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Background: Daily dosing of tenofovir disoproxil fumarate, with or without emtricitabine, has high efficacy in preventing human immunodeficiency virus (HIV) infection when individuals are adherent. The target protective plasma concentration of tenofovir (TFV), however, is not fully understood. The aim of this study is to estimate the protective TFV plasma concentration., Methods: Participant data from TFV-based daily oral and topical active arms of phase 3 trials (iPrEx, VOICE, and Partners PrEP) were pooled (n = 2950). Individual specific risk scores (low and high risk) of acquiring HIV, based on an earlier placebo analysis, were created. Longitudinal TFV pharmacokinetics (PK), HIV outcome, individual risk scores and the effect of sex at birth data were integrated and analyzed using non-linear mixed effects models., Results: Around 50% of the individuals were estimated to be adherent, which differed from self-reported adherence (∼90%) and large variation between longitudinal adherence patterns were identified. Following oral administration, the estimated protective TFV trough concentration was substantially higher in high-risk females (45.8 ng/mL) compared with high-risk males (16.1 ng/mL) and to low-risk individuals (∼7.5 ng/mL). Dosing simulations indicated that high-risk women require full adherence to maintain protective levels., Conclusions: Using the largest PK-HIV outcome database to date, we developed a population adherence-PK-risk-outcome model. Our results indicate that high-risk females need higher levels of plasma TFV to achieve HIV protection compared with males. HIV protection exceeds 90% in all populations if daily adherence is achieved., Competing Interests: Potential conflicts of interest. D. V. G. has served on an Advisory Board for Merck and has personal fees from Gilead. C. W. H. contracts for clinical research, paid to Hopkins and unrelated to this work, from Gilead, Merck, and ViiV Healthcare; consulting fees from Gilead (scientific Advisory Board, travel support, paid to author), Merck (scientific Advisory Board, travel support and honoraria, paid to author), and ViiV Healthcare (scientific Advisory Board, travel support and honoraria, paid to author); US patents (2 issued patents related to HIV prevention technology); and a leadership role as founder of Prionde Biopharma, LLC (company to develop human immunodeficiency virus (HIV) prevention product). P. J. reports grants or contracts unrelated to this work: T32 GM007546 from the National Institute of General Medical Sciences (NIGMS). R. G. reports grants or contracts unrelated to this work from Gilead Sciences: employer, UCSF, has received funding to support work as a site investigator for clinical trials related to preexposure prophylaxis using agents other than FTC/TDF; and payment for expert testimony from the US Department of Justice (related to a patent held by the US Government related to preexposure prophylaxis using tenofovir esters and emtricitabine). C. L. C. reports consulting fees as a scientific advisor to Merck and Gilead Sciences. J. M. B. reports grants to institution, unrelated to this work, from NIH and BMGF and is an employee of Gilead Sciences (salary, stock, options). J. M. reports consulting fees and participation on Scientific Advisory Board from Merck and Gilead Sciences and is treasurer and board member for the Infectious Disease Society of America. P. A. reports contracts or grants unrelated to this work from Gilead Sciences (paid to institution); and consulting fees paid to author from Gilead Sciences, Merck, and ViiV. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In trials of oral HIV pre-exposure prophylaxis (PrEP), multiple approaches have been used to measure adherence, including self-report, pill counts, electronic dose monitoring devices, and biological measures such as drug levels in plasma, peripheral blood mononuclear cells, hair, and/or dried blood spots. No one of these measures is ideal and each has strengths and weaknesses. However, accurate estimates of adherence to oral PrEP are important as drug efficacy is closely tied to adherence, and secondary analyses of trial data within identified adherent/non-adherent subgroups may yield important insights into real-world drug effectiveness. We develop a statistical approach to combining multiple measures of adherence and show in simulated data that the proposed method provides a more accurate measure of true adherence than self-report. We then apply the method to estimate adherence in the ADAPT study (HPTN 067) in South African women., (© 2022 John Wiley & Sons Ltd.)

