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OBJECTIVES: Voluntary medical male circumcision (VMMC) is an important component of combination HIV prevention. Inclusion of traditionally circumcised HIV negative men in VMMC uptake campaigns may be important if traditional male circumcision is less protective against HIV acquisition than VMMC. METHODS: We used data from the HIV Prevention Trials Network (HPTN) 071 (PopART) study. This cluster-randomized trial assessed the impact of a combination prevention package on population-level HIV incidence in 21 study communities in Zambia and South Africa. We evaluated uptake of VMMC, using a two-stage analysis approach and used discrete-time survival analysis to evaluate the association between the types of male circumcision and HIV incidence. RESULTS: A total of 10 803 HIV-negative men with self-reported circumcision status were included in this study. At baseline, 56% reported being uncircumcised, 26% traditionally circumcised and 18% were medically circumcised. During the PopART intervention, 11% of uncircumcised men reported uptake of medical male circumcision. We found no significant difference in the uptake of VMMC in communities receiving the PopART intervention package and standard of care {adj. rate ratio=1·10 [95% confidence interval (CI) 0.82, 1.50, P = 0.48]}. The rate of HIV acquisition for medically circumcised men was 70% lower than for those who were uncircumcised adjusted hazard ratio (adjHR) = 0.30 (95% CI 0.16-0.55; P

To estimate the effect of intimate partner violence (IPV) on oral pre-exposure prophylaxis (PrEP) adherence among adolescent girls and young women (AGYW).We conducted a secondary analysis of data from HIV Prevention Trials Network 082 (HPTN 082), a multisite prospective study designed to assess oral PrEP adherence among AGYW in southern Africa.We estimated the relative prevalence of high PrEP adherence 3 and 6 months after initiation among AGYW 16-25 years who reported a history of any IPV in the past year at enrollment versus AGYW who did not, both overall and by age. High adherence was defined as an intracellular tenofovir-diphosphate concentration at least 700 fmol/punch or more dried blood spots.Among 409 PrEP-initiating AGYW, half (49%) reported experiencing any IPV by a current/recent partner in the year prior to enrollment. Overall, a similar proportion of AGYW who reported IPV had high PrEP adherence at months 3 and 6 as AGYW who did not report IPV. There was, however, evidence of effect modification by age at month 3: among AGYW less than 21 years old, those who reported IPV were less than half as likely to have high adherence [adjusted PR (aPR) = 0.43, 95% confidence interval (CI) 0.22-0.86]; among AGYW aged 21 years or older, those who reported IPV were more than twice as likely to have high adherence (aPR = 2.21, 95% CI 1.34-3.66). At month 6, effect estimates within each age stratum were consistent in direction to those at month 3.IPV events may either impede or motivate PrEP adherence among African AGYW, with age appearing to be an important consideration for IPV-related adherence interventions.

Background Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine has proven highly effective in preventing HIV acquisition and is therefore offered to all participants in the control group as part of the standard of care package in many new HIV prevention studies. We propose a methodology for predicting HIV incidence in a hypothetical "placebo arm" for open-label studies or clinical trials with active control among African women. We apply the method to an open-label PrEP study, HIV Prevention Trials Network 082, which tested strategies to improve PrEP adherence in young African women all of whom were offered PrEP. Methods Our model predicted HIV infection risk for female study cohorts in sub-Saharan Africa using baseline behavioral risk factors and contemporary HIV prevalence and viral suppression in the local male population. The model was calibrated to HIV incidence in the Vaginal and Oral Interventions to Control the Epidemic study. Results Our model reproduced the annual HIV incidence of 3.2%-4.8% observed over 1 year of follow-up in the placebo groups of 4 completed clinical studies. We predicted an annual HIV incidence of 3.7% (95% confidence interval: 3.2 to 4.2) among HIV Prevention Trials Network 082 participants in the absence of PrEP and other risk reduction interventions. Conclusions We demonstrated the potential of the proposed methodology to provide HIV incidence predictions based on assessment of individual risk behaviors and community and time-specific HIV exposure risk using HIV treatment and viral suppression data. These estimates may serve as comparators in HIV prevention trials without a placebo group.

Author(s): Wanga, Valentine; Mackelprang, Romel D; Thomas, Katherine K; Donnell, Deborah; Cohen, Craig R; Mugo, Nelly R; Bukusi, Elizabeth A; de Bruyn, Guy; Irungu, Elizabeth; Celum, Connie; Baeten, Jared M; Lingappa, Jairam R; Partners in Prevention HSV/HIV Transmission Study and the Partners PrEP Study | Abstract: BackgroundWhether bacterial vaginosis (BV) and CD101 immunoglobulin-like (Ig-like) variants independently increase HIV risk through mucosal inflammation is not well understood. We evaluated whether the impact of BV on HIV acquisition in women differs by the presence or absence of candidate CD101 Ig-like variants.MethodsWe used data from 2 studies of HIV serodiscordant couples in east (Kenya, Tanzania, and Uganda) and southern (Botswana, South Africa, and Zambia) Africa, which longitudinally assessed HIV acquisition (by ELISA) and BV (by Nugent score ≥7). We used previously generated CD101 sequence data for each case and control participant to create a binary variable indicating the presence/absence of any of 5 CD101 Ig-like variants.ResultsConfirming previously shown results in this cohort, Ig-like variants increased HIV-infection risk (adjusted hazard ratio [aHR], = 2.63; 95% confidence interval [CI], 1.41 to 4.89). BV was associated with 2.5-fold higher HIV-infection risk only in the absence of Ig-like variants (aHR = 2.47; 95% CI, 0.99 to 6.15; P = 0.052), whereas in the presence of Ig-like variants, BV was not associated with higher HIV-infection risk (aHR = 0.87; 95% CI, 0.35 to 2.15; P = 0.765); however, a test for interaction was nonsignificant (P = 0.116).ConclusionsWe hypothesized that both BV and CD101 Ig-like variants facilitate HIV acquisition by augmenting similar genital inflammation pathways. Our findings indicate that inflammatory mucosal effects of Ig-like variants may influence the impact of BV on HIV risk. Host-defined inflammatory pathways may be useful targets for HIV prevention.

