Acceptability, safety, and patterns of use of oral tenofovir disoproxil fumarate and emtricitabine for HIV pre-exposure prophylaxis in South African adolescents: an open-label single-arm phase 2 trial.

HIV incidence among adolescents in southern Africa remains unacceptably high. Pre-exposure prophylaxis (PrEP) is an effective HIV prevention intervention but there are few data on its implementation among adolescents. We aimed to investigate the safety, feasibility, and acceptability of PrEP with oral tenofovir disoproxil fumarate and emtricitabine as part of a comprehensive HIV prevention package in an adolescent population in South Africa. This open-label single-arm phase 2 study (PlusPills) was done in two research clinics in Cape Town and Johannesburg, South Africa. Adolescents aged 15-19 years were recruited into the study through recruitment events and outreach in the community. Potential participants were eligible for enrolment if they reported being sexually active. Exclusion criteria were a positive test for HIV or pregnancy at enrolment, breastfeeding, or any relevant co-morbidities. Participants were given oral tenofovir disoproxil fumarate and emtricitabine for PrEP to take daily for the first 12 weeks and were then given the choice to opt in or out of PrEP use at three monthly intervals during scheduled clinic visits. Participants were invited to monthly visits for adherence counselling and HIV testing during the study period. The primary outcomes were acceptability, use, and safety of PrEP. Acceptability was measured by the proportion of participants who reported willingness to take up PrEP and remain on PrEP at each study timepoint. Use was defined as the number of participants who continued to use PrEP after the initial 12-week period until the end of the study (week 48). Safety was measured by grade 2, 3, and 4 laboratory and clinical adverse events using the Division of AIDS table for grading the severity of adult and paediatric adverse events, version 1.0. Dried blood spot samples were collected at each study time-point to measure tenofovir diphosphate concentrations. This trial is registered with ClinicalTrials.gov, NCT02213328. Between April 28, 2015, and Nov 11, 2016, 244 participants were screened, and 148 participants were enrolled (median age was 18 years; 99 participants [67%] were female) and initiated PrEP. PrEP was stopped by 26 of the 148 (18%) participants at 12 weeks. Cumulative PrEP opt-out, from the total cohort, was 41% (60 of 148 participants) at week 24 and 43% (63 of 148 participants) at week 36. PrEP was well tolerated with only minor adverse events (grade 2) thought to be related to study drug, which included headache (n=4, 3%), gastrointestinal upset (n=8, 5%), and skin rash (n=2, 1%). Two participants (1%) experienced grade 3 weight loss, which was deemed related to the study drug and resolved fully when PrEP was discontinued. Tenofovir diphosphate concentrations were detectable (>16 fmol/punch) in dried blood spot samples in 108 (92%) of 118 participants who reported PrEP use at week 12, in 74 (74%) of 100 participants at week 24, and in 22 (59%) of 37 participants by the study end at week 48. In this cohort of self-selected South African adolescents at risk of HIV acquisition, PrEP appears safe and tolerable in those who continued use. PrEP use decreased throughout the course of the study as the number of planned study visits declined. Adolescents in southern Africa needs access to PrEP with tailored adherence support and possibly the option for more frequent and flexible visit schedules. National Institute of Allergy and Infectious Diseases of the US National Institutes of Health.

Gill K ，Johnson L ，Dietrich J ，Myer L ，Marcus R ，Wallace M ，Pidwell T ，Mendel E ，Fynn L ，Jones K ，Wiesner L ，Slack C ，Strode A ，Spiegel H ，Hosek S ，Rooney J ，Gray G ，Bekker LG ... -  《-》

HIV-1 infection kinetics, drug resistance, and long-term safety of pre-exposure prophylaxis with emtricitabine plus tenofovir alafenamide (DISCOVER): week 144 open-label extension of a randomised, controlled, phase 3 trial.

