scispace - formally typeset
Search or ask a question

Showing papers by "Myron S. Cohen published in 2018"


Journal ArticleDOI
TL;DR: In this study, CAB LA was well tolerated at the doses and dosing intervals used and was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test.
Abstract: Background Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States. Methods and findings HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18-65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population. Conclusions In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress. Trial registration ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800.

126 citations


Journal ArticleDOI
TL;DR: A computational tool is developed to track recombination in patients, identify recombination hot spots, and show contribution of recombination to antibody escape, which provides insight into molecular mechanisms by which viral recombination contributes to HIV-1 persistence and immunopathogenesis.
Abstract: Recombination in HIV-1 is well documented, but its importance in the low-diversity setting of within-host diversification is less understood. Here we develop a novel computational tool (RAPR (Recombination Analysis PRogram)) to enable a detailed view of in vivo viral recombination during early infection, and we apply it to near-full-length HIV-1 genome sequences from longitudinal samples. Recombinant genomes rapidly replace transmitted/founder (T/F) lineages, with a median half-time of 27 days, increasing the genetic complexity of the viral population. We identify recombination hot and cold spots that differ from those observed in inter-subtype recombinants. Furthermore, RAPR analysis of longitudinal samples from an individual with well-characterized neutralizing antibody responses shows that recombination helps carry forward resistance-conferring mutations in the diversifying quasispecies. These findings provide insight into molecular mechanisms by which viral recombination contributes to HIV-1 persistence and immunopathogenesis and have implications for studies of HIV transmission and evolution in vivo.

77 citations



Journal ArticleDOI
TL;DR: This Review endeavoured to provide a framework to assist researchers, public health practitioners, and funding institutions to ensure that HIV phylogenetic studies are designed, done, and disseminated in an ethical manner.

35 citations


Journal ArticleDOI
TL;DR: The need to continue to refine estimates of efficacy and effectiveness of tenofovir-based oral PrEP so as to best develop the next generation of HIV prevention tools, and to inform public policies directed toward HIV prevention is emphasized.
Abstract: As oral tenofovir-based regimens for preexposure prophylaxis (PrEP) are adopted as standard of care for HIV prevention, their utilization in clinical trials among women in southern Africa will require an accurate estimate of oral PrEP efficacy in this population. This information is critical for women in choosing this prevention strategy, and in public health policy making. Estimates of the efficacy of oral PrEP regimens containing tenofovir have varied widely across trials that enrolled women, with some studies reporting high efficacy and others reporting no efficacy. Although poor adherence is strongly associated with lack of efficacy, other factors, such as mode of transmission (sexual vs. parenteral), predominant HIV subtype (C vs. non-C), intensity of exposure, and percentage of stable serodiscordant couples, may also contribute to the variation in efficacy estimates. In this article, we evaluate the evidence for PrEP efficacy in women and propose potential explanations for the observed differences in efficacy among studies. Our review emphasizes the need to continue to refine estimates of efficacy and effectiveness of tenofovir-based oral PrEP so as to best develop the next generation of HIV prevention tools, and to inform public policies directed toward HIV prevention.

24 citations


Journal ArticleDOI
TL;DR: Lower CD4 levels and older age predicted retention in ART care, suggesting that first-year retention measures likely overestimate retention over longer periods.
Abstract: Quantifying HIV service provision along the HIV care continuum is increasingly important for monitoring and evaluating HIV interventions. We examined factors associated with linkage and retention in care longitudinally among MSM (n = 1974, 4933 person-years) diagnosed and living in Guangzhou, China, in 2008–2014. We measured longitudinal change of retention in care (≥2 CD4 tests per year) from linkage and antiretroviral therapy initiation (ART). We examined factors associated with linkage using logistic regression and with retention using generalized estimating equations. The rate of linkage to care was 89% in 2014. ART retention rate dropped from 71% (year 1) to 46% (year 2), suggesting that first-year retention measures likely overestimate retention over longer periods. Lower CD4 levels and older age predicted retention in ART care. These data can inform interventions to improve retention about some subgroups.

16 citations


Book ChapterDOI
TL;DR: The history of HIV research in serodiscordant couples, the implications for management of couples, subsequent research on treatment as prevention in other key populations, and challenges in community implementation of these strategies are explored.
Abstract: The scientific breakthrough proving that antiretroviral therapy (ART) can halt heterosexual HIV transmission came in the form of a landmark clinical trial conducted among serodiscordant couples. Study findings immediately informed global recommendations for the use of treatment as prevention in serodiscordant couples. The extent to which these findings are generalizable to other key populations or to groups exposed to HIV through nonsexual transmission routes (i.e., anal intercourse or unsafe injection of drugs) has since driven a large body of research. This review explores the history of HIV research in serodiscordant couples, the implications for management of couples, subsequent research on treatment as prevention in other key populations, and challenges in community implementation of these strategies.

14 citations


Journal ArticleDOI
TL;DR: The receiver operating characteristic area under the curve (AUC) of RT and V1-V3 combined showed excellent discrimination of recent infection <9 months: using π and the first quintile of pairwise diversity distributions over time.
Abstract: Intrahost viral sequence diversity can be evaluated over multiple genomic regions using next-generation sequencing (NGS) and scaled to population-level diversity to identify recent human immunodeficiency virus type 1 infection. Using Primer-ID NGS, we sequenced the reverse transcriptase (RT) and env V1-V3 regions from persons with known infection dates, and assessed the mean (π) and first quintile of pairwise diversity distributions over time. The receiver operating characteristic area under the curve (AUC) of RT and V1-V3 combined showed excellent discrimination of recent infection <9 months: using π (only single transmitted variants: AUC, 0.98; threshold <1.03%; sensitivity, 97%; specificity, 89%) and the first quintile (including all variants: AUC, 0.90; threshold <0.60%; sensitivity, 91%; specificity, 92%).

12 citations


Journal ArticleDOI
TL;DR: The transmitted virus in a cohort of people who inject drugs and who are at risk of HIV-1 infection through blood contamination when injecting in a group is examined, indicating that a single viral variant was transmitted in each case, consistent with a model where the exposure to virus during transmission was limited.
Abstract: Understanding features of the HIV-1 transmission process has the potential to inform biological interventions for prevention. We have examined the transmitted virus in a cohort of people who inject drugs and who are at risk of HIV-1 infection through blood contamination when injecting in a group. This study focused on seven newly infected participants in St. Petersburg, Russia, who were in acute or early infection. We used end-point dilution polymerase chain reaction to amplify single viral genomes to assess the complexity of the transmitted virus. We also used deep sequencing to further assess the complexity of the virus. We interpret the results as indicating that a single viral variant was transmitted in each case, consistent with a model where the exposure to virus during transmission was limited. We also looked at phenotypic properties of the viral Env protein in isolates from acute and chronic infection. Although differences were noted, there was no consistent pattern that distinguished the...

10 citations


Journal ArticleDOI
TL;DR: Differences in cell phenotype and lineage in the MGT may have an impact on selecting and dosing ARVs used in cure strategies, and TAF SP PK was unexpected.
Abstract: BackgroundThe male genital tract (MGT) is a viral sanctuary and likely HIV reservoir; understanding MGT pharmacokinetics (PK) of antiretrovirals (ARVs) used for curative strategies is critical to e...

7 citations