We previously reported a higher incidence of non-albumin proteinuria and a small but significant decline in estimated glomerular filtration rate (eGFR) among HIV-negative adults randomized to emtricitabine/tenofovir disoproxil fumarate preexposure prophylaxis (FTC/TDF PrEP) versus placebo. In a nested case--control study among participants randomized to FTC/TDF PrEP, established kidney injury biomarkers measured at 12 months were not significantly different between participants who subsequently experienced one of these kidney endpoints and randomly selected controls who did not.

Supplemental Digital Content is Available in the Text., Introduction: Understanding the role of opiate dependency treatment in risky sexual behavior could help optimize interventions for people who inject drugs (PWID). Objectives: We evaluated whether long-term medication-assisted treatment (LT-MAT) of opiate dependency with buprenorphine/naloxone influenced risky sexual behavior among HIV-uninfected PWID and identified predictors of risky sexual behavior. Methods: We used data from HPTN 058, a randomized controlled trial of LT-MAT vs. short-term medication-assisted treatment among PWID in China and Thailand. We evaluated associations between randomized opiate dependency treatment group and self-reported risky sexual behaviors within the past month: condomless sex with primary partner, condomless sex with nonprimary partner, multiple partners, and more than 3 sexual acts. We used generalized estimating equations to conduct intention-to-treat, as-treated, and exploratory analyses of these associations. Results: Of 1250 participants included in the analysis, 92% were male, with median age of 34 years (interquartile range 28–39). At baseline, referring to the past month, 36% of participants reported condomless sex with primary partner, 4% reported condomless sex with nonprimary partner, 6% reported multiple sex partners, and 30% reported more than 3 sexual acts. Risky sexual behaviors did not differ significantly between treatment groups at any point. Significant predictors (P < 0.05) of condomless sex with nonprimary partner were history of incarceration and noninjection drug use. Number of needle-sharing partners, noninjection drug use, and higher income were predictors for multiple sexual partners. Conclusions: LT-MAT did not significantly modify risky sexual behavior among HIV-uninfected PWID. Interventions that reduce sexual risk should target PWID with history of incarceration, alcohol use, and needle sharing.

Supplemental Digital Content is available in the text, Objectives: To review the main factors influencing the costs of nondaily oral preexposure prophylaxis (PrEP) with tenofovir (±emtricitabine). To estimate the cost reductions possible with nondaily PrEP compared with daily PrEP for different populations (MSM and heterosexual populations). Design: Systematic review and data triangulation. Methods: We estimated the required number of tablets/person/week for dosing regimens used in the HPTN 067/ADAPT (daily/time-driven/event-driven) and IPERGAY (on-demand) trials for different patterns of sexual intercourse. Using trial data, and behavioural and cost data obtained through systematic literature reviews, we estimated cost savings resulting from tablet reductions for nondaily versus daily oral PrEP, assuming 100% adherence. Results: Among different populations being prioritized for PrEP, the median reported number of days of sexual activity varied between 0 and 2 days/week (0–1.5 days/week for MSM, 1–2 days/week for heterosexual populations). With 100% adherence and two or fewer sex-days/week, HPTN 067/ADAPT nondaily regimens reduced the number of tablets/week by more than 40% compared with daily PrEP. PrEP program costs were reduced the most in settings with high drug costs, for example, by 66–69% with event-driven PrEP for French/US populations reporting on average one sex-day/week. Conclusion: Nondaily oral PrEP could lower costs substantially (>50%) compared with daily PrEP, particularly in high-income countries. Adherence and efficacy data are needed to determine cost-effectiveness.

Supplemental Digital Content is available in the text, Objective: To investigate whether oral preexposure prophylaxis (PrEP) alters timing and patterns of seroconversion when PrEP use continues after HIV-1 infection. Design: Retrospective testing of the timing of Fiebig stage HIV-1 seroconversion in the Partners PrEP Study, a randomized placebo-controlled clinical trial of PrEP conducted in Kenya and Uganda. Methods: Specimens from 138 seroconverters were collected every 3 months and when HIV-1 infection was suspected based on monthly rapid HIV-1 tests. Progression of seroconversion was compared between randomized groups (PrEP versus placebo) and per-protocol groups (placebo versus PrEP participants with detectable tenofovir during the seroconversion period) using laboratory assessment of Fiebig stage. Delay in site-detection of seroconversion and association with PrEP drug-regimen resistant virus were assessed using logistic regression. Analysis of time to each Fiebig stage used maximum likelihood estimation with a parametric model to accommodate the varying lengths of HIV-infection intervals. Results: There was a significant increase in delayed site detection of infection associated with PrEP (odds ratio = 3.49, P = 0.044). Delay in detection was not associated with increased risk of resistance in the PrEP arm (odds ratio = 0.93, P = 0.95). Estimated time to each Fiebig stage was elongated in seroconverters with evidence of ongoing PrEP use, significantly for only Stage 5 (28 versus 17 days, P = 0.05). Adjusted for Fiebig stage, viral RNA was ∼2/3 log lower in those assigned to PrEP compared with placebo; no differences were found in Architect signal to cut-off at any stage. Conclusion: Ongoing PrEP use in seroconverters may delay detection of infection and elongate seroconversion, although the delay does not increase risk of resistance.

