Evaluation of a behavior-centered design strategy for creating demand for oral PrEP among young women in Cape Town, South Africa.

BACKGROUND: There is an urgent need to find effective interventions that reduce young South African women's vulnerability to HIV, and pre-exposure prophylaxis (PrEP) is highly effective when taken consistently. As national programs in Africa launch PrEP programs for young women, it is critical to understand how to effectively create awareness, stimulate interest, and increase uptake of PrEP. METHODS: Behavior-centered design (BCD) guided the development of a PrEP social marketing campaign for young women. Ethnographic observations, in-depth interviews, and focus-group discussions with young South African women informed the content and design of a 90-second PrEP demand creation video and two informational brochures. A short survey was administered to young women at their homes after watching a video to evaluate PrEP interest. Of 800 households with a 16-25-year-old female identified from a Cape Town township census, 320 women in these households viewed the video and completed a survey about the video and their interest in PrEP. RESULTS: In focus groups, young women from the township preferred local characters and messaging that was empowering, simple, and motivational. From the household survey of young women who viewed the video, most reported interest in learning more about PrEP (67.7% 'definitely interested' and 9.4% 'somewhat interested') and taking PrEP (56.4% 'definitely interested' and 12.5% 'somewhat interested'). Factors significantly associated with interest in taking PrEP were having a primary partner with whom they regularly have sex (80.0% vs. 65.2% without a primary partner; adjusted odds ratio (AOR)=3.1, 95% CI: 1.3, 7.0) and being in a sexual partnership for <6 months (86.8% vs. 68.5% for >12 months; AOR=3.0, 95% CI: 1.2, 7.3). CONCLUSIONS: A positively framed PrEP demand creation video generated high interest in PrEP among young South African women, particularly among women with a primary partner and a shorter-term relationship. Registration: NCT03142256; registered on 5 May 2017.

Inflammatory cytokine biomarkers of asymptomatic sexually transmitted infections and vaginal dysbiosis: a multicentre validation study.

OBJECTIVES: Vaginal dysbiosis and STIs are important drivers of the HIV epidemic and reproductive complications. These conditions remain prevalent, partly because most cases are asymptomatic. We have shown that inflammatory cytokines interleukin (IL)-1α, IL-1ß and interferon-γ-induced protein (IP)-10 are biomarkers for detecting asymptomatic STIs and vaginal dysbiosis (bacterial vaginosis (BV) or intermediate microbiota). This study aimed to validate the performance of these biomarkers in African women recruited regardless of symptoms. METHODS: IL-1α, IL-1ß and IP-10 were measured in menstrual cup secretions, endocervical, lateral vaginal wall and vulvovaginal swabs from 550 women from Pretoria, Soweto and Cape Town, South Africa and Bondo, Kenya using Luminex and ELISA. STIs were assessed by PCR, BV by Nugent scoring and vaginal microbiota by 16S rRNA sequencing. RESULTS: Across four study populations and four types of genital specimens, the performance of IL-1α, IL-1ß and IP-10 for identification of women with STIs, BV or intermediate microbiota was consistent. Of the genital samples assessed, biomarkers measured in lateral vaginal wall swabs performed best, correctly classifying 76%(95% CI 70% to 81%) of women according to STI, BV or intermediate microbiota status (sensitivity 77%, specificity 71%) and were more accurate than clinical symptoms (sensitivity 41%, specificity 57%) (p=0.0003). Women incorrectly classified as STI/BV positive using the biomarkers had more abundant dysbiosis-associated bacteria, including Prevotella bivia and Gardnerella sp, detected by 16S rRNA sequencing, but not Nugent scoring. Including vaginal pH with the cytokine biomarkers improved the accuracy of the test (82% (95% CI 75% to 88%) correctly classified), although pH alone had poor specificity (61%). CONCLUSIONS: An inexpensive, point-of-care screening test including IL-1α, IL-1ß and IP-10 (and potentially pH) could be used in resource-limited settings to identify women with asymptomatic STIs and dysbiosis. These women could then be referred for aetiological testing, followed by specific treatment.

Performance of serological and molecular tests within acute HIV infection.