Background: Young men of color who have sex with men face a continual increase in rates of HIV infection. Pre-exposure prophylaxis (PrEP) is an important prevention method for these young men., Setting: The Connecting Resources for Urban Sexual Health (CRUSH) demonstration project provided sexual health services, including PrEP, to young men who have sex with men aged 18-29 years. We report on adherence and factors influencing it., Methods: Participants were offered HIV and sexually transmitted infection testing, prevention counseling, PrEP, and when appropriate, sexually transmitted infection treatment and postexposure prophylaxis. Participants taking PrEP had erythrocyte tenofovir diphosphate and emtricitabine levels measured through dried blood spot testing at 4, 12, and 24 weeks to estimate medication adherence. Participants also completed surveys to assess demographic and psychosocial measures., Results: From February 2014 to November 2015, CRUSH enrolled 257 participants. Ninety-three percent started PrEP, 81% of whom initiated it at their first visit. Twelve percent required postexposure prophylaxis before starting PrEP. Adherence at protective levels was initially high with 87% demonstrating levels consistent with at least 4 doses per week at week 4, compared with 77% at the 48-week follow-up. African American race, exposure to violence, and having survival needs were associated with significantly lower levels of adherence [odds ratio (OR): 0.33; confidence interval (CI): 0.11 to 0.97, P < 0.04; OR: 0.79; CI: 0.59 to 1.04, P < 0.10; OR: 0.51; CI: 0.24 to 1.05, P < 0.07]., Conclusions: Most young men who initiate PrEP adhere at levels that confer protection against HIV infection. Interventions should account for differences in life experiences, particularly addressing the structural challenges facing young African American men.

Although pre-exposure prophylaxis (PrEP)-the use of antiretroviral drugs by non-infected people to prevent the acquisition of HIV-is a promising preventive option, important public health questions remain. Daily oral emtricitabine (FTC)-tenofovir disoproxil fumarate (TDF) is highly efficacious in preventing the acquisition of HIV in people at risk as a result of a range of different types of sexual exposure. There is good evidence of efficacy in women and men, and when men who have sex with men use event based dosing. Studies have been conducted in several countries and epidemics. Because adherence to this treatment varies greatly there are questions about its public health benefit. Oral FTC-TDF is extremely safe, with minimal impact on kidney, bone, or pregnancy outcomes, and there is no evidence that its effectiveness has been reduced by risk compensation during open label and programmatic follow-up. It is too early to assess the impact of this treatment on the incidence of sexually transmitted infections (STIs) at a population level. Many challenges remain. Access to pre-exposure prophylaxis is limited and disparities exist, including those governed by race and sex. Different pricing and access models need to be explored to avoid further widening inequalities. The optimal combination prevention program needs to be defined, and this will depend on local epidemiology, service provision, and cost effectiveness. This review updates the evidence base for pre-exposure prophylaxis regarding its effectiveness, safety, and risk compensation., Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following interests: SMcC was the principal investigator and MD the trial physician in the PROUD study, which was funded in part by Gilead, which provided the drugs for free. MD, NF, and SMcC were on the writing group of the UK national pre-exposure prophylaxis guidelines. RG was the principal investigator of the iPrEx study., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Recent advances in biomedical HIV prevention have led to optimistic projections of a dramatic worldwide reduction of new infections by 2030. This optimism is counterbalanced by concerns that the protective benefits of one such technology, HIV pre-exposure prophylaxis (PrEP), may be negated by increases in other behaviours that offset these benefits (risk compensation). To contribute to a deeper understanding of concepts of safety and risk in the context of HIV PrEP, we draw on the narrative accounts of 61 male PrEP users who participated in the inaugural PrEP demonstration project: the iPrEx open-label extension study. We conducted in-depth interviews with a purposeful sample of iPrEx participants. Overall, participants did not report significant changes to their sexual practices once they had begun taking PrEP. Rather, participants reported experiencing a sense of relief or reprieve from HIV-related stress. This unburdening of fear did not necessarily lead to condomless sex. Instead, men expressed feeling a sense of security and less free-floating fear of HIV. We contend that no longer living under the threat of HIV is a significant benefit that has not been adequately explored in HIV prevention research.