Background: While most recent evidence does not support a role for pregnancy in accelerating HIV disease progression, very little information is available on the effects of incident pregnancy in response to antiretroviral therapy (ART). Hormonal, immune, and behavioral changes during pregnancy may influence response to ART. We sought to explore the effects of incident pregnancy (after ART initiation) on virologic, immunologic, and clinical response to ART. Methods: Data were collected from HIV-infected women participating in 3 prospective studies (Partners in Prevention Herpes simplex virus/HIV Transmission Study, Couples Observational Study, and Partners Preexposure Prophylaxis Study) from 7 countries in Africa from 2004 to 2012. Women were included in this analysis if they were ≤45 years of age, were started on ART during the study and were not pregnant at ART initiation. Pregnancy was treated as a time-dependent exposure variable covering the duration of pregnancy, including all pregnancies occurring after ART initiation. Virologic failure was defined as a viral load (VL) greater than 400 copies per milliliter ≥6 months after ART initiation and viral suppression was defined as VL ≤400 copies per milliliter. Multivariable Cox proportional hazards models were used to assess the association between pregnancy and time to viral suppression, virologic failure, World Health Organization clinical stage III/IV, and death. Linear mixed-effects models were used to assess the association between pregnancy and CD4+ count and VL. All analyses were adjusted for confounders, including pre-ART CD4+ count and plasma VL. Results: A total of 1041 women were followed, contributing 1196.1 person-years of follow-up. Median CD4+ count before ART initiation was 276 cells per cubic millimeter (interquartile range, 209–375); median pre-ART VL was 17,511 copies per milliliter (interquartile range, 2480–69,286). One hundred ten women became pregnant after ART initiation. Pregnancy was not associated with time to viral suppression (adjusted hazard ratio [aHR], 1.20, 95% confidence interval [CI]: 0.82 to 1.77), time to virologic failure (aHR, 0.67, 95% CI: 0.37 to 1.22), time to World Health Organization clinical stage III or IV (aHR, 0.79, 95% CI: 0.19 to 3.30), or time to death (aHR, 2.04, 95% CI: 0.25 to 16.8). Incident pregnancy was associated with an adjusted mean decrease in CD4+ T-cell count of 47.3 cells per cubic millimeter (P < 0.001), but not with difference in VL (P = 0.06). Conclusions: For HIV-infected women on ART, incident pregnancy does not affect virologic control or clinical HIV disease progression. A modest decrease in CD4+ T-cell count could be due to physiologic effects of pregnancy.

Background Randomized controlled trials (RCTs) suggest that the efficacy of tenofovir-based preexposure prophylaxis (PrEP) strongly depends on the consistency of PrEP use. We explore how the patterns of pill taking and waning of PrEP protection may affect PrEP efficacy for HIV prevention. Methods A 2-arm RCT was simulated by mathematical models assuming that the prescribed daily doses were skipped periodically, randomly, or in large blocks. Risk-driven adherence, in which PrEP was taken when sex was expected, was also investigated. Three temporal PrEP protection profiles were explored: long (5 days), intermediate (3 days), and short (24 hours). Modeling results were compared to the efficacy observed in completed RCTs. Results The expected PrEP efficacy was 60% with periodic, 50% with random, and 34% with block adherence when PrEP had a long protection profile and pills were taken only 50% of the days. Risk-driven pill taking resulted in 29% and 37% daily pills taken and efficacy of 43% and 51%, respectively, for long protection. High PrEP efficacy comparable with that observed in Partners PrEP and Centers for Disease Control and Prevention Botswana trials was simulated under long protection, high overall adherence, and limited block pill taking; the moderate efficacy observed in iPrEx and Bangkok trials was comparable with the 50% adherence scenarios under random pill taking and long protection. Conclusions Pill-taking patterns may have a substantial impact on the protection provided by PrEP even when the same numbers of pills are taken. When PrEP retains protection for longer than a day, pill-taking patterns can explain a broad range of efficacies observed in PrEP RCTs.

OBJECTIVE Two distinct hypotheses have been proposed for T-cell involvement in protection from HIV-1 acquisition. First, HIV-1-specific memory T-cell responses generated on HIV-1 exposure could mount an efficient response to HIV-1 and inhibit the establishment of an infection. Second, a lower level of immune activation could reduce the numbers of activated, HIV-1-susceptible CD4 T cells, thereby diminishing the likelihood of infection. METHODS To test these hypotheses, we conducted a prospective study among high-risk heterosexual men and women, and tested peripheral blood samples from individuals who subsequently acquired HIV-1 during follow-up (cases) and from a subset of those who remained HIV-1 uninfected (controls). RESULTS We found no difference in HIV-1-specific immune responses between cases and controls, but Treg frequency was higher in controls as compared with cases and was negatively associated with frequency of effector memory CD4 T cells. CONCLUSIONS Our findings support the hypothesis that low immune activation assists in protection from HIV-1 infection.