Data characterising the long-term use and safety of emtricitabine plus tenofovir disoproxil fumarate as daily oral pre-exposure prophylaxis (PrEP) are scarce and there are uncertainties regarding the value of routine HIV-1 RNA testing during oral PrEP follow-up. The DISCOVER trial was a randomised, controlled, phase 3 trial in which cisgender men and transgender women aged 18 years and older with a high likelihood of acquiring HIV were recruited from 94 clinics in Europe and North America and randomly assigned to receive either emtricitabine plus tenofovir disoproxil fumarate (200/25 mg) tablets daily, with matched placebo tablets, or emtricitabine plus tenofovir alafenamide (200/300 mg) tablets daily, with matched placebo tablets, for at least 96 weeks. After completion of the trial, participants were offered enrolment in this 48-week open-label extension study of emtricitabine plus tenofovir alafenamide. In participants diagnosed with HIV during the randomised and open-label phases of the study, we characterised HIV-1 test results and measured HIV-1 RNA viral load retrospectively when available. Adherence based on tenofovir diphosphate concentrations in dried blood spots and genotypic resistance were assessed in participants diagnosed with HIV. Safety assessments included adverse events, laboratory parameters, and, in a subset of participants, bone mineral density. HIV-1 incidence in participants initially randomly assigned to receive emtricitabine plus tenofovir alafenamide was estimated using a Poisson distribution. Changes from baseline in safety endpoints were described in participants assigned to received emtricitabine plus tenofovir alafenamide and in those who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase. This trial is registered with ClinicalTrials.gov, NCT02842086, and is ongoing. Between Sept 13, 2016, and June 30, 2017, 5399 participants were enrolled and randomly assigned in DISCOVER. 2699 were assigned to receive emtricitabine plus tenofovir disoproxil fumarate and 2700 were assigned to receive emtricitabine plus tenofovir alafenamide, of whom 2693 and 2694, respectively, received at least one dose of study drug. 2115 (79%) assigned to emtricitabine plus tenofovir disoproxil fumarate switched to emtricitabine plus tenofovir alafenamide in the open-label phase, and 2070 (77%) continued with emtricitabine plus tenofovir alafenamide in the open-label phase. As of data cutoff (Dec 10, 2020), after 15 817 person-years of follow-up, 27 new HIV-1 diagnoses were observed across the total study period, with three occurring during the open-label phase. In participants who were initially assigned to emtricitabine plus tenofovir alafenamide, the incidence was 0·13 per 100 person-years (95% CI 0·061-0·23; ten of 2670). Stored plasma samples were available for 23 of 27 participants, including 22 with incident infection. In four (17%) of 23 participants, retrospective testing detected HIV-1 RNA before serological HIV-1 test positivity; one was a suspected baseline infection. Of the three incident cases, all three were non-adherent to PrEP and none developed drug resistance. Among participants taking emtricitabine plus tenofovir alafenamide for up to 144 weeks, markers of glomerular filtration and proximal renal tubule dysfunction (β2-microglobulin to creatinine ratio and retinol-binding protein to creatinine ratio) improved or remained stable at 144 weeks compared with baseline, bone mineral density in hip and lumbar spine increased or remained stable from baseline to week 144 (n=191), cholesterol and glucose concentrations remained stable, and median bodyweight increased by less than 1 kg per year. In participants who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase (2115 [79%] of 2693), markers of glomerular filtration and proximal renal tubule dysfunction improved or remained stable, bone mineral density increased, cholesterol concentrations increased, glucose concentrations were similar, and median bodyweight increased more compared with those who remained on emtricitabine and tenofovir alafenamide. Routine HIV-1 RNA testing for follow-up of individuals on daily oral PrEP provides modest additional clinical benefit. Long-term use of emtricitabine and tenofovir alafenamide as daily oral PrEP is safe and well tolerated and can be an especially appropriate choice for people with bone or renal morbidities. Gilead Sciences.

Wohl DA ，Spinner CD ，Flamm J ，Hare CB ，Doblecki-Lewis S ，Ruane PJ ，Molina JM ，Mills A ，Brinson C ，Ramgopal M ，Clarke A ，Crofoot G ，Martorell C ，Carter C ，Cox S ，Hojilla JC ，Shao Y ，Das M ，Kintu A ，Baeten JM ，Grant RM ，Mounzer K ，Mayer K ... -  《Lancet HIV》

Adherence, safety, and choice of the monthly dapivirine vaginal ring or oral emtricitabine plus tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis among African adolescent girls and young women: a randomised, open-label, crossover trial.

