Importance of early identification of PrEP breakthrough infections in a generalized HIV epidemic: a case report from a PrEP demonstration project in South Africa

Background The World Health Organisation recommends the use of tenofovir-containing pre-exposure prophylaxis (PrEP) as an additional Human Immunodeficiency Virus (HIV) prevention choice for men and women at substantial risk of HIV infection. PrEP could fill an important HIV prevention gap, especially for sexually active young women who are limited in their ability to negotiate mutual monogamy or condom use. As PrEP is scaled up in high HIV incidence settings, it is crucial to consider the importance of early identification of HIV infection during PrEP use, to allow for rapid discontinuation of PrEP to reduce the risk of antiretroviral (ARV) resistance. The purpose of this case study is to provide this critical evidence. Case presentation This report describes a 20-year-old woman in a HIV sero-discordant relationship who initiated oral PrEP (tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC)) through a demonstration project (CAPRISA 084) in October 2017. Despite good adherence throughout her PrEP use, she tested HIV antibody positive at month nine of study participation. Retrospective testing showed increasing HIV viral load over time, and retrospective use of fourth-generation rapid HIV tests showed HIV detection (positive antigen/antibody) at month one. Sequencing confirmed a dominant wild type at month one with dual therapy resistance patterns emerging by month three (M184V and K65R mutations), which is suggestive of protracted PrEP use during an undetected HIV infection. The participant was referred to infectious diseases for further management of her HIV infection and was initiated on a first line, tenofovir-sparing regimen. At the time of this report (January 2020), the participant had been on ARV- therapy (ART) for 13 months and had no signs of either clinical, immunologic or virologic failure. Conclusions This case report highlights the importance of appropriate HIV screening during wider oral PrEP scale-up in high HIV incidence settings to circumvent the consequences of prolonged dual therapy in an undiagnosed HIV infection and in turn prevent ARV resistance

Recruitment of high risk women for HIV prevention trials: baseline HIV prevalence and sexual behavior in the CAPRISA 004 tenofovir gel trial

<p>Abstract</p> <p>Background</p> <p>Young women in sub-Saharan Africa bear a disproportionate burden of HIV infection compared to men but have limited options to reduce their HIV risk. Microbicides could fill an important HIV prevention gap for sexually active women who are unable to successfully negotiate mutual monogamy or condom use.</p> <p>Purpose</p> <p>This paper describes the baseline sample characteristics in the CAPRISA 004 trial which assessed the safety and effectiveness of the vaginal microbicide, 1% tenofovir gel for HIV prevention in South Africa.</p> <p>Methods</p> <p>This analysis assessed the baseline demographic, clinical and sexual behavior data of women screened and enrolled into the trial. The characteristics were summarized using descriptive summary measures; expressed as means and percent for categorical variables.</p> <p>Results</p> <p>HIV prevalence at screening was 25.8% [95% Confidence Interval (CI):23.9-27.7). Of the 889 eligibly enrolled women who contributed follow-up data, rural participants recruited from a family planning (FP) clinic were younger, more likely to be living apart from their regular partner, reported lower coital frequency, had lower condom use (p < 0.001). In contrast, urban participants recruited from a sexually transmitted disease (STD) clinic reported higher numbers of lifetime sexual partners, new partners in the last 30 days and receiving money in exchange for sex (p < 0.001).</p> <p>Conclusion</p> <p>The populations selected provide suitable diverse target groups for HIV prevention intervention studies.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00441298">NCT 00441298</a></p

Tenofovir gel for the prevention of herpes simplex virus type 2 infection.

CAPRISA, 2015.Abstract available in pdf

Social context of adherence in an open-label 1% tenofovir gel trial : gender dynamics and disclosure in KwaZulu-Natal, South Africa.

CAPRISA, 2016.Abstract available in PDF file

Quantifiable plasma tenofovir among South African women using daily oral pre-exposure prophylaxis during the ECHO trial