BACKGROUND: Early diagnosis of acute HIV infection can be challenging and is critical in regards to early therapeutic decision making. OBJECTIVES: To evaluate the performance of different HIV tests in detecting early infections. STUDY DESIGN: A total of 83 leftover specimens of 61 study participants who seroconverted were used in this sub-study. 35 HIV RNA positive but still seronegative specimens (acute infections) were used for analysis of the sensitivity of the different assays in detecting early infections and 42 HIV RNA and antibody negative specimens were used for specificity analysis. RESULTS: Four (11%) specimens out of 35 acute infections were reactive with the Enzygnost® Anti-HIV 1/2 Plus and 12/35 (34%) with the Vironostika® HIV Ag/Ab. 16 (46%) specimens were confirmed as acute by the INNOTEST® HIV antigen mAb Antigen test. Only three (9%), 10 (29%) and 9 (27%) specimens were reactive with the Determine HIV-1/2 Ag/Ab Combo, SD Bioline HIV Ag/Ab Combo test and the HIV Combo test, respectively. The specificity of the different tests were 100%, 95%, 100%, 93%, 100% and 93% for Enzygnost® Anti-HIV 1/2 Plus, Vironostika® HIV Ag/Ab, INNO-Test HIV antigen mAb, Determine HIV-1/2 Ag/Ab Combo, SD Bioline HIV Ag/Ab Combo test and HIV Combo test respectively. CONCLUSION: RNA test, 4th generation ELISA and Single Ag test are the most sensitive tests for detection of an acute infection. As an alternative, the HIV Combo test is generally slightly more sensitive compared to its previous version, but the SD Bioline HIV Ag/Ab Combo tests has the best performance compared to the other simple rapid tests (SRTs) but none of them are precise in detecting Ag in the determination of acute infections.

Detection of new HIV infections in a multicentre HIV antiretroviral pre-exposure prophylaxis trial.

BACKGROUND: Monthly specimens collected from FEM-PrEP-a Phase III trial [1] were investigated for the detection of acute HIV (AHI) infection. OBJECTIVES: To evaluate the efficiency of the study-specific HIV algorithm in detecting AHI, and the performance of each of the serological and molecular tests used in diagnosing new infections, and their contribution to narrowing the window period. STUDY DESIGN: A total of 83 pre-seroconversion specimens from 61 seroconverters from the FEM-PrEP trial were further analyzed in a sub-study. During the trial, HIV seroconversion was diagnosed on site using a testing algorithm with simple/rapid tests (SRTs) and confirmed with a gold standard testing algorithm (see short communication: Fig. 1). The infection date was determined more accurately by the use of standard ELISAs and Nucleic Acid Amplification Tests (NAAT) in a look-back procedure. For this sub-study, the international central laboratory repeated the study algorithm using SRTs. RESULTS: A total of 83 pre-seroconversions specimens from 61 seroconverters were analyzed in a look-back procedure. RNA was detected in 35/61 seroconverters at the visit before the seroconversion visit as determined at the study sites. Four seroconversion dates were inaccurate at one study site as the international central laboratory detected the HIV infection one visit earlier using the same test algorithm. Using the gold standard, an additional seroconversion was detected at an earlier visit. The combined antigen/antibody and the single antigen test had a higher sensitivity compared to the SRTs in detecting acute infections. CONCLUSIONS: In the FEM-PrEP trial, the international central laboratory detected a small number of seroconversions one month earlier than the study sites using the same study algorithm. Standard tests are still the most sensitive tests in detecting pre-seroconversion or acute HIV infection, but they are costly, time consuming and not recommended for use on-site in a clinical trial.

Medroxyprogesterone acetate levels among Kenyan women using depot medroxyprogesterone acetate in the FEM-PrEP trial.

