ALIGN: A Non-randomised Study Delivering Injectable Lenacapavir for HIV Prevention Within a Pre-exposure Prophylaxis (PrEP) Choice Context in Cape Town, South Africa.

The ALIGN study will evaluate the delivery of injectable Lenacapavir (LEN), a long-acting injectable formulation for HIV pre-exposure prophylaxis (PrEP), amongst adolescents and young people (aged 15-35 years) living within the Klipfontein-Mitchell's health sub-district of Cape Town, South Africa. LEN will be offered alongside injectable Cabotegravir long-acting (CAB LA), an injectable PrEP product already approved for use in South Africa, and oral PrEP (F/TDF) modalities (including intermittent dosing where appropriate), the current standard of care (SOC) biomedical HIV prevention in South Africa. Following counselling, participants will be able to choose which PrEP product (LEN, CAB LA, or oral PrEP) to initiate, with the option to switch at any future clinical visit, and followed for 18 months. These options will be offered from two types of delivery sites, namely public health facilities and established mobile service delivery trucks, where various forms of PrEP are currently delivered as part of outreach services and ongoing research studies (FastPrEP UCT HREC nr. 713/2021 and PrEPared to Choose 567/2023).

Lenacapavir (LEN) is a novel, first-in-class, multi-stage HIV-1 capsid inhibitor with high potency and a long half-life, allowing administration by subcutaneous injection twice yearly (1). The PURPOSE 1 study, a phase 3, double-blind, randomized, controlled trial involved adolescent girls and young women in South Africa and Uganda. Purpose 1 study found that none of the participants receiving twice-yearly LEN injection acquired HIV infection (1). Purpose 2, which was conducted amongst cisgender men who have sex with men, transgender, and non-binary populations, reported two incident infections amongst 2179 LEN users. CAB LA is an alternative long-acting injectable formulation administered by intra-muscular injection every two months. CAB LA efficacy and safety was established in the HPTN 083 and HPTN 084 studies, which indicated a 66% and 88% reduction in HIV risk compared to oral PrEP users respectively. The ongoing PrEPared to Choose study, conducted by this study team, (UCT HREC 567/2023) offers CAB LA and oral PrEP products and has demonstrated the feasibility and impact of many of the PrEP choice and delivery processes put forward in this protocol. As such, this study team has extensive experience in CAB LA and oral PrEP real-world delivery.

The ALIGN study will provide one of the first real-world (outside of the clinical trial research site) evaluations of LEN delivery with the view to evaluate firstly, what implementation strategies best support LEN initiation and persistence at the level of the PrEP provider and the PrEP user, and secondly, persistence (defined as consistent, uninterrupted use as prescribed) on LEN compared to alternative injectable products and SOC oral PrEP. The proposed study will utilise a hybrid implementation study design, with co-primary implementation and clinical aims, in the form of a non-randomised, quasi-experimental trial design. Findings from this study will be used to inform the anticipated LEN rollout into public health facilities (including ANC clinics) as well as the implementation of PrEP choice service delivery in a new era of expanded biomedical HIV prevention products. The addition of LEN will build on the experiences of implementing previous long-acting PrEP products (such as injectable long-acting Cabotegravir) and will generate practical insights to inform the scale of this innovative tool while national regulatory approvals are being sought. This will include working with communities to harness their insights and answering specific questions to support effective delivery and drive uptake and effective use of injectable PrEP (LEN and CAB LA).

Study purpose:

To evaluate the delivery strategies (public health facility and community-based) and potential impact of Lenacapavir (LEN) as PrEP, on the relative persistence of up to 3700 young people (aged 15-35 years) initiating on LEN compared to an alternative injectable product (CAB LA) and oral PrEP products (standard of care).

We hypothesize that people who select injectable PrEP will be more likely to persist on PrEP when compared with people who select oral PrEP, and further that injectable LEN will show enhanced persistence compared to injectable CAB LA.

Primary study objectives:

The primary objectives of this study are to distinguish PrEP persistence patterns across different PrEP modalities (oral PrEP vs injectable CAB vs injectable LEN as PrEP) and identify successful implementation strategies that will aid the provision of PrEP choice to adolescents and young people in South Africa from two distinct delivery platforms (public health facilities and mobile services).