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Background The long-term impact of universal home-based testing and treatment as part of universal testing and treatment (UTT) on HIV incidence is unknown. We made projections using a detailed individual-based model of the effect of the intervention delivered in the HPTN 071 (PopART) cluster-randomised trial. Methods In this modelling study, we fitted an individual-based model to the HIV epidemic and HIV care cascade in 21 high prevalence communities in Zambia and South Africa that were part of the PopART cluster-randomised trial (intervention period Nov 1, 2013, to Dec 31, 2017). The model represents coverage of home-based testing and counselling by age and sex, delivered as part of the trial, antiretroviral therapy (ART) uptake, and any changes in national guidelines on ART eligibility. In PopART, communities were randomly assigned to one of three arms: arm A received the full PopART intervention for all individuals who tested positive for HIV, arm B received the intervention with ART provided in accordance with national guidelines, and arm C received standard of care. We fitted the model to trial data twice using Approximate Bayesian Computation, once before data unblinding and then again after data unblinding. We compared projections of intervention impact with observed effects, and for four different scenarios of UTT up to Jan 1, 2030 in the study communities. Findings Compared with standard of care, a 51% (95% credible interval 40–60) reduction in HIV incidence is projected if the trial intervention (arms A and B combined) is continued from 2020 to 2030, over and above a declining trend in HIV incidence under standard of care. Interpretation A widespread and continued commitment to UTT via home-based testing and counselling can have a substantial effect on HIV incidence in high prevalence communities. Funding National Institute of Allergy and Infectious Diseases, US President's Emergency Plan for AIDS Relief, International Initiative for Impact Evaluation, Bill & Melinda Gates Foundation, National Institute on Drug Abuse, and National Institute of Mental Health.

Delayed hemothorax is a potentially life-threatening complication of thoracic trauma that should be carefully considered in all patients presenting with thoracic injury. We report a case of delayed hemothorax in a 77-year-old male presenting eleven days’ status post multiple right mid- to high-rib fractures. His case was complicated by retained hemothorax after CT-guided chest-tube with subsequent video-assisted tube thoracostomy (VATS) revealing fibrothorax necessitating conversion to open thoracotomy. Known risk factors for development of delayed hemothorax include older patient age, three or more rib fractures, and presence of mid- to high-rib fractures, and should be used in risk stratification of thoracic trauma. Tube thoracostomy is often sufficient in management of delayed hemothorax. In rare cases, hemothoraces can be complicated by retained hemothorax or fibrothorax, which require more invasive therapy and carry greater morbidity and mortality.

Introduction In 2020, there were 37.7 million people living with HIV (PLHIV) globally, of which 20,6 million (55%) were living in Eastern and Southern Africa. Longitudinal studies, inclusive of community randomized trial (CRTs), provide critical evidence to guide a broad range of health care interventions, including HIV prevention. In this study, we have used an individual-level cohort study design to evaluate the association between sex and other baseline characteristics and participant retention in HPTN 071 (PopART) in Zambia and South Africa. Methods HPTN 071 (PopART) was a community randomized trial (CRT) conducted from 2013-2018, in 21 communities. The PopART primary outcome was measured in a randomly selected population cohort (PC), followed up over 3 to 4 years at annual rounds. PC retention was defined as completion of an annual follow up survey. Baseline characteristics were described by study arm and Poisson regression analyses used to measure the association between baseline factors and retention. In addition, we present a description of researcher-documented reasons for study termination by study participants in the population cohort (Table 3). Results Overall, 48301 individuals aged 18-44 years were enrolled, of whom 15 225 (40%) were aged 18-24 years. Most participants were women (27 139, 71%). Of the 38 474 participants enrolled at during the first round of the trial (PC0), 73. completed at least one follow up visit. Retention was lower in men (RR: 0.895; 95% CI: 0.875, 0.914) and higher amongst older participants (RR: 1.220; 95% CI 1.188, 1.253) when comparing age>35 to 18-24 years. Retention was also higher amongst individuals with high socio-economic status (SES) when compared to medium SES (RR 1.161; 95% CI 1.135, 1.188) and low SES (RR 1.117; 95% CI 1.093, 1.142) . The most common reasons for study termination were study refusal (23%) and relocation outside the CRT catchment area (66%). Conclusion Despite challenges, satisfactory retention outcomes were achieved in PopART with limited variability across study arms. In keeping with other studies, age, sex and SES were associated with lower levels of retention, relocation outside of catchment area was the most common reason for non- retention in this CRT.