OBJECTIVE: To describe medroxyprogesterone acetate (MPA) levels among Kenyan depot medroxyprogesterone acetate (DMPA) users in the FEM-PrEP HIV prevention trial, and to compare MPA levels between ARV for HIV prevention (treatment) and placebo groups. STUDY DESIGN: We measured MPA in previously collected plasma samples from 63 Kenyan trial participants who used DMPA for one or two complete intervals. We separately assessed MPA levels among the nine DMPA users who became pregnant at this site. RESULTS: Mean MPA levels at the end of each 12week injection interval were 0.37ng/ml (95% CI: 0.25, 1.99) and 0.28ng/ml (95% CI: 0.19, 1.22) among participants assigned TDF/FTC and 0.49 (95% CI: 0.40, 1.27) and 0.39 (95% CI: 0.31, 1.17) among those assigned placebo. The difference between groups was not statistically significant overall, or in an analysis which adjusted for the observed low adherence to TDF/FTC. Unanticipated findings of this analysis were low 12-week MPA levels among DMPA users in both study arms. Of 61 women who contributed data for the first DMPA injection interval, 26.2% had MPA levels<0.1ng/ml and 9.8% had levels below the detection level (0.02ng/ml) at 12weeks post-injection. Levels were similar at the end of the second injection interval. Five of nine women who became pregnant had levels below 0.15ng/mL at the time of their last negative pregnancy test. CONCLUSIONS: Use of TDF/FTC did not appear to affect serum MPA levels, however we found lower than expected MPA concentrations at the end of the dosing interval among DMPA users in the FEM-PrEP trial, the cause of which are unknown. IMPLICATIONS: This study presents some of the few available data on MPA levels among DMPA users in Africa. The low levels among users described here, together with a number of pregnancies among DMPA users, are potentially concerning and require further investigation.

Participants' Explanations for Nonadherence in the FEM-PrEP Clinical Trial.

BACKGROUND: FEM-PrEP-a clinical trial of daily, oral emtricitabine/tenofovir disoproxil fumarate for HIV prevention among women in sub-Saharan Africa-did not show a reduction in HIV acquisition because of low adherence to the study pill. We conducted a follow-up study to identify reasons for nonadherence. METHODS: Qualitative, semistructured interviews (n = 88) and quantitative, audio computer-assisted self-interviews (n = 224) were conducted with former FEM-PrEP participants in Bondo, Kenya, and Pretoria, South Africa. Thematic analysis was used to analyze the qualitative data, and descriptive statistics were used to describe audio computer-assisted self-interviews responses. Data are presented within the 5 categories of Ickovics' and Meisler's conceptual framework on adherence: (1) the individual, (2) trial characteristics and study pill regimen, (3) patient-provider relationship, (4) clinical setting, and (5) the disease. RESULTS: Participants' explanations for nonadherence were primarily situated within 3 of the framework's 5 categories: (1) the individual, (2) trial characteristics and study pill regimen, and (3) the disease. Concerns about the investigational nature of the drug being tested and side effects were the prominent reasons reported for nonadherence. Participants also described being discouraged from taking the study pill by members of the community, their sexual partners, and other participants, primarily because of these same concerns. Limited acceptability of the pill's attributes influenced nonadherence for some participants as did concerns about HIV-related stigma. In addition, many participants reported that others continued in FEM-PrEP while not taking the study pill because of the trial's ancillary benefits and visit reimbursement-factors related to the clinical setting. Negative patient-provider relationships were infrequently reported as a factor that influenced nonadherence. CONCLUSIONS: Despite substantial study staff engagement with participants and communities, concerns about the study pill and discouragement from others seemed to have influenced nonadherence considerably. Alternative study designs or procedures and enhanced community engagement paradigms may be needed in future studies.

Verification of chemistry reference ranges using a simple method in sub-Saharan Africa.

BACKGROUND: Chemistry safety assessments are interpreted by using chemistry reference ranges (CRRs). Verification of CRRs is time consuming and often requires a statistical background. OBJECTIVES: We report on an easy and cost-saving method to verify CRRs. METHODS: Using a former method introduced by Sigma Diagnostics, three study sites in sub-Saharan Africa, Bondo, Kenya, and Pretoria and Bloemfontein, South Africa, verified the CRRs for hepatic and renal biochemistry assays performed during a clinical trial of HIV antiretroviral pre-exposure prophylaxis. The aspartate aminotransferase/alanine aminotransferase, creatinine and phosphorus results from 10 clinically-healthy participants at the screening visit were used. In the event the CRRs did not pass the verification, new CRRs had to be calculated based on 40 clinically-healthy participants. RESULTS: Within a few weeks, the study sites accomplished verification of the CRRs without additional costs. The aspartate aminotransferase reference ranges for the Bondo, Kenya site and the alanine aminotransferase reference ranges for the Pretoria, South Africa site required adjustment. The phosphorus CRR passed verification and the creatinine CRR required adjustment at every site. The newly-established CRR intervals were narrower than the CRRs used previously at these study sites due to decreases in the upper limits of the reference ranges. As a result, more toxicities were detected. CONCLUSION: To ensure the safety of clinical trial participants, verification of CRRs should be standard practice in clinical trials conducted in settings where the CRR has not been validated for the local population. This verification method is simple, inexpensive, and can be performed by any medical laboratory.

