Lenacapavir and the Future of HIV Prevention: PURPOSE Trials, Long-Acting PrEP, and What Comes Next

The PURPOSE trials did not simply add a new option to the HIV prevention toolkit. They reframed what adherence in HIV prevention could look like — and, in doing so, exposed how much of the existing PrEP gap has never been about willingness. In PURPOSE 1, conducted among cisgender women and adolescent girls in sub-Saharan Africa, lenacapavir (Yeztugo; Gilead Sciences), a twice-yearly subcutaneous injectable, reduced HIV incidence by 100% compared with background incidence, with more than 90% of participants receiving injections on time and maintaining protection for 6 months at a stretch.¹

In PURPOSE 2, conducted among gay, bisexual, and other men who have sex with men, transgender women, transgender men, and gender nonbinary individuals across multiple countries, lenacapavir reduced HIV incidence by 96% compared with background incidence.² The contrast with daily oral PrEP adherence in both trials—where fewer than 5% of participants in PURPOSE 1 achieved high and sustained adherence to the daily pill—clarified a point the field has long understood but rarely quantified so starkly: a prevention tool is only as effective as a person’s ability to use it consistently.³

The FDA approved lenacapavir for HIV pre-exposure prophylaxis in June 2025, making it the first long-acting injectable PrEP agent approved in the United States and the first new PrEP mechanism since the approval of cabotegravir in 2021.⁴ The approval arrived against a backdrop of significant structural tension. The CDC estimates that approximately 2.2 million Americans could benefit from PrEP, yet 2024 data from AIDSVu reported approximately 600,000 people using any form of PrEP—a gap that reflects not a shortage of effective options but a web of structural, provider-level, and systemic barriers that have proven resistant to incremental solutions.^5,6 Long-acting options like lenacapavir address one layer of that web—the burden of daily dosing—while the deeper questions of insurance coverage, provider capacity, community trust, and equitable distribution remain unresolved.

READ MORE>>Once-Weekly HIV Pill Meets Phase 3 Endpoints, Advancing Potential First Long-Acting Oral Treatment

In the conversation that follows, conducted as part of Contagion’s HIV Awareness Month series, Jared Baeten, MD, PhD, the senior vice president of clinical development and virology therapeutic area head at Gilead Sciences, and an affiliate professor in the Departments of Global Health, Medicine, and Epidemiology at the University of Washington, addresses the clinical and programmatic implications of the PURPOSE data: what the trial findings reveal beyond topline efficacy, how to think about candidate selection across the expanding PrEP armamentarium, how lenacapavir’s PrEP approval affects the development of next-generation ART regimens, and what the pipeline toward once-yearly and fully injectable first-line HIV treatment actually looks like.

Transcript edited for clarity.

Contagion: What does the PURPOSE trial data tell us that the press releases don’t about lenacapavir?

Jared Baeten, MD, PhD: There is a great deal to the PURPOSE story beyond the topline efficacy results—the 2 decades of discovery and development work that made the trials possible; the deep engagement with community and advocacy from before the trials began all the way through readout, and the team’s unwavering dedication to making a prevention option that responded to the needs of people who wanted something infrequent and private. Along those lines, some of the most compelling data in the trials relates to preexposure prophylaxis (PrEP) adherence. In PURPOSE 1 (NCT05568355), for example, over 90% of women received lenacapavir injections on time, which then meant they had HIV prevention for six months thereafter; in contrast, just 4% of those taking daily oral PrEP achieved high and sustained adherence. HIV prevention only works when people can take it and stay on it consistently. Removing the burden of daily dosing allowed people to remain protected in a sustained way over time.

Contagion: Who is the ideal candidate for lenacapavir-based PrEP vs oral daily PrEP in 2026, and who is not?

Baeten: In the US, the CDC estimates that up to 2.2 million individuals could potentially benefit from preventive HIV medications. In 2024, AIDSVu reported that roughly 600,000 people in the United States used some form of PrEP. Each week, there are still about 700 new HIV infections in the US. Progress has been made, but significant gaps remain.

HIV prevention is not a one-size-fits-all approach, and no single PrEP option is universally optimal for every individual. Instead, the goal should be to give people options so they can make the choice that will work for them, fitting their needs, preferences, and lives.