Half of new HIV acquisitions in Africa occur in adolescent girls and young women. Pre-exposure prophylaxis (PrEP) with oral tenofovir disoproxil fumarate plus emtricitabine or the monthly dapivirine vaginal ring is efficacious but has lower adherence and effectiveness among adolescent girls and young women. We aimed to assess product adherence, safety, and choice of oral PrEP compared with the dapivirine ring among African adolescent girls and young women. MTN-034/REACH was a randomised, open-label, phase 2a crossover trial among HIV-seronegative, non-pregnant adolescent girls and young women aged 16-21 years at four clinical research sites in South Africa, Uganda, and Zimbabwe. Participants were randomly assigned (1:1) to either the dapivirine ring or daily oral PrEP (200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) for 6 months, then switched to the other product option for 6 months, followed by a third 6-month period in which participants were given a choice of oral PrEP, the dapivirine ring, or neither. Fixed block randomisation was used, stratified by site. The primary adherence endpoint was use of each product during the randomised periods, with high use defined as tenofovir-diphosphate concentrations greater than or equal to 700 fmol/punch (associated with taking an average of four or more tablets per week in the previous month) and greater than or equal to 4 mg dapivirine released from the returned ring (continuous use for 28 days in the previous month) based on residual drug concentrations. The primary safety endpoint was grade 2 or higher adverse events during each randomised period of 24 weeks of ring and oral PrEP. This trial is registered at ClinicalTrials.gov, NCT03593655. From Feb 6, 2019 to Sept 9, 2021, 396 adolescent girls and young women were screened, 247 of whom were enrolled and randomly assigned (6 months of the ring followed by 6 months of oral PrEP n=124; 6 months of oral PrEP followed by 6 months of the ring n=123). Median age was 18 years (IQR 17-19). 54 grade 2 or higher product-related adverse events were reported during oral PrEP and five during dapivirine ring use, with no product-related serious adverse events. High adherence was observed in 753 (57%) of the 1316 oral PrEP visits and 806 (57%) of the 1407 dapivirine ring visits. Four women acquired HIV during follow-up. Adherence was moderately high and similar between oral PrEP and the dapivirine ring with favourable safety and tolerability. Oral PrEP and the dapivirine ring are effective, safe, and well tolerated HIV prevention options for adolescent girls and young women who would benefit from a choice of PrEP formulations to meet their needs and preferences. National Institutes of Health.

Nair G ，Celum C ，Szydlo D ，Brown ER ，Akello CA ，Nakalega R ，Macdonald P ，Milan G ，Palanee-Phillips T ，Reddy K ，Tahuringana E ，Muhlanga F ，Nakabiito C ，Bekker LG ，Siziba B ，Hillier SL ，Baeten JM ，Garcia M ，Johnson S ，McClure T ，Levy L ，Livant E ，Jacobson C ，Soto-Torres L ，van der Straten A ，Hosek S ，Rooney JF ，Steytler J ，Bunge K ，Parikh U ，Hendrix C ，Anderson P ，Ngure K ，REACH Protocol Team ... -  《Lancet HIV》

Daily and non-daily pre-exposure prophylaxis in African women (HPTN 067/ADAPT Cape Town Trial): a randomised, open-label, phase 2 trial.

The relative feasibility and acceptability of daily versus non-daily dosing of oral HIV pre-exposure prophylaxis (PrEP) among women are unknown. We aimed to investigate the feasibility of non-daily PrEP regimens in adult women. We did a randomised, open-label, phase 2 clinical trial (HPTN 067/ADAPT) of oral PrEP with emtricitabine plus tenofovir disoproxil fumarate at a research centre in Cape Town, South Africa. Participants were adult women (age ≥18 years) who received directly observed dosing once a week for 5 weeks followed by random assignment (1:1:1) at week 6 to one of three unblinded PrEP regimens for self-administered dosing over 24 weeks: daily; time-driven (twice a week plus a post-sex dose); or event-driven (one tablet both before and after sex). Primary outcomes were PrEP coverage (at least one dose within the 4 days before sex and one dose within 24 h after sex), pills needed or used to achieve regimen-specific adherence and coverage, and symptoms and side-effects. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01327651; the trial is completed and this report presents the final analysis. Between Sept 12, 2011, and Oct 3, 2012, 191 women were enrolled to the trial. 178 (93%) completed directly observed dosing and were randomly assigned one of the three PrEP regimens for the self-administered phase: 59 were allocated the daily regimen, 59 the time-driven regimen, and 60 the event-driven regimen. Median age of women was 26 years (IQR 21-37; range 18-52). In women allocated the daily regimen, 1459 (75%) of 1952 sex events were covered by PrEP, compared with 599 (56%) of 1074 sex events among those assigned the time-driven regimen (odds ratio [OR] 2·35, 95% CI 1·43-3·83; p=0·0007) and 798 (52%) of 1542 sex events among those allotted the event-driven regimen (2·76, 1·68-4·53; p<0·0001). Fewer pills were needed for complete adherence in women allocated non-daily regimens (vs daily regimen, relative mean 2·53 [95% CI 2·39-2·69] for the time-driven regimen and 4·16 [3·59-4·82] for the event-driven regimen; p<0·0001). Side-effects were uncommon. Eight HIV seroconversions occurred overall, with four documented during the self-administered phase (two with the time-driven regimen and two with the event-driven regimen). Adherence to the assigned regimen was 75% (7283 of 9652 doses taken) for women allocated the daily regimen compared with 65% for those assigned the time-driven regimen (2367 of 3616 doses taken; p=0·0028) and 53% for those allotted the event-driven regimen (1161 of 2203 doses taken; p<0·0001). When sex was reported in the previous week, PrEP drugs were detected (above the lower limits of quantification) more frequently in women assigned the daily regimen (73 [68%] of 107 samples) than in those allocated the time-driven regimen (42 [58%] of 72 samples) and the event-driven regimen (41 [41%] of 99 samples). Daily PrEP dosing resulted in higher coverage of sex events, increased adherence to the regimen, and augmented drug concentrations than did either time-driven or event-driven dosing. These findings support recommendations for daily use of PrEP with oral emtricitabine plus tenofovir disoproxil fumarate in women. HIV Prevention Trials Network.