New objective measures of antiretroviral adherence are needed. We determined if emtricitabine triphosphate (FTC-TP) in dried blood spots (DBS) can be used as a marker of recent dosing with tenofovir disoproxil fumarate-emtricitabine (TDF-FTC). The half-life of FTC-TP was estimated in DBS samples obtained from an intensive pharmacokinetic (PK) study of coformulated TDF-FTC in HIV-negative and HIV-infected participants. The concordance of quantifiable FTC-TP in DBS with tenofovir (TFV)/FTC in plasma was evaluated by utilizing paired plasma-DBS samples from participants enrolled in 2 large preexposure prophylaxis (PrEP) open-label trials. The time to FTC-TP nondetectability after TDF-FTC dosing was evaluated utilizing DBS from HIV-negative participants enrolled in a directly observed therapy study of variable adherence to TDF-FTC. The mean (95% confidence interval [CI]) terminal half-life of FTC-TP in the PK study was 35 (23 to 47) h. A total of 143/163 (88%) samples obtained 0 to 48 h post-TDF-FTC dose had quantifiable FTC-TP in DBS, compared with 2/93 (2%) and 0/87 (0%) obtained >48 and >96 h postdose. In 746 paired plasma-DBS samples from 445 participants enrolled in PrEP trials, when both TFV/FTC in plasma were below the limit of quantification, FTC-TP was as well in 98.9% of the samples, and when either TFV or FTC in plasma was quantifiable, FTC-TP was as well in 90.5% of the samples. The half-life of FTC-TP in DBS is short relative to that of TFV-diphosphate (TFV-DP), making it a surrogate for TFV-FTC detection in plasma. FTC-TP can be quantified in DBS simultaneously with TFV-DP, which quantifies cumulative adherence to TDF-FTC. (The clinical trials discussed in this article have been registered at ClinicalTrials.gov under identifiers NCT01040091, NCT02022657, NCT00458393, NCT01772823, and NCT02012621.)., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Introduction: Globally, transgender ("trans") women are one of the key populations most disproportionately impacted by HIV. Pre-exposure prophylaxis (PrEP) is the newest and most promising biomedical HIV prevention intervention to date. This paper reviews relevant literature to describe the current state of the science and describes the potential role of PrEP among trans women, including a discussion of unique considerations for maximizing the impact of PrEP for this vulnerable population., Methods: Available information, including but not limited to existing scientific literature, about trans women and PrEP was reviewed and critiqued based on author expertise, including PrEP clinical trials and rollout., Results: To date, PrEP demonstration projects and clinical trials have largely excluded trans women, or have not included them in a meaningful way. Data collection strategies that fail to identify trans women in clinical trials and research further limit the ability to draw conclusions about trans women's unique needs and devise strategies to meet them. Gender-affirming providers and clinic environments are essential components of any sexual health programme that aims to serve trans women, as they will largely avoid settings that may result in stigmatizing encounters and threats to their identities. While there is currently no evidence to suggest drug-drug interactions between PrEP and commonly used feminizing hormone regimens, community concerns about potential interactions may limit interest in and uptake of PrEP among trans women., Conclusions: In scaling up PrEP for trans women, it is essential to engage trans communities, utilize trans-inclusive research and marketing strategies and identify and/or train healthcare providers to provide gender-affirming healthcare to trans women, including transition-related care such as hormone provision. PrEP implementation guidelines must consider and address trans women's unique barriers and facilitators to uptake and adherence., Competing Interests: JMS, MBD and RG are principal investigators on a PrEP demonstration project for transgender people, funded by the California HIV/AIDS Research Program, to which Gilead has donated study drug.

Monitoring adherence to pre-exposure prophylaxis (PrEP) is part of the recommended package for PrEP prescribing, yet ongoing concerns about how to do so confidently are exacerbated by gross discrepancies in reported and actual use in clinical trials. We evaluated concordance between reports of recent PrEP dosing collected via neutral interviewing and drug quantitation in the iPrEx open-label extension, where participants (n = 1172) had the choice to receive or not receive PrEP. Self-report of recent dosing (at least one PrEP dose in the past 3-day) was the most common report (84 % of participants), and among these 83 % did have quantifiable levels of drug. The vast majority of those reporting no doses in the past 3-day (16 % of the sample) did not have quantifiable levels of drug (82 %). Predictors of over-report of dosing included younger age and lower educational attainment. Monitoring recent PrEP use through neutral interviewing may be a productive approach for clinicians to consider in implementation of real-world PrEP. Strategies to capture longer term or prevention-effective PrEP use, particularly for younger cohorts, are needed.