Comprehensive HIV prevention strategies have raised concerns that knowledge of interventions to reduce risk of HIV infection might mitigate an individual's perception of risk, resulting in riskier sexual behaviour. We investigated the prespecified secondary outcomes of the HPTN 071 (PopART) trial to determine whether a combination HIV prevention strategy, including universal HIV testing and treatment, changed sexual behaviour; specifically, we investigated whether there was evidence of sexual risk compensation.HPTN 071 (PopART) was a cluster-randomised trial conducted during 2013-18, in which we randomly assigned 21 communities with high HIV prevalence in Zambia and South Africa (total population, approximately 1 million) to combination prevention intervention with universal antiretroviral therapy (ART; arm A), prevention intervention with ART provided according to local guidelines (universal since 2016; arm B), or standard of care (arm C). The trial included a population cohort of approximately 2000 randomly selected adults (aged 18-44 years) in each community (N=38 474 at baseline) who were followed up for 36 months. A prespecified secondary objective was to evaluate the impact of the PopART intervention compared with standard of care on herpes simplex virus type 2 (HSV-2) and sexual behaviour (N=20 422 completed final visit). Secondary endpoints included differences in sexual risk behaviour measures at 36 months and were assessed using a two-stage method for matched cluster-randomised trials. This trial is registered with ClinicalTrials. gov, number NCT01900977.The PopART intervention did not substantially change probability of self-reported multiple sex partners, sexual debut, or pregnancy in women at 36 months. Adjusted for baseline community prevalence, reported condomless sex was significantly lower in arm A versus arm C (adjusted prevalence ratio 0·80 [95% CI 0·64-0·99]; p=0·04) but not in arm B versus arm C (0·94 [0·76-1·17]; p=0·55). 3-year HSV-2 incidence was reduced in arm B versus arm C (adjusted risk ratio 0·76 [95% CI 0·63-0·92]; p=0·010); no significant change was shown between arm A versus arm C (0·89 [0·73-1·08]; p=0·199).We found little evidence of any change in sexual behaviour owing to the PopART interventions, and reassuringly for public health, we saw no evidence of sexual risk compensation. The findings do not help to explain the differences between the two intervention groups of the HPTN 071 (PopART) trial.National Institute of Allergy and Infectious Diseases, the National Institutes of Health, the International Initiative for Impact Evaluation (3ie), the Billamp; Melinda Gates Foundation, the US President's Emergency Plan for AIDS Relief, and the Medical Research Council UK.

To improve adherence with pre-surgical screening for Staphylococcus aureus nasal carriage and decolonization, we need more information about patients' experiences with these protocols.We surveyed patients undergoing orthopedic, neurosurgical, or cardiac operations at Johns Hopkins Hospitals (JHH), the University of Iowa Hospitals and Clinics (UIHC) at MercyOne Northeast Iowa Neurosurgery (MONIN) to assess patients' experiences with decolonization protocols.Five hundred thirty-four patients responded. Respondents at JHH were significantly more likely than those at the UIHC to report using mupirocin and were significantly more likely than those at the UIHC and MONIN to feel they received adequate information about surgical site infection (SSI) prevention and decolonization. Respondents at JHH were the least likely to not worry about SSI and they were more willing to do anything they could to prevent SSI. Few patients reported barriers to adherence and side effects of mupirocin or chlorhexidine.Respondents did not report either major side effects or barriers to adherence. Patients varied in their level of concern about SSI, their willingness to invest effort in preventing SSI, and their assessments of preoperative information. To improve patients' adherence, clinicians and hospitals should assess their patients' needs and desires and tailor their preoperative processes, education, and prophylaxis accordingly.

To investigate the association between individual and community-level measures of HIV stigma and HIV incidence within the 21 communities participating in the HPTN (071) PopART trial in Zambia and South Africa.Secondary analysis of data from a population-based cohort followed-up over 36 months between 2013 and 2018. The outcome was rate of incident HIV infection among individuals who were HIV negative at cohort entry. Individual-level exposures, measured in a random sample of all participants, were: (1) perception of stigma in the community, (2) perception of stigma in health settings and (3) fear and judgement towards people living with HIV. Individual-level analyses were conducted with adjusted, individual-level Poisson regression. Community-level HIV stigma exposures drew on data reported by people living with HIV, health workers and community members. We used linear regression to explore the association between HIV stigma and community-level HIV incidence.Among 8172 individuals who were HIV negative and answered individual-level stigma questions at enrolment to the cohort, there was no evidence of a statistically significant association between any domain of HIV stigma and risk of incident HIV infection. Among the full cohort of 26,110 individuals among whom HIV incidence was measured, there was no evidence that community-level HIV incidence was associated with any domain of HIV stigma.HIV stigma is often cited as a barrier to the effectiveness of HIV prevention programming. However, in the setting for the HPTN 071 "PopART trial," measured stigma alone was not associated with the risk of HIV infection.