Background Tenofovir disoproxil fumarate (TDF) pre-exposure prophylaxis (PrEP) use is associated with a small but statistically significant decline in estimated glomerular filtration rate (eGFR). We investigated the reversibility of eGFR decline among HIV-uninfected adults discontinuing PrEP. Methods Data were from the Partners PrEP Study, a randomized trial of daily oral TDF and emtricitabine (FTC)-TDF PrEP among African HIV-uninfected men and women with baseline creatinine clearance ≥60 mL/min. Serum creatinine was measured quarterly while on-study medication and at month 1 and 2 after discontinuation. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration Equation. Results A total of 3924 individuals had a poststudy drug serum creatinine measurement after the scheduled drug discontinuation (1271 for TDF, 1308 for FTC-TDF, and 1345 for placebo); 65% were men, median age was 35 (range 18-64) years. Median time on study drug was 33 (interquartile range 25-36) months overall, and 36 months (interquartile range 30-36) for TDF and FTC-TDF. Mean eGFR at the last on-treatment visit was 129 mL·min·1.73 m for TDF and 128 mL·min·1.73 m for FTC-TDF versus 131 mL·min·1.73 m for placebo (2-3 mL·min·1.73 m mean decline for PrEP versus placebo, P ≤ 0.01), and this difference reversed by 4 weeks after drug discontinuation (mean eGFR at the first postdrug visit: 130 mL·min 1.73 m in all groups). More than 96% of participants had a confirmed >75% eGFR rebound to baseline level by 8 weeks after drug discontinuation, with similar proportions across treatment groups. Conclusions In this large, placebo-controlled study of TDF-based PrEP, the small reduction in mean eGFR associated with PrEP reversed within weeks after discontinuation.

Objective: Early initiation of antiretroviral treatment (ART) at CD4+ cell count greater or equal to 500 cells per microliter reduces morbidity and mortality in HIV-infected adults. We determined the proportion of HIV-infected people with high viral load (VL) for whom transmission prevention would be an additional benefit of early treatment. Design: A randomly selected subset of a nationally representative sample of HIV-infected adults in Swaziland in 2012. Methods: Eight to 12 months after a national survey to determine adult HIV prevalence 1067 of 5802 individuals identified as HIV-infected were asked to participate in a follow-up cross-sectional assessment. CD4+ cell enumeration VL measurements and ART status were obtained to estimate the proportion of currently untreated adults and of the entire HIV-infected population with high VL (greater than or equal to 1000 copies/mL) whose treatment under a test-and-treat or VL threshold eligibility strategy would reduce HIV transmission. Results: Of the 927 (87% of 1067) participants enrolled 466 (50%) reported no ART use. Among them 424 (91%) had VL greater than or equal to 1000 copies per milliliter; of these 148 (35%) were eligible for ART at the then existing CD4+ count threshold of less than 350 cells per microliter; an additional 107 (25%) were eligible with expanded CD4+ criterion of less than 500 cells per microliter; and 169 (40%) remained ART ineligible. Thus 36% of the 466 currently untreated and 18% of the total 927 had high VL yet remained ART ineligible under a CD4+ criterion of less than 500 cells per microliter. Conclusions: A test-and-treat or VL threshold for treatment eligibility is necessary to maximize the HIV transmission prevention benefits of ART. Copyright © 2015 Wolters Kluwer Health Inc.

Objective Resistance to emtricitabine plus tenofovir disoproxil fumarate (FTC/TDF) or TDF alone used as preexposure prophylaxis (PrEP) has been detected in individuals who initiated PrEP during unrecognized acute HIV infection and, rarely, in PrEP breakthrough infections. PrEP-selected resistance could alter future treatment options, and therefore we sought to determine how long resistance persisted after PrEP cessation. Methods The Partners PrEP Study was a randomized placebo-controlled trial of FTC/TDF or TDF as PrEP for HIV prevention. We previously reported that PrEP-related mutations (K65R, K70E or M184IV) were detected by 454 sequencing following seroconversion in nine individuals who acquired HIV during the Partners PrEP Study. In the current study, we used 454 sequencing to detect and quantify PrEP-related mutations in HIV RNA-positive plasma samples prior to seroconversion, as well as in plasma from 6, 12, and 24 months after PrEP cessation from these nine individuals. Results HIV RNA-positive, antibody-negative samples were available prior to seroconversion for four of nine individuals with resistance detected at seroconversion. In all four cases, K65R, K70E and M184IV were not detected prior to seroconversion, suggesting PrEP-related resistance was selected and not transmitted. All PrEP-selected mutations were no longer detectable by 6 months after PrEP cessation and remained undetectable at 12 and 24 months in the absence of antiretroviral therapy. Conclusion Using highly sensitive assays, PrEP-selected resistance in plasma decays below detection by 6 months following drug cessation and remains undetectable for at least 24 months. Even high levels of resistance mutations during acute infection decay rapidly in the absence of ongoing PrEP exposure.

