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

Abstract

Background: 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.

Methods: 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.

Findings: 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.

Interpretation: 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.

Funding: National Institutes of Health.

Figure 1:. Consort flow diagram for MTN-034, the REACH Study

DPV ring is the monthly dapivirine ring. Oral PrEP is daily oral emtricitabine/tenofovir. Participants were first randomized 1:1 to one of two sequences of either the ring or oral PrEP for six months, then switched to the other product option for six months (Periods 1 and 2 and Sequences A and B). At month 12, participants were given a choice of oral PrEP, the ring, or neither product for 6 months (Period 3).

Figure 2:. Adherence to monthly dapivirine vaginal ring (DVR) and daily oral emtricitabine-tenofovir disoproxyl fumarate (oral PrEP) during the randomized periods

The upper panels represents the proportion of dried blood spots (DBS) with semi-quantitative thresholds for adherence in the randomized oral PrEP period on the left (Figure 2a) and among those who chose oral PrEP in the choice period on the right (Figure 2b). The green zone for oral PrEP use depicts the threshold for high adherence with intracellular TFV-DP levels ≥700 fmol/DBS punch, which correlates with ≥4 doses/per week on average in directly-observed dosing studies and was associated with 100% efficacy in an open-label extension study of FTC/TDF among men who have sex with men (efficacy for cisgender women with less than 6–7 doses of FTC/TDF per week is not known and currently being studied).The yellow zone depicts any to moderate oral PrEP adherence, defined as 16.6–700 fmol/punch, and the red zone depicts no use (<16.6 fmol/punch, the lower limit of detection). The lower panels represent dapivirine (DPV) ring use based on calculated release of DPV in returned rings in the randomized DPV ring user period on the left (Figure 2c) and among those who chose the DPV ring in the choice period (Figure 2d). The green zone for high use (>4.0 mg DPV released per month DPV with 28 days of use), yellow zone as some to moderate use (0.9 mg–4.0 mg DPV released per month associated with 1–27 days of use), and red zone as no use (<0.9 mg DPV released), based on the rate of DPV release over 28 days and the correlation of >4 mg released per month with reduced risk of HIV acquisition in the HOPE trial. To provide a comparable level of daily use of monthly use of the ring with the highest level of adherence to oral PrEP, 6–7 doses of oral PrEP per week is correlated with TFV-DP levels >1200 fmol/punch, which was observed in 374 (22%) of DBS samples.