Hepatitis B virus reactivation or reinfection in a FEM-PrEP participant: a case report.

INTRODUCTION: The FEM-PrEP trial was a pre-exposure prophylaxis clinical trial to test the safety and efficacy of Truvada (tenofovir disoproxil fumarate and emtricitabine) in the prevention of human immunodeficiency virus infection. Because Truvada can suppress hepatitis B virus replication, and withdrawal of Truvada can cause hepatic flares in patients with chronic hepatitis B, pre-enrollment screening included serological screening for hepatitis B virus markers. Women with chronic infections were not enrolled in the trial. Women found to be unprotected against hepatitis B were enrolled and offered three doses of hepatitis B vaccine. Reinfection and reactivation of previously resolved hepatitis B virus infections have been documented in immunosuppressed individuals but not in healthy individuals. We present the case of a participant enrolled in the FEM-PrEP clinical trial with baseline evidence of immunity against hepatitis B virus who subsequently developed acute hepatitis B. CASE PRESENTATION: A 21-year-old Black non-pregnant woman was enrolled in the FEM-PrEP trial. She was human immunodeficiency virus-negative and a serological test for hepatitis B virus was negative. She had evidence of low levels of protection against hepatitis B virus and normal liver function. She had no hepatitis B vaccination history, thus it was concluded that she had post-infection immunity. At week 36 she presented with severely elevated liver enzyme levels that, upon further investigation, were a result of acute hepatitis B virus infection. The infection followed an asymptomatic course until full recovery of her liver enzymes a few weeks later. At study unblinding, the participant was found to be on the Truvada arm. Retrospective plasma drug level testing found low levels of study drugs from week 4. The participant remained human immunodeficiency virus-negative throughout the study. CONCLUSION: Hepatitis B virus infection reactivation or reinfection is a rare phenomenon in healthy individuals. However, reactivations have been reported in patients being treated for chronic hepatitis B with the drugs contained in Truvada, after treatment had been withdrawn. This participant may have reactivated after stopping Truvada, or she may have reactivated spontaneously owing to relatively low levels of protective antibodies against hepatitis B. Alternatively, she may have been reinfected. Clinicians should be aware that hepatitis B virus reactivation or reinfection may cause elevated transaminases even in the presence of low baseline immunity.

Injectable Progestin-Only Contraception is Associated With Increased Levels of Pro-Inflammatory Cytokines in the Female Genital Tract.

PROBLEM: Genital inflammatory changes may be a mechanism of increased HIV risk among injectable progestin-only contraception (IPC) users. METHOD OF STUDY: We conducted a cross-sectional analysis of 376 Kenyan and South African women. Genital cytokines and secretory leukocyte peptidase inhibitor concentrations in a reference population were compared to IPC users and women with reproductive tract infections. RESULTS: No significant variability in marker concentrations was observed by age or site. Depot medroxyprogesterone acetate (DMPA) users had significantly higher MIP-1α, MIP-1ß, IL-6, IL-8, IP-10, and RANTES concentrations. Norethisterone oenanthate users had significantly higher IL-6, IL-8, and RANTES concentrations. Women with sexually transmitted infections had variable inflammation, and women with bacterial vaginosis exhibited a mixed profile of up and downregulation. CONCLUSION: The finding of substantial mucosal inflammation among DMPA users provides evidence which, combined with the results of prior studies, suggests that DMPA may create an immune environment conducive to HIV target cell recruitment and inhibitory for antiviral activity.

Facilitators of adherence to the study pill in the FEM-PrEP clinical trial.