Introduction There is an urgent need to identify men who have sex with men (MSM) living with HIV with unsuppressed viral loads to prevent transmission. Though respondent‐driven sampling (RDS) is traditionally used for hard‐to‐reach populations, we compare how RDS and direct recruitment (DR) perform in identifying MSM living with HIV with unsuppressed viral loads and identifying MSM with socio‐demographics characteristic of hard‐to‐reach populations. Methods This is a cross‐sectional analysis among 1305 MSM who were recruited from March 2016 to December 2017 for a case management intervention trial (HPTN 078). We recruited participants across four cities using RDS and DR methods: Birmingham, AL; Atlanta, GA; Baltimore, MD; and Boston, MA. Participants completed a socio‐demographic questionnaire and underwent HIV testing. We compare the proportion of MSM with HIV and unsuppressed viral loads (HIV RNA ≥ 1000 copies/ml) based on recruitment method using Pearson chi‐square tests. We also compare differences in race, income, healthcare coverage, education, sexual orientation, hidden sexuality and comfort with participating in the LGBT community between recruitment methods and perform non‐parametric trend tests to see how demographics change across RDS recruitment waves. Results RDS recruited 721 men (55.2%) and DR yielded 584 men (44.8%). Overall, 69% were living with HIV, of whom 18% were not virally suppressed. HIV prevalence was higher among those recruited via DR (84%) compared to RDS (58%), p < 0.0001. Twenty per cent of DR recruits were not virally suppressed compared to 15% of RDS, though this was not significant. DR yielded a significantly higher proportion of Black participants and those with less than a high school diploma. The prevalence of low income, no healthcare coverage, bisexuality and hidden sexuality increased across RDS waves. Conclusions DR was more efficient in identifying MSM living with HIV with unsuppressed viral loads; however, there was a higher proportion of hard‐to‐reach MSM who were low income, lacked health coverage, were bisexual and were not open with their sexuality in deeper waves of RDS. Researchers should consider supplementing RDS recruitment with DR efforts if aiming to identify MSM with unsuppressed viral loads via RDS.

Mathematical models are powerful tools in HIV epidemiology, producing quantitative projections of key indicators such as HIV incidence and prevalence. In order to improve the accuracy of predictions, such models need to incorporate a number of behavioural and biological heterogeneities, especially those related to the sexual network within which HIV transmission occurs. An individual-based model, which explicitly models sexual partnerships, is thus often the most natural type of model to choose. In this paper we present PopART-IBM, a computationally efficient individual-based model capable of simulating 50 years of an HIV epidemic in a large, high-prevalence community in under a minute. We show how the model calibrates within a Bayesian inference framework to detailed age- and sex-stratified data from multiple sources on HIV prevalence, awareness of HIV status, ART status, and viral suppression for an HPTN 071 (PopART) study community in Zambia, and present future projections of HIV prevalence and incidence for this community in the absence of trial intervention., Author summary In this paper we present PopART-IBM, an individual-based model used to simulate HIV transmission in communities in high prevalence settings. We show that PopART-IBM can simulate transmission over a span of decades in a large community in less than a minute. This computational efficiency allows us to calibrate the model within an inference framework, and we show an illustrative example of calibration using an adaptive population Monte Carlo Approximate Bayesian Computation algorithm for a community in Zambia that was part of the HPTN-071 (PopART) trial. We compare the detailed model output to real-world data collected during the trial from this community. Finally, we project how the HIV epidemic would have changed over time in this community if no intervention from the trial had occurred.

