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1.  Pre-exposure prophylaxis for HIV-1 prevention does not diminish the pregnancy prevention effectiveness of hormonal contraception 
AIDS (London, England)  2014;28(12):1825-1830.
Background
For women at risk of HIV-1, effective contraception and effective HIV-1 prevention are global priorities.
Methodology
In a clinical trial of pre-exposure prophylaxis (PrEP) for HIV-1 prevention in HIV-1 serodiscordant couples, we estimated the effectiveness of hormonal contraceptives (oral contraceptive pills, injectable depot medroxyprogesterone acetate, and hormonal implants) for pregnancy prevention relative to no contraception among 1785 HIV-1 uninfected women followed up to 36 months. We compared the effectiveness of each method among women assigned PrEP versus placebo. Contraception was not required for participation but was offered on-site and was recorded monthly; incident pregnancy was determined by monthly urine testing.
Results
For women using no contraception, overall pregnancy incidence was 15.4% per year. Women reporting oral contraceptive use had comparable pregnancy incidence to women using no contraception, and this lack of contraceptive effectiveness was similar for those assigned PrEP and placebo (17.7% and 10.0% incidence per year respectively; p-value for difference in effect by PrEP use=0.24). Women reporting injectable contraception had reduced pregnancy incidence compared to those reporting no contraception, which did not differ by arm (PrEP 5.1%, placebo 5.3% per year; p-value for difference=0.47). Contraceptive effectiveness was highest among women using implants (pregnancy incidence <1% per year in both arms).
Conclusions
PrEP had no adverse impact on hormonal contraceptive effectiveness for pregnancy prevention. As seen previously in similar populations, women reporting contraceptive pill use had little protection from pregnancy, possibly due to poor adherence. Injectable or implantable hormonal contraception plus PrEP provides effective prevention for pregnancy and HIV-1.
doi:10.1097/QAD.0000000000000290
PMCID: PMC4136509  PMID: 24785951
2.  Choosing a metric for measurement of pre-exposure prophylaxis 
The Lancet. Infectious diseases  2014;14(12):1177-1178.
doi:10.1016/S1473-3099(14)70989-2
PMCID: PMC4507263  PMID: 25455980
3.  Pregnancy Incidence and Outcomes among Women Receiving Pre-Exposure Prophylaxis for HIV Prevention: A Randomized Clinical Trial 
JAMA  2014;312(4):362-371.
Importance
Antiretroviral pre-exposure prophylaxis (PrEP), using tenofovir disoproxil fumarate and combination tenofovir disoproxil fumarate / emtricitabine, is efficacious for prevention of HIV acquisition. PrEP could reduce periconception HIV risk, but the effect on pregnancy outcomes is not well defined.
Objective
To assess pregnancy incidence and outcomes among women using PrEP during the periconception period.
Design
Randomized trial among 1785 HIV serodiscordant heterosexual couples (the Partners PrEP Study) in which the female partner was HIV uninfected that demonstrated that PrEP was efficacious for HIV prevention, conducted between July 2008 and June 2013 at 9 sites in Kenya and Uganda.
Intervention
Daily oral tenofovir disoproxil fumarate (TDF) (n=598), combination tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) (n=566), or placebo (n=621) through July 2011, when PrEP demonstrated efficacy for HIV prevention; thereafter, participants continued receiving active PrEP, without placebo. Pregnancy testing occurred monthly and study medication was discontinued upon pregnancy detection.
Main Outcomes
Pregnancy incidence, birth outcomes (pregnancy loss, preterm birth, congenital anomalies), infant growth.
Results
A total of 431 pregnancies occurred. Pregnancy incidence was 10.0 per 100 person-years among women assigned placebo, 11.9 among those assigned TDF (incidence difference 1.9, 95% confidence interval [CI] −1.1–4.9, p=0.22 versus placebo), and 8.8 among those assigned TDF-FTC (incidence difference −1.3, 95% CI −4.1–1.5, p=0.39 versus placebo). Prior to discontinuation of the placebo treatment group in July 2011, the occurrence of pregnancy loss (96 of 288 pregnancies), was 42.5% for women receiving TDF-FTC compared with 32.3% for those receiving placebo (difference for TDF-FTC versus placebo 10.2%, 95% CI −5.3–25.7, p=0.16) and was 27.7% for those receiving TDF alone (difference versus placebo −4.6%, 95% CI −18.1–8.9, p=0.46). After July 2011, the frequency of pregnancy loss (52 of 143 pregnancies) was 37.5% for TDF-FTC and 36.7% for TDF alone (difference 0.8%, 95% CI −16.8–18.5, p=0.92). Preterm birth and congenital anomalies did not differ significantly for those who received PrEP versus placebo. Infants born to women randomized to PrEP had growth throughout the first year of life not statistically different than placebo and with point estimates that did not suggest growth restriction.
