Feasibility of Short-Term PrEP Uptake for Men Who Have Sex With Men With Episodic Periods of Increased HIV Risk.

BACKGROUND: Pre-exposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate is efficacious in reducing HIV acquisition. For some gay, bisexual, and other men who have sex with men (MSM), daily ongoing PrEP may be unsuitable for use as a long-term prevention strategy because of episodic risk, cost issues, or concerns about the biological consequences of medication. SETTING: This study evaluated the feasibility of short-term, fixed-interval episodic PrEP (Epi-PrEP) for use among vacationing MSM. We describe the feasibility of implementing a clinic-based Epi-PrEP pilot program for 48 MSM who reported occasional condomless sex and anticipated a defined high-risk time. METHODS: This was a nonrandomized naturalistic study of an observational clinical intervention. The primary outcome assessed was adherence, as measured by self-report and plasma tenofovir levels. RESULTS: Of 54 MSM who enrolled in the study, 48 completed the 3-month visit. The majority (93.7%) had tenofovir concentrations consistent with daily use on returning from vacation. Almost 3/4 reported condomless sex during vacation, and about 1/3 reported recreational drug use. During the 3-month follow-up, 1 participant had become HIV-infected because of a lapse in continued access to the PrEP after study. Although adverse events were common, none were serious. More than 70% of participants indicated an interest in daily ongoing PrEP use. CONCLUSIONS: Epi-PrEP was well tolerated by at risk MSM in this study, with high levels of medication adherence. Many participants felt the experience of initiating PrEP while on vacation could be a means for transition to long-term PrEP use.

Pharmacokinetic and Pharmacodynamic Impacts of Depot Medroxyprogesterone Acetate Use on HIV Pre-exposure Prophylaxis in Women.

BACKGROUND: Depot medroxyprogesterone acetate (DMPA) is a commonly used contraceptive in areas where use of tenofovir disoproxil fumarate and emtricitabine for HIV pre-exposure prophylaxis (PrEP) is increasing. OBJECTIVES: We aimed to investigate the impact of DMPA on PrEP drug pharmacokinetics and pharmacodynamics in women using PrEP before and after DMPA administration. METHODS: In this pilot study, 12 HIV-negative women ages 18-45 underwent biological sample collection at 3 time points: before study drug, after 2 weeks of daily PrEP use alone, and after 2 weeks of daily PrEP and concomitant DMPA use. We measured drug and drug metabolites in plasma, peripheral blood mononuclear cells, cervicovaginal fluid, cervical tissue, and rectal fluid after each 2-week course of PrEP. We measured HIV replication ex vivo in genital tissue biopsies and innate anti-HIV activity in cervicovaginal fluid before PrEP and after both courses. We compared drug concentrations after PrEP alone to after PrEP and DMPA in the same participant using Wilcoxon signed-rank tests. We used mixed effects linear regression models to compare pharmacodynamic measures for each participant at predrug baseline, after PrEP alone, and after PrEP and DMPA. RESULTS: We found no significant differences in PrEP drug and drug metabolite concentrations in any compartment during concomitant DMPA use compared with use of PrEP alone, except for a reduction in emtricitabine concentration in cervical tissue. We found no difference in HIV replication in cervical tissue or anti-HIV activity in cervicovaginal fluid during concomitant DMPA and PrEP use compared with during PrEP use alone. CONCLUSIONS: Concomitant use of DMPA does not clinically alter pharmacokinetics or pharmacodynamics of PrEP in women. These data support the safety of DMPA use in women using PrEP.

Tail-phase safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in HIV-uninfected adults: a secondary analysis of the HPTN 077 trial.