This study aimed to gain a better understanding of the association between participation in a blinded antiretroviral pre-exposure prophylaxis (PrEP) clinical trial and sexual practices among men who have sex with men and transgender women. This study utilized both quantitative and qualitative methodologies. Data included reported PrEP medication adherence and sexual behavior among 114 study participants. Forty-six participants took part in qualitative data collection, 32 were interviewed and 14 participated in one of three focus group discussions. The average percentage of study medication adherence, number of sex partners and rates of sex without a condom were calculated. For qualitative data, content analysis was used to identify repeated normative themes, some of which arose spontaneously from interview interactions. Participants at the Chiang Mai site reported good adherence to the study medication. The sexual risk behavior of these participants had decreased by their final study visit; this was unrelated to level of adherence. Qualitative findings describe sexual practices that were highly contextual; participants used risk assessments to determine sex practices. Condoms were used with casual partners but not necessarily with primary partners. Our findings suggest that while PrEP is an exciting new development for HIV prevention, it must be paired with behavioral interventions to fully address sexual risk among this population. Interventions should provide this population with skills to negotiate condom use with their primary partners as well as in situations in which their sexual partners do not support condom use.

Importance: Several randomized clinical trials have demonstrated the efficacy of preexposure prophylaxis (PrEP) in preventing human immunodeficiency virus (HIV) acquisition. Little is known about adherence to the regimen, sexual practices, and overall effectiveness when PrEP is implemented in clinics that treat sexually transmitted infections (STIs) and community-based clinics serving men who have sex with men (MSM)., Objective: To assess PrEP adherence, sexual behaviors, and the incidence of STIs and HIV infection in a cohort of MSM and transgender women initiating PrEP in the United States., Design, Setting, and Participants: Demonstration project conducted from October 1, 2012, through February 10, 2015 (last date of follow-up), among 557 MSM and transgender women in 2 STI clinics in San Francisco, California, and Miami, Florida, and a community health center in Washington, DC. Data were analyzed from December 18, 2014, through August 8, 2015., Interventions: A combination of daily, oral tenofovir disoproxil fumarate and emtricitabine was provided free of charge for 48 weeks. All participants received HIV testing, brief client-centered counseling, and clinical monitoring., Main Outcomes and Measures: Concentrations of tenofovir diphosphate in dried blood spot samples, self-reported numbers of anal sex partners and episodes of condomless receptive anal sex, and incidence of STI and HIV acquisition., Results: Overall, 557 participants initiated PrEP, and 437 of these (78.5%) were retained through 48 weeks. Based on the findings from the 294 participants who underwent measurement of tenofovir diphosphate levels, 80.0% to 85.6% had protective levels (consistent with ≥4 doses/wk) at follow-up visits. African American participants (56.8% of visits; P = .003) and those from the Miami site (65.1% of visits; P < .001) were less likely to have protective levels, whereas those with stable housing (86.8%; P = .02) and those reporting at least 2 condomless anal sex partners in the past 3 months (88.6%; P = .01) were more likely to have protective levels. The mean number of anal sex partners declined during follow-up from 10.9 to 9.3, whereas the proportion engaging in condomless receptive anal sex remained stable at 65.5% to 65.6%. Overall STI incidence was high (90 per 100 person-years) but did not increase over time. Two individuals became HIV infected during follow-up (HIV incidence, 0.43 [95% CI, 0.05-1.54] infections per 100 person-years); both had tenofovir diphosphate levels consistent with fewer than 2 doses/wk at seroconversion., Conclusions and Relevance: The incidence of HIV acquisition was extremely low despite a high incidence of STIs in a large US PrEP demonstration project. Adherence was higher among those participants who reported more risk behaviors. Interventions that address racial and geographic disparities and housing instability may increase the impact of PrEP.

