You’ve probably heard of PrEP, pre-exposure prophylaxis, for HIV prevention. For over a decade, the primary form of PrEP has been a daily pill, highly effective in theory, but only if taken every day. The PrEP regimen is safe but not free of side effects including nausea, headaches and diarrhea. In practice, adherence to daily oral PrEP drops off sharply within the first six months of use, drastically weakening its real-world impact.
A new modeling study in the Journal of the International AIDS Society led by Dr. Mia Moore in the Dimitrov Lab at Fred Hutch, in collaboration with Gilead Sciences, asks a timely question: what happens to the US HIV epidemic if a twice-yearly shot replaces the daily PrEP pill?
The original form of PrEP, approved in 2012 is a combination pill containing two antiretroviral drugs that target HIV reverse transcriptase: emtricitabine and tenofovir disoproxil fumarate (together abbreviated F/TDF). In 2019, a newer formulation of tenofovir was approved, leading to the emtricitabine and tenofovir alafenamide (F/TAF) combination pill. Cabotegravir (HIV integrase inhibitor), an intramuscular injection administered every two months, was approved in 2021. In June 2025, the FDA approved lenacapavir (an HIV capsid formation inhibitor), a subcutaneous injection given just twice yearly. Two phase 3 clinical trials (PURPOSE 1 and PURPOSE 2) showed that lenacapavir outperformed daily oral PrEP at preventing HIV. This is an exciting advance, but the real-world impact of a new prevention tool ultimately depends on who ends up adopting its use, and how quickly and consistently they do so.
As lead author Mia Moore explains: "These are the first estimates of the potential population-level impact of injectable lenacapavir for HIV pre-exposure prophylaxis in the United States.As it doesn't require daily adherence, lenacapavir will potentially be much more effective. We used a mixture of real-world and clinical trial data to create an extremely detailed simulation of who was likely to use lenacapavir vs. other forms of PrEP, based on variables such as age, race, gender, geographic region, and insurance status."
To estimate the potential impact, the team constructed a model representing the entire US population aged 15 and older. They divided the population into groups based on demographic characteristics, insurance status, sexual behavior, and intravenous drug use, allowing them to account for differences in HIV risk and PrEP access.
The team combined clinical trial data on the effectiveness of each PrEP option with real-world prescribing data and usage data from IQVIA, a health information technology and clinical research company., The model then projected new HIV diagnoses from 2026 through 2030 under six different adoption scenarios, ranging from a slight increase in lenacapavir use to it becoming the dominant PrEP choice nationwide.
The model projects that if PrEP use grows as expected and lenacapavir uptake rises steadily (37% of PrEP users by 2030), roughly 13,700 new HIV cases averted between 2026 and 2030: an 8% reduction compared to 2025-level PrEP use. If lenacapavir adoption is faster and more complete (85% of users by 2030), that number climbs to nearly 24,000 cases averted. In the most optimistic scenario: every PrEP user on lenacapavir, combined with overall PrEP expansion, the model projects over 37,000 averted cases, translating to roughly a 26% drop in new diagnoses. By comparison, simply expanding PrEP access without introducing lenacapavir at all only prevented about 9,400 cases, underscoring that the drug itself, not just broader access, would be a key factor.
Not everyone is projected to benefit equally, however. Projected benefits were concentrated among men who have sex with men and people with insurance, while uninsured individuals and heterosexual populations saw far smaller reductions—a reflection of existing disparities in PrEP access and usage.
Dr. Moore is already looking ahead: "These estimates were based on current trends in PrEP use. We naturally wondered how much better we could do if lenacapavir were distributed more equitably, and we're currently working on a follow-up paper examining that possibility. We're also looking at applications of the model to other forms of HIV prevention and potentially extending the model past a five-year time horizon."
The spotlighted research was funded by a Gilead Sciences, Inc. and a research grant from Gilead Sciences, Inc. to Fred Hutch Cancer Center.
Moore M, Lee S, Matrajt L, Stansfield SE, Tao L, Yang J, Mezzio D, Jarrett J, Castro JC, Hsiao A, Zachry W, Dimitrov D. 2026. Modelling the 5-Year Impact of Twice-Yearly Injectable Lenacapavir for HIV Pre-Exposure Prophylaxis in the United States. J Int AIDS Soc. doi: 10.1002/jia2.70188.
Science Spotlight writer Kelly Mitchell is a postdoctoral fellow in the Paddison Lab at Fred Hutch Cancer Center. She utilizes live cell reporters and CRISPR screening to study how glioblastoma cancer cells resist chemotherapy and radiation treatment. She obtained her PhD in cellular biology from Albert Einstein College of Medicine.