Conclusions and Relevance
Among HIV serodiscordant heterosexual African couples, differences in pregnancy incidence, birth outcomes, and infant growth were not statistically different for women receiving PrEP with TDF alone or combination TDF-FTC compared to placebo at the time of conception. Given that PrEP was discontinued when pregnancy was detected and that confidence intervals for the birth outcomes were wide, definitive statements about safety of PrEP in the periconception period cannot be made. These results should be discussed with HIV uninfected women receiving PrEP who are considering becoming pregnant. (ClinicalTrials.gov number, NCT00557245)
doi:10.1001/jama.2014.8735
PMCID: PMC4362516  PMID: 25038355
pre-exposure prophylaxis; HIV; pregnancy
4.  Frequency of False Positive Rapid HIV Serologic Tests in African Men and Women Receiving PrEP for HIV Prevention: Implications for Programmatic Roll-Out of Biomedical Interventions 
PLoS ONE  2015;10(4):e0123005.
Background
Rapid HIV assays are the mainstay of HIV testing globally. Delivery of effective biomedical HIV prevention strategies such as antiretroviral pre-exposure prophylaxis (PrEP) requires periodic HIV testing. Because rapid tests have high (>95%) but imperfect specificity, they are expected to generate some false positive results.
Methods
We assessed the frequency of true and false positive rapid results in the Partners PrEP Study, a randomized, placebo-controlled trial of PrEP. HIV testing was performed monthly using 2 rapid tests done in parallel with HIV enzyme immunoassay (EIA) confirmation following all positive rapid tests.
Results
A total of 99,009 monthly HIV tests were performed; 98,743 (99.7%) were dual-rapid HIV negative. Of the 266 visits with ≥1 positive rapid result, 99 (37.2%) had confirmatory positive EIA results (true positives), 155 (58.3%) had negative EIA results (false positives), and 12 (4.5%) had discordant EIA results. In the active PrEP arms, over two-thirds of visits with positive rapid test results were false positive results (69.2%, 110 of 159), although false positive results occurred at <1% (110/65,945) of total visits.
Conclusions
When HIV prevalence or incidence is low due to effective HIV prevention interventions, rapid HIV tests result in a high number of false relative to true positive results, although the absolute number of false results will be low. Program roll-out for effective interventions should plan for quality assurance of HIV testing, mechanisms for confirmatory HIV testing, and counseling strategies for persons with positive rapid test results.
doi:10.1371/journal.pone.0123005
PMCID: PMC4401675  PMID: 25885664
5.  HIV-1 subtype C is not associated with higher risk of heterosexual HIV-1 transmission: a multinational study among African HIV-1 serodiscordant couples 
AIDS (London, England)  2014;28(2):235-243.
Background
HIV-1 subtype C has emerged as the most prevalent strain of HIV-1 worldwide, leading to speculation that subtype C may be more transmissible than other subtypes. We compared the risk of HIV-1 transmission for subtype C versus non-C subtypes (A, D, G and recombinant forms) among heterosexual African HIV-1 serodiscordant couples.
Methods
We conducted a nested case-control analysis using data from two prospective cohort studies of heterosexual HIV-1 serodiscordant couples from 6 countries in eastern and southern Africa. Cases (N=121) included incident HIV-1 transmissions that were established as linked within the serodiscordant partnership by viral sequencing; controls (N=501) were non-transmitting HIV-1 infected partners. Subtype was determined for partial env and gag genes. Multiple logistic regression controlled for age and gender of the HIV-1 infected partner and self-reported unprotected sex. Plasma and genital HIV-1 RNA concentrations were compared between subtype C and non-C subtypes using generalized estimating equations.