INTRODUCTION: FEM-PrEP did not demonstrate a reduction in HIV acquisition because of low study pill adherence. Yet, plasma and intracellular drug concentrations indicated that some participants had evidence of recent pill use. We conducted a follow-up study to identify, among other topics, participants' reasons for taking the study pill. METHODS: Qualitative, semi-structured interviews (SSIs) were conducted with 88 FEM-PrEP participants. Participants were purposefully selected based on their adherence drug concentrations collected during FEM-PrEP and placed into three adherence interview groups: "high," "moderate," and "none/scarce." Participants in the high and moderate groups described reasons why they adhered most or some of the time, including factors that facilitated their adherence. Participants in all groups described what they believed made it possible for other FEM-PrEP participants to adhere. In addition, 224 FEM-PrEP participants reported on their reasons for taking the study pills through a quantitative, audio computer-assisted self-interview (ACASI). Thematic analysis and descriptive statistics were used to analyze the qualitative and quantitative data, respectively. RESULTS: Five themes were identified from the SSIs as facilitating factors of adherence: 1) participants' support for the research, 2) HIV risk reduction, 3) routine formation and use of tools, 4) adherence counseling, and 5) partner awareness and support. Participants described similar facilitators when they spoke about other participants' adherence. Among the 172 participants who reported in ACASI that they had taken a study pill, wanting to help answer the research question was the most frequently stated reason for taking the pills (94%, n = 161). We also found evidence of preventive misconception. CONCLUSIONS: Adherence was facilitated by personal motivations, such as risk reduction and interest in the research outcome, and by adherence strategies consisting of external cues, reminders, and support. These findings can inform future HIV prevention clinical trials and the rollout of effective antiretroviral-based HIV prevention technologies for women.

The science of being a study participant: FEM-PrEP participants' explanations for overreporting adherence to the study pills and for the whereabouts of unused pills.

BACKGROUND: FEM-PrEP was unable to determine whether once-daily, oral emtricitabine/tenofovir disoproxil fumarate reduces the risk of HIV acquisition among women because of low adherence. Self-reported adherence was high, and pill-count data suggested good adherence. Yet, drug concentrations revealed limited pill use. We conducted a follow-up study with former participants in Bondo, Kenya, and Pretoria, South Africa, to understand factors that had influenced overreporting of adherence and to learn the whereabouts of unused pills. METHODS: Qualitative, semistructured interviews were conducted with 88 participants, and quantitative, audio computer-assisted self-interviews were conducted with 224 participants. We used thematic analysis and descriptive statistics to analyze the qualitative and quantitative data, respectively. RESULTS: In audio computer-assisted self-interviews, 31% (n = 70) said they had overreported adherence; the main reason was the belief that nonadherence would result in trial termination (69%, n = 48). A considerable percentage (35%, n = 78) acknowledged discarding unused pills. Few acknowledged giving their pills to someone else (4%, n = 10), and even fewer acknowledged giving them to someone with HIV (2%, n = 5). Many participants in the semistructured interviews said other participants had counted and removed pills from their bottles to appear adherent. CONCLUSIONS: Despite repeated messages that nonadherence would not upset staff, participants acknowledged several perceived negative consequences of reporting nonadherence, which made it difficult to report accurately. Uneasiness continued in the follow-up study, as many said they had not overreported during the trial. Efforts to improve self-reported measures should include identifying alternative methods for creating supportive environments that allow participants to feel comfortable reporting actual adherence.

Prevalence and incidence estimation of HSV-2 by two IgG ELISA methods among South African women at high risk of HIV.

INTRODUCTION: Previous comparison studies of the Kalon and HerpeSelect 2 ELISA IgG assays on sub-Saharan samples have found differences in the sensitivity and specificity of these assays. Using longitudinal samples from an HIV prevention study, we compared both assays and determined the HSV-2 prevalence and incidence in a South African young female population at elevated risk of acquiring HIV. METHODS: Samples at baseline were tested in both assays using the manufacturers' guidelines (cut-off > 1.10). When non-reactive in one assay, the final visit samples were tested to determine the incidence rate. Using correlation and regression analyses, the intra- and inter-assay variabilities were assessed. RESULTS: The prevalence rate was 41.1% and 44.9% for Kalon and HerpeSelect using the manufacturer guidelines, respectively. Agreement between the two tests were high (kappa = 0.92). The original optical density values of both assays were highly correlated (R = 0.94), but the calibrator and correspondingly cut-off index values differed between the assays. Lowering the index value cut-off for the Kalon assay by 40% (to 0.66) resulted in a HSV-2 prevalence of 43.2%, and increased agreement between the assays (to kappa = 0.96). The incidence rate was 16.3/100 Person Years using the lower cut-off for the Kalon assay. DISCUSSION: In this longitudinal study, we showed that the performance of the two assays was very similar. After lowering the cut-off for the Kalon assay to 0.66 early infections were detected without impairing its specificity. The prevalence and incidence rates are in line with previously described rates for sub-Saharan African cohorts.

