Pregnancy rates and clinical outcomes among women living with HIV enrolled in HPTN 052.

HPTN 052 was a multi-country clinical trial of cART for preventing heterosexual HIV-1 transmission. The study allowed participation of pregnant women and provided access to cART and contraceptives. We explored associations between pregnancy and clinical measures of HIV disease stage and progression. Of 869 women followed for 5.70 (SD = 1.62) years, 94.7% were married/cohabitating, 96% initiated cART, and 76.3% had >2 past pregnancies. Of 337 women who experienced pregnancy, 89.3% were from countries with lower contraceptive coverage, 56.1% first started cART with PI-based regimens and 57.6% were 25-34 years old. Mean cART duration and condom use were similar among pregnant and nonpregnant individuals. Adjusting for confounders, viral load suppression (VLS) was not (aHR(CI) = 0.82(0.61, 1.08)) and CD4 was slightly associated with decreased rates of first pregnancy over time (aHR(CI) = 0.9(0.84, 0.95)); baseline VLS was associated with increased (aRR(CI) = 2.48(1.71, 3.59)) and baseline CD4 was slightly associated with decreased number of pregnancies (aRR(CI) = 0.9(0.85,0.96)) over study duration. Partner seroconversion was univariably associated with higher rates of first pregnancy (HR(CI) = 2.02(1.32,3.07)). Despite a background of higher maternal morbidity and mortality rates, our findings suggest that becoming pregnant does not pose a threat to maternal health in women with HIV when there is access to medical care and antiretroviral treatment.

Effect of Universal Testing and Treatment on HIV Incidence - HPTN 071 (PopART).

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 (<400 copies of HIV RNA per milliliter) was assessed in all HIV-positive participants at 24 months. 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.).

PopART-IBM, a highly efficient stochastic individual-based simulation model of generalised HIV epidemics developed in the context of the HPTN 071 (PopART) trial.

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.

HIV Prevention Trials Network 078: High Prevalence of Hepatitis C Virus Antibodies Among Urban US Men Who Have Sex With Men, Independent of Human Immunodeficiency Virus Status.

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.

PrEP uptake, persistence, adherence, and effect of retrospective drug level feedback on PrEP adherence among young women in southern Africa: Results from HPTN 082, a randomized controlled trial.

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.

A Comprehensive Genomics Solution for HIV Surveillance and Clinical Monitoring in Low-Income Settings.

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 generalized 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 of >1,000 copies/ml. The cost of the assay (30 GBP per sample) compares favorably 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.

Performance of a high-throughput next-generation sequencing method for analysis of HIV drug resistance and viral load.

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 <1000 copies/mL). For samples with results from both methods, drug resistance mutations (DRMs) were detected in 33 samples using ViroSeq and 42 samples using veSEQ-HIV (detection threshold: 5.0%). Overall, 146 major DRMs were detected; 107 were detected by both methods, 37 were detected by veSEQ-HIV only (frequency range: 5.0%-30.6%) and two were detected by ViroSeq only. HIV viral loads estimated by veSEQ-HIV strongly correlated with results from the Abbott RealTime Viral Load assay (R2 = 0.85; n = 142). 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.

Phylogenetic Methods Inconsistently Predict the Direction of HIV Transmission Among Heterosexual Pairs in the HPTN 052 Cohort.

BACKGROUND: We evaluated use of phylogenetic methods to predict the direction of human immunodeficiency virus (HIV) transmission. METHODS: For 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. RESULTS: DoT 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. CONCLUSIONS: Phylogenetic methods based solely on the tree topology of HIV env sequences, particularly without consideration of phylogenetic uncertainty, may be insufficient for determining DoT.

Privacy-Preserving Gaze Data Streaming in Immersive Interactive Virtual Reality: Robustness and User Experience.