Results
HIV-1 subtype C was not associated with increased risk of HIV-1 transmission compared to non-C subtypes: env adjusted odds ratio (adjOR) 1.14 (95% confidence interval [CI] 0.74–1.75, p=0.6) and gag adjOR 0.98 (95% CI 0.63–1.52, p=0.9). Plasma and genital HIV-1 RNA levels did not differ significantly for subtype C versus non-C.
Conclusion
In a geographically diverse population of heterosexual African HIV-1 serodiscordant couples, subtype C was not associated with greater risk of HIV-1 transmission compared to non-C subtypes, arguing against the hypothesis that subtype C is more transmissible compared to other common subtypes.
doi:10.1097/QAD.0000000000000024
PMCID: PMC4090091  PMID: 24413311
HIV-1 subtype; transmission; serodiscordant couples; Africa
6.  High Incidence Is Not High Exposure: What Proportion of Prevention Trial Participants Are Exposed to HIV? 
PLoS ONE  2015;10(1):e0115528.
Objective
Randomized clinical trials of HIV prevention in high-risk populations of women often assume that all participants have similar exposure to HIV. However, a substantial fraction of women enrolled in the trial may have no or low exposure to HIV. Our objective was to estimate the proportion of women exposed to HIV throughout a hypothetical high-risk study population.
Methods
A stochastic individual-based model was developed to simulate the sexual behavior and the risk of HIV acquisition for a cohort of sexually active HIV-uninfected women in high HIV prevalence settings. Key behavior and epidemic assumptions in the model were based on published studies on HIV transmission in South Africa. The prevalence of exposure, defined as the proportion of women who have sex with HIV-infected partner, and HIV incidence were evaluated.
Results
Our model projects that in communities with HIV incidence rate of 1 per 100 person years, only 5-6% of women are exposed to HIV annually while in communities with an HIV incidence of 5 per 100 person years 20-25% of women are exposed to HIV. Approximately 70% of the new infections are acquired from partners with asymptomatic HIV.
Conclusions
Mathematical models suggest that a high proportion of women enrolled in HIV prevention trials may be unexposed to HIV even when incidence rates are high. The relationship between HIV exposure and other risk factors should be carefully analyzed when future clinical trials are planned.
doi:10.1371/journal.pone.0115528
PMCID: PMC4287619  PMID: 25569838
7.  Supporting research sites in resource-limited settings: Challenges in implementing IT infrastructure 
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.
doi:10.1097/QAI.0000000000000039
PMCID: PMC4195443  PMID: 24321986
Information technology (IT); research infrastructure; data management; electronic data capture (EDC); mHealth; mobile technology
8.  Long Term Follow-up of Children in the HIVNET 012 Perinatal HIV Prevention Trial: Five-Year Growth and Survival 
Objectives
To describe five year growth, survival and long-term safety among children exposed to nevirapine or zidovudine in an African perinatal prevention trial, HIVNET 012.
Methods
All study children who were alive at eighteen months of age were eligible for an extended follow-up study. Children whose families consented were enrolled and evaluated every six months from 24 to 60 months. At each visit, history, physical exam and growth measures were taken. From these measurements Z scores based on World Health Organization (WHO) standards were computed. Serious adverse event data were collected. Data from the initial and extended follow-up cohorts were included in the analysis.
Results
528 study children were alive at age 18 months, and 491 (426 HIV uninfected; 65 infected) were enrolled into the follow-up study. Both exposed but uninfected children and HIV infected children were substantially below WHO growth standards for weight and height. Head circumference Z scores for uninfected children were comparable to WHO norms. Five-year survival rates were 93% for uninfected children versus 43% for infected children. Long-term safety and growth outcomes in the two study arms were similar.
Conclusions
Both infected and uninfected children in the five-year HIVNET 012 follow-up showed poor height and weight growth outcomes, underscoring the need for early nutritional interventions to improve long-term growth of all infants born to HIV-infected women in resource limited settings. Likewise, the low five year survival among HIV infected children support the importance of early initiation of antiretroviral therapy. Both peripartum nevirapine and zidovudine were safe.
doi:10.1097/QAI.0000000000000015
PMCID: PMC4172334  PMID: 24121753
9.  PrEP is Efficacious for HIV-1 prevention among Women using DMPA for Contraception 
AIDS (London, England)  2014;28(18):2771-2776.
Objective
To evaluate pre-exposure 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 to 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).