Lenacapavir-based PrEP—including the twice-yearly injection now and potentially other long-acting options that are still under study—may be especially well suited for people who want an alternative to daily oral dosing. Many people seeking prevention face challenges with adherence because of competing priorities or difficulties taking a pill every day, or prefer more discreet or less frequent regimens for reasons related to privacy or stigma.

Daily oral PrEP remains an important and effective choice for many individuals who are comfortable with a daily routine and have consistent access to care. For some people, the consistency of a daily pill helps sustain adherence. Ultimately, expanding the range of options is key, so more people can start and stay on PrEP with an approach that works best for them.

Contagion: How do the therapeutic pieces fit in the treatment armamentarium now that lenacapavir is approved for PrEP?

Baeten: Like HIV prevention, HIV treatment options should respond to the needs of individuals, and expanding the number of effective options available gives healthcare providers and patients more flexibility to find approaches that work best for them. Gilead is building HIV treatment combinations because all HIV treatment requires a combination of medicines to avoid the virus developing resistance, in contrast to PrEP, where 1 medicine can be sufficient—combining lenacapavir with other long-acting agents. In treatment as in prevention, both oral and injectable options are being evaluated because some people feel confident with a pill taken every day, others prefer a pill taken once a week, and others prefer an injection every 6 months without needing to think about their treatment in between doses. Having lenacapavir approved for HIV prevention is key to advancing next-generation combinations for HIV treatment.

Contagion: What are the real-world access and insurance coverage barriers for long-acting therapies, and how are clinicians navigating them?

Baeten: There are significant barriers to PrEP uptake in the US that need to be overcome in order to expand access to all people who need or want it: stigma, discrimination, provider capacity, logistical hurdles, and low awareness by providers, especially in communities disproportionately affected by HIV.

Multiple studies have found that the cost of PrEP medicines is not a primary barrier to PrEP, and most patients can access prevention with little to no out-of-pocket cost. Lenacapavir for PrEP, for example, has more than 90% coverage, including broad access through major payers and, for most, a $0 copay. In addition, patient support programs, such as Gilead’s Advancing Access program, are available for eligible insured and uninsured individuals who need assistance.

While more PrEP choices help address key barriers to uptake, successful HIV prevention strategies must include a comprehensive approach that can help address these barriers, with multilateral support between healthcare organizations, healthcare providers, community members, payers, consumers, and more.

Contagion: What does the pipeline toward a once-yearly or fully injectable first-line ART regimen actually look like?

Baeten: Gilead’s pipeline reflects a clear ambition to continue advancing innovation across the science of what is possible. Right now, that includes investigating a once-yearly lenacapavir injection, with data expected in the coming year. Gilead recently submitted to the FDA a once-weekly pill version of lenacapavir for HIV prevention, which could be the first long-acting oral PrEP agent. In HIV treatment, Gilead has multiple programs in early- and late-phase clinical trials looking at once-weekly and even once-monthly pills and twice-yearly injections. Across all of these programs, patient needs remain central to the development approach.

References

1. Bekker LG, Rabe L, Spiegel H, et al. Twice-yearly lenacapavir for HIV prevention in women. N Engl J Med. 2024;391(21):1966-1980. doi:10.1056/NEJMoa2407001

2. Landovitz RJ, et al. Lenacapavir for HIV prevention in men who have sex with men and transgender individuals: PURPOSE 2. Presented at: International AIDS Conference; 2024; Munich, Germany.

3. Mayer KH, Molina JM, Thompson MA, et al. Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis. Lancet HIV. 2020;7(1):e8-e17. doi:10.1016/S2352-3018(19)30262-2

4. Gilead Sciences. Yeztugo® (Lenacapavir) Is Now the First and Only FDA-Approved HIV Prevention Option Offering 6 Months of Protection. Published June 2025. Accessed June 2026. https://www.gilead.com/news/news-details/2025/yeztugo-lenacapavir-is-now-the-first-and-only-fda-approved-hiv-prevention-option-offering-6-months-of-protection

5. Centers for Disease Control and Prevention. PrEP for HIV prevention in the US. Accessed June 2026. https://www.cdc.gov/hiv/risk/prep/index.html

6. Smith DK, Van Handel M, Grey J. Estimates of adults with indications for HIV pre-exposure prophylaxis by jurisdiction, transmission risk group, and race/ethnicity, United States, 2015. Ann Epidemiol. 2018;28(12):850-857. doi:10.1016/j.annepidem.2018.05.003