious adverse event. Two individuals died in the bictegravir group (recreational drug overdose and suicide, neither of which was treatment related) and none died in the dolutegravir group. No participants discontinued because of adverse events in the bictegravir group compared with five (2%) of 315 in the dolutegravir group. Study drug-related adverse events were reported for 89 (28%) participants in the bictegravir group and 127 (40%) in the dolutegravir group.These week 96 data support bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people living with HIV-1 with no emergent resistance.Gilead Sciences, Inc.
View details for DOI 10.1016/S2352-3018(19)30077-3
View details for PubMedID 31068270
Switching to coformulated rilpivirine (RPV), emtricitabine (FTC) and tenofovir alafenamide from either RPV, FTC and tenofovir disoproxil fumarate (TDF) or efavirenz, FTC and TDF: 96-week results from two randomized clinical trials
2018; 19 (10): 724–33
The single-tablet regimen rilpivirine, emtricitabine and tenofovir alafenamide (RPV/FTC/TAF) for treatment of HIV-1-infected adults was approved based on bioequivalence. We assessed the clinical efficacy, safety and tolerability of switching to RPV/FTC/TAF from either RPV/FTC/tenofovir disoproxil fumarate (TDF) or efavirenz (EFV)/FTC/TDF.We conducted two distinct randomized, double-blind, active-controlled, noninferiority trials in participants taking RPV/FTC/TDF (Study 1216) and EFV/FTC/TDF (Study 1160). Each study randomized virologically suppressed (HIV-1 RNA < 50 copies/mL) adults (1:1) to switch to RPV/FTC/TAF or continue their current regimen for 96 weeks. We evaluated efficacy as the proportion with HIV-1 RNA < 50 copies/mL using the Food and Drug Administration snapshot algorithm and prespecified bone and renal endpoints at week 96.We randomized and treated 630 participants in Study 1216 (RPV/FTC/TAF, n = 316; RPV/FTC/TDF, n = 314) and 875 in Study 1160 (RPV/FTC/TAF, n = 438; EFV/FTC/TDF, n = 437). In both studies, the efficacy of switching to RPV/FTC/TAF was noninferior to that of continuing baseline therapy at week 96, with respective percentages of patients with HIV RNA < 50 copies/mL being 89.2% versus 88.5% in Study 1216 [difference 0.7%; 95% confidence interval (CI) -4.3 to +5.8%] and 85.2% versus 85.1% in Study 1160 (difference 0%; 95% CI -4.8 to +4.8%). No participant on RPV/FTC/TAF developed treatment-emergent resistance versus two on EFV/FTC/TDF and one on RPV/FTC/TDF. Compared with continuing baseline therapy, significant improvements in bone mineral density and renal tubular markers were observed in the RPV/FTC/TAF groups (P < 0.001).Switching to RPV/FTC/TAF from RPV/FTC/TDF or EFV/FTC/TDF was safe and effective and improved bone mineral density and renal biomarkers up to 96 weeks with no cases of treatment-emergent resistance.
View details for PubMedID 30101539
Coformulated bictegravir, emtricitabine, tenofovir alafenamide after initial treatment with bictegravir or dolutegravir and emtricitabine/tenofovir alafenamide
2018; 32 (12): 1723–25
: A phase 2, randomized, active-controlled study of initial antiretroviral therapy with bictegravir or dolutegravir in combination with emtricitabine and tenofovir alafenamide showed excellent efficacy. After 60 weeks of blinded treatment, participants switched to a single-tablet regimen of bictegravir, emtricitabine, and tenofovir alafenamide. Switching maintained viral suppression in all participants who remained on the study through 12 weeks in the open-label phase, and was safe and well tolerated.
