on behalf of the CAPRISA 004 Trial Group ‡ The Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 trial assessed the effectiveness and safety of a 1% vaginal gel formulation of tenofovir, a nucleotide reverse transcriptase inhibitor, for the prevention of HIV acquisition in women. A double-blind, randomized controlled trial was conducted comparing tenofovir gel (n = 445 women) with placebo gel (n = 444 women) in sexually active, HIV-uninfected 18-to 40-year-old women in urban and rural KwaZulu-Natal, South Africa. HIV serostatus, safety, sexual behavior, and gel and condom use were assessed at monthly follow-up visits for 30 months. HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years (person time of study observation) (38 out of 680.6 women-years) compared with 9.1 per 100 women-years (60 out of 660.7 women-years) in the placebo gel arm (incidence rate ratio = 0.61; P = 0.017). In high adherers (gel adherence > 80%), HIV incidence was 54% lower (P = 0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50 to 80%) and low adherers (gel adherence < 50%), the HIV incidence reduction was 38 and 28%, respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall, and by 54% in women with high gel adherence. No increase in the overall adverse event rates was observed. There were no changes in viral load and no tenofovir resistance in HIV seroconverters. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use. W omen are disproportionately affected by the Acquired Immunodeficiency Syndrome (AIDS) epidemic in Africa, the region that accounts for 70% of global burden of Human Immunodeficiency Virus (HIV) infection (1). Current HIV prevention behavioral messages on abstinence, faithfulness, and condom promotion have had limited impact on HIV incidence rates in women, especially in sub-Saharan Africa, where young women bear the greatest HIV burden (2). The search for new technologies to prevent sexually transmitted HIV infection over the past three decades has had limited success. Only five of 37 randomized controlled trials, which tested 39 HIV prevention strategies, have demonstrated protection against sexual transmission of HIV infection (3). The successful trials tested medical male circumcision in South Africa (4), Kenya (5), and Uganda (6) (combined effectiveness in reducing HIV acquisition was 57%), sexually transmitted infection (STI) treatment in Tanzania (effectiveness in reducing HIV acquisition was 42%) (7), and a HIV vaccine combination in Thailand (effectiveness in reducing HIV acquisition was 31%) (8). Hence, HIV prevention technologies that women can use and control remain a pressing priority (9).Microbicides are products that can be applied to the vagina or rectum with the intention of reducing the acquisition of STIs, including HIV. An effective microbicide has the potential to alter the trajectory of the global HIV pandemic (10). Over the ...

Elevated genital concentrations of HIV target cell-recruiting chemokines and a genital inflammatory profile contributes to the high risk of HIV acquisition in these African women.

Antiretroviral-based strategies for HIV prevention have shown inconsistent results in women. We investigated whether vaginal microbiota modulated tenofovir gel microbicide efficacy in the CAPRISA (Centre for the AIDS Program of Research in South Africa) 004 trial. Two major vaginal bacterial community types-one dominated by (59.2%) and the other where predominated with other anaerobic bacteria (40.8%)-were identified in 688 women profiled. Tenofovir reduced HIV incidence by 61% ( = 0.013) in dominant women but only 18% ( = 0.644) in women with non- bacteria, a threefold difference in efficacy. Detectible mucosal tenofovir was lower in non- women, negatively correlating with and other anaerobic bacteria, which depleted tenofovir by metabolism more rapidly than target cells convert to pharmacologically active drug. This study provides evidence linking vaginal bacteria to microbicide efficacy through tenofovir depletion via bacterial metabolism.

The presence of pictograms had a positive effect in the acquisition and comprehension of drug information.

Several clinical trials have demonstrated that antiretroviral (ARV) drugs, taken as pre-exposure prophylaxis (PrEP), can prevent HIV infection1, with the magnitude of protection ranging from -49 to 86%2–11. While these divergent outcomes are thought to be due primarily to product adherence12, biological factors likely contribute13. Despite selective recruitment of higher risk participants for prevention trials, HIV risk is heterogeneous, even within higher risk groups14–16. To determine whether this heterogeneity could influence PrEP outcomes, we undertook a post-hoc prospective analysis of the CAPRISA 004 tenofovir 1% gel trial (n=774), one of the first trials to demonstrate protection against HIV infection. Concentrations of nine pro-inflammatory cytokines were measured in cervicovaginal lavages at >2,000 visits, and a graduated cytokine score was used to define genital inflammation. In women without genital inflammation, tenofovir was 57% protective against HIV (95% CI: 7 to 80%), compared to 3% (95% CI: −104 to 54%) if genital inflammation was present. Among high gel adherers, tenofovir protection was 75% (95% CI: 25 to 92%) in women without inflammation compared to −10% (95% CI: −184 to 57%) in women with inflammation. Host immune predictors of HIV risk may modify the effectiveness of HIV prevention tools; reducing genital inflammation in women may augment HIV prevention efforts.

Adherence is a critical component of the success of antiretroviral-based pre-exposure prophylaxis (PrEP) in averting new HIV-infections. Ensuring drug availability at the time of potential HIV exposure relies on self-directed product use. A deeper understanding of how to best support sustained PrEP adherence remains critical to current and future PrEP efforts. This paper provides a succinct synthesis of the adherence support experiences from four pivotal PrEP trials—Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004, FEM-PrEP, Iniciativa Prophylaxis (iPrEx), and Vaginal and Oral Interventions to Control the Epidemic (VOICE). Notwithstanding variability in the design, population/cohort, formulation, drug, dosing strategy, and operationalization of adherence approaches utilized in each trial, the theoretical basis and experiences in implementation and monitoring of the approaches used by these trials provide key lessons for optimizing adherence in future research and programmatic scale-up of PrEP. Recommendations from across these trials include participant-centered approaches, separating measurement of adherence from adherence counseling, incorporating tailored strategies that go beyond education, fostering motivation, and addressing the specific context in which an individual incorporates and negotiates PrEP use.

After two decades of microbicide clinical trials it remains uncertain if vaginally- delivered products will be clearly shown to reduce the risk of HIV infection in women and girls. Furthermore, a microbicide product with demonstrated clinical efficacy must be used correctly and consistently if it is to prevent infection. Information on adherence that can be gleaned from microbicide trials is relevant for future microbicide safety and efficacy trials, pre-licensure implementation trials, Phase IV post-marketing research, and microbicide introduction and delivery. Drawing primarily from data and experience that has emerged from the large-scale microbicide efficacy trials completed to-date, the paper identifies six broad areas of adherence lessons learned: (1) Adherence measurement in clinical trials, (2) Comprehension of use instructions/Instructions for use, (3) Unknown efficacy and its effect on adherence/Messages regarding effectiveness, (4) Partner influence on use, (5) Retention and continuation and (6) Generalizability of trial participants' adherence behavior. Each is discussed, with examples provided from microbicide trials. For each of these adherence topics, recommendations are provided for using trial findings to prepare for future microbicide safety and efficacy trials, Phase IV post-marketing research, and microbicide introduction and delivery programs.

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