Bekker LG ，Roux S ，Sebastien E ，Yola N ，Amico KR ，Hughes JP ，Marzinke MA ，Hendrix CW ，Anderson PL ，Elharrar V ，Stirratt M ，Rooney JF ，Piwowar-Manning E ，Eshleman SH ，McKinstry L ，Li M ，Dye BJ ，Grant RM ，HPTN 067 (ADAPT) study team ... -  《-》

Retention, engagement, and adherence to pre-exposure prophylaxis for men who have sex with men and transgender women in PrEP Brasil: 48 week results of a demonstration study.

PrEP Brasil was a demonstration study to assess feasibility of daily oral tenofovir diphosphate disoproxil fumarate plus emtricitabine provided at no cost to men who have sex with men (MSM) and transgender women at high risk for HIV within the Brazilian public health system. We report week 48 pre-exposure prophylaxis (PrEP) retention, engagement, and adherence, trends in sexual behaviour, and incidence of HIV and sexually transmitted infections in this study cohort. PrEP Brasil was a 48 week, open-label, demonstration study that assessed PrEP delivery at three referral centres for HIV prevention and care in Rio de Janeiro, Brazil (Fundação Oswaldo Cruz), and São Paulo, Brazil (Universidade de São Paulo and Centro de Referência e Treinamento em DST e AIDS). Eligible participants were MSM and transgender women who were HIV negative, aged at least 18 years, resident in Rio de Janeiro or São Paulo, and reported one or more sexual risk criteria in the previous 12 months (eg, condomless anal sex with two or more partners, two or more episodes of anal sex with an HIV-infected partner, or history of sexually transmitted infection [STI] diagnosis). Participants were seen at weeks 4, 12, 24, 36, and 48 for PrEP provision, clinical and laboratory evaluation, and HIV testing. Computer-assisted self-interviews were also done at study visits 12, 24, 36, and 48, and assessed sexual behaviour and drug use. PrEP retention was defined by attendance at the week 48 visit, PrEP engagement was an ordinal five-level variable combining presence at the study visit and drug concentrations, and PrEP adherence was evaluated by measuring tenofovir diphosphate concentrations in dried blood spots. Logistic regression models were used to quantify the association of variables with high adherence (≥4 doses per week). The study is registered with ClinicalTrials.gov, number NCT01989611. Between April 1, 2014, and July 8, 2016, 450 participants initiated PrEP, 375 (83%) of whom were retained until week 48. At week 48, 277 (74%) of 375 participants had protective drug concentrations consistent with at least four doses per week: 183 (82%) of 222 participants from São Paulo compared with 94 (63%) of 150 participants from Rio de Janeiro (adjusted odds ratio 1·88, 95% CI 1·06-3·34); 119 (80%) of 148 participants who reported sex with HIV-infected partners compared with 158 (70%) of 227 participants who did not (1·78, 1·03-3·08); 67 (87%) of 77 participants who used stimulants compared with 210 (71%) of 298 participants who did not (2·23, 1·02-4·92); and 232 (80%) of 289 participants who had protective concentrations of tenofovir disphosphate at week 4 compared with 42 (54%) of 78 participants who did not (3·28, 1·85-5·80). Overall, receptive anal sex with the last three partners increased from 45% at enrolment to 49% at week 48 (p=0·17), and the mean number of sexual partners in the previous 3 months decreased from 11·4 (SD 28·94) at enrolment to 8·3 (19·55) at week 48 (p<0·0013). Two individuals seroconverted during follow-up (HIV incidence 0·51 per 100 person-years, 95% CI 0·13-2·06); both of these patients had undetectable tenofovir concentrations at seroconversion. Our results support the effectiveness and feasibility of PrEP in a real-world setting. Offering PrEP at public health-care clinics in a middle-income setting can retain high numbers of participants and achieve high levels of adherence without risk compensation in the investigated populations. Brazilian Ministry of Health, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Secretaria de Vigilancia em Saúde, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, and Fundação de Amparo à Pesquisa do Estado de São Paulo.

Grinsztejn B ，Hoagland B ，Moreira RI ，Kallas EG ，Madruga JV ，Goulart S ，Leite IC ，Freitas L ，Martins LMS ，Torres TS ，Vasconcelos R ，De Boni RB ，Anderson PL ，Liu A ，Luz PM ，Veloso VG ，PrEP Brasil Study Team ... -  《Lancet HIV》