Background Pre-exposure prophylaxis (PrEP) is highly effective and an important prevention tool for African adolescent girls and young women (AGYW), but adherence and persistence are challenging. PrEP adherence support strategies for African AGYW were studied in an implementation study. Methods and findings HIV Prevention Trials Network (HPTN) 082 was conducted in Cape Town, Johannesburg (South Africa) and Harare (Zimbabwe) from October 2016 to October 2018 to evaluate PrEP uptake, persistence, and the effect of drug level feedback on adherence. Sexually active HIV–negative women ages 16–25 were offered PrEP and followed for 12 months; women who accepted PrEP were randomized to standard adherence support (counseling, 2-way SMS, and adherence clubs) or enhanced adherence support with adherence feedback from intracellular tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS). PrEP uptake, persistence through 12 months (no PrEP hold or missed visits), and adherence were assessed. The primary outcome was high adherence (TFV-DP ≥700 fmol/punch) at 6 months, compared by study arm. Of 451 women enrolled, median age was 21 years, and 39% had curable sexually transmitted infections (STIs). Most (95%) started PrEP, of whom 55% had uninterrupted PrEP refills through 12 months. Of those with DBS, 84% had detectable TFV-DP levels at month 3, 57% at month 6, and 31% at month 12. At 6 months, 36/179 (21%) of AGYW in the enhanced arm had high adherence and 40/184 (22%) in the standard adherence support arm (adjusted odds ratio [OR] of 0.92; 95% confidence interval [CI] 0.55, 1.34; p = 0.76). Four women acquired HIV (incidence 1.0/100 person-years), with low or undetectable TFV-DP levels at or prior to seroconversion, and none of whom had tenofovir or emtricitabine resistance mutations. The study had limited power to detect a modest effect of drug level feedback on adherence, and there was limited awareness of PrEP at the time the study was conducted. Conclusions In this study, PrEP initiation was high, over half of study participants persisted with PrEP through month 12, and the majority of young African women had detectable TFV-DP levels through month 6 with one-fifth having high adherence. Drug level feedback in the first 3 months of PrEP use did not increase the proportion with high adherence at month 6. HIV incidence was 1% in this cohort with 39% prevalence of curable STIs and moderate PrEP adherence. Strategies to support PrEP use and less adherence-dependent formulations are needed for this population. Trial registration ClinicalTrials.gov NCT02732730., Connie Celum and co-workers report on use of pre-exposure prophylaxis by young women in Southern Africa., Author summary Why was this study done? HIV incidence remains high (4%) in young African women. Pre-exposure prophylaxis (PrEP) has over 90% efficacy in preventing HIV infection when used consistently and could reduce HIV incidence in young African women. Adherence was low in placebo-controlled efficacy trials of oral PrEP among young African women. Qualitative research among a subset of women at unblinding of the efficacy trials indicated that women thought drug level feedback would support their adherence and foster open discussions with counselors about adherence. Drug level feedback should be evaluated as a strategy to increase PrEP adherence among young African women. What did the researchers do and find? A cohort of 451 young women in South Africa and Zimbabwe who were at risk for HIV were recruited and offered PrEP, among whom 95% initiated PrEP. Half were randomized to receive drug level feedback at months 2 and 3 plus the standard adherence support package (2-way SMS, brief counseling, and optional PrEP adherence clubs), and half received the standard adherence support package without drug level feedback. The majority had detectable intracellular drug levels through the first 6 months, and 21% had high adherence at month 6, defined as intracellular tenofovir-diphosphate (TFV-DP) ≥700 fmol/punch. PrEP adherence did not differ based on whether they were randomized to receive drug level feedback at months 2 and 3 or to standard of care (SOC) PrEP adherence support without drug level feedback. What do these findings mean? Drug level feedback was not associated with improved PrEP adherence among young African women. Additional strategies need to be evaluated for their effectiveness in increasing adherence with oral PrEP for young African women. Longer-acting and less user-dependent PrEP formulations may also overcome adherence challenges with daily oral PrEP.

We evaluated the relationship between 2 types of social relationships, ie, (1) external support for use of HIV pre-exposure prophylaxis (PrEP) and related study supplies and (2) participants' disclosure of PrEP use and condom use and HIV PrEP adherence among daily-dosing regimen participants in HIV Prevention Trials Network (HPTN) 067, an open-label trial of oral tenofovir (TFV) disoproxil fumarate (TDF) 300 mg/emtricitabine (FTC) 200 mg.Using HPTN 067 survey data, we developed scales examining (1) Low Perceived External Support for PrEP: low perceived support by others for PrEP use or perceived negative reactions to the pill case (scoring ranges from 0 to 2) and (2) Participant-Staff Disclosure Challenges Scale, which identifies challenges to sharing nonuse of PrEP or condoms to study staff (scoring ranges from 0 to 4); these scales are the primary independent variables. Adherence, the dependent variable, was determined using log-transformed plasma TFV concentrations. generalized estimating equation (GEE) linear regression was used to assess the association between both scales and adherence.Participants (n = 161) included HIV-uninfected women in South Africa, and men who have sex with men and transgender women, in Thailand and the United States. In multivariable analyses, higher scores in the Participant-Staff Disclosure Challenges Scale were significantly associated with lower PrEP adherence [exp(β) = 0.62, 95% CI: (0.46 to 0.84); P = 0.002] as were increased days since the last PrEP dose [exp(β) = 0.73, 95% CI: (0.65 to 0.83); P ≤ 0.001].Given the association with adherence, study staff-participant interactions and participants' disclosure of PrEP challenges may be worthwhile intervention targets for improving PrEP adherence in confirmatory studies.