Pregnancy and contraceptive use among women participating in the FEM-PrEP trial.

BACKGROUND: Pregnancy among study participants remains a challenge for trials of new HIV prevention agents despite promotion and provision of contraception. We evaluated contraceptive use, pregnancy incidence, and study drug adherence by contraceptive method among women enrolled in the FEM-PrEP trial of once-daily oral tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) for HIV prevention. METHODS: We required women to be using effective non-barrier contraception at enrollment. At each monthly follow-up visit, women were counseled on contraceptive use and tested for pregnancy. TDF-FTC adherence was determined by measuring plasma drug concentrations at 4-week intervals. We used Cox proportional hazards models to assess factors associated with incident pregnancy and multivariate logistic regression to examine the relationship between contraceptive method used at enrollment and TDF-FTC adherence. RESULTS: More than half of women were not using effective contraception before enrollment. Ninety-eight percent of these women adopted either injectable (55%) or oral (43%) contraceptives. The overall pregnancy rate was 9.6 per 100 woman-years. Among injectable users and new users of combined oral contraceptives (COCs), the rates were 1.6 and 35.1, respectively. New users of injectables had significantly greater odds of adhering to TDF-FTC than new COC users [odds ratio (95% confidence interval): 4.4 (1.7 to 11.6), P = 0.002], existing COC users [3.1 (1.3 to 7.3), P = 0.01], and existing injectable users [2.4 (1.1 to 5.6), P = 0.04]. CONCLUSIONS: Women using COCs during FEM-PrEP, particularly new adopters, were more likely to become pregnant and less likely to adhere to study product than injectable users. HIV prevention trials should consider requiring long-acting methods, including injectables, for study participation.

Hormonal contraception and the risk of HIV acquisition: an individual participant data meta-analysis.

BACKGROUND: Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC. METHODS AND FINDINGS: Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15-49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24-1.83) for DMPA use, 1.24 (95% CI 0.84-1.82) for NET-EN use, and 1.03 (95% CI 0.88-1.20) for COC use. Between-study heterogeneity was mild (I(2) < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23-1.67) and NET-EN use (aHR 1.32, 95% CI 1.08-1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99-1.50; for NET-EN use 0.67, 95% CI 0.47-0.96; and for COC use 0.91, 95% CI 0.73-1.41) compared to those at higher risk of bias (p(interaction) = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC-HIV relationship. CONCLUSIONS: This IPD meta-analysis found no evidence that COC or NET-EN use increases women's risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.

Accuracy of Self-Report and Pill-Count Measures of Adherence in the FEM-PrEP Clinical Trial: Implications for Future HIV-Prevention Trials.

Oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) has been evaluated as pre-exposure prophylaxis (PrEP). We describe the accuracy of self-reported adherence to FTC/TDF and pill counts when compared to drug concentrations in the FEM-PrEP trial. Using drug concentrations of plasma tenofovir (TFV) and intracellular tenofovir diphosphate (TFVdp) among a random sub-sample of 150 participants assigned to FTC/TDF, we estimated the positive predictive value (PPV) of four adherence measures. We also assessed factors associated with misreporting of adherence using multiple drug-concentration thresholds and explored pill use and misreporting using semi-structured interviews (SSIs). Reporting use of ≥1 pill in the previous 7 days had the highest PPV, while pill-count data consistent with missing ≤1 day had the lowest PPV. However, all four measures demonstrated poor PPV. Reported use of oral contraceptives (OR 2.26; p = 0.014) and weeks of time in the study (OR 1.02; p < 0.001) were significantly associated with misreporting adherence. Although most SSI participants said they did not misreport adherence, participant-dependent adherence measures were clearly unreliable in the FEM-PrEP trial. Pharmacokinetic monitoring remains the measure of choice until more reliable participant-dependent measures are developed.