Eye tracking is routinely being incorporated into virtual reality (VR) systems. Prior research has shown that eye tracking data, if exposed, can be used for re-identification attacks [14]. The state of our knowledge about currently existing privacy mechanisms is limited to privacy-utility trade-off curves based on data-centric metrics of utility, such as prediction error, and black-box threat models. We propose that for interactive VR applications, it is essential to consider user-centric notions of utility and a variety of threat models. We develop a methodology to evaluate real-time privacy mechanisms for interactive VR applications that incorporate subjective user experience and task performance metrics. We evaluate selected privacy mechanisms using this methodology and find that re-identification accuracy can be decreased to as low as 14% while maintaining a high usability score and reasonable task performance. Finally, we elucidate three threat scenarios (black-box, black-box with exemplars, and white-box) and assess how well the different privacy mechanisms hold up to these adversarial scenarios. This work advances the state of the art in VR privacy by providing a methodology for end-to-end assessment of the risk of re-identification attacks and potential mitigating solutions. f.

Refractory Lateral Leg Pain in a 25-Year-Old Competitive Runner: A Report of a Case of Fascial Herniation of the Peroneus Brevis With Complete Resolution After Surgical Decompression.

Fascial herniations of the leg occur when an intracompartmental leg muscle protrudes through weaknesses in the overlying fascial sheath. These fascial defects may be congenital or acquired from trauma involving penetrating injuries to the fascia. Increases in intracompartmental pressure, often resulting from muscular hypertrophy, can lead to muscular herniation through the weakened fascia. This may present as a leg mass which is often misdiagnosed as a hematoma, varicosity, or soft-tissue mass, leading to significant delays in treatment. We present a case of a peroneus brevis herniation in a 25-year-old male competitive runner with a history of a tibial stress fracture. This patient was referred to the senior author following three years of lateral leg pain worsened by activity. After confirmation of the herniation on MRI, the patient underwent a limited lateral compartment fasciotomy with complete resolution of symptoms at a six-month follow-up. This case demonstrates common pitfalls in the diagnosis of fascial herniations in refractory leg pain of runners. A comprehensive knowledge of this diagnosis and its risk factors can aid in the successful treatment of this patient cohort.

Current Surgical Techniques in the Treatment of Adult Developmental Dysplasia of the Hip.

The surgical protocols currently used for the treatment of developmental dysplasia of the hip (DDH) are varied, with sufficient differences in clinical outcomes that warrant a review of the role of practicing orthopedic surgeons. This paper aims to summarize the current novel techniques within the realm of surgical treatment for adult DDH, thus serving as a guide to surgeons looking to quickly familiarize themselves with available techniques. We performed computer systematic literature searches of the Embase and PubMed databases from 2010 to 2 April 2022. Study parameters as well as their respective patient reported outcomes (PROMs) were described in detail and compiled into diagrams. Two novel techniques were identified for the treatment of borderline or low-grade DDH. Six techniques which included modifications to the Bernese periacetabular osteotomy (PAO) were identified for the treatment of symptomatic DDH. Three techniques which include combinations of arthroscopy and osteotomy were identified for the treatment of DDH with concomitant hip pathologies such as cam deformities. Finally, six techniques, all of which are modifications to total hip arthroplasty (THA), were identified for the treatment of high-grade DDH. The techniques detailed in this review therefore equip surgeons with the necessary knowledge to improve outcomes in patients with varying degrees of DDH.

Patients' experiences and compliance with preoperative screening and decolonization.

BACKGROUND: To improve adherence with pre-surgical screening for Staphylococcus aureus nasal carriage and decolonization, we need more information about patients' experiences with these protocols. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Scoping Review of Interventions and Experiences Increasing Medical Student Interest in Physical Medicine and Rehabilitation.

ABSTRACT: Increasing medical student exposure to physical medicine and rehabilitation is an important factor for future growth of the field. Therefore, it is important to determine which types of interventions during medical school have the greatest impact on medical students' decision to pursue a career in physical medicine and rehabilitation. The purpose of this study is to perform a scoping review of the current literature that has analyzed how different interventions and experiences impact medical school students' decision to pursue a career in physical medicine and rehabilitation. A systematic and comprehensive search strategy was implemented across five different journal databases and yielded 18 articles meeting the inclusion criteria. Most studies analyzing specific interventions looked only at presurvey and postsurvey comparisons of the immediate impact of the intervention on interest in physical medicine and rehabilitation, and few looked at longitudinal outcomes, such as match characteristics. The most frequently cited factor that was shown to positively impact interest in physical medicine and rehabilitation was early exposure. Participating in clinical rotations also had a positive impact but was most effective when combined with early exposure. This review highlights the need for national recommendations for integrating physical medicine and rehabilitation into all 4 yrs of medical education.