BACKGROUND In resource-limited settings, HIV infection is often diagnosed using 2 rapid tests. If the results are discordant, a third tie-breaker test is often used to determine HIV status. This study characterized samples with discordant rapid tests and compared different testing strategies for determining HIV status in these cases. METHODS Samples were previously collected from 173 African adults in a population-based survey who had discordant rapid test results. Samples were classified as HIV positive or HIV negative using a rigorous testing algorithm that included two fourth-generation tests, a discriminatory test, and 2 HIV RNA tests. Tie-breaker tests were evaluated, including rapid tests (1 performed in-country), a third-generation enzyme immunoassay, and two fourth-generation tests. Selected samples were further characterized using additional assays. RESULTS Twenty-nine samples (16.8%) were classified as HIV positive and 24 of those samples (82.8%) had undetectable HIV RNA. Antiretroviral drugs were detected in 1 sample. Sensitivity was 8.3%-43% for the rapid tests; 24.1% for the third-generation enzyme immunoassay; 95.8% and 96.6% for the fourth-generation tests. Specificity was lower for the fourth-generation tests than the other tests. Accuracy ranged from 79.5% to 91.3%. CONCLUSIONS In this population-based survey, most HIV-infected adults with discordant rapid tests were virally suppressed without antiretroviral drugs. Use of individual assays as tie-breaker tests was not a reliable method for determining HIV status in these individuals. More extensive testing algorithms that use a fourth-generation screening test with a discriminatory test and HIV RNA test are preferable for determining HIV status in these cases.

BACKGROUND Injection opioid use plays a significant role in the transmission of HIV infection in many communities and several regions of the world. Access to evidence-based treatments for opioid use disorders is extremely limited. METHODS HIV Prevention Trials Network 058 (HPTN 058) was a randomized controlled trial designed to compare the impact of 2 medication-assisted treatment (MAT) strategies on HIV incidence or death among opioid-dependent people who inject drugs (PWID). HIV-negative opioid-dependent PWID were recruited from 4 communities in Thailand and China with historically high prevalence of HIV among PWID. A total of 1251 participants were randomly assigned to either (1) a 1-year intervention consisting of 2 opportunities for a 15-day detoxification with buprenorphine/naloxone (BUP/NX) combined with up to 21 sessions of behavioral drug and risk counseling [short-term medication-assisted treatment (ST-MAT)] or (2) thrice-weekly dosing for 48 weeks with BUP/NX and up to 21 counseling sessions [long-term medication-assisted treatment (LT-MAT)] followed by dose tapering. All participants were followed for 52 weeks after treatment completion to assess durability of impact. RESULTS Although the study was stopped early due to lower than expected occurrence of the primary end points, sufficient data were available to assess the impact of the interventions on drug use and injection-related risk behavior. At week 26, 22% of ST-MAT participants had negative urinalyses for opioids compared with 57% in the LT-MAT (P < 0.001). Differences disappeared in the year after treatment: at week 78, 35% in ST-MAT and 32% in the LT-MAT had negative urinalyses. Injection-related risk behaviors were significantly reduced in both groups after randomization. CONCLUSIONS Participants receiving BUP/NX 3 times weekly were more likely to reduce opioid injection while on active treatment. Both treatment strategies were considered safe and associated with reductions in injection-related risk behavior. These data support the use of thrice-weekly BUP/NX as a way to reduce exposure to HIV risk. Continued access to BUP/NX may be required to sustain reductions in opioid use.

Objective To evaluate preexposure prophylaxis (PrEP) efficacy for HIV-1 prevention among women using depot medroxyprogesterone acetate (DMPA) for contraception and men whose HIV-1-infected partners use DMPA. Design Secondary analysis of data from a randomized placebo-controlled trial of daily oral tenofovir and emtricitabine/tenofovir PrEP among heterosexual Kenyan and Ugandan HIV-1 serodiscordant couples. Methods PrEP efficacy for HIV-1 prevention was compared among HIV-1-uninfected women using DMPA versus no hormonal contraception and among HIV-1 uninfected men whose HIV-1-infected female partners used DMPA versus no hormonal contraception. Results Of 4747 HIV-1 serodiscordant couples, 901 HIV-1-uninfected women used DMPA at some point during follow-up, 1422 HIV-1-uninfected women used no hormonal contraception, 1568 HIV-1-uninfected men had female partners who used DMPA, and 2626 men had female partners who used no hormonal contraception. PrEP efficacy estimates for HIV-1 prevention, compared with placebo, were similar among women using DMPA and those using no hormonal contraception (64.7 and 75.5%, adjusted interaction P = 0.65). Similarly, for men whose female partners used DMPA, PrEP efficacy did not differ from men whose partners used no hormonal contraception (90.0 versus 81.7%, adjusted interaction P = 0.52). Conclusion PrEP is efficacious for HIV-1 prevention among women using DMPA and men whose partners use DMPA, suggesting PrEP could mitigate the potential increased HIV-1 acquisition and transmission risks that have been associated with DMPA use. Women at risk for HIV-1 choosing DMPA could maintain this contraceptive method and add PrEP to achieve prevention of unintended pregnancy and HIV-1.