Introduction: After the initial approval of the use of tenofovir disoproxil fumarate-emtricitabine (TDF/FTC) by the US Food and Drug Administration in 2012 for anti-HIV pre-exposure prophylaxis (PrEP), uptake was initially limited, but more recent community surveys and expert opinion suggest wider acceptance in some key populations., Discussion: Demonstration projects are underway to determine the best practices in the United States to identify at-risk individuals in primary care and sexually transmitted disease clinics who could benefit from PrEP. Studies of PrEP in combination with behavioural interventions are being evaluated. Studies to evaluate the use of PrEP by HIV-uninfected women in HIV-discordant couples interested in safe conception are also getting underway. The optimal deployment of PrEP as part of a comprehensive national HIV/AIDS strategy in the United States has been limited by lack of knowledge among some at-risk people and by some medical providers indicating that they do not feel sufficiently knowledgeable and comfortable in prescribing PrEP. Studies are underway to determine how to assist busy clinicians to determine which of their patients could benefit from PrEP. Although most federal health insurance programmes will cover most of the costs associated with PrEP, underinsured patients in states that have not enacted health reform face additional challenges in paying for PrEP medication and appropriate clinical monitoring., Conclusions: PrEP implementation in the United States is a work in progress, with increasing awareness and uptake among some individuals in key populations.

Background: Adherence to pre-exposure prophylaxis (PrEP) is critical for efficacy. Antiretroviral concentrations are an objective measure of PrEP use and correlate with efficacy. Understanding patterns and correlates of drug detection can identify populations at risk for nonadherence and inform design of PrEP adherence interventions., Methods: Blood antiretroviral concentrations were assessed among active arm participants in iPrEx, a randomized placebo-controlled trial of emtricitabine/tenofovir in men who have sex with men and transgender women in 6 countries. We evaluated rates and correlates of drug detection among a random sample of 470 participants at week 8 and a longitudinal cohort of 303 participants through 72 weeks of follow-up., Results: Overall, 55% of participants (95% confidence interval: 49 to 60) tested at week 8 had drug detected. Drug detection was associated with older age and varied by study site. In longitudinal analysis, 31% never had drug detected, 30% always had drug detected, and 39% had an inconsistent pattern. Overall detection rates declined over time. Drug detection at some or all visits was associated with older age, indices of sexual risk, including condomless receptive anal sex, and responding "don't know" to a question about belief of PrEP efficacy (0-10 scale)., Conclusions: Distinct patterns of study product use were identified, with a significant proportion demonstrating no drug detection at any visit. Research literacy may explain greater drug detection among populations having greater research experience, such as older men who have sex with men in the United States. Greater drug detection among those reporting highest risk sexual practices is expected to increase the impact and cost-effectiveness of PrEP.

Objective: To evaluate the concordance between adherence estimated by self-report (in-person interview or computer-assisted self-interview), in-clinic pill counts, and pharmacy dispensation records and drug detection among participants in a placebo-controlled pre-exposure prophylaxis HIV prevention trial (iPrEx)., Design: Cross-sectional evaluation of 510 participants who had drug concentration data and matched adherence assessments from their week-24 study visit., Methods: Self-reported adherence collected through (1) interview and (2) computer-assisted self-interview surveys, (3) adherence estimated by pill count, and (4) medication possession ratio was contrasted to having a detectable level of drug concentrations [either tenofovir diphosphate (TFV-DP) or emtricitabine triphosphate (FTC-TP)], as well as to having evidence of consistent dosing (tenofovir diphosphate ≥ 16 fmol/10⁶ cells), focusing on positive predictive values, overall and by research site., Results: Overall, self-report and pharmacy records suggested high rates of product use (over 90% adherence); however, large discrepancies between these measures and drug detection were noted, which varied considerably between sites (positive predictive values from 34% to 62%). Measures of adherence performed generally well in the US sites but had poor accuracy in other research locations. Medication possession ratio outperformed other measures but still had relatively low discrimination., Conclusions: The sizable discrepancy between adherence measures and drug detection in certain regions highlights the potential contribution of factors that may have incentivized efforts to seem adherent. Understanding the processes driving adherence reporting in some settings, but not others, is essential for finding effective ways to increase accuracy in measurement of product use and may generalize to promotion efforts for open-label pre-exposure prophylaxis.

Background: Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults., Methods: A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs)., Results: Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60-93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair., Conclusions: This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs., Trial Registration: ClinicalTrials.gov NCT00903084.