Conclusions
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.
doi:10.1097/QAD.0000000000000493
PMCID: PMC4266161  PMID: 25493602
HIV-1 prevention; pre-exposure prophylaxis efficacy; hormonal contraception; DMPA
10.  Summary measures of adherence using pill counts in two HIV prevention trials: the need for standardisation in reporting 
AIDS and behavior  2013;17(9):10.1007/s10461-013-0542-9.
For trials of user-dependent HIV prevention products, accurate adherence measurements are essential to interpret and compare results across trials. We used pill count data from two recent HIV prevention trials of herpes simplex virus type 2 (HSV-2) suppression, to show that estimates of adherence vary substantially depending on assumptions that are made in analysing pill count data. We associate calculated adherence with biological markers of anti-HSV-2 activity. In both trials, calculated adherence varied considerably, depending on the summary measure used, and the handling of intervals with apparent ‘over-adherence’ (fewer pills returned than expected), and unreturned pills. Intervals of apparent over-adherence were associated with reduced antiviral effects on biological markers of herpes reactivation, indicating these are likely to represent periods of non-adherence. Our results demonstrate the clear need for standardisation in reporting of adherence data that are based on pill counts.
doi:10.1007/s10461-013-0542-9
PMCID: PMC3812335  PMID: 23801018
Adherence; HIV prevention; pill counts
11.  Daily Short Message Service Surveys to Measure Sexual Behavior and Pre-exposure Prophylaxis Use Among Kenyan Men and Women 
AIDS and behavior  2013;17(9):10.1007/s10461-013-0510-4.
Pre-exposure prophylaxis (PrEP) is a novel HIV prevention strategy which requires high adherence. We tested the use of daily short message service (i.e., SMS/text message) surveys to measure sexual behavior and PrEP adherence in Kenya. Ninety-six HIV-uninfected adult individuals, taking daily oral PrEP in a clinical trial, received daily SMS surveys for 60 days. Most participants (96.9 %) reported taking PrEP on ≥80 % days, but 69.8 % missed at least one dose. Unprotected sex was reported on 4.9 % of days; however, 47.9 % of participants reported unprotected sex at least once. Unprotected sex was not correlated with PrEP use (OR = 0.95). Participants reporting more sex were less likely to report PrEP non-adherence and those reporting no sex were most likely to report missing a PrEP dose (adjusted OR = 1.87). PrEP adherence was high, missed doses were correlated with sexual abstinence, and unprotected sex was not associated with decreased PrEP adherence.
doi:10.1007/s10461-013-0510-4
PMCID: PMC3812384  PMID: 23695519
HIV prevention; Pre-exposure prophylaxis; Sexual behavior; Adherence; HIV serodiscordant couples
12.  Differential Regulatory T Cell Activity in HIV Type 1-Exposed Seronegative Individuals 
AIDS Research and Human Retroviruses  2013;29(10):1321-1329.
Abstract
The potential role of conventional and regulatory T cells (Tregs) in protection from HIV-1 infection remains unclear. To address this question, we analyzed samples from 129 HIV-1-exposed seronegative individuals (HESN) from an HIV-1-serodiscordant couples cohort. To assess the presence of HIV-specific T cell responses and Treg function, we measured the proliferation of T cells in response to HIV-1 peptide pools in peripheral blood mononuclear cells (PBMCs) and PBMCs depleted of Tregs. We identified HIV-specific CD4+ and CD8+ T cell responses and, surprisingly, the overall CD4+ and CD8+ T cell response rate was not increased when Tregs were removed from cell preparations. Of the 20 individuals that had HIV-1-specific CD4+ T cell responses, only eight had Tregs that could suppress this proliferation. When compared with individuals whose Tregs could suppress HIV-1-specific CD4+ T cell proliferation, individuals with Tregs unable to suppress showed a trend toward increased T cell activation and Treg frequency and a significant increase in HIV-1-specific production of microphage inflammatory protein-1β (MIP-1β) by CD4+ T cells, autocrine production of which has been shown to be protective in terms of HIV-1 infection of CD4+ T cells.