View details for PubMedID 29794828
Mass Spectrometric Identification of Urinary Biomarkers of Pulmonary Tuberculosis
2018; 31: 157–65
Tuberculosis (TB) is the leading infectious cause of death worldwide. A major barrier to control of the pandemic is a lack of clinical biomarkers with the ability to distinguish active TB from healthy and sick controls and potential for development into point-of-care diagnostics.We conducted a prospective case control study to identify candidate urine-based diagnostic biomarkers of active pulmonary TB (discovery cohort) and obtained a separate blinded "validation" cohort of confirmed cases of active pulmonary TB and controls with non-tuberculous pulmonary disease for validation. Clean-catch urine samples were collected and analyzed using high performance liquid chromatography-coupled time-of-flight mass spectrometry.We discovered ten molecules from the discovery cohort with receiver-operator characteristic (ROC) area-under-the-curve (AUC) values >85%. These 10 molecules also significantly decreased after 60 days of treatment in a subset of 20 participants followed over time. Of these, a specific combination of diacetylspermine, neopterin, sialic acid, and N-acetylhexosamine exhibited ROC AUCs >80% in a blinded validation cohort of participants with active TB and non-tuberculous pulmonary disease.Urinary levels of diacetylspermine, neopterin, sialic acid, and N-acetylhexosamine distinguished patients with tuberculosis from healthy controls and patients with non-tuberculous pulmonary diseases, providing a potential noninvasive biosignature of active TB.This study was funded by Weill Cornell Medicine, the National Institute of Allergy and Infectious Diseases, the Clinical and Translational Science Center at Weill Cornell, the NIH Fogarty International Center grants, and the NIH Tuberculosis Research Unit (Tri-I TBRU).
View details for DOI 10.1016/j.ebiom.2018.04.014
View details for Web of Science ID 000433078300022
View details for PubMedID 29752217
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
2016; 3 (3): ofw141-?
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
Modifying Antiretroviral Therapy in Virologically Suppressed HIV-1-Infected Patients
2016; 76 (1): 75-98
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
Tuberculosis in the aftermath of the 2010 earthquake in Haiti
BULLETIN OF THE WORLD HEALTH ORGANIZATION
2015; 93 (7): 498-502
In 2010, Haiti sustained a devastating earthquake that crippled the health-care infrastructure in the capital city, Port-au-Prince, and left 1.5 million people homeless. Subsequently, there was an increase in reported tuberculosis in the affected population.We conducted active tuberculosis case finding in a camp for internally displaced persons and a nearby slum. Community health workers screened for tuberculosis at the household level. People with persistent cough were referred to a physician. The National Tuberculosis Program continued its national tuberculosis reporting system.Even before the earthquake, Haiti had the highest tuberculosis incidence in the Americas. About half of the tuberculosis cases occur in the Port-au-Prince region.The number of reported tuberculosis cases in Haiti has increased after the earthquake, but data are too limited to determine if this is due to an increase in tuberculosis burden or to improved case detection. Compared to previous national estimates (230 per 100,000 population), undiagnosed tuberculosis was threefold higher in a camp for internally displaced persons (693 per 100,000) and fivefold higher in an urban slum (1165 per 100,000). With funding from the World Health Organization (WHO), active case finding is now being done systematically in slums and camps.Household-level screening for prolonged cough was effective in identifying patients with active tuberculosis in this study. Without accurate data, early detection of rising tuberculosis rates is challenging; data collection should be incorporated into pragmatic disease response programmes.
View details for DOI 10.2471/BLT.14.145649
View details for Web of Science ID 000358888100017
View details for PubMedID 26170508
View details for PubMedCentralID PMC4490810
CD4 deficit and tuberculosis risk persist with delayed antiretroviral therapy: 5-year data from CIPRA HT-001.