Viral genetic sequencing can be used to monitor the spread of HIV drug resistance, identify appropriate antiretroviral regimes, and characterize transmission dynamics. Despite decreasing costs, next-generation sequencing (NGS) is still prohibitively costly for routine use in generalised HIV epidemics in low- and middle-income countries. Here, we present veSEQ-HIV, a high-throughput, cost-effective NGS sequencing method and computational pipeline tailored specifically to HIV, which can be performed using leftover blood drawn for routine CD4 cell count testing. This method overcomes several major technical challenges that have prevented HIV sequencing from being used routinely in public health efforts: it is fast, robust, and cost-efficient, and generates full genomic sequences of diverse strains of HIV without bias. The complete veSEQ-HIV pipeline provides viral load estimates and quantitative summaries of drug resistance mutations; it also exploits information on within-host viral diversity to construct directed transmission networks. We evaluated the method's performance using 1,620 plasma samples collected from individuals attending 10 large urban clinics in Zambia as part of the HPTN 071-2 study (PopART Phylogenetics). Whole HIV genomes were recovered from 91% of samples with a viral load >1,000 copies/ml. The cost of the assay (30 GBP per sample) compares favourably with existing VL and HIV genotyping tests, proving an affordable option for combining HIV clinical monitoring with molecular epidemiology and drug resistance surveillance in low-income settings.

Background Sexual transmission of hepatitis C virus (HCV) is uncommon, yet documented among men who have sex with men (MSM), primarily among those with human immunodeficiency virus (HIV). Methods In the HIV Prevention Trials Network 078 study (HPTN 078), which assessed an integrated strategy to achieve HIV viral suppression, 1305 MSM were screened across 4 geographically diverse US cities. At screening, demographic/behavioral/psychosocial questionnaires were completed, along with HIV and HCV testing. Multivariable logistic regression was used to evaluate associations with HCV antibody positivity. Results Among the 1287 (99%) of the MSM with HCV antibody results, the median age was 41, 69% were black, 85% had a high school education or more, 35% were employed, 70% had HIV, and 21% had undergone substance use counseling. The median lifetime number of male sexual partners was 17 (interquartile range, 6–50), and 246 (19%) were HCV antibody positive. HCV antibody positivity was high in MSM with HIV (20%) and MSM without HIV (17%) (P = .12) and was higher in those receiving substance use counseling (36%) than in those who had not (15%) (P ≤ .01). Substance use counseling (odds ratio, 2.51; 95% confidence interval, 1.80–3.51) and unstable housing (2.16; 1.40–3.33) were associated with HCV antibody positivity. Conclusions Nearly 1 in 5 MSM screened for HPTN 078 have been infected with HCV. The prevalence is high regardless of HIV status and is high even in those who did not undergo substance use counseling. In HIV burden networks, high HCV infection prevalence may occur in MSM without HIV. As implementation of preexposure prophylaxis expands and condom use declines, routine HCV counseling and screening among MSM are important.

Objectives To evaluate the performance of a high-throughput research assay for HIV drug resistance testing based on whole genome next-generation sequencing (NGS) that also quantifies HIV viral load. Methods Plasma samples (n = 145) were obtained from HIV-positive MSM (HPTN 078). Samples were analysed using clinical assays (the ViroSeq HIV-1 Genotyping System and the Abbott RealTime HIV-1 Viral Load assay) and a research assay based on whole-genome NGS (veSEQ-HIV). Results HIV protease and reverse transcriptase sequences (n = 142) and integrase sequences (n = 138) were obtained using ViroSeq. Sequences from all three regions were obtained for 100 (70.4%) of the 142 samples using veSEQ-HIV; results were obtained more frequently for samples with higher viral loads (93.5% for 93 samples with >5000 copies/mL; 50.0% for 26 samples with 1000–5000 copies/mL; 0% for 23 samples with Conclusions The NGS-based veSEQ-HIV method provided results for most samples with higher viral loads, was accurate for detecting major DRMs, and detected mutations at lower levels compared with a method based on population sequencing. The veSEQ-HIV method also provided HIV viral load data.