doi:10.1089/aid.2013.0075
PMCID: PMC3785803  PMID: 23815575
13.  Anal Sex Role Segregation and Versatility among Men Who Have Sex with Men: EXPLORE Study 
Anal sex role patterns and correlates during unprotected anal sex were examined longitudinally among HIV-negative men who have sex with men (MSM). 9.6% were exclusively receptive, 16.7% exclusively insertive, and 63.0% versatile. Versatility was more likely with primary and HIV-negative/unknown status partners and among younger men and substance users, but less likely among Blacks and with higher number of partners. Exclusively receptive role was more likely with HIV-negative/unknown status partners and among younger men and substance users, but less likely with higher number of partners. Examining anal sex role patterns helps understand the factors that drive the epidemic among MSM.
doi:10.1097/QAI.0b013e318299cede
PMCID: PMC3804162  PMID: 23945255
Role Segregation; Versatility; Anal Sex Role; men who have sex with men; HIV
14.  Efficacy of pre-exposure prophylaxis for HIV-1 prevention among high risk heterosexuals: subgroup analyses from the Partners PrEP Study 
AIDS (London, England)  2013;27(13):10.1097/QAD.0b013e3283629037.
Background
Daily oral antiretroviral pre-exposure 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 >5.0, efficacy estimates ranged from 64% to 84%. Monthly visit attendance for PrEP refills and tenofovir detection in plasma were high.
Conclusions
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.
doi:10.1097/QAD.0b013e3283629037
PMCID: PMC3882910  PMID: 24384592
antiretroviral agents; HIV-1 acquisition; primary prevention; women; Africa
15.  Effect of community-based voluntary counselling and testing on HIV incidence and social and behavioural outcomes (NIMH Project Accept; HPTN 043): a cluster-randomised trial 
The lancet global health  2014;2(5):e267-e277.
Background
NIMH Project Accept (HPTN 043) was a cluster-randomized trial that tested whether a multicomponent, multi-level prevention strategy (community-based voluntary counselling and testing [CBVCT]) reduced HIV incidence compared to standard voluntary counselling and testing (SVCT).
Methods
Forty-eight communities were enrolled at five sites in South Africa, Tanzania, Zimbabwe, and Thailand. CBVCT was designed to make testing more accessible in communities, engage communities through outreach, and provide post-test support services. SVCT comprised standard VCT services established at existing facilities. Communities were randomized in matched pairs to 36 months of CBVCT or SVCT. Data were collected at baseline (n=14,567) and post-intervention (n=56,683) by cross-sectional random surveys of 18–32 year-old community residents. HIV incidence was estimated using a cross-sectional multi-assay algorithm. Thailand was excluded from incidence analyses due to low HIV prevalence.
Findings
The estimated incidence in the CBVCT was 1.52% vs. 1.81% in the SVCT with an estimated reduction in HIV incidence of 13·9% (relative risk [RR]=0·86; 95% confidence interval [CI]=0·725–1·023; p=0·08). Women older than 24 years had RR=0·70 (95% CI=0·54–0·90; p=0·009). CBVCT increased testing rates by 25% overall (95% CI=12%–39%; p=0·0003), by 45% among men and 15% among women. No overall effect on sexual risk behaviour was observed. However, among HIV-infected participants, CBVCT reduced the number of sexual partners by 8% (95% CI=1%–15%; p=0.03) and the proportion of multiple partnerships by 30% (95% CI=8%-46%; p=0.01). Social norms regarding HIV testing were improved in CBVCT communities.
Interpretations
The intervention was effective in increasing HIV testing, particularly among men, promoted positive social norms regarding testing, and reduced behavioural risk among HIV-infected participants. A modest reduction in HIV incidence was observed. This intervention focused primarily on HIV detection. Current and future studies that include strategies for HIV treatment and viral suppression should demonstrate further incidence reductions.
doi:10.1016/S2214-109X(14)70032-4
PMCID: PMC4131207  PMID: 25103167
HIV; incidence; Project Accept; Africa; HPTN 043
16.  Study Design Considerations for Evaluating Efficacy of Systemic Pre-Exposure Prophylaxis Interventions 
Background
The development of interventions for systemic Pre-Exposure Prophylaxis (PrEP) faces several significant challenges following the US Food and Drug Administration’s (FDA) approval of Emtricitabine/Tenofovir (FTC/TDF) for HIV prevention. This development is particularly complex because of inconsistency of efficacy results of FTC/TDF PrEP trials for HIV prevention.
Methods
Possible designs for a PrEP Phase 3 efficacy trial are obtained by considering scenarios for potential experimental PrEP and control regimens, including consideration of placebo and active controls, longer acting PrEP and alternate dosing schedules.