Community- and individual-level correlates of HIV incidence in HPTN 071 (PopART).

INTRODUCTION: Universal HIV testing and treatment aims to identify all people living with HIV and offer them treatment, decreasing the number of individuals with unsuppressed HIV and thus reducing HIV transmission. Longitudinal follow-up of individuals with and without HIV in a cluster-randomized trial of communities allowed for the examination of community- and individual-level measures of HIV risk and HIV incidence. METHODS: HPTN 071 (PopART) was a three-arm cluster-randomized trial conducted between 2013 and 2018 that evaluated the use of two combination HIV prevention strategies implemented at the community level to reduce HIV incidence compared to the standard of care. The trial, conducted in 21 communities in Zambia and South Africa, measured HIV incidence over 36 months in a population cohort of ∼2000 randomly selected adults per community aged 18-44. Multilevel models were used to assess the association between HIV incidence and community- and individual-level socio-demographic and behavioural risk factors, as well as prevalence of detectable virus (PDV) defined as the estimated proportion of the community with unsuppressed viral load. RESULTS: Overall HIV incidence was 1.49/100 person-years. Communities with less financial wealth and communities with more individuals reporting having sex partners outside of the community or two or more sexual partners had higher HIV incidence. PDV at 2 years of study was 6.8% and was strongly associated with HIV incidence: for every 50% relative reduction in community PDV, there was a 49% (95% confidence interval [CI]: 37%-58%, p < 0.001) relative decrease in HIV incidence. At the individual level; socio-economic status, AUDIT score, medical male circumcision and certain sexual behaviours were associated with HIV risk. CONCLUSIONS: Using data from the PopART randomized trial, we found several associations of HIV incidence with community-level measures reflecting the sexual behaviour and socio-economic make-up of each community. We also found a strong association between community PDV and HIV incidence supporting the use of PDV as a tool for monitoring progress in controlling the epidemic. Lastly, we found significant individual-level factors of HIV risk that are generally consistent with previous HIV epidemiological research. These results have the potential to identify high high-incidence communities, inform structural-level interventions, and optimize individual-level interventions for HIV prevention. CLINICAL TRIAL NUMBER: ClinicalTrials.gov number, NCT01900977, HPTN 071 [PopArt].

Predictors of participant retention in a community-based HIV prevention cohort: perspectives from the HPTN 071 (PopART) study.

INTRODUCTION: In 2021, there were 38.4 million people living with HIV (PLHIV) globally, of which 20.6 million (54%) were living in Eastern and Southern Africa. Longitudinal studies, inclusive of community randomized trials (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 the HPTN 071 (PopART) trial in Zambia and South Africa. METHODS: HPTN 071 (PopART) was a community randomized trial (CRT) conducted from 2013 to 2018, in 21 communities. The 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 questionnaire. 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 withdrawal by PC participants. RESULTS: Of the 38,474 participants enrolled during the first round of the trial (PC0), most were women (27,139, 71%) and 73% completed at least one follow-up visit. Retention was lower in men (adj RR: 0.90; 95% CI: 0.88, 0.91) and higher among older participants (adj RR: 1.23; 95% CI 1.20, 1.26) when comparing ages 35-44 to 18-24 years. Retention was higher among individuals with high socioeconomic status (SES) (adj RR 1.16; 95% CI 1.14, 1.19) and medium SES (adj RR 1.12; 95% CI 1.09, 1.14) compared to low SES. The most common reasons for study withdrawal 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, younger age, male sex, and lower 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 profiling of pre-infection antibodies identifies HIV targets associated with viremic control and viral load.