BACKGROUND: Daily preexposure prophylaxis (PrEP) is an effective HIV prevention strategy but adherence is required for maximum benefit. To date there are no empirically supported PrEP adherence interventions. This article describes the process of developing a PrEP adherence intervention and presents results on its impact on adherence. METHODS: The Partners PrEP Study was a placebo-controlled efficacy trial of daily oral tenofovir and emtricitabine/tenofovir PrEP among uninfected members of HIV-serodiscordant couples. An ancillary adherence study was conducted at 3 study sites in Uganda. Participants with

The concentration of viral RNA in plasma is the primary risk factor for sexual transmission of HIV-1 [1–3], and reductions in plasma HIV-1 RNA levels due to antiretroviral therapy (ART) result in marked decreases in HIV-1 transmission risk [4,5]. Results from studies of HIV-1 transmission and disease progression may be more difficult to interpret if a substantial proportion of HIV-1 infected partners have low or undetectable viral loads on ART, and thus, ART use at study enrollment is often an exclusion factor.

As Information and Communication Technology infrastructure becomes more reliable, new methods of Electronic Data Capture (EDC), datamarts/Data warehouses, and mobile computing provide platforms for rapid coordination of international research projects and multisite studies. However, despite the increasing availability of internet connectivity and communication systems in remote regions of the world, there are still significant obstacles. Sites with poor infrastructure face serious challenges participating in modern clinical and basic research, particularly that relying on EDC and internet communication technologies. This report discusses our experiences in supporting research in resource-limited settings (RLS). We describe examples of the practical and ethical/regulatory challenges raised by use of these newer technologies for data collection in multisite clinical studies.

BACKGROUND: Daily oral antiretroviral preexposure prophylaxis (PrEP) is a promising strategy for prevention of HIV-1 acquisition. Three clinical trials demonstrated PrEP efficacy; however two PrEP trials among women did not find protection against HIV-1. One hypothesis proposed for these divergent results is that PrEP efficacy may be reduced in populations with higher HIV-1 incidence. METHODS: Using data from the Partners PrEP Study a randomized placebo-controlled trial of daily oral tenofovir (TDF) and emtricitabine/tenofovir (FTC/TDF) PrEP among heterosexual HIV-1 serodiscordant couples from Kenya and Uganda we assessed PrEP efficacy among subgroups at higher risk for HIV-1 acquisition including subgroups of women with high HIV-1 incidence. RESULTS: The overall placebo arm HIV-1 incidence was 2.0 per 100 person-years. Among higher risk subgroups placebo arm HIV-1 incidence ranged from 3.9 to 6.6 per 100 person-years. In all subgroups PrEP was protective against HIV-1 acquisition with efficacy point estimates ranging from 64 to 84%. Among subgroups of women with placebo-arm HIV-1 incidence more than 5.0 efficacy estimates ranged from 64 to 84%. Monthly visit attendance for PrEP refills and tenofovir detection in plasma were high. CONCLUSION: Among higher-risk subgroups in the Partners PrEP Study including groups solely of higher-risk women both TDF alone and combined FTC/TDF PrEP had consistently high efficacy for HIV-1 protection. PrEP when used with high adherence is a highly effective prevention strategy for higher risk heterosexuals. Prioritizing PrEP for persons at high risk of HIV-1 will maximize its prevention impact.

HIV-infected infants usually have homogenous viral populations, suggesting that one or a few HIV variants initiate the infection [1]. Several factors promote rapid evolution of HIV viruses following infection, including the short half-life of HIV virions, the large number of virions in an infected individual (large viral population size), lack of proof-reading by HIV reverse transcriptase, and frequent viral recombination [2]. Children with established HIV infection generally harbor diverse viral populations [3]. The high level of viral diversity and the capacity of HIV to evolve rapidly in response to selective pressures can complicate HIV treatment [4, 5]. To date, studies of HIV diversity in HIV-infected infants and children have been limited because of the time, effort, and cost associated with analyzing sequences from individual HIV variants. We recently developed a rapid assay for analysis of HIV diversity that is based on high resolution melting (HRM) of DNA duplexes [6]. The HRM diversity assay uses the LightScanner instrument (Idaho Technology, Inc., Salt Lake City, UT) to measure the range of melting temperatures for DNA duplexes amplified from HIV. The assay provides a simple, single numeric measure of the level of genetic diversity in each region analyzed, which we refer to as the HRM score [6]. DNA duplexes with different sequences have different melting properties, and DNA heteroduplexes also have unique melting characteristics. In the HRM diversity assay, more diverse DNA populations (e.g., amplicons from more diverse HIV populations in clinical samples) melt over a broader range of temperatures, which is reflected in higher HRM scores. Our recent work demonstrates that the HRM diversity assay can detect single base mutations that are present at levels as low as 5% in plasmid mixtures, and can also detect insertions and deletions at low levels [7]. The HRM diversity assay is highly reproducible [8], and HRM scores are significantly associated with sequence-based measures of HIV diversity obtained from analysis of cloned HIV DNA [6] and next generation sequencing [9]. This assay facilitates studies of factors associated with HIV diversity and diversification in different regions of the viral genome. In a previous study, we used the HRM diversity assay to compare the level of diversity in the HIV gag region in HIV-infected Ugandan infants and their mothers [6]. That study confirmed that the viral populations in 6–8 week old HIV-infected infants were very homogeneous [6]. In a subsequent study, we used the HRM diversity assay to analyze diversity in three regions of the HIV genome (two regions in HIV gag and one region in HIV pol) in 31 HIV-infected Ugandan infants 6 weeks to 18 months of age. Higher HRM scores in all three regions were associated with older age, demonstrating diversification of the virus in these regions over time following infection. Furthermore, higher HRM scores at 6–8 weeks of age (scores above the 75th percentile) were associated with a significantly increased risk of death by 5 years of age [8]. In this report, we examined HIV diversity in the gag, pol, and env regions in 76 Ugandan children from 0.6 to 12.4 years of age who were enrolled in an observational study of antiretroviral therapy (ART). We analyzed the association of pre-treatment HRM scores with age (as a surrogate for the duration of HIV infection), the relationship between HIV diversity and treatment outcome, and the impact of exposure to non-suppressive ART on HIV diversity.

