Background HIV prevalence in prisons is three times higher than in the general community, and ongoing transmission risks highlight the importance of prevention, including pre-exposure prophylaxis (PrEP). We evaluated the effectiveness and cost-effectiveness of prison-based PrEP programs in four US states. Methods We developed a dynamic compartmental model simulating HIV transmission in both general and incarcerated populations, instantiated for four representative US states (standardized population of five million people). We assessed five strategies involving PrEP for specific risk groups in prison compared to the status quo of no PrEP. We assumed 25% uptake among eligible individuals for 20 years. We estimated total lifetime costs (in 2024 USD) and quality-adjusted life-years (QALYs), discounted at 3% annually, incremental cost-effectiveness ratios (ICERs), and HIV infections averted from a healthcare sector perspective. Findings In Washington, New York, and Georgia, providing PrEP to 25% of people who inject drugs (PWID) in prison prevented 12%–14% of new infections in incarcerated people, and 0.01%–0.02% of new infections in the community, and was cost-saving compared to no PrEP. Expanding eligibility to all high-risk persons (PWID and men who have sex with men (MSM)) prevented more infections and cost less than $60,000 per QALY gained compared to more restrictive policies. In California, where the epidemic is concentrated among MSM rather than PWID, providing PrEP to only MSM costs $32,000 per QALY gained. Interpretation Prison-based PrEP programs can be cost-saving or cost-effective, averting infections within and outside the prison system. These findings support expanding access to PrEP in prisons, with implementation and funding decisions guided by local HIV epidemiology. Funding Canada Research Chairs Program, Natural Sciences and Engineering Research Council of Canada, National Institute on Drug Abuse.
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