Optimising scale-up of injectable lenacapavir for HIV pre-exposure prophylaxis in South Africa: A modelling study and economic evaluation

BACKGROUND: South Africa accounts for 20% of global HIV infections. Six-monthly injectable lenacapavir (LEN) for HIV pre-exposure prophylaxis (PrEP) has superior efficacy to oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), and similar efficacy to 2-monthly injectable cabotegravir (CAB). With LEN's regulatory approval, South Africa faces critical implementation decisions amid constrained domestic resources and reduced international funding. We evaluated the epidemiological impact, cost-effectiveness, and optimal populations for LEN roll-out in South Africa. METHODS AND FINDINGS: Using Thembisa v4.8, a deterministic compartmental HIV transmission model, we simulated the impact of LEN scale-up, expanded oral TDF/FTC, and CAB scale-up, compared to a baseline of current TDF/FTC provision over 20 years (2026-2045) in South Africa. We modelled PrEP among women, including adolescent girls and young women (AGYW), female sex workers (FSW), pregnant and breastfeeding women (PBFW), men who have sex with men (MSM), and heterosexual men. For TDF/FTC scale-up, we doubled baseline initiation rates. For LEN and CAB, conservative and optimistic scenarios assumed initiation rates similar to or double those under TDF/FTC scale-up, respectively. Duration of use varied by subpopulation under TDF/FTC (3-6 months), conservative (LEN: 6-12 months, CAB: 4-8 months), and optimistic (LEN: 12-24 months, CAB: 8-16 months) scenarios. We modelled strategies to maximise impact of ~500,000 LEN doses allocated for 2026-2027, and national roll-out by subpopulations. We compared LEN cost-effectiveness to other HIV interventions, including antiretroviral treatment (ART). Costs are presented from the South African government's perspective in undiscounted 2025 United States Dollars (USD). Providing LEN to 1.7-2.9 million South Africans annually averted 19%-31% of infections and saved 3%-5% of life years lost to HIV, reaching incidence