Background The use of cost-effectiveness modeling to guide decisions on biomedical HIV prevention modalities such as pre-exposure prophylaxis (PrEP) remains an emerging activity in Eswatini. We determined the cost-effectiveness of PrEP scale-up scenarios in Eswatini using local epidemiological, programmatic, and cost data. Methods We used a validated HIV transmission model calibrated to Eswatini to evaluate scale-up of LA-PrEP, oral PrEP, ring PrEP, including "choice-based PrEP" option targeting key populations: adolescent girls and young women 15–24 years [AGYW], adolescent boys and young men 15–23 years [ABYM], males aged 24–35, female sex workers [FSW], men who have sex with men [MSMs], and people with at least one conditions of alcohol, substance and mood (CASM). Interventions were simulated at 10%, 50%, and 70% coverage over an 8-year horizon, from a payer's perspective. Outcomes included HIV infections averted, QALYs gained, and cost-effectiveness metrics, with costs and outcomes discounted at 3%. Findings Targeting FSW with LA-PrEP was the most cost-effective strategy, projected to avert 200–1500 additional infections through 2030 costing US$2300 per infection averted (US$2293–US$3675 per QALY gained). Sequentially adding MSM and AGYW averted 1541 and 5312 additional infections at US$13,220 and US$19,418 per infection averted respectively. Expanding coverage to all populations averted 9623 infections but at far higher cost (US$69,041 per infection averted; 112,033 per QALY gained). Offering choice-based PrEP slightly increases the ICERs. Interpretation The most cost-effective PrEP scale-up strategies involved LA-PrEP and or choice-based PrEP, but never oral PrEP alone. These findings underscore the importance of maintaining PrEP choice. Funding This work was supported by NIH National Institute on Alcohol Abuse and Alcoholism grants R01-AA027481, R01-AA027976.
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Ngcamphalala et al. (2026) studied this question.