Results
Non-inferiority (NI) trials with hazard ratio NI margins ranging from 1.10 to 1.25 can be justified in the contexts of the three PrEP trials demonstrating efficacy of FTC/TDF. However these HIV endpoint trials may require extremely large numbers of participants, particularly in settings where FTC/TDF has been shown to reduce the risk of HIV acquisition. NI trials also are often difficult to interpret because they depend on prior placebo-controlled efficacy results. Superiority trials for PrEP are plausible in settings where FTC/TDF efficacy is not yet established, possibly due to low adherence (i.e. women at risk as in FemPrEP and VOICE): a new product with potential for higher adherence and potency would be a promising candidate in this setting.
Conclusions
Following FDA approval of FTC/TDF for PrEP, trials to establish efficacy of new PrEP regimens require stringent design standards, together with rigorous debate about adherence within study populations and many important ethical issues.
doi:10.1097/QAI.0b013e3182986fac
PMCID: PMC3725298  PMID: 23764624
Pre-exposure Prophylaxis; Non-inferiority; efficacy; phase 3; clinical trials; adherence
17.  Cross-Sectional HIV Incidence Estimation in HIV Prevention Research 
Accurate methods for estimating HIV incidence from cross-sectional samples would have great utility in prevention research. This report describes recent improvements in cross-sectional methods that significantly improve their accuracy. These improvements are based on the use of multiple biomarkers to identify recent HIV infections. These multi-assay algorithms (MAAs) use assays in a hierarchical approach for testing that minimizes the effort and cost of incidence estimation. These MAAs do not require mathematical adjustments for accurate estimation of the incidence rates in study populations in the year prior to sample collection. MAAs provide a practical, accurate, and cost-effective approach for cross-sectional HIV incidence estimation that can be used for HIV prevention research and global epidemic monitoring.
doi:10.1097/QAI.0b013e3182986fdf
PMCID: PMC3737594  PMID: 23764641
HIV; incidence; cross-sectional; multi-assay algorithm
18.  The dynamic relationship between social norms and behaviors: The results of an HIV prevention network intervention for injection drug users 
Addiction (Abingdon, England)  2013;108(5):934-943.
Aims
Social norms are a key source of influence on health behaviors. This study examined changes in social norms and relationships between HIV injection risk behaviors and social norms among injection drug users (IDUs) involved in an experimental intervention.
Design
Randomized clinical trial.
Setting
An HIV Prevention Trials Network study, Philadelphia, USA.
Participants
IDUs, called indexes, and their social network members, who were drug or sex partners, were recruited for an HIV prevention intervention and followed for up to 30 months (N=652). Indexes were randomized into a peer education intervention or control condition.
Measurements
Outcomes of injection related HIV risk behaviors (sharing needles, sharing cookers, sharing cotton, front/back-loaded) were measured every 6 months and social norm of these 4 risk behaviors were assessed every 12 months.
Findings
There was a statistically significant intervention effect on all four social norms of injection behaviors, with participants in the intervention reporting less risky social norms compared with controls (changes in mean score: needles, -0.24, p.<01; cookers, -0.33, p.<01; cottons, -0.28, p.<05; front/back loading, -0.23, p.<01). There was also a statistically significant bidirectional association with social norms predicting injection risk behaviors at the next assessment and risk behaviors predicting social norms at the subsequent visit.
Conclusions
Through social network interventions it is feasible to change both injection risk behaviors and associated social norms. However, it is critical that social network interventions focus on publically highlighting behavior changes since changing social norms without awareness of behaviors change may lead to relapse of risk behaviors.
doi:10.1111/add.12095
PMCID: PMC3628934  PMID: 23362861
19.  Prevalence and Seroincidence of Hepatitis B and Hepatitis C Infection in High Risk People Who Inject Drugs in China and Thailand 
We determined the prevalence and incidence of HBV and HCV infection in people who inject drugs (PWIDs) at high risk for HIV in China and Thailand and determined the association of HBV and HCV incidence with urine opiate test results and with short-term versus long-term buprenorphine-naloxone (B-N) treatment use in a randomized clinical trial (HPTN 058). 13.8% of 1049 PWIDs in China and 13.9% of 201 PWIDs in Thailand were HBsAg positive at baseline. Among HBsAg negative participants, the HBsAg incidence rate was 2.7/100 person years in China and 0/100 person years in Thailand. 81.9% of 1049 PWIDs in China and 59.7% of 201 in Thailand were HCV antibody positive at baseline. The HCV confirmed seroincidence rate among HCV antibody negative PWIDs was 22/100 person years in China and 4.6/100 person years in Thailand. Incident HBsAg was not significantly different in the short-term versus long-term B-N arm in China or Thailand. Participants with positive opiate results in at least 75% of their urines during the time period were at increased risk of incident HBsAg (HR = 5.22; 95% CI, 1.08 to 25.22; P = 0.04) in China, but not incident HCV conversion in China or Thailand.
