The LEN4PrEP study: protocol for a phase 3B, non-randomised clinical trial integrating lenacapavir PrEP within multi-product HIV prevention services in primary care clinics in South Africa

Abstract

Despite the scale-up of HIV pre-exposure prophylaxis (PrEP), HIV incidence remains high. The highly effective, twice-yearly subcutaneous injectable lenacapavir for PrEP (L4P) has provided a potential breakthrough for HIV prevention, but there is limited real-world data on uptake, patterns of use and service delivery requirements when offered in public health settings. The LEN4PrEP study will evaluate the integration of L4P within existing multi-product HIV prevention services in real-world settings in South Africa. The study is a prospective, mixed-methods, phase 3B clinical trial utilizing a non-randomised, open-label, effectiveness-implementation hybrid type 3 design. The study will take place in two fixed primary healthcare facilities and one linked roving mobile clinic in the Tshwane region, South Africa. Clients aged 16–65 years accessing comprehensive sexual and reproductive health services at the sites will be invited to enrol in the prospective cohort and offered a choice of L4P or oral PrEP. Clinical and socio-behavioural data will be collected over 12 months, with participants free to switch, discontinue and restart either PrEP product for the duration of the study. Ongoing safety monitoring will be conducted, with pregnancy and birth outcomes captured from pregnant participants, as well as HIV drug resistance monitoring in those who seroconvert. In-depth qualitative data will be collected from a sub-set of cohort participants to understand reasons for L4P use, as well as from healthcare providers involved in L4P delivery to explore health system requirements for implementation. Outcomes of the study will be guided by the RE-AIM framework and include patterns of use (uptake, adherence, persistence, continuation, switching, re-initiation, discontinuation), effectiveness (pregnancy and birth outcomes, seroconversions, adverse events) and facilitators and barriers to implementation. The LEN4PrEP study will provide real-world data on L4P implementation when offered within existing HIV prevention services in public health settings in South Africa, offering a more generalisable reflection on use, service delivery, effectiveness and safety. The data generated can be used alongside programmatic data to inform demand forecasting, training and planning for the national roll-out of L4P. South African National Clinical Trials Registry, DOH-27-102025-4927 ( https://sanctr.samrc.ac.za/TrialDisplay.aspx?TrialID=13831 ). Registered on 22 April 2025.