OBJECTIVES: Six-monthly injectable lenacapavir is a promising investigational product for HIV pre-exposure prophylaxis (PrEP). However, the health and budget impact and threshold price at which lenacapavir could be cost-effective in Africa is unknown.

METHODS: We utilized an agent-based model, EMOD-HIV, to simulate realistic lenacapavir uptake in Zimbabwe, South Africa, and western Kenya. Uptake assumptions were informed by a systematic review of long-acting PrEP preferences and varied by subgroup modeled. We assumed lenacapavir implementation from 2026-2036 at 32-40% coverage among female sex workers (FSWs), male clients of FSWs, adolescent girls/young women, and adults in multiple partnerships (base-case); we also assessed a higher uptake scenario of 64-72% coverage among subgroups. We estimated maximum per-dose lenacapavir price that achieved cost-effectiveness (<US$500/disability-adjusted life-year averted) and 5-year budget impact, compared to a scenario of daily oral PrEP only. Costs (2021 USD from payer perspective) were based on literature review and expert opinion.

RESULTS: In the base-case, lenacapavir was projected to achieve 1.4-3.5% population coverage across settings and avert 12.3-18.0% of infections. Maximum per-dose price was highest in South Africa ($106.30), followed by Zimbabwe ($21.10), and lowest in western Kenya ($16.60). The 5-year budget impact (in millions) was US$507 in South Africa, US$17 in Zimbabwe, and US$4 in western Kenya. In high-uptake scenarios, lenacapavir prevented 21.2-31.0% of infections at 2.7-6.9% population coverage with a lower maximum per-dose price: US$88.3 (South Africa), US$17.7 (Zimbabwe), and US$14.8 (western Kenya). The 5-year budget impact (in millions) were US$835 in South Africa, US$29 in Zimbabwe, and US$7 in western Kenya. Lenacapavir drug costs made up the majority of the budget impact.

CONCLUSIONS: Lenacapavir can avert substantial HIV incidence at affordable costs if delivered at cost-effective prices, which vary by setting and level of uptake. Setting-specific estimates like these can inform policy deliberations regarding lenacapavir pricing and resource planning.