doi:10.1155/2014/296958
PMCID: PMC3985324  PMID: 24860664
20.  Clinician Practices and Attitudes Regarding Early Antiretroviral Therapy in the US 
Background
Use of antiretroviral therapy (ART) to prevent HIV transmission has received substantial attention following 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 HPTN 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, prior to any participation in the HPTN 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/mm3, and 14 percent 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.
doi:10.1097/QAI.0b013e31826a184c.
PMCID: PMC3957230  PMID: 23183150
HIV prevention; early antiretroviral therapy; test and treat; clinician survey
21.  Sexual Behavior of Heterosexual Men and Women Receiving Antiretroviral Pre-Exposure Prophylaxis for HIV Prevention: A Longitudinal Analysis 
The Lancet infectious diseases  2013;13(12):1021-1028.
Background
Limited data are available to assess sexual behavior by persons using antiretroviral pre-exposure prophylaxis (PrEP) for HIV prevention. Increased sexual risk taking by persons using effective HIV prevention strategies, like PrEP, could offset HIV prevention benefits.
Methods
The Partners PrEP Study, a randomized, placebo-controlled trial of daily oral PrEP among heterosexual HIV-uninfected members of HIV serodiscordant couples, publicly reported efficacy for HIV prevention in July 2011 and participants continued monthly follow-up thereafter. We used regression analyses to compare the frequency of sex unprotected by a condom during the 12 months after compared to before July 2011 to assess whether knowledge of PrEP efficacy for HIV prevention resulted in increased sexual risk behavior.
Results
We analyzed 56, 132 person-months from 3024 HIV-uninfected subjects (64% male). The average frequency of unprotected sex with the HIV-infected study partner was 59 per 100 person-months pre- versus 53 post-unblinding, reflecting no immediate change or change over time after July 2011 (p=0·66 and 0·25, respectively). There was a statistically significant increase in unprotected sex with outside partners over time after July 2011 but the effect was modest (average of 6.8 unprotected sex acts per year versus 6.2 acts in a predicted counterfactual scenario had unblinding not occurred, p=0·04). Compared to pre-July 2011, there was no significant increase in incident sexually transmitted infections or pregnancy after July 2011.
Interpretation
The transition from a blinded, placebo-controlled efficacy trial to all participants aware they were receiving active, efficacious PrEP in the Partners PrEP Study provided a “natural experiment” to evaluate sexual risk compensation. PrEP, provided as part of a comprehensive prevention package, may not result in substantial changes in risk-taking sexual behavior for heterosexual couples.
doi:10.1016/S1473-3099(13)70226-3
PMCID: PMC3920826  PMID: 24139639
23.  HIV Incidence Determination in the United States: A Multiassay Approach 
The Journal of Infectious Diseases  2012;207(2):232-239.
Background. Accurate testing algorithms are needed for estimating human immunodeficiency virus (HIV) incidence from cross-sectional surveys.
Methods. We developed a multiassay algorithm (MAA) for HIV incidence that includes the BED capture enzyme immunoassay (BED-CEIA), an antibody avidity assay, HIV load, and CD4+ T-cell count. We analyzed 1782 samples from 709 individuals in the United States who had a known duration of HIV infection (range, 0 to >8 years). Logistic regression with cubic splines was used to compare the performance of the MAA to the BED-CEIA and to determine the window period of the MAA. We compared the annual incidence estimated with the MAA to the annual incidence based on HIV seroconversion in a longitudinal cohort.
Results. The MAA had a window period of 141 days (95% confidence interval [CI], 94–150) and a very low false-recent misclassification rate (only 0.4% of 1474 samples from subjects infected for >1 year were misclassified as indicative of recent infection). In a cohort study, annual incidence based on HIV seroconversion was 1.04% (95% CI, .70%–1.55%). The incidence estimate obtained using the MAA was essentially identical: 0.97% (95% CI, .51%–1.71%).
