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Antiretroviral pre-exposure prophylaxis (PrEP) is recommended to prevent HIV infection among high-risk men who have sex with men (MSM) though not available in Brazil where the HIV epidemic persists unabated in this group. This cross-sectional study describes PrEP awareness and willingness and associated factors among MSM and transvestite/transgender women (trans women) pre-screened for the PrEP Brasil study. Awareness was reported by 61.3 % of the participants and was associated with age, education, site, study period and prior HIV testing. Most participants (82.1 %) were willing to use PrEP, which was associated with site, study period, number of male condomless anal sexual partners and anal sex with HIV positive/unknown partners. PrEP information is need among young and less educated individuals. Willingness to use PrEP was high and future studies should be conducted to confirm PrEP acceptability and the characteristics of the population who chose to adopt this intervention. [ABSTRACT FROM AUTHOR]

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 (t 1/2app ) 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). t 1/2app 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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Efficacy of daily emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) for PrEP is strongly dependent on the adherence. We examined the concordance between indirect adherence measures and protective drug levels among participants retained through 48 weeks in the PrEP Brasil Study., Methods: PrEP Brasil was a prospective, multicenter, open-label demonstration project evaluating PrEP provision for men who have sex with men (MSM) and transgender women (TGW) at higher risk for HIV infection within the setting of Brazilian Public Health System. Three indirect adherence measures were obtained at week 48: medication possession ratio (MPR), pill count and self-report (30-days recall). Tenofovir diphosphate (TFV-DP) concentration in Dried Blood Spot (DBS) was measured at week 48. Areas under (AUC) the receiver operating characteristics (ROC) curve were used to evaluate the concordance between achieving protective drug levels (TFV-DP≥700fmol/punch) and the indirect adherence measures. Youden's index and distance to corner were used to determine the optimal cutoff points for each indirect adherence measure. We calculated sensitivity, specificity, negative (NPV) and positive (PPV) predictive values for the found cutoff points. Finally, Delong test was used to compare AUCs., Results and Discussion: From April, 2014 to July, 2016, 450 participants initiated PrEP, 375(83.3%) were retained through 48 weeks. Of these, 74% (277/375) had TFV-DP ≥700fmol/punch. All adherence measures discriminated between participants with and without protective drug levels (AUC>0.5). High indirect adherence measure was predictive of protective drug levels (PPV>0.8) while low indirect adherence measure was not predictive of lack of protective drug levels (NPV<0.5). No significant differences were found between the adherence methods (p = 0.44)., Conclusions: Low-burden measurements such as MPR and self-report can be used to predict PrEP adherence in a public health context in Brazil for MSM and TGW retained through 48 weeks. Clinical Trial Number: NCT01989611., Competing Interests: The authors have declared that no competing interests exist.

Background: HIV epidemics disproportionately affect transwomen worldwide. Trans-specific guidance, outreach, and interventions to increase pre-exposure prophylaxis (PrEP) use among transwomen are scarce., Setting: Rio de Janeiro, Brazil., Methods: We measured awareness and willingness to use PrEP and examined factors associated with those outcomes among transwomen in Rio de Janeiro and estimated how many transwomen would be eligible for PrEP. Data originate from Transcender study, a respondent-driven sampling survey conducted from August 2015 to January 2016. We performed regression models for PrEP awareness and willingness., Results: One hundred thirty-one (38.0%) of 345 participants had heard of PrEP. Among transwomen who self-reported as HIV-negative, 162 (76.4%, N = 212 with available data) reported willingness to use it and 163 (66.8%, N = 244) met PrEP behavioral eligibility criteria. Transwomen with health access in the previous 6 months who reported HIV-infected sexual partner and with 8+ years of schooling had increased odds of PrEP awareness. Lower PrEP awareness was associated with condomless anal intercourse and newly diagnosed HIV infection. Younger age and perceiving themselves at risk of HIV infection increased the odds of PrEP willingness. Lower odds of PrEP willingness were associated with concerns about long-term effects of PrEP and with difficulties in getting access to health care due to transphobia., Conclusion: Combination of low awareness, high willingness, and substantial PrEP eligibility corroborates transwomen as a key population for HIV prevention. PrEP is a promising and empowering strategy for HIV prevention among transwomen, but trans-specific recommendations are needed to effectively implement PrEP in this population.