Introduction The HPTN 071 (PopART) trial evaluated the impact of an HIV combination prevention package that included “universal testing and treatment” on HIV incidence in 21 communities in Zambia and South Africa during 2013‐2018. The primary study endpoint was based on the results of laboratory‐based HIV testing for> 48,000 participants who were followed for up to three years. This report evaluated the performance of HIV assays and algorithms used to determine HIV status and identify incident HIV infections in HPTN 071, and assessed the impact of errors on HIV incidence estimates. Methods HIV status was determined using a streamlined, algorithmic approach. A single HIV screening test was performed at centralized laboratories in Zambia and South Africa (all participants, all visits). Additional testing was performed at the HPTN Laboratory Center using antigen/antibody screening tests, a discriminatory test and an HIV RNA test. This testing was performed to investigate cases with discordant test results and confirm incident HIV infections. Results HIV testing identified 978 seroconverter cases. This included 28 cases where the participant had acute HIV infection at the first HIV‐positive visit. Investigations of cases with discordant test results identified cases where there was a participant or sample error (mixups). Seroreverter cases (errors where status changed from HIV infected to HIV uninfected, 0.4% of all cases) were excluded from the primary endpoint analysis. Statistical analysis demonstrated that exclusion of those cases improved the accuracy of HIV incidence estimates. Conclusions This report demonstrates that the streamlined, algorithmic approach effectively identified HIV infections in this large cluster‐randomized trial. Longitudinal HIV testing (all participants, all visits) and quality control testing provided useful data on the frequency of errors and provided more accurate data for HIV incidence estimates.

Introduction The exceedingly high rate of failed trials in Alzheimer's disease (AD) calls for immediate attention to improve efficiencies and learning from past, ongoing, and future trials. Accurate, highly rigorous standardized data are at the core of meaningful scientific research. Data standards allow for proper integration of clinical data sets and represent the essential foundation for regulatory endorsement of drug development tools. Such tools increase the potential for success and accuracy of trial results. Methods The development of the Clinical Data Interchange Standards Consortium (CDISC) AD therapeutic area data standard was a comprehensive collaborative effort by CDISC and Coalition Against Major Diseases, a consortium of the Critical Path Institute. Clinical concepts for AD and mild cognitive impairment were defined and a data standards user guide was created from various sources of input, including data dictionaries used in AD clinical trials and observational studies. Results A comprehensive collection of AD-specific clinical data standards consisting of clinical outcome measures, leading candidate genes, and cerebrospinal fluid and imaging biomarkers was developed. The AD version 2.0 (V2.0) Therapeutic Area User Guide was developed by diverse experts working with data scientists across multiple consortia through a comprehensive review and revision process. The AD CDISC standard is a publicly available resource to facilitate widespread use and implementation. Discussion The AD CDISC V2.0 data standard serves as a platform to catalyze reproducible research, data integration, and efficiencies in clinical trials. It allows for the mapping and integration of available data and provides a foundation for future studies, data sharing, and long-term registries in AD. The availability of consensus data standards for AD has the potential to facilitate clinical trial initiation and increase sharing and aggregation of data across observational studies and among clinical trials, thereby improving our understanding of disease progression and treatment.

OBJECTIVE: To analyze HIV drug resistance among men who have sex with men (MSM) recruited for participation in the HPTN 078 study, which evaluated methods for achieving and maintaining viral suppression in HIV-infected MSM. METHODS: Individuals were recruited at four study sites in the United States (Atlanta, Georgia; Baltimore, Maryland; Birmingham, Alabama; and Boston, Massachusetts; 2016–2017). HIV genotyping was performed using samples collected at study screening or enrollment. HIV drug resistance was evaluated using the Stanford v8.7 algorithm. A multi-assay algorithm was used to identify individuals with recent HIV infection. Clustering of HIV sequences was evaluated using phylogenetic methods. RESULTS: High-level HIV drug resistance was detected in 44 (31%) of 142 individuals (Atlanta: 21%, Baltimore: 29%, Birmingham: 53%, Boston: 26%); 12% had multi-class resistance, 16% had resistance to tenofovir or emtricitabine, and 8% had resistance to integrase strand transfer inhibitors (INSTIs); 3% had intermediate-level resistance to second-generation INSTIs. In a multivariate model, self-report of ever having been on antiretroviral therapy (ART) was associated with resistance (p=0.005). One of six recently-infected individuals had drug resistance. Phylogenetic analysis identified five clusters of study sequences; two clusters had shared resistance mutations. CONCLUSIONS: High prevalence of drug resistance was observed among MSM. Some had multi-class resistance, resistance to drugs used for pre-exposure prophylaxis (PrEP), and INSTI resistance. These findings highlight the need for improved HIV care in this high-risk population, identification of alternative regimens for PrEP, and inclusion of integrase resistance testing when selecting ART regimens for MSM in the US.