Sino-implant (II)® continuation and effect of concomitant tenofovir disoproxil fumarate-emtricitabine use on plasma levonorgestrel concentrations among women in Bondo, Kenya.

OBJECTIVE: The objective was to assess associations between tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) exposure and levonorgestrel (LNG) concentrations among Kenyan HIV prevention trial participants using Sino-implant (II) LNG implants for contraception. METHODS: Women were offered implants among other contraceptive methods, were randomized to daily TDF-FTC or placebo, and followed monthly up to 56weeks. Associations between TDF-FTC exposure and mean LNG values were analyzed with linear mixed models. RESULTS: Of 739 women, 29 (3.9%) received implants with no incident pregnancies and one discontinuation. Mean LNG concentrations over 56weeks among 28 women contributing data ranged between 214.0 and 659.8pg/mL with no significant difference between TDF-FTC and placebo arms or between variable levels of TDF-FTC adherence. CONCLUSION: Concomitant TDF-FTC use was not associated with a significant change in plasma LNG concentrations among women using Sino-implant (II) in the first year of use.

Liver and renal safety of tenofovir disoproxil fumarate in combination with emtricitabine among African women in a pre-exposure prophylaxis trial.

BACKGROUND: Safety of tenofovir disoproxil fumarate/emtricitabine (TDF-FTC) has been studied more extensively among HIV-infected patients than among HIV-uninfected people. Using data from a pre-exposure trial - FEM-PrEP -, we determined the cumulative probabilities of grade 1+ ALT, AST and creatinine and grade 2+ phosphorus toxicities; ALT/AST toxicities by baseline hepatitis B status; and change in mean creatinine, phosphorus, ALT and AST levels controlling for TDF-FTC adherence. METHODS AND FINDINGS: FEM-PrEP was a randomized, blinded, placebo-controlled trial of daily TDF-FTC among women in Africa. Enrolled women were in general good health, HIV antibody negative, 18 to 35 years old, hepatitis B surface antigen negative, and had normal hepatic and renal function at baseline. AST, ALT, phosphorus and serum creatinine were measured regularly throughout the trial. TDF-FTC concentrations were measured to assess adherence to TDF-FTC. The cumulative probabilities of grade 1+ creatininemia and grade 2+ phosphatemia toxicities were not statistically different between TDF-FTC and placebo arms. The cumulative probabilities of grade 1+ ALT and AST toxicities were higher among participants in the TDF-FTC arm than in the placebo arm (p = 0.03 for both). The proportions of grade 1+ and grade 2+ ALT or AST toxicities were significantly higher in participants who were hepatitis B virus surface antibody (HBsAb) positive than in those who were HBsAb-negative. Women with good adherence had higher mean change from baseline to week 4 in their AST levels (2.90 (0.37, 5.42); p = 0.025) than women with less than good adherence. CONCLUSIONS: We did not observe a significant relationship between randomization to TDF-FTC and creatinine or phosphorus toxicities. Women randomized to TDF-FTC had higher rates of mild to moderate ALT/AST toxicities, especially women with prior hepatitis B virus exposure. We also observed a significant increase in AST from baseline to week 4 among women who had higher adherence to TDF-FTC during that interval. TRIAL REGISTER: #NCT00625404, February 19, 2008.

Perception of HIV risk and adherence to a daily, investigational pill for HIV prevention in FEM-PrEP.

BACKGROUND: FEM-PrEP was unable to demonstrate the effectiveness of oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as pre-exposure prophylaxis for HIV prevention because of low adherence. We hypothesized that one reason for the poor adherence was low perceived HIV risk. METHODS: At enrollment and at quarterly follow-up visits, we assessed participants' perceived HIV risk for the subsequent 4 weeks. We used logistic regression to assess factors associated with some (small, moderate, or high) perceived HIV risk. We also used logistic regression with robust variance estimation to assess the association between risk perceptions (none versus some) reported at enrollment and at weeks 12, 24, and 36 and good adherence based on drug concentrations of plasma tenofovir and intracellular tenofovir diphosphate in specimens collected 4 weeks later (at weeks 4, 16, 28, and 40) among 150 randomly selected participants assigned FTC/TDF. RESULTS: Multiple factors were statistically associated with having some perceived risk, including having sex without a condom, having multiple partners, and not knowing if a partner has HIV. We observed a significant association between having some risk perception and good adherence (odds ratio: 2.0; 95% confidence interval: 1.1 to 3.5; P = 0.016). CONCLUSIONS: Data suggest that participants are likely knowledgeable about factors that increase their HIV risk. Perceived risk seemed to have influenced some participants' decisions to adhere to the study pill within the context of a placebo-controlled clinical trial. Future research can explore the role of risk perception in the uptake of and adherence to pre-exposure prophylaxis, now that FTC/TDF has been shown efficacious.