In 2010, the iPrEx study demonstrated efficacy of daily emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) pre-exposure prophylaxis (PrEP) in reducing HIV acquisition among men who have sex with men. Adherence to study product was critical for PrEP efficacy, and varied considerably, with FTC/TDF detection rates highest in the United States. We conducted a qualitative study to gain insights into the experiences of iPrEx participants in San Francisco (SF) where there was high confirmed adherence, to understand individual and contextual factors influencing study product use in this community. In 2009 and 2011, we conducted focus groups and in-depth interviews in 36 and 16 SF iPrEx participants, respectively. Qualitative analyses indicate that participants joined the study out of altruism. They had a clear understanding of study product use, and pill taking was facilitated by establishing or building on an existing routine. Participants valued healthcare provided by the study and relationships with staff, whom they perceived as nonjudgmental, and found client-centered counseling to be an important part of the PrEP package. This facilitated pill taking and accurate reporting of missed doses. Adherence barriers included changes in routine, side effects/intercurrent illnesses, and stress. Future PrEP adherence interventions should leverage existing routines and establish client-centered relationships/ environments to support pill taking and promote accurate reporting.

In 2008, the Pre-exposure Prophylaxis Initiative (iPrEx) study expanded to include men who have sex with men (MSM) in Chiang Mai, Thailand. In full, 114 participants from Chiang Mai joined this international double-blinded trial of daily FTC-TDF (Truvada®) or placebo as a pre-exposure prophylaxis (PrEP) HIV prevention strategy. To better understand the characteristics of iPrEx participants specifically from this underserved population in Thailand, and gain insights into their experiences of trying to take a daily tablet as part of this blinded PrEP trial, we conducted a qualitative study. In 2010, 32 MSM iPrEx participants provided in-depth interviews and an additional 14 joined focus group discussions. Results of the qualitative analyzes suggested that participants held generally positive attitudes toward the iPrEx study and study medication and related this to high rates of adherence to the daily regimen. Participants also reflected on the provision of quality health care as part of participation in the trial, as well as support from clinical research staff, family and friends as helpful in supporting high rates of study medication adherence. Discourse concerning challenges to adherence included medication taking behavior, which was contextualized by lifestyle, living arrangement, social life, social stigma in terms of being mistakenly identified as HIV positive or unintentional disclosure of sexual identity to family and friends, and relationship conflicts with partners. The results provide broader perspectives of participant experiences of the study medication and daily adherence in the larger contexts of the MSM community, close relationships, and the study climate, and can be leveraged in constructing PrEP adherence support approaches within these communities.

Pre-exposure prophylaxis (PrEP), in which HIV uninfected persons with ongoing HIV risk use antiretroviral medications as chemoprophylaxis against sexual HIV acquisition, is a promising new HIV prevention strategy. Proof-of-concept that PrEP, as oral or vaginal topical tenofovir-based products, protects against sexual HIV acquisition has been demonstrated in clinical trials conducted among men who have sex with men and heterosexual men and women. The degree of HIV protection in these trials was strongly related to the level of adherence to PrEP. Many questions are yet unanswered--including how to motivate uptake of and sustain adherence to PrEP for HIV prevention, how much PrEP use is enough to achieve HIV protection, and the potential of "next-generation" PrEP agents to improve on this effective technology.

Background: Preexposure prophylaxis with antiretroviral drugs has been effective in the prevention of human immunodeficiency virus (HIV) infection in some trials but not in others., Methods: In this randomized, double-blind, placebo-controlled trial, we assigned 2120 HIV-negative women in Kenya, South Africa, and Tanzania to receive either a combination of tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) or placebo once daily. The primary objective was to assess the effectiveness of TDF-FTC in preventing HIV acquisition and to evaluate safety., Results: HIV infections occurred in 33 women in the TDF-FTC group (incidence rate, 4.7 per 100 person-years) and in 35 in the placebo group (incidence rate, 5.0 per 100 person-years), for an estimated hazard ratio in the TDF-FTC group of 0.94 (95% confidence interval, 0.59 to 1.52; P=0.81). The proportions of women with nausea, vomiting, or elevated alanine aminotransferase levels were significantly higher in the TDF-FTC group (P=0.04, P<0.001, and P=0.03, respectively). Rates of drug discontinuation because of hepatic or renal abnormalities were higher in the TDF-FTC group (4.7%) than in the placebo group (3.0%, P=0.051). Less than 40% of the HIV-uninfected women in the TDF-FTC group had evidence of recent pill use at visits that were matched to the HIV-infection window for women with seroconversion. The study was stopped early, on April 18, 2011, because of lack of efficacy., Conclusions: Prophylaxis with TDF-FTC did not significantly reduce the rate of HIV infection and was associated with increased rates of side effects, as compared with placebo. Despite substantial counseling efforts, drug adherence appeared to be low. (Supported by the U.S. Agency for International Development and others; FEM-PrEP ClinicalTrials.gov number, NCT00625404.).