international journal of tuberculosis and lung disease
2015; 19 (1): 50-57
Port-au-Prince, Haiti.To determine long-term effects of early vs. delayed initiation of antiretroviral therapy (ART) on immune recovery and tuberculosis (TB) risk in human immunodeficiency virus (HIV) infected individuals.Open-label randomized controlled trial of immediate ART in HIV-infected adults with CD4 counts between 200 and 350 cells/mm(3) vs. deferring ART until the CD4 count was <200 cells/mm(3). The primary comparisons were CD4 counts over time and risk for incident TB, with 5 years of follow-up.A total of 816 participants were enrolled, with 408 in each treatment arm. The early treatment group started ART within 2 weeks, while the deferred treatment group started ART a median of 1.3 years after enrollment. After 5 years, the mean CD4 count in the early treatment group was significantly higher than in the deferred treatment group (496 cells/mm(3), 95% confidence interval [CI] 477-515 vs. 373 cells/mm(3), 95%CI 357-389; P < 0.0001). TB risk was higher in the deferred treatment group (unadjusted HR 2.41, 95%CI 1.56-3.74; P < 0.0001) and strongly correlated with lower CD4 counts in time-dependent multivariate analysis.Delays in ART initiation for HIV-infected adults with CD4 counts of 200-350 cells/mm(3) can result in long-term immune dysfunction and persistent increased risk for TB.
View details for DOI 10.5588/ijtld.14.0217
View details for PubMedID 25519790
Whole Genome Sequencing Investigation of a Tuberculosis Outbreak in Port-au-Prince, Haiti Caused by a Strain with a "Low-Level" rpoB Mutation L511P - Insights into a Mechanism of Resistance Escalation.
2015; 10 (6)
The World Health Organization recommends diagnosing Multidrug-Resistant Tuberculosis (MDR-TB) in high burden countries by detection of mutations in Rifampin (RIF) Resistance Determining Region of Mycobacterium tuberculosis rpoB gene with rapid molecular tests GeneXpert MTB/RIF and Hain MTBDRplus. Such mutations are found in >95% of Mycobacterium tuberculosis strains resistant to RIF by conventional culture-based drug susceptibility testing (DST). However routine diagnostic screening with molecular tests uncovered specific "low level" rpoB mutations conferring resistance to RIF below the critical concentration of 1 μg/ml in some phenotypically susceptible strains. Cases with discrepant phenotypic (susceptible) and genotypic (resistant) results for resistance to RIF account for at least 10% of resistant diagnoses by molecular tests and urgently require new guidelines to inform therapeutic decision making. Eight strains with a "low level" rpoB mutation L511P were isolated by GHESKIO laboratory between 2008 and 2012 from 6 HIV-negative and 2 HIV-positive patients during routine molecular testing. Five isolates with a single L511P mutation and two isolates with double mutation L511P&M515T had MICs for RIF between 0.125 and 0.5 μg/ml and tested susceptible in culture-based DST. The eighth isolate carried a double mutation L511P&D516C and was phenotypically resistant to RIF. All eight strains shared the same spoligotype SIT 53 commonly found in Haiti but classic epidemiological investigation failed to uncover direct contacts between the patients. Whole Genome Sequencing (WGS) revealed that L511P cluster isolates resulted from a clonal expansion of an ancestral strain resistant to Isoniazid and to a very low level of RIF. Under the selective pressure of RIF-based therapy the strain acquired mutation in the M306 codon of embB followed by secondary mutations in rpoB and escalation of resistance level. This scenario highlights the importance of subcritical resistance to RIF for both clinical management of patients and public health and provides support for introducing rpoB mutations as proxy for MICs into laboratory diagnosis of RIF resistance. This study illustrates that WGS is a promising multi-purpose genotyping tool for high-burden settings as it provides both "gold standard" sequencing results for prediction of drug susceptibility and a high-resolution data for epidemiological investigation in a single assay.
