A Stepped Care, Peer-Delivered Intervention to Improve Substance Use and HIV Medication Adherence in Primary Care in South Africa (Project Khanya): Protocol for a Hybrid Type 2 Effectiveness-Implementation Randomized Controlled Trial

Background: A substance use disorder (SUD) treatment gap exists globally, with the greatest gaps in settings with the fewest resources. Integrating SUD care into primary care is needed to expand access to SUD care and support adherence to chronic disease services, especially HIV, in high-burden areas. Guided by stakeholder feedback, our team has previously adapted and piloted a peer-delivered behavioral intervention for antiretroviral therapy (ART) adherence for people with HIV and SUD in HIV care ("Khanya")-based on behavioral activation, problem-solving, motivational interviewing, and mindfulness-based relapse prevention skills-which was shown to be feasible, acceptable, and preliminarily effective. Objective: This study builds upon prior work to conduct a fully powered, randomized hybrid type 2 effectiveness-implementation trial (n=160) to evaluate the effectiveness of a stepped-care model of Khanya versus enhanced treatment as usual (ETAU) on ART adherence and substance use, implementation outcomes, and cost-effectiveness over 12 months. Methods: The trial is being conducted at two public primary care clinics that integrate HIV and other chronic disease services in a high-prevalence HIV setting in South Africa. We are recruiting people with HIV who self-report SUD and demonstrate one or more indicators of ART nonadherence. Eligible participants are randomized 1:1 to Khanya or ETAU. Participants randomized to Khanya first receive "step 1"-a single-session Life-Steps intervention for ART adherence delivered by a peer interventionist, followed by 2 weeks of real-time electronically monitored ART adherence using Wisepill to determine step-up decisions (ie, <80% triggers a step-up to receive the full 6-session Khanya intervention). The RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework guided outcome measure selection, including effectiveness (ART adherence: Wisepill; substance use: urinalysis and WHO ASSIST [World Health Organization's Alcohol, Smoking and Substance Involvement Screening Test]); implementation (feasibility, acceptability, fidelity, and uptake assessed using 2 validated quantitative measures and qualitative feedback over 6 months); and cost-effectiveness (microcosting, health care use, and health-related quality of life using the EuroQol-5D). Descriptive analysis will be used to summarize implementation outcomes, and intent-to-treat analysis using a linear mixed model will be conducted for effectiveness outcomes. Results: Funded in August 2022, recruitment for the trial began in June 2023, and primary data collection is projected to be completed in February 2027. Recruitment for the clinical trial (n=162) was completed in March 2026. It is projected that all exit interviews will be completed by March 2027. Conclusions: This trial builds upon formative work to evaluate the effectiveness, implementation, and cost of a peer-delivered, stepped care intervention integrated into primary care. A stepped-care design to maximize optimal use of resources and integration into primary care is a necessary step to increase accessible intervention programs for people with HIV with comorbid SUD globally.