Background: Long-acting injectable HIV pre-exposure prophylaxis (PrEP), including Lenacapavir, has the potential to accelerate HIV incidence declines in eastern and southern Africa (ESA). However, high product and delivery costs and constrained budgets necessitate efficient prioritization strategies to maximize impact and achieve cost-effectiveness. Methods: We used district-level HIV incidence estimates published by UNAIDS to estimate the direct health and economic impact of prioritizing Lenacapavir delivery according to geography, age, and sex across 837 districts in 11 high-burden ESA countries. Infections and disability-adjusted life years (DALY) averted, number needed to treat (NNT), cost per DALY averted, and price thresholds to achieve cost-effectiveness were estimated across geographic prioritization scenarios. Cost-effectiveness was assessed against a $500 per DALY averted threshold, assuming $5,000 discounted lifetime HIV treatment costs and 10 DALYs per HIV infection. Sensitivity analyses varied Lenacapavir costs (commodities + delivery) per person per year (pppy) ($125 versus $55), DALYs per HIV infection (7.5), and the risk differentiation among those who uptake long-acting PrEP. Results: HIV incidence varied substantially across ESA, with 50% of new infections in districts containing less than 20% of at-risk adults. Lenacapavir cost-effectiveness varied accordingly, with high-incidence districts exhibiting substantially lower NNT and higher price thresholds for cost-effective delivery. In high-incidence districts, [>5/1,000 person-years (py)], of South Africa, Mozambique, Lesotho, and eSwatini, Lenacapavir would be cost-effective at $50-100 pppy. In South Africa, at annual cost $55 pppy, Lenacapavir was cost-effective in all 52 districts when provided to women aged 15-24 years with incidence exceeding twice the district average and could reach approximately 18-20% of new infections while covering 4% of the full HIV-negative adult population aged 15-49 years. Geographically optimized prioritization in South Africa with minimal age and risk-group stratification achieved efficiency comparable to country-level prioritization to high-risk groups and key populations (~20% incidence reduction with 3-5% coverage). Impact and cost-effectiveness were sensitive to assumptions about risk heterogeneity. Conclusions: Lenacapavir impact and cost-effectiveness varies substantially across geographic settings, driven primarily by variation in HIV incidence. Simple incidence-based models can identify where universal provision to certain demographic groups is both impactful and cost-effective, particularly in high-incidence districts and age groups.