Background A universal testing and treatment strategy is a potential approach to reduce the incidence of human immunodeficiency virus (HIV) infection, yet previous trial results are inconsistent. Methods In the HPTN 071 (PopART) community-randomized trial conducted from 2013 through 2018, we randomly assigned 21 communities in Zambia and South Africa (total population, approximately 1 million) to group A (combination prevention intervention with universal antiretroviral therapy [ART]), group B (the prevention intervention with ART provided according to local guidelines [universal since 2016]), or group C (standard care). The prevention intervention included home-based HIV testing delivered by community workers, who also supported linkage to HIV care and ART adherence. The primary outcome, HIV incidence between months 12 and 36, was measured in a population cohort of approximately 2000 randomly sampled adults (18 to 44 years of age) per community. Viral suppression ( Results The population cohort included 48,301 participants. Baseline HIV prevalence was 21% or 22% in each group. Between months 12 and 36, a total of 553 new HIV infections were observed during 39,702 person-years (1.4 per 100 person-years; women, 1.7; men, 0.8). The adjusted rate ratio for group A as compared with group C was 0.93 (95% confidence interval [CI], 0.74 to 1.18; P=0.51) and for group B as compared with group C was 0.70 (95% CI, 0.55 to 0.88; P=0.006). The percentage of HIV-positive participants with viral suppression at 24 months was 71.9% in group A, 67.5% in group B, and 60.2% in group C. The estimated percentage of HIV-positive adults in the community who were receiving ART at 36 months was 81% in group A and 80% in group B. Conclusions A combination prevention intervention with ART provided according to local guidelines resulted in a 30% lower incidence of HIV infection than standard care. The lack of effect with universal ART was unanticipated and not consistent with the data on viral suppression. In this trial setting, universal testing and treatment reduced the population-level incidence of HIV infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 071 [PopArt] ClinicalTrials.gov number,NCT01900977.)

High-throughput viral genetic sequencing is needed to monitor the spread of drug resistance, direct optimal antiretroviral regimes, and to identify transmission dynamics in generalised HIV epidemics. Public health efforts to sequence HIV genomes at scale face three major technical challenges: (i) minimising assay cost and protocol complexity, (ii) maximising sensitivity, and (iii) recovering accurate and unbiased sequences of both the genome consensus and the within-host viral diversity. Here we present a novel, high-throughput, virus-enriched sequencing method and computational pipeline tailored specifically to HIV (veSEQ-HIV), which addresses all three technical challenges, and can be used directly on leftover blood drawn for routine CD4 testing. We demonstrate its performance on 1,620 plasma samples collected from consenting individuals attending 10 large urban clinics in Zambia, partners of HPTN 071 (PopART). We show that veSEQ-HIV consistently recovers complete HIV genomes from the majority of samples of different subtypes, and is also quantitative: the number of HIV reads per sample obtained by veSEQ-HIV estimates viral load without the need for additional testing. Both quantitativity and sensitivity were assessed on a subset of 126 samples with clinically measured viral loads, and with standardized quantification controls (VL 100 – 5,000,000 RNA copies/ml). Complete HIV genomes were recovered from 93% (85/91) of samples when viral load was over 1,000 copies per ml. The quantitative nature of the assay implies that variant frequencies estimated with veSEQ-HIV are representative of true variant frequencies in the sample. Detection of minority variants can be exploited for epidemiological analysis of transmission and drug resistance, and we show how the information contained in individual reads of a veSEQ-HIV sample can be used to detect linkage between multiple mutations associated with resistance to antiretroviral therapy. Less than 2% of reads obtained by veSEQ-HIV were identified as in silico contamination events using updates to the phyloscanner software (phyloscanner clean) that we show to be 95% sensitive and 99% specific at ‘decontaminating’ NGS data. The cost of the assay — approximately 45 USD per sample — compares favourably with existing VL and HIV genotyping tests, and provides the additional value of viral load quantification and inference of drug resistance with a single test. veSEQ-HIV is well suited to large public health efforts and is being applied to all ∼9000 samples collected for the HPTN 071-2 (PopART Phylogenetics) study.

BackgroundWe evaluated use of phylogenetic methods to predict the direction of human immunodeficiency virus (HIV) transmission.MethodsFor 33 pairs of HIV-infected patients (hereafter, “index patients”) and their partners who acquired genetically linked HIV infection during the study, samples were collected from partners and index patients close to the time when the partner seroconverted (hereafter, “SC samples”); for 31 pairs, samples collected from the index patient at an earlier time point (hereafter, “early index samples”) were also available. Phylogenies were inferred using env next-generation sequences (1 tree per pair/subtype). The direction of transmission (DoT) predicted from each tree was classified as correct or incorrect on the basis of which sequences (those from the index patient or the partner) were closest to the root. DoT was also assessed using maximum parsimony to infer ancestral node states for 100 bootstrap trees.ResultsDoT was predicted correctly for both single-pair and subtype-specific trees in 22 pairs (67%) by using SC samples and in 23 pairs (74%) by using early index samples. DoT was predicted incorrectly for 4 pairs (15%) by using SC or early index samples. In the bootstrap analysis, DoT was predicted correctly for 18 pairs (55%) by using SC samples and for 24 pairs (73%) by using early index samples. DoT was predicted incorrectly for 7 pairs (21%) by using SC samples and for 4 pairs (13%) by using early index samples.ConclusionsPhylogenetic methods based solely on the tree topology of HIV env sequences, particularly without consideration of phylogenetic uncertainty, may be insufficient for determining DoT.