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., Competing Interests: RJL has received study medication, consulting fees and travel support from Gilead Sciences. He has received consulting fees and travel support from Merck, Inc. HD has received honoraria from Pfizer-South Africa, Novartis-South Africa, MSD-South Africa and Adcock Ingram for speaking engagements and has received travel support from Mylan-South Africa, Novartis-South Africa and Aspen-South Africa. AYL received research grants from NIH and has led studies in which study drug was donated by Gilead Sciences. DM and ARR are paid employees of ViiV Healthcare. WRS is a paid employee of ViiV Healthcare with stock in ViiV Healthcare and GlaxoSmithKline. CWH has research contracts with ViiV/GlaxoSmithKline and the NIH through Johns Hopkins and the University of Washington. MAM received grant support through the NIH, and received grant support through ViiV/GSK on work external to this study. JS is a member of Merck KGaA's Bioethics Advisory Panel and Stem Cell Research Oversight Committee; and he is a member of IQVIA's (formerly Quintiles) Ethics Advisory Panel. JJE is a consultant to Merck, Gilead Sciences, Janssen, and ViiV Healthcare; and he is an investigator on research contracts from ViiV Healthcare, Janssen, and Gilead Sciences.

Background: As pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine for the prevention of HIV infection is rolled out internationally, strategies to maintain effectiveness and to minimise adverse effects merit consideration. In this study, we aimed to assess reductions in renal function and predictors of renal toxicity in a large open-label study of PrEP., Methods: As part of the iPrEx open-label extension (OLE) study, men who have sex with men or transgender women aged 18-70 years who were HIV negative and had participated in three previous PrEP trials from Brazil, Ecuador, Peru, South Africa, Thailand, and the USA were enrolled into an open-label PrEP study. There were no restrictions on current renal function for enrolment into iPrEx OLE, in which participants were given combination tablets of tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg) and advised to take one tablet per day. At follow-up sessions every 12 weeks, participants' creatinine clearance on PrEP was estimated and in a subset of participants, hair samples were collected to measure tenofovir and emtricitabine concentrations (a measure of adherence and exposure) via liquid-chromatography-tandem-mass-spectrometry. Reductions in creatinine clearance from baseline were calculated and predictors of decline were identified by use of multivariate models. iPrEx is registered with ClinicalTrials.com, number NCT00458393., Findings: Baseline characteristics were similar between all participants in iPrEx-OLE (1224 participants with 7475 person-visits) and those participating in the hair substudy (220 participants with 1114 person-visits). During a median of 72 weeks, the mean decline in creatinine clearance was -2·9% (95% CI -2·4 to -3·4; p trend <0·0001), but declines were greater for those who started PrEP at older ages: participants aged 40-50 years at baseline had declines of -4·2% (95% CI -2·8 to -5·5) and participants older than 50 years at baseline had declines of -4·9% (-3·1 to -6·8). In multivariate models, age and baseline creatinine clearance less than 90 mL/min predicted declines in renal function. We identified a monotonic association between percentage decrease in creatinine clearance and the number of doses of tenofovir disoproxil fumarate and emtricitabine taken per week, as estimated by hair concentrations of tenofovir and emtricitabine (p trend =0·008)., Interpretation: Our data suggest that the frequency of safety monitoring for PrEP might need to be different between age groups and that pharmacological measures can monitor for toxic effects as well as adherence., Funding: National Institutes of Health., (Copyright © 2016 Elsevier Ltd. All rights reserved.)