The sexual risk context among the FEM-PrEP study population in Bondo, Kenya and Pretoria, South Africa.

BACKGROUND: Incidence rates in the FEM-PrEP and VOICE trials demonstrate that women from diverse sub-Saharan African communities continue to be at substantial HIV risk. OBJECTIVE: To describe and compare the sexual risk context of the study population from two FEM-PrEP trial sites-Bondo, Kenya, and Pretoria, South Africa. METHODS: At baseline we collected information about demographics, sexual behaviors, and partnership beliefs through quantitative questionnaires with all participants (Bondo, n = 720; Pretoria, n = 750). To explore the sexual risk context, we also conducted qualitative, semi-structured interviews with HIV-negative participants randomly selected at several time points (Bondo, n = 111; Pretoria, n = 69). RESULTS: Demographics, sexual behavior, and partnership beliefs varied significantly between the sites. Bondo participants were generally older, had fewer years of schooling, and were more likely to be employed and married compared to Pretoria participants. Bondo participants were more likely to report multiple partners and not knowing whether their partner had HIV than Pretoria participants. A significantly higher percentage of Bondo participants reported engaging in sex without a condom with their primary and other partners compared to Pretoria participants. We found a borderline association between participants who reported not using condoms in the 4 weeks prior to baseline and lower risk of HIV infection, and no association between having more than one sexual partner at baseline and HIV infection. DISCUSSION: Despite significantly different demographics, sexual behaviors, and partnership beliefs, many women in the FEM-PrEP trial were at risk of acquiring HIV as demonstrated by the sites' high HIV incidence. Though gender dynamics differed between the populations, they appear to play a critical role in women's sexual practices. The findings highlight different ways women from diverse contexts may be at-risk for HIV and the importance of providing HIV prevention options that are both effective and feasible given personal and social circumstances.

FEM-PrEP: adherence patterns and factors associated with adherence to a daily oral study product for pre-exposure prophylaxis.

BACKGROUND: Several clinical trials have demonstrated the safety and effectiveness of oral tenofovir disoproxil fumarate (TDF), with or without emtricitabine (FTC), as pre-exposure prophylaxis (PrEP) for reducing the risk of HIV acquisition. Adherence to the study product was insufficient to demonstrate the effectiveness of FTC/TDF in 2 PrEP clinical trials conducted among women (FEM-PrEP and the Vaginal and Oral Interventions to Control the Epidemic study), but further analyses of adherence in these studies may inform PrEP demonstration projects and future HIV prevention clinical trials. METHODS: We randomly selected a subcohort of 150 participants randomized to FTC/TDF in 3 FEM-PrEP sites (Bondo, Kenya; Bloemfontein, South Africa; and Pretoria, South Africa) to examine adherence levels over time and to assess factors associated with adherence, based on plasma tenofovir and intracellular tenofovir diphosphate drug concentrations in specimens collected at 4-week visit intervals. RESULTS: We observed drug concentrations consistent with good adherence in 28.5% of all visit intervals when drug was available to use, but only 12% of participants achieved good adherence throughout their study participation. In multivariate analysis, the Bloemfontein site [odds ratio (OR): 2.43; 95% confidence interval (CI): 1.32 to 4.48] and liking the pill color (OR: 2.93; 95% CI: 1.18 to 7.27) were positively associated with good adherence, whereas using oral contraceptive pills at enrollment was negatively associated with good adherence (OR: 0.37; 95% CI: 0.18 to 0.74). CONCLUSIONS: Most participants did not regularly adhere to the study product throughout their trial participation, although a small minority did. Few factors associated with good adherence to the study product were identified in FEM-PrEP.