Conclusions. The MAA is as sensitive for detecting recent HIV infection as the BED-CEIA and has a very low rate of false-recent misclassification. It provides a powerful tool for cross-sectional HIV incidence determination.
doi:10.1093/infdis/jis659
PMCID: PMC3532826  PMID: 23129760
HIV; incidence testing; United States; epidemiology
24.  HPTN 071 (PopART): A Cluster-Randomized Trial of the Population Impact of an HIV Combination Prevention Intervention Including Universal Testing and Treatment: Mathematical Model 
PLoS ONE  2014;9(1):e84511.
Background
The HPTN 052 trial confirmed that antiretroviral therapy (ART) can nearly eliminate HIV transmission from successfully treated HIV-infected individuals within couples. Here, we present the mathematical modeling used to inform the design and monitoring of a new trial aiming to test whether widespread provision of ART is feasible and can substantially reduce population-level HIV incidence.
Methods and Findings
The HPTN 071 (PopART) trial is a three-arm cluster-randomized trial of 21 large population clusters in Zambia and South Africa, starting in 2013. A combination prevention package including home-based voluntary testing and counseling, and ART for HIV positive individuals, will be delivered in arms A and B, with ART offered universally in arm A and according to national guidelines in arm B. Arm C will be the control arm. The primary endpoint is the cumulative three-year HIV incidence.
We developed a mathematical model of heterosexual HIV transmission, informed by recent data on HIV-1 natural history. We focused on realistically modeling the intervention package. Parameters were calibrated to data previously collected in these communities and national surveillance data.
We predict that, if targets are reached, HIV incidence over three years will drop by >60% in arm A and >25% in arm B, relative to arm C. The considerable uncertainty in the predicted reduction in incidence justifies the need for a trial. The main drivers of this uncertainty are possible community-level behavioral changes associated with the intervention, uptake of testing and treatment, as well as ART retention and adherence.
Conclusions
The HPTN 071 (PopART) trial intervention could reduce HIV population-level incidence by >60% over three years. This intervention could serve as a paradigm for national or supra-national implementation. Our analysis highlights the role mathematical modeling can play in trial development and monitoring, and more widely in evaluating the impact of treatment as prevention.
doi:10.1371/journal.pone.0084511
PMCID: PMC3893126  PMID: 24454728
25.  Development of Methods for Cross-Sectional HIV Incidence Estimation in a Large, Community Randomized Trial 
PLoS ONE  2013;8(11):e78818.
Background
Accurate methods of HIV incidence determination are critically needed to monitor the epidemic and determine the population level impact of prevention trials. One such trial, Project Accept, a Phase III, community-randomized trial, evaluated the impact of enhanced, community-based voluntary counseling and testing on population-level HIV incidence. The primary endpoint of the trial was based on a single, cross-sectional, post-intervention HIV incidence assessment.
Methods and Findings
Test performance of HIV incidence determination was evaluated for 403 multi-assay algorithms [MAAs] that included the BED capture immunoassay [BED-CEIA] alone, an avidity assay alone, and combinations of these assays at different cutoff values with and without CD4 and viral load testing on samples from seven African cohorts (5,325 samples from 3,436 individuals with known duration of HIV infection [1 month to >10 years]). The mean window period (average time individuals appear positive for a given algorithm) and performance in estimating an incidence estimate (in terms of bias and variance) of these MAAs were evaluated in three simulated epidemic scenarios (stable, emerging and waning). The power of different test methods to detect a 35% reduction in incidence in the matched communities of Project Accept was also assessed. A MAA was identified that included BED-CEIA, the avidity assay, CD4 cell count, and viral load that had a window period of 259 days, accurately estimated HIV incidence in all three epidemic settings and provided sufficient power to detect an intervention effect in Project Accept.
Conclusions
In a Southern African setting, HIV incidence estimates and intervention effects can be accurately estimated from cross-sectional surveys using a MAA. The improved accuracy in cross-sectional incidence testing that a MAA provides is a powerful tool for HIV surveillance and program evaluation.
doi:10.1371/journal.pone.0078818
PMCID: PMC3827276  PMID: 24236054

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