Background: High HIV viral load (VL) is associated with increased transmission risk and faster disease progression. HIV controllers achieve viral suppression without antiretroviral (ARV) treatment. We evaluated viremic control in a community-randomized trial with >48,000 participants. Methods: A massively multiplexed antibody profiling system, VirScan, was used to quantify pre- and post-infection antibody reactivity to HIV peptides in 664 samples from 429 participants (13 controllers, 135 viremic non-controllers, 64 other non-controllers, 217 uninfected persons). Controllers had VLs <2,000 copies/mL with no ARV drugs detected at the first HIV-positive visit and one year later. Viremic non-controllers had VLs 2,000 copies/mL with no ARV drugs detected at the first HIV-positive visit. Other non-controllers had either ARV drugs detected at the first HIV-positive visit (n=47) or VLs <2,000 copies/mL with no ARV drugs detected at only one HIV-positive visit (n=17). Results: We identified pre-infection HIV antibody reactivities that correlated with post-infection VL. Pre-infection reactivity to an epitope in the HR2 domain of gp41 was associated with controller status and lower VL. Pre-infection reactivity to an epitope in the C2 domain of gp120 was associated with non-controller status and higher VL. Different patterns of antibody reactivity were observed over time for these two epitopes. Conclusion: These studies suggest that pre-infection HIV antibodies are associated with controller status and modulation of HIV VL. These findings may inform research on antibody-based interventions for HIV treatment.

HIV drug resistance in a community-randomized trial of universal testing and treatment: HPTN 071 (PopART).

INTRODUCTION: Universal HIV testing and treatment (UTT) has individual and public health benefits. HPTN 071 (PopART), a community-randomized trial in Zambia and South Africa, demonstrated that UTT decreased HIV incidence. This endpoint was assessed in a cohort of >48,000 randomly selected adults in the study communities. We evaluated the impact of UTT on HIV drug resistance in this cohort and compared other resistance-related outcomes in participants with recent versus non-recent HIV infection. METHODS: Two years after the start of HPTN 071 (2016-2017), 6259 participants were HIV positive and 1902 were viremic (viral load >400 copies/ml). HIV genotyping and antiretroviral (ARV) drug testing were performed for viremic participants in three groups: seroconverters (infected <1 year), non-seroconverters (infected >1 year, random subset) and participants with unknown duration of infection (random subset). A two-stage cluster-based approach was used to assess the impact of the study intervention on drug resistance. Treatment failure was defined as being viremic with ARV drugs detected. Participants were classified as ARV naïve based on self-report and ARV drug testing. RESULTS: Genotyping results were obtained for 758 participants (143 seroconverters; 534 non-seroconverters; and 81 unknown duration of infection). The estimated prevalence of resistance in the study communities was 37% for all viremic persons and 11% for all HIV-positive persons. There was no association between UTT and drug resistance. Resistance was detected in 14.0% of seroconverters and 40.8% of non-seroconverters (non-nucleoside reverse transcriptase inhibitor resistance: 14.0% and 39.9%; nucleoside/nucleotide reverse transcriptase inhibitor resistance: 0.7% and 15.5%; protease inhibitor resistance: 0% and 1.9%; multi-class resistance: 0.7% and 16.1%, respectively). ARV drugs were detected in 2/139 (1.4%) of seroconverters and 94/534 (17.6%) of non-seroconverters tested. These participants were classified as failing ART; 88 (93.6%) of the non-seroconverters failing ART had resistance. Mutations used for surveillance of transmitted drug resistance were detected in 10.5% of seroconverters and 15.1% of non-seroconverters who were ARV naive. CONCLUSIONS: UTT was not associated with an increase in drug resistance in this cohort. Higher rates of drug resistance and multi-class resistance were observed in non-seroconverters compared to seroconverters.

Impact of universal testing and treatment on sexual risk behaviour and herpes simplex virus type 2: a prespecified secondary outcomes analysis of the HPTN 071 (PopART) community-randomised trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: National Institute of Allergy and Infectious Diseases, the National Institutes of Health, the International Initiative for Impact Evaluation (3ie), the Bill & Melinda Gates Foundation, the US President's Emergency Plan for AIDS Relief, and the Medical Research Council UK.

Projected outcomes of universal testing and treatment in a generalised HIV epidemic in Zambia and South Africa (the HPTN 071 [PopART] trial): a modelling study.

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.

The association between HIV stigma and HIV incidence in the context of universal testing and treatment: analysis of data from the HPTN 071 (PopART) trial in Zambia and South Africa.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.