Adolescent girls and young women (AGYW) in South Africa and Zimbabwe are disproportionately affected by HIV. Daily oral pre-exposure prophylaxis (PrEP), bimonthly injectable PrEP, and the monthly PrEP ring are promising biomedical strategies to reduce HIV incidence, but low adherence and continuation on these methods among AGYW threatens their public health impact. The evidence-informed Comprehensive Adherence Resource and Empowerment Support (CARES) intervention aims to support PrEP adherence and continuation among AGYW through counseling, adherence biomarker feedback, and choice from a menu of additional strategies, including support clubs, phone calls, and SMS. In a preliminary study (MTN-034) in South Africa, Zimbabwe, and Uganda, AGYW received CARES and achieved protective adherence levels for ring and oral PrEP at 57% of visits, versus 14%–32% in comparable studies. However, CARES was designed for a highly resourced clinical trial; there is need to establish whether it can be implemented with fidelity, feasibility, and acceptability in real-world programs. The goals of the proposed study, led by multiple principal investigators from RTI International, the Desmond Tutu HIV Foundation, and the Pangaea Zimbabwe AIDS Trust, are to adapt CARES to be implementable, incorporating injectable PrEP, and to evaluate effectiveness and implementation of the adapted intervention in Zimbabwe and South Africa. In Aim 1, we will adapt CARES by conducting formative research (literature review; 24 key informant interviews with PrEP providers, program leaders, policy makers and funders; and six focus groups with AGYW PrEP users) and then applying the findings in collaborative adaptation workshops with youth experts to streamline CARES while retaining core components. The adapted materials will be pretested before finalization. In Aim 2, we will test the effectiveness of CARES to increase PrEP continuation and adherence among AGYW at four PrEP delivery sites. We will employ a rigorous interrupted time series (ITS) design with monthly pre- and post-implementation assessments over 24 months. The primary outcome will be the proportion of AGYW continuing on any PrEP product for 3 months after initiation, per clinical records. The secondary outcome is the proportion with high PrEP adherence, assessed by clinic records or biomarkers among a subsample of 100 AGYW per month. In Aim 3, we will evaluate the feasibility, acceptability, and fidelity of CARES in the same ITS study using a parallel convergent mixed-methods design. Data will include quantitative surveys (N = 1,500) and in-depth interviews (N = 32) with AGYW; semistructured interviews with 12 CARES providers, 8 PrEP providers, and 8 clinic or program leaders; and records of program implementation and cost. If effective, CARES could significantly increase PrEP adherence and continuation among AGYW in real-world PrEP delivery settings, reducing HIV incidence. By addressing feasibility, acceptability, and fidelity at this stage of development, we will ensure that CARES is ideally positioned for scale-up to programs throughout the region.

Project Narrative The proposed study will adapt and evaluate CARES, an intervention that aims to prevent HIV among adolescent girls and young women by increasing their use of pre-exposure prophylaxis (PrEP) methods. We will test whether CARES increases PrEP use and whether it is acceptable and feasible to implement in real-world programmatic settings in Zimbabwe and South Africa. If successful, the study will provide an effective tool to support PrEP use in this priority population and ensure that CARES ideally positioned for scale-up to programs throughout the region.