Taking injectable PrEP to scale: Optimising the value of lenacapavir for South Africa's HIV response

BackgroundSouth Africa accounts for 20% of the global HIV infections and has one of the highest HIV incidence rates in the world. 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 LENs recent regulatory approval and the newly negotiated generic price of $40 per person per year, South Africa faces critical implementation decisions amid constrained domestic resources and reduced international funding. We evaluated the epidemiological impact on HIV infections and life years lost, cost-effectiveness, and optimal populations for LEN roll-out in South Africa. Methods and FindingsUsing Thembisa v4.8, a deterministic compartmental HIV transmission model of the South African HIV epidemic, 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). We scaled PrEP among 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). We modelled strategies to maximise the impact of ~500,000 LEN doses currently allocated for 2026-2027, or large-scale roll-out. Costs are presented from the South African governments perspective in undiscounted 2025 USD. Providing LEN to 1.7-2.9 million South Africans per year averted 19-31% of infections and saved 3-5% of life years anticipated to be lost to HIV, reaching incidence <0.1% in 2039-2043, 10-14 years earlier than baseline. Estimating the number of individuals needed to initiate each PrEP type to avert one HIV infection, LEN required 35-65 initiations/infection averted, compared to CAB (45-125 initiations/infection averted) and TDF/FTC (280 initiations/infection averted). TDF/FTC and conservative LEN scale-up increased HIV programme costs by 3%; however, LEN was more cost-effective, costing $2,301-$3,567/life year saved (LYS) versus $8,143/LYS (TDF/FTC scale-up) and $11,114-$16,118/LYS (CAB). Prioritising PBFW, MSM, and FSW for the initial allocation maximized infections averted. Large-scale roll-out strategies prioritizing FSW and MSM were most cost-effective ($276-$958/LYS). Limitations to this study include uncertainty in achieving modelled uptake and assumptions of risk-differentiated uptake of long-acting products, and limited data on real-world implementation costs. InterpretationDelivering LEN to persons with elevated HIV risk in South Africa is more cost-effective than existing PrEP options and can speed up HIV incidence reduction. Prioritising uptake among groups at highest risk is essential to maximise impact and cost-effectiveness.