Access to data from the ECHO study may be requested through submission of a research concept to ude.wu@crci. The concept must include the research question, data requested, analytic methods, and steps taken to ensure ethical use of the data. Access will be granted if the concept is evaluated to have scientific merit and if sufficient data protections are in place. As of the time of publication, data access applications are in process with the governing institutional review boards of the ECHO study to make deidentified data publicly available.BACKGROUND : HIV endpoint–driven clinical trials provide oral pre-exposure prophylaxis (PrEP) as HIV prevention standard of care. We evaluated quantifiable plasma tenofovir among South African women who used oral PrEP during the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. METHODS : ECHO, a randomized trial conducted in 4 African countries between 2015 and 2018, assessed HIV incidence among HIV-uninfected women, aged 16–35 years, randomized to 1 of 3 contraceptives. Oral PrEP was offered onsite as part of the HIV prevention package at the South African trial sites. We measured tenofovir in plasma samples collected at the final trial visit among women reporting ongoing PrEP use. We used bivariate and multivariate logistical regression to assess demographic and sexual risk factors associated with plasma tenofovir quantification. RESULTS : Of 260 women included, 52% were ≤24 years and 22% had Chlamydia trachomatis at enrollment. At PrEP initiation, 68% reported inconsistent/nonuse of condoms. The median duration of PrEP use was 90 days (IQR: 83–104). Tenofovir was quantified in 36% (n = 94) of samples. Women >24 years had twice the odds of having tenofovir quantified vs younger women (OR = 2.12; 95% confidence interval = 1.27 to 3.56). Women who reported inconsistent/nonuse of condoms had lower odds of tenofovir quantification (age-adjusted OR = 0.47; 95% confidence interval = 0.26 to 0.83). CONCLUSIONS : Over a third of women initiating PrEP and reporting ongoing use at the final trial visit had evidence of recent drug exposure. Clinical trials may serve as an entry point for PrEP initiation among women at substantial risk for HIV infection with referral to local facilities for ongoing access at trial end. CLINICAL TRIAL NUMBER : NCT02550067.The Bill & Melinda Gates Foundation, the American people through the United States Agency for International Development, the Swedish International Development Cooperation Agency, the South Africa Medical Research Council, and the United Nations Population Fund. Contraceptive supplies were donated by the Government of South Africa and US Agency for International Development.http://journals.lww.com/jaidshj2023Family MedicineMedical Microbiolog

A drug evaluation of 1% tenofovir gel and tenofovir disoproxil fumarate tablets for the prevention of HIV infection.

Introduction: More than a million people acquire HIV infection annually. Pre-exposure prophylaxis (PrEP) using antiretrovirals is currently being investigated for HIV prevention. Oral and topical formulations of tenofovir have undergone preclinical and clinical testing to assess acceptability, safety and effectiveness in preventing HIV infection. Areas covered: The tenofovir drug development pathway from compound discovery, preclinical animal model testing and human testing were reviewed for safety, tolerability and efficacy. Tenofovir is well tolerated and safe when used both systemically or applied topically for HIV prevention. High drug concentrations at the site of HIV transmission and concomitant low systemic drug concentrations are achieved with vaginal application. Coitally applied gel may be the favored prevention option for women compared with the tablets, which may be more suitable for prevention in men and sero-discordant couples. However, recent contradictory effectiveness outcomes in women need to be better understood. Expert opinion: Emerging evidence has brought new hope that antiretrovirals can potentially change the course of the HIV epidemic when used as early treatment for prevention, as topical or oral PrEP. Although some trial results appear conflicting, behavioral factors, adherence to dosing and pharmacokinetic properties of the different tenofovir formulations and dosing approaches offer plausible explanations for most of the variations in effectiveness observed in different trials

Monitoring microbicide gel use with real-time notification of the container’s opening events : results of the CAPRISA Wisebag study.

CAPRISA, 2014.Accurate estimation of the effectiveness of a microbicide for HIV prevention requires valid measurement of adherence to product use. A microbicide gel applicator container (Wisebag), fitted with cell phone technology to transmit opening events and text message reminders, was developed to monitor each opening event of the container as a proxy for gel use and adherence. Ten women were enrolled in a pilot study and followed for up to 4 months. Wisebag opening (WBO) dates and times were recorded and correlated with self-reported sex acts and gel applicator returns. During the 33 monthly follow-up visits, 47.8% (77/161) of the recorded number of WBO events were concordant with the number of empty (used) applicators returned. The discrepancies were likely due to removal of more than one applicator during a single opening event. When the date and time of the WBO event data was assessed in relation to three different self-report adherence measures, agreement was fairly modest. The Wisebag was found to be acceptable as a storage container and the cell phone reminders generated were useful in supporting the dosing strategy. We recommend that the Wisebag be considered for larger scale and lengthier testing in microbicide trials

Disclosure of microbicide gel use to sexual partners: influence on adherence in the CAPRISA 004 trial.

CAPRISA, 2014.Abstract available in pdf

The preventive misconception: experiences from CAPRISA 004.

CAPRISA, 2014.Abstract available in pdf

Measuring adherence by visual inspection of returned empty gel applicators in the CAPRISA 004 microbicide trial.

CAPRISA, 2014.Abstract not available in pdf