BACKGROUND: As African countries scale-up couples HIV testing little is known about sexual behaviors and HIV risk for HIV-uninfected partners in known HIV-serodiscordant relationships. METHODS: We conducted a prospective study of 3380 HIV-serodiscordant partnerships from 7 African countries. Self-reported sexual behavior data were collected quarterly from HIV-uninfected partners. RESULTS: The proportion of HIV-uninfected partners reporting sex with their known primary HIV-infected partner decreased during follow-up (from 93.5% in the prior month at baseline to 73.2% at 24 months P < 0.001). Simultaneously an increasing proportion reported sex with an outside partner (from 3.1% to 13.9% P < 0.001). A small proportion (

The design of studies evaluating the safety and efficacy of interventions for HIV prevention is challenging in the US context, where there is low generalized prevalence. HIV incidence is sufficiently high in the at-risk US population of men who have sex with men that prevention trials using HIV infection end points are feasible. In other US populations at higher risk of HIV exposure, efficacy trials of HIV prevention are likely not feasible. However, for interventions where efficacy is already established, conducting trials that test different implementation strategies in these populations could provide definitive evidence about how to achieve high levels of coverage.

OBJECTIVES : To measure mortality rates and assess predictors of all-cause mortality in a cohort of Thai injection drug users (IDUs) who were enrolled and followed up from 2004 through 2006. METHODS : In this prospective cohort study, we enrolled 314 community-dwelling IDUs (95% being men; 42% of ethnic minority; median age, 29 years [range, 18-69 years]) and followed up them at 6-month intervals. Mortality rates were calculated based on person-years of follow-up. Marginal Cox proportional hazards models for clustered data were constructed to determine the factors associated with all-cause mortality. FINDINGS : During 445.7 person-years of follow-up, 17 of 314 (5.4%) IDUs died. The all-cause mortality rate was 3.8 per 100 person-years (95% confidence interval [CI] = 2.2-6.1). The standardized mortality ratio was 5.8 (95% CI = 3.5-9.1). The mortality rate among HIV-positive IDUs was 13.4 per 100 person-years (95% CI = 5.4-27.6). In a marginal Cox proportional-hazards model for clustered data, the excess mortality was associated with HIV-positivity (hazard ratio [HR] = 7.0, 95% CI = 2.8-17.6), benzodiazepine use (HR = 3.1, 95% CI = 1.1-9.4), and excessive alcohol consumption at enrollment (HR = 3.5, 95% CI = 1.3-9.1). CONCLUSIONS : The all-cause mortality among the drug injectors is high. The increased mortality was associated with HIV infection, benzodiazepine use, and excessive alcohol consumption.

Objective: Antiretroviral drug treatment may be complicated in individuals infected with antiretroviral drug-resistant or non-subtype B HIV-1 strains. HIV-1 tropism may also affect disease progression. We analyzed antiretroviral drug resistance, HIV-1 subtype, and HIV-1 tropism among 195 men who have sex with men from six major cities in the United States, using samples collected within 6 months of HIV-1 seroconversion (1999-2003). Methods: HIV-1 genotyping was performed using the ViroSeq HIV-1 Genotyping System. HIV-1 tropism was determined using a commercial assay. HIV-1 subtyping was performed by phylogenetic analysis of pol region sequences. Results: Thirty-one (15.9%) of the men had evidence of antiretroviral drug resistance. Seven (3.6%) men had multi-class resistance, including three (1.5%) with resistance to all three antiretroviral drug classes. We found no statistically significant association of antiretroviral drug resistance with demographic factors, sexual practices, self-reported sexually transmitted infections, use of recreational drugs, or use of antiretroviral drug post-exposure prophylaxis. All samples were HIV-1 subtype B. Four men had CXCR4-using HIV-1 strains. One man with a CXCR4-using strain also had antiretroviral drug resistance. Conclusions: Antiretroviral drug resistance is relatively common among recently infected men who have sex with men in the United States. CXCR4-using strains were detected in a small number of these infections, which were all subtype B HIV-1.