Introduction: We evaluated HIV drug resistance in adults who received early vs. delayed antiretroviral therapy (ART) in a multinational trial [HIV Prevention Trials Network (HPTN) 052, enrollment 2005-2010]. In HPTN 052, 1763 index participants were randomized to start ART at a CD4 cell count of 350-550 cells/mm 3 (early ART arm) or 1000 copies/mL >24 weeks after ART initiation. Drug resistance testing was performed for pretreatment (baseline) and failure samples from participants with virologic failure. Results: HIV genotyping results were obtained for 211/249 participants (128 early ART arm and 83 delayed ART arm) with virologic failure. Drug resistance was detected in 4.7% of participants at baseline; 35.5% had new resistance at failure. In univariate analysis, the frequency of new resistance at failure was lower among participants in the early ART arm (compared with delayed ART arm, P = 0.06; compared with delayed ART arm with ART initiation before May 2011, P = 0.032). In multivariate analysis, higher baseline viral load (P = 0.0008) and ART regimen (efavirenz/lamivudine/zidovudine compared with other regimens, P = 0.024) were independently associated with higher risk of new resistance at failure. Conclusions: In HPTN 052, the frequency of new drug resistance at virologic failure was lower in adults with early ART initiation. The main factor associated with reduced drug resistance with early ART was lower baseline viral load.

Higher HIV diversity has been associated with virologic outcomes in children on antiretroviral treatment (ART). We examined the association of HIV diversity with virologic outcomes in adults from the HPTN 052 trial who initiated ART at CD4 cell counts of 350-550 cells/mm3. A high resolution melting (HRM) assay was used to analyze baseline (pre-treatment) HIV diversity in six regions in the HIV genome (two in gag, one in pol, and three in env) from 95 participants who failed ART. We analyzed the association of HIV diversity in each genomic region with baseline (pre-treatment) factors and three clinical outcomes: time to virologic suppression after ART initiation, time to ART failure, and emergence of HIV drug resistance at ART failure. After correcting for multiple comparisons, we did not find any association of baseline HIV diversity with demographic, laboratory, or clinical characteristics. For the 18 analyses performed for clinical outcomes evaluated, there was only one significant association: higher baseline HIV diversity in one of the three HIV env regions was associated with longer time to ART failure (p = 0.008). The HRM diversity assay may be useful in future studies exploring the relationship between HIV diversity and clinical outcomes in individuals with HIV infection.

Introduction: The HIV Prevention Trials Network (HPTN) 052 trial demonstrated that early antiretroviral therapy (ART) prevented 93% of HIV transmission events in serodiscordant couples. Some linked infections were observed shortly after ART initiation or after virologic failure. Objective: To evaluate factors associated with time to viral suppression and virologic failure in participants who initiated ART in HPTN 052. Methods: 1566 participants who had a viral load (VL) > 400 copies/mL at enrollment were included in the analyses. This included 832 in the early ART arm (CD4 350–550 cells/mm3 at ART initiation) and 734 in the delayed ART arm (204 with a CD4 < 250 cells/mm3 at ART initiation; 530 with any CD4 at ART initiation). Viral suppression was defined as two consecutive VLs ≤ 400 copies/mL after ART initiation; virologic failure was defined as two consecutive VLs > 1000 copies/mL > 24 weeks after ART initiation. Results: Overall, 93% of participants achieved viral suppression by 12 months. The annual incidence of virologic failure was 3.6%. Virologic outcomes were similar in the two study arms. Longer time to viral suppression was associated with younger age, higher VL at ART initiation, and region (Africa vs. Asia). Virologic failure was strongly associated with younger age, lower educational level, and lack of suppression by three months; lower VL and higher CD4 at ART initiation were also associated with virologic failure. Conclusions: Several clinical and demographic factors were identified that were associated with longer time to viral suppression and virologic failure. Recognition of these factors may help optimize ART for HIV treatment and prevention.