View details for DOI 10.1371/journal.pone.0129207
View details for PubMedID 26039194
- Gender inequality and HIV transmission: a global analysis JOURNAL OF THE INTERNATIONAL AIDS SOCIETY 2014; 17
Correlation between Genotypic and Phenotypic Testing for Resistance to Rifampin in Mycobacterium tuberculosis Clinical Isolates in Haiti: Investigation of Cases with Discrepant Susceptibility Results
2014; 9 (3)
The World Health Organization has recommended use of molecular-based tests MTBDRplus and GeneXpert MTB/RIF to diagnose multidrug-resistant tuberculosis in developing and high-burden countries. Both tests are based on detection of mutations in the Rifampin (RIF) Resistance-Determining Region of DNA-dependent RNA Polymerase gene (rpoB). Such mutations are found in 95-98% of Mycobacterium tuberculosis strains determined to be RIF-resistant by the "gold standard" culture-based drug susceptibility testing (DST). We report the phenotypic and genotypic characterization of 153 consecutive clinical Mycobacterium tuberculosis strains diagnosed as RIF-resistant by molecular tests in our laboratory in Port-au-Prince, Haiti. 133 isolates (86.9%) were resistant to both RIF and Isoniazid and 4 isolates (2.6%) were RIF mono-resistant in MGIT SIRE liquid culture-based DST. However the remaining 16 isolates (10.5%) tested RIF-sensitive by the assay. Five strains with discordant genotypic and phenotypic susceptibility results had RIF minimal inhibitory concentration (MIC) close to the cut-off value of 1 µg/ml used in phenotypic susceptibility assays and were confirmed as resistant by DST on solid media. Nine strains had sub-critical RIF MICs ranging from 0.063 to 0.5 µg/ml. Finally two strains were pan-susceptible and harbored a silent rpoB mutation. Our data indicate that not only detection of the presence but also identification of the nature of rpoB mutation is needed to accurately diagnose resistance to RIF in Mycobacterium tuberculosis. Observed clinical significance of low-level resistance to RIF supports the re-evaluation of the present critical concentration of the drug used in culture-based DST assays.
View details for DOI 10.1371/journal.pone.0090569
View details for Web of Science ID 000332479400094
View details for PubMedID 24599230
Integrating integrase inhibitors into an antiretroviral regimen
CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES
2014; 6 (2)
View details for DOI 10.1007/s40506-013-0009-6
Outcomes of HIV-infected patients treated for recurrent tuberculosis with the standard retreatment regimen
INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE
2012; 16 (6): 841-845
The Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (the GHESKIO AIDS and TB Center) in Port-au-Prince, Haiti.To measure the effectiveness of the standard TB retreatment regimen (2HRZES/1HRZE/5HRE) in human immunodeficiency virus (HIV) infected adults.Cohort study.Of 1318 HIV-infected patients with access to antiretroviral therapy following World Health Organization guidelines, 56 were diagnosed with recurrent pulmonary TB and retreated with the standard retreatment regimen: 10 patients (18%) died during retreatment, 3 (5%) defaulted, and 2 (4%) failed treatment. Forty-one patients (73%) achieved retreatment 'success' (cure, treatment completed). Of these, 8 (20%) died during follow-up, 5 (12%) were lost, and 5 (12%) had a second recurrence of TB. Only 26 (46%) of the 56 patients remained alive, in care, and TB-free after a median of 36 months of follow-up.HIV-infected patients treated for recurrent TB with the standard retreatment regimen have high mortality and poor long-term outcomes.
View details for DOI 10.5588/ijtld.11.0210
View details for Web of Science ID 000304580400024
View details for PubMedID 22507948
High Mortality among Patients with AIDS Who Received a Diagnosis of Tuberculosis in the First 3 Months of Antiretroviral Therapy
CLINICAL INFECTIOUS DISEASES
2009; 48 (6): 829-831
We analyzed mortality among 201 patients with AIDS and tuberculosis in Haiti. Patients who received a diagnosis of tuberculosis during the first 3 months after the initiation of antiretroviral therapy were 3.25 times more likely to die than were other patients with AIDS and tuberculosis. Failure to recognize active tuberculosis at initiation of antiretroviral therapy leads to increased mortality.
View details for DOI 10.1086/597098
View details for Web of Science ID 000263949000022
View details for PubMedID 19207078