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

Abstract

Introduction: Pre-exposure prophylaxis (PrEP) is a highly effective HIV prevention strategy and is recommended for populations at risk of HIV, including adolescent girls and young women (AGYW) in HIV endemic settings. However, PrEP continuation and high adherence remain challenges to its impact. Existing PrEP adherence interventions can be time- and cost-intensive. Widescale PrEP delivery will require the identification of layered PrEP support strategies for AGYW with diverse prevention needs. We describe the design of a sequential multiple assignment randomized trial (SMART) to evaluate a PrEP adherence support model using scalable, stepped interventions in AGYW in South Africa.

Methods: "PrEP SMART" is a randomized trial in Johannesburg, South Africa, enrolling AGYW who are between 18 and 25 years of age, sexually active, newly initiating PrEP, and have regular access to a mobile phone. Participants are randomized 1:1 to standard-of-care PrEP counseling with either two-way SMS or WhatsApp group adherence support. Adherence is assessed at three months using tenofovir diphosphate (TFV-DP) levels from dried blood spots collected at month 2 to categorize participants as "responders" (TFV-DP ≥500 fmol/punch) or "non-responders" (TFV-DP <500 fmol/punch). AGYW defined as 'non-responders' undergo a secondary 1:1 randomization to either quarterly drug-level feedback counseling or monthly issue-focused counseling, in addition to their first-level intervention. The primary outcome is PrEP adherence at nine months (TFV-DP ≥700 fmol/punch). We will assess the effect of our two initial interventions on TFV-DP levels among responders, assess the effect of our intensified interventions on TFV-DP levels among non-responders, and identify the optimal sequence of adherence interventions through nine months.

Trial registration: ClinicalTrials.gov, NCT04038060. Registered on 30 July 2019.

Fig 1. Schedule of enrollment, interventions, and assessments for PrEP SMART study.

ENR = enrollment; M1 = Month 1; CASI = computer assisted self-interview; STI = sexually transmitted infection; TFV-DP = tenofovir diphosphate; DBS = dried blood spots. ¹Only participants who are “non-responders” to their primary intervention will be randomized at the Month 3 study visit. ²Drug concentration testing will occur at Month 2 for all participants to determine whether they are “non-responders” to the primary intervention; drug concentration testing will occur at Months 3 and 6 only for participants in the drug-level feedback counseling arm. TFV-DP levels will also be assessed among all participants at Month 9 for primary outcome assessment.

Fig 2. Flow diagram of study enrollment, randomization, and intervention arms.

¹A participant is considered a “non-responder” if they have Month 2 TFV-DP levels <500 fmol/punch or missed PrEP refills at the Month 1 and/or Month 2 study visits. Secondary randomization takes place at the Month 3 study visit.

Fig 3. Drug-level feedback counseling messages and corresponding TFV-DP thresholds.

“Sample month” refers to the month when the TFV-DP sample was collected. “Results month” refers to the month when the results were given to the participant (e.g., for blood samples drawn at the Month 2 visit, TFV-DP results were reported to participants during their Month 3 visit. For TFV-DP levels greater than or equal to 500 fmol/punch, participants were shown the green wifi signal as a visual representation of their drug levels and they were told the accompanying counseling message by the counselor. For TFV-DP levels between detectable (>16 fmol/punch) and 499 fmol/punch, participants were shown the yellow wifi signal and were told the accompanying counseling message. Finally, for TFV-DP levels below the limit of quantification, participants were shown the red wifi signal and were told the accompanying counseling message.