Background: Distinct homosexual and heterosexual HIV epidemics have previously been recognised in South Africa. However, linked HIV prevalence and self-reported sexual risk behaviour data have not been reported for men who have sex with men (MSM) in Cape Town since 1986., Methods: We conducted a cross-sectional, anonymous, venue-based HIV risk behaviour and prevalence study of 542 self-identified MSM in greater Cape Town using a self-administered risk questionnaire and the OraSure testing device to asses HIV-1 prevalence., Results: This sample had an overall HIV prevalence of 10.4% (56/539). We found that self-identifying as gay, homosexual or queer (adjusted odds ratio (AOR) 4.5, 95% confidence interval (CI) 1.0-20.0) and reporting ever having had a sexually transmissible infection diagnosis (AOR 4.3, 95% CI: 2.3-8.3) were significantly predictive of testing HIV-1 positive, while reporting unprotected anal intercourse with a known HIV-negative partner (AOR 0.4, 95% CI: 0.2-0.9) was significantly protective., Conclusion: These data suggest a mature epidemic with consistent high-risk taking among MSM in Cape Town, and significant associations of select self-reported risk behaviours and HIV-1 serostatus. There is a need for continued and robust HIV surveillance along with detailed risk behaviour trends over time to inform the development of targeted risk-reduction interventions for this population.

Objective: HIV-1 viral load in early infection predicts the risk of subsequent disease progression but the factors responsible for the differences between individuals in viral load during this period have not been fully identified. We sought to determine the relationship between HIV-1 RNA levels in the source partner and recently infected recipient partners within transmission pairs., Methods: We recruited donor partners of persons who presented with acute or recent (<6 months) HIV infection. Transmission was confirmed by phylogenetic comparison of virus sequence in the donor and recipient partners. We compared viral load in the donor partner and the recipient in the first 6 months of HIV infection., Results: We identified 24 transmission pairs. The median estimated time from infection to evaluation in acutely/recently infected recipient individuals was 72 days. The viral load in the donor was closely associated with viral load at presentation in the recipient case (r = 0.55, P = 0.006)., Conclusion: The strong correlation between HIV-1 RNA levels within HIV transmission pairs indicates that virus characteristics are an important determinant of viral load in early HIV infection.

The impact of transient viral load blips on anti-HIV-1 immune responses and on HIV-1 rebound following treatment interruption (TI) is not known. Clinical and immunological parameters were measured during 40 weeks of antiretroviral therapy (ART) and following TI in an observational cohort of 16 chronically HIV-1-infected subjects with or without observed viral load blips during ART. During therapy, blips in seven subjects were associated with higher anti-HIV-1 (p24) CD4+ T cell lymphoproliferative responses (p = 0.04), without a significant difference in T cell activation or total anti-HIV-1 CD8+ T cell interferon-gamma (IFN-gamma) responses when compared to nine matched non-blippers. Therapy interruption resulted in a significantly higher viral rebound in blippers by 8 week despite retention of higher lymphoproliferative p24 responses (p = 0.01) and a rise in CD3+ T cell activation (p = 0.04) and anti-HIV-1 CD8+ T cell responses in blippers by week 4 when compared to non-blippers. Past week 4 of interruption, therapy re-initiation criteria were also met by a higher frequency in blippers by week 14 (p < 0.04) with no difference between groups by week 24. These data support that blippers have higher anti-HIV lymphoproliferative responses while on ART but experience equal to higher viral rebound as compared to matched non-blippers upon TI.