BACKGROUND: Long-acting injectable cabotegravir is a novel integrase inhibitor currently in advanced clinical development for HIV prevention and treatment. We aimed to assess the terminal phase pharmacokinetics and safety of long-acting injectable cabotegravir in participants included in the HPTN 077 trial. METHODS: HPTN 077 was a multicentre, double-blind, randomised, placebo-controlled phase 2a trial done at eight sites in Brazil, Malawi, South Africa, and the USA. Participants (aged 18-65 years), who were HIV-uninfected and at low-risk for HIV, were randomly assigned (3:1) to long-acting injectable cabotegravir (800 mg given three times at 12 week intervals or 600 mg given five times, administered at one 4 week interval, and every 8 weeks thereafter) or placebo. Participants were followed up to 76 weeks after final injection. In a prespecified analysis of secondary and exploratory outcomes, we assessed the safety, measured by the proportion of participants with grade 2 or worse adverse events, and pharmacokinetics, measured by apparent terminal phase half-life (t1/2app) and estimated time to lower limit of quantification (LLOQ) of long-acting injectable cabotegravir during the injection phase (defined as the time between first injection and 12 weeks or 8 weeks after the last injection in cohort 1 or cohort 2 respectively) and tail phase (defined as the time between final injection and 52-76 weeks post-final injection). Safety was analysed in all participants who received at least one injection. Pharmacokinetic analyses included all participants who had received at least one injection and had at least three cabotegravir measurements higher than the LLOQ after the final injection. Pharmacokinetic outcomes were estimated using non-compartmental methods. The trial is completed, and was registered with ClinicalTrials.gov, NCT02178800. FINDINGS: Between Feb 9, 2015, and May 27, 2016, 177 participants (134 participants in the cabotegravir group [74 participants in cohort 1; 60 participants in cohort 2] and 43 participants in the placebo group [25 participants in cohort 1; 18 participants in cohort 2) were enrolled and received at least one injection and thus were included in the safety analysis. The incidence of grade 2 or worse adverse events was significantly lower during the tail phase than the injection phase (p<0·0001). At 52-60 weeks after final injection, nine (23%) of 40 male participants had detectable cabotegravir concentrations and at week 76, four (13%) of 30 male participants had detectable cabotegravir concentrations compared with 52 (63%) of 82 female participants and 27 (42%) of 64 female participants at the same timepoints. The median time from the last injection to the time when cabotegravir concentration decreased below the LLOQ was 43·7 weeks (IQR 31·1-66·6; range 20·4-152·5) for male participants and 67·3 weeks (29·1-89·6; 17·7-225·5) for female participants (p=0·0003). t1/2app was longer for female participants than male participants (geometric mean fold-change 1·33, 95% CI 1·06-1·68; p=0·014), and longer for participants with a high body-mass index (BMI) than those with a low BMI (1·31, 1·06-1·63; p=0·015). INTERPRETATION: The clinical significance of the long pharmacokinetic tail of cabotegravir observed in female participants compared with male participants, and those with higher BMI compared with a lower BMI, need to be addressed in future trials. FUNDING: National Institute of Allergy and Infectious Diseases.

Brief Report: Hormonal Contraception Use and Cabotegravir Pharmacokinetics in HIV-Uninfected Women Enrolled in HPTN 077.

OBJECTIVES: To evaluate whether hormonal contraceptive use among cisgender women is associated with differences in pharmacokinetic (PK) parameters of a long-acting injectable formulation of the integrase strand transfer inhibitor, cabotegravir (CAB-LA). SETTING: This is a secondary analysis of 85 cisgender women enrolled in HPTN 077, a phase 2a multicenter study that enrolled HIV-uninfected, low-risk individuals in Malawi, Brazil, South Africa, and the United States. METHODS: Participants received 4-week daily oral cabotegravir lead-in, followed by CAB-LA 800 mg injection every 12 weeks (cohort 1) or 600 mg every 8 weeks (after 4-week initial interval between injections, cohort 2), over 41 weeks. Participants were followed 52-76 weeks subsequent to final injection. Generalized estimating equations and linear regression were used to evaluate differences in CAB-LA PK parameters (peak concentration, trough concentration, area under the curve, apparent terminal half-life, and time to lower limit of quantification) and self-reported hormonal contraceptive stratified by type (oral, injectable, implants, and other), controlling for body mass index and cohort. RESULTS: Compared to women reporting no hormonal contraception (n = 6), oral contraceptive use (n = 18) was associated with lower CAB-LA peak concentration but was not associated with differences in other PK parameters. No other hormonal contraceptive type (injectable, implants, and other) was associated with significant differences in CAB-LA PK parameters. CONCLUSION: Although oral contraceptive use was associated with differences in CAB-LA peak concentration, no differences were observed in other PK parameters, suggesting that this association is not likely to be clinically significant. However, these data highlight the need for further research exploring potential drug-drug interactions between CAB-LA and hormonal contraceptives.