Objective To investigate evidence for resistance to HIV-1 infection associated with the heterozygous genotype CCR5-+/Delta32 and with the homozygous genotype CCR5-Delta32/Delta32, which results in a nonfunctional CCR5 receptor. Design Cohort study of initially HIV-seronegative high-risk individuals from eight different cities. Enrollment data were analyzed to investigate the association of demographic factors and risk behaviors with CCR5 genotypes on the assumption that increased genotype prevalence among persons with histories of longer or more intensive exposure to HIV would indicate HIV resistance associated with that genotype. Longitudinal data were analyzed to investigate the association of HIV seroincidence with CCR5 genotypes. The cohort of 2996 individuals included 1892 men who have sex with men (MSM), 474 male injection drug users (IDUs), 347 women at heterosexual risk, and 283 female IDUs. Measurements CCR5 genotype, HIV serostatus, demographic factors, and risk behaviors during the 6 months before enrollment, followed by measurement of HIV seroincidence during the subsequent 18 months (for men) and 24 months (for women). Results Forty (1.3%) subjects were homozygous CCR5-Delta32/Delta32 and 387 (12.9%) were heterozygous CCR5-+/Delta32. All but 1 CCR5-Delta32/Delta32 individuals and 51 CCR5-+/Delta32 individuals were Caucasian. Among 1531 Caucasian MSM, CCR5-+/Delta32 individuals were present more frequently (22.3%) among those reporting unprotected receptive anal intercourse than among those not reporting this risk (15.9%) (p =.002), suggesting a selective advantage of the heterozygous genotype. CCR5-+/Delta32 individuals also had a significantly reduced relative risk of HIV seroconversion adjusted for unprotected receptive anal intercourse compared with CCR5-/+ individuals (relative risk = 0.30, 95% confidence interval [CI]: 0.08-0.97). CCR5-Delta32/Delta32 prevalence among Caucasian MSM was significantly associated with age among subjects recruited from high HIV seroprevalence cities (New York City and San Francisco) (odds ratio [OR] for each decade increase in age = 2.57, CI: 1.56-4.21) but not among those recruited from lower HIV prevalence sites (Boston, Chicago, Philadelphia, Seattle, and Providence/Pawtucket, Rhode Island) (OR = 1.20, CI: 0.75-1.89). Conclusions Cross-sectional and longitudinal analyses indicated that among high-risk HIV seronegative MSM, CCR5-+/Delta32 and CCR5-Delta32/Delta32 are associated with protection against HIV infection. These findings imply that strategies aimed at reducing susceptibility to HIV infection by blocking CCR5 receptor sites need not seek blockage of all receptor sites to achieve an imperfect but substantial degree of protection.

Background: Use of antiretroviral therapy (ART) to prevent HIV transmission has received substantial attention after a recent trial demonstrating efficacy of ART to reduce HIV transmission in HIV-discordant couples. Objective: To assess practices and attitudes of HIV clinicians regarding early initiation of ART for treatment and prevention of HIV at sites participating in the HIV Prevention Trials Network 065 study. Design: Cross-sectional internet-based survey. Methods: ART-prescribing clinicians (n = 165 physicians, nurse practitioners, physician assistants) at 38 HIV care sites in Bronx, NY, and Washington, DC, completed a brief anonymous Internet survey, before any participation in the HIV Prevention Trials Network 065 study. Analyses included associations between clinician characteristics and willingness to prescribe ART for prevention. Results: Almost all respondents (95%), of whom 59% were female, 66% white, and 77% HIV specialists, “strongly agreed/agreed” that early ART can decrease HIV transmission. Fifty-six percent currently recommend ART initiation for HIV-infected patients with CD4+ count ,500 cells per cubic millimeter, and 14% indicated that they initiate ART irrespective of CD4+ count. Most (75%) indicated that they would consider initiating ART earlier than otherwise indicated for patients in HIV-discordant sexual partnerships, and 40% would do so if a patient was having unprotected sex with a partner of unknown HIV status. There were no significant differences by age, gender, or clinician type in likelihood of initiating ART for reasons including HIV transmission prevention to sexual partners. Conclusions: This sample of US clinicians indicated support for early ART initiation to prevent HIV transmission, especially for situations where such transmission would be more likely to occur.

Background: To correlate nevirapine presence and concentration in cord bloods ofinfants born to HIV-1 infected women with report of timing of dose and HIV-1transmission at 6 weeks of age.Methods: All available cord blood samples from the infants of mothers enrolled in theHIVNET 012 trial who were randomly assigned to receive either nevirapine orzidovudine at the onset of labor were tested for a nevirapine concentration.Results: Nevirapine was detected in the cord blood of 244 of 259 (94%) infants whosemothers reported they took nevirapine in labor more than 1 h before delivery and in 12of 13 (92%) infants whose mothers reported they took nevirapine less than 1 h beforedelivery. The median nevirapine cord blood concentration was 1238 ng/ml [inter-quartile range (IQR), 905–1474 ng/ml] and 122 ng/ml (IQR, 64–321 ng/ml) for womenwho reported taking nevirapine more or less than 1 h before delivery, respectively(P < 0.001). The median nevirapine cord blood concentration of infants who wereHIV-1 negative at birth, but positive at 6–8 weeks of age (n ¼ 11), was 916 ng/ml (IQR,737–1245 ng/ml) compared with 1192 ng/ml (IQR, 875–1471 ng/ml) for uninfectedinfants (n ¼ 236).Conclusions: Cord blood nevirapine concentration correlated well with report ofnevirapine administration and timing of dose before delivery. The nevirapine cordblood concentration was modestly lower in infected infants, although the number ofinfants infected between birth and 6–8 weeks of age was small (n ¼ 11). The highadherence rate in the HIVNET 012 study supports the efficacy, simplicity and deliver-ability of this regimen.