Adaptive HIV pre-exposure prophylaxis adherence interventions for young women in Johannesburg, South Africa: a sequential multiple-assignment randomised trial.

Adherence to daily oral pre-exposure prophylaxis (PrEP) is low among African young women, and layered support strategies are needed to improve PrEP adherence in this population. We aimed to evaluate potentially scalable adherence-support strategies for young women aged 18-25 years who initiated PrEP in Johannesburg, South Africa. We conducted a sequential multiple-assignment randomised trial at Ward 21 of the Wits Reproductive Health and HIV Institute clinical research site, affiliated with University of the Witwatersrand, Johannesburg, South Africa. Participants were eligible if they were assigned female sex at birth, aged 18-25 years, not living with HIV, sexually active, newly initiating PrEP, had regular access to a mobile telephone, and could read. Using sequentially numbered, sealed, opaque envelopes containing group allocation, a staff member assigned enrolled participants (1:1) to receive one of two adherence-support interventions: once per week two-way SMS communication or participation in a WhatsApp peer-support group. Participants assigned to WhatsApp were put into groups with approximately 25 participants, during which they were prompted by staff facilitators to discuss any challenges with PrEP use or other events happening in their lives. The allocation sequence was generated by the data manager using random numbers with variable block sizes between 10 and 14. Only trial investigators were masked to participant intervention assignments; participants, people giving interventions, people assessing outcomes, and people analysing data were not masked to group assignment. All enrolled participants were offered PrEP (ie, co-formulated, once per day oral emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg). The primary outcome was high PrEP adherence at month 9, defined as concentration of tenofovir diphosphate on dried blood sample of 700 fmol per punch or more. At month 3, participants with low PrEP adherence were randomly assigned to a secondary, intensified intervention of issue-focused counselling once per month or drug-level feedback counselling based on PrEP drug concentrations at months 3 and 6. The protocol was registered at ClinicalTrials.gov (NCT04038060) and the trial is complete. Participants were enrolled and followed up between May 16, 2019, and Jan 25, 2022. From May 16, 2019, to Jan 29, 2021, 401 participants were screened and 360 were enrolled and initiated PrEP. 180 (50%) were randomly assigned to two-way SMS and 180 (50%) were randomly assigned to WhatsApp support groups. At month 9, 34 (20%) of 174 participants in the two-way SMS arm had tenofovir diphosphate 700 fmol per punch or more, compared with 32 (18%) of 174 in the WhatsApp arm (relative risk 1·06, 95% CI 0·69-1·64; p=0·78). At month 9, four (5%) of 76 participants in the drug-level feedback arm had tenofovir diphosphate 700 fmol per punch or more, compared with three (4%) of 76 participants in the monthly counselling arm (1·33, 0·31-5·76; p=0·70). 22 serious adverse events were reported during the trial, but were all deemed unrelated to the trial. PrEP adherence did not differ across interventions among young women in Johannesburg, South Africa. Future research is needed on whether and how to scale-up PrEP support for young women in resource-constrained settings. US National Institutes of Health.

Velloza J ，Poovan N ，Meisner A ，Ndlovu N ，Ndimande-Khoza N ，Grabow C ，Zwane P ，Mbele S ，Molefe M ，Donnell D ，Baeten JM ，Hosek S ，Celum C ，Delany-Moretlwe S ... -  《Lancet HIV》

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 ... -  《-》

Adaptive HIV pre-exposure prophylaxis adherence interventions for young South African women: Study protocol for a sequential multiple assignment randomized trial.

Velloza J ，Poovan N ，Ndlovu N ，Khoza N ，Morton JF ，Omony J ，Mkwanazi E ，Grabow C ，Donnell D ，Munthali R ，Baeten JM ，Hosek S ，Celum C ，Delany-Moretlwe S ... -  《-》

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》

Alignment of PrEP adherence with periods of HIV risk among adolescent girls and young women in South Africa and Zimbabwe: a secondary analysis of the HPTN 082 randomised controlled trial.

Adolescent girls and young women in southern and eastern Africa have adherence challenges with daily oral HIV pre-exposure prophylaxis (PrEP). High adherence is most important during periods of HIV risk (prevention-effective adherence). We aimed to describe HIV risk behaviour and to understand patterns in PrEP adherence during periods of risk among adolescent girls and young women from sub-Saharan Africa. We did a secondary analysis of the HPTN 082 trial, an open-label, interventional, randomised controlled trial of sexually active adolescent girls and young women (aged 16-25 years) testing negative for HIV in Johannesburg and Cape Town, South Africa, and in Harare, Zimbabwe. The primary outcomes were high cumulative PrEP adherence, dichotomised as intracellular tenofovir diphosphate concentrations of at least 700 fmol/punch in dried blood spots at weeks 13, 26, and 52, and high recent PrEP adherence, dichotomised as plasma tenofovir concentrations of at least 40 ng/mL at weeks 13, 26, and 52, among participants who accepted PrEP. We collected data on sexual behaviour every 3 months. We categorised visits into a binary variable of any HIV risk based on condomless sex, more than one sexual partner, primary partner's HIV status and antiretroviral use, transactional sex, drug or alcohol use around sexual activity, and laboratory-diagnosed STIs. We used generalised estimating equations to evaluate associations between HIV risk (reflecting behaviour during the previous 3 months) and high cumulative and recent adherence to PrEP and any PrEP use (quantifiable drug concentrations). The trial is registered with ClinicalTrials.gov, NCT02732730. Between Oct 12, 2016, and Oct 25, 2018, 451 women were recruited, and 427 participants (median age 21·0 years [IQR 19·0-22·0]) were eligible for inclusion in this analysis. The proportion of participants reporting at least one HIV risk factor decreased significantly over follow-up, from 364 (85%) participants at enrolment, 226 (60%) at week 13, and 243 (65%) at week 26, to 224 (61%) at week 52 (p<0·0001). Any HIV risk was significantly associated with high PrEP adherence, measured by both tenofovir diphosphate concentrations of at least 700 fmol/punch (adjusted relative risk 1·57 [95% CI 1·09-2·25]; p=0·014) and plasma tenofovir concentrations of at least 40 ng/mL (1·36 [1·11-1·65]; p=0·0025). Any HIV risk was also associated with quantifiable concentrations of tenofovir diphosphate (1·15 [1·03-1·29]; p=0·013) and tenofovir (1·27 [1·09-1·49]; p=0·0022). We observed significant dose-response relationships between number of HIV risk factors and PrEP drug concentrations. The association between any HIV risk and high PrEP adherence suggests that adolescent girls and young women were able to use PrEP during periods of risk, an indicator of prevention-effective PrEP adherence. Our findings support a shift in the PrEP framework to acknowledge prevention-effective adherence practices, which might improve PrEP delivery and adherence support for adolescent girls and young women in HIV-endemic settings. US National Institutes of Health.

Velloza J ，Donnell D ，Hosek S ，Anderson PL ，Chirenje ZM ，Mgodi N ，Bekker LG ，Marzinke MA ，Delany-Moretlwe S ，Celum C ... -  《Lancet HIV》