Brief Report: Phase IIa Safety Study of a Vaginal Ring Containing Dapivirine in Adolescent Young Women.

BACKGROUND: Young women aged 15-24 years are disproportionately affected by the HIV epidemic. Two phase III trials of a vaginal ring containing 25-mg dapivirine demonstrated HIV-1 risk reduction in adult women older than 21 years but not in those aged 18-21 years. Lack of protection was correlated with low adherence. METHODS: In this phase-IIa, randomized, double-blind, placebo-controlled, US, multicenter trial of the dapivirine ring in sexually active females, aged 15-17 years, participants were randomized 3:1 to a dapivirine or placebo ring to be inserted monthly for 6 months (NCT02028338). Primary safety end points included grade 2 product related adverse events and any grade 3 and higher adverse events. Adherence to ring use was assessed by plasma dapivirine concentrations, residual levels in used rings, and self-report. A plasma dapivirine concentration of >95 pg/mL was used to define short-term adherence; a residual ring level of <23.5 mg was used to define long-term adherence. Acceptability was assessed through computer-assisted self-interviews. RESULTS: Ninety-six participants were enrolled across 6 US sites. The median age was 16.0 years. There were no differences in safety outcomes between treatment arms. Adherence to the dapivirine ring was demonstrated by both plasma measurements (87%) and residual drug levels in rings (95%). Forty-two percent (95% confidence interval: 32 to 52) of participants reported that they never removed the ring. Participants noted no discomfort due to the ring at 87% of visits and "liking" the ring at 93% of visits. CONCLUSION: The dapivirine vaginal ring, a promising topical microbicide, was well tolerated and acceptable in young US adolescents.

Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial.

BACKGROUND: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States. METHODS AND FINDINGS: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18-65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population. CONCLUSIONS: In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress. TRIAL REGISTRATION: ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800.

Vaginal washing and lubrication among female sex workers in the Mexico-US border region: implications for the development of vaginal PrEP for HIV prevention.

BACKGROUND: To assess the potential acceptability and inform the development of behaviorally-congruent vaginal douche- or gel-based HIV pre-exposure prophylaxis (PrEP) products, we examined vaginal washing and lubrication practices among female sex workers (FSWs) in Tijuana and Ciudad Juarez, two northern Mexico cities bordering the United States (US). METHODS: Two hundred and ninety-five HIV-negative FSWs (145 Tijuana; 150 Ciudad Juarez) enrolled in a behavioral HIV prevention intervention trial completed surveys assessing vaginal washing and lubrication practices, as well as motivators and barriers to performing each practice. Logistic regression was used to identify potential predictors of each practice in the past month. RESULTS: In the past month, vaginal washing was performed by 56 and 22% of FSWs in Tijuana and Ciudad Juarez (p <  0.0001), respectively, while vaginal lubrication was performed by 64 and 45% of FSWs in Tijuana and Ciudad Juarez (p = 0.001), respectively. Vaginal washing was positively associated with living in Tijuana (adjusted odds ratio [AOR] = 4.35, 95% confidence interval [CI]: 2.60-7.30), older age (AOR = 1.04 per year, 95% CI: 1.01-1.06), and vaginal lubrication (AOR = 2.99, 95% CI: 1.67-5.35), while it was negatively associated with being born in the same state as the study site (AOR = 0.50, 95% CI: 0.31-0.82), earning a monthly income ≥3500 pesos (AOR = 0.53, 95% CI: 0.28-1.00), and hazardous alcohol consumption (AOR = 0.56, 95% CI: 0.33-0.95). Vaginal lubrication was positively associated with living in Tijuana (AOR = 2.21, 95% CI: 1.37-3.54) and vaginal washing (AOR = 2.91, 95% CI: 1.64-5.18), while it was negatively associated with being born in the same state as the study site (AOR = 0.47, 95% CI: 0.29-0.75). CONCLUSIONS: The moderate and high prevalence of vaginal washing and lubrication, respectively, suggest behaviorally-congruent, multi-purpose, vaginal douche- and gel-based PrEP products that simultaneously address FSWs' needs and prevent HIV infection may be acceptable to many FSWs along the Mexico-US border. Future product development and implementation should also consider the link between vaginal washing and lubrication to ensure existing practices do not undermine vaginal PrEP product effectiveness. TRIAL REGISTRATION: ClincialTrials.gov ( NCT02447484 ).