Twice-Yearly Lenacapavir Approval Marks Major Milestone in Prevention of HIV

Prevention of HIV has become even easier with the FDA approval of lenacapavir (Yeztugo; Gilead Sciences), a twice-yearly long-acting injectable treatment that can prevent HIV in those who receive the treatment.¹ For those who prefer an injectable form of pre-exposure prophylaxis (PrEP), this approval reduces the number of injections needed from 6 per year to just 2, potentially improving adherence in those who had difficulty attending bimonthly clinic appointments.

The approval of lenacapavir offers a means of preventing HIV that only requires 2 doses per year | Image credit: Corona Borealis - stock.adobe.com

Lenacapavir had previously been approved as a method of antiretroviral therapy (ART) in December 2022.² The approval was aimed at treating patients with limited options for treatment due to treatment resistance, safety, or intolerance. The capsid inhibitor attacks the protein shell of the HIV-1 virus, which prevents the viral lifecycle. The treatment could be given every 6 months in combination with other ART. At the same time as this method of ART was being approved, scientists were working on establishing whether the capsid inhibitor could also work in prevention.

The FDA approval of lenacapavir for use as PrEP is based on the results of the phase 3 trials PURPOSE 1 and PURPOSE 2, whose interim findings were published in the New England Journal of Medicine. The PURPOSE 1 trial was initiated in August 2021 and enrolled cisgender women from South Africa and Uganda.³ The researchers split the 5338 participants in a 2:2:1 ratio to receive either lenacapavir twice per year, daily oral emtricitabine-tenofovir alafenamide (F/TAF), or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF).⁴

PURPOSE 1’s results, published in 2024, indicated that none of the women included in the lenacapavir group had contracted HIV by the end of the trial compared with 39 in the F/TAF group and 16 in the F/TDF group. The researchers also found that adherence to F/TAF and F/TDF was low. Patients in the lenacapavir group reported more injection site reactions compared with the placebo groups (68.8% vs 34.9%), and 0.2% of the participants in the lenacapavir group discontinued the treatment due to these reactions.

The results of PURPOSE 2 were also published in 2024 and focused on men and gender-diverse individuals, including transgender women, transgender men, and gender nonbinary individuals.⁵ The PURPOSE 2 trial compared lenacapavir twice-yearly with F/TDF in this population, with the incidence of HIV acting as the primary end point in the 3265 participants. Through the end of the analysis, only 2 individuals in the lenacapavir group had contracted the virus compared with 9 in the F/TDF group. Although no safety concerns were found, 1.2% of those in the lenacapavir group discontinued the treatment due to injection site reactions.

These results indicated a promising new method of preventing HIV that was nearly 100% effective and only needed to be taken twice per year when compared with oral PrEP that needs to be taken daily and cabotegravir (Apretude; ViiV Healthcare) that needs to be taken 6 times per year. The major concern, according to the principal investigators, is affordability and accessibility to vulnerable populations. Gilead Sciences has claimed that they still intend to supply lenacapavir to low-income countries even though funding for overseas HIV aid has been reduced significantly by the Trump administration.⁶ When it comes to accessibility and affordability in the US, the answer is less clear.

According to Colleen Kelley, MD, MPH, professor of medicine in the Department of Infectious Diseases at Emory University and a principal investigator on PURPOSE 2, the supply of lenacapavir should not be a problem, as it’s already been approved for use in HIV treatment. However, whether it will be covered by insurance is less certain.

“What will the assistance look like for people that don't have health insurance? Which health insurance programs will cover it, which will not? All of that kind of remains to be seen,” she said. “That's where the devil's in the details, and that's where delays in access are potentially barriers to people getting it if their insurance company doesn't cover it for whatever reason, if people can't afford the medication for whatever reason.”

Gordon Crofoot, MD, PA, president and principal investigator at The Crofoot Research Center, expressed similar concerns, “I've loved the drug from the beginning. I love the way it works. I love that it's easy to use, long-acting, and doesn't have side effects, but it's going to be hard for me to use this drug for PrEP initially, with the finances… That's going to be the biggest problem to getting this drug going.”

Despite that, Onyema Ogbuagu, MBBCh, FACP, FIDSA, associate professor of medicine (AIDS) and of pharmacology at Yale School of Medicine and a principal investigator on PURPOSE 2, is excited for the prospect of lenacapavir when it comes to getting different kinds of people on PrEP that perhaps wouldn’t be inclined to due to the current methods of distribution.

“A twice-yearly injection can make us totally reimagine the kind of people we can get on PrEP, including people who may think intramuscular injection is too frequent for them [and] those who don't really like orals. But the huge driver of the uptake would also be its affordability and access, as you can imagine,” he said.

References

1. Yeztugo (lenacapavir) is now the first and only FDA-approved HIV prevention option offering 6 months of protection. News release. Gilead Sciences. June 18, 2025. Accessed June 18, 2025. 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.

2. FDA approves new HIV drug for adults with limited treatment options. News Release. FDA. December 22, 2022. Accessed June 13, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-new-hiv-drug-adults-limited-treatment-options

3. Guinle MIB. A new way to prevent HIV delivers dramatic results in trial. NPR. July 3, 2024. Accessed June 13, 2025. https://www.npr.org/sections/goats-and-soda/2024/07/03/g-s1-7988/hiv-prevention-drug-clinical-trial

4. Bekker LG, Das M, Karim QA, et al. Twice-yearly lenacapavir or daily F/TAF for HIV prevention in cisgender women. N Engl J Med. 2024;391:1179-1192. doi:10.1056/NEJMoa2407001

5. Kelley CF, Acevedo-Quiñones M, Agwu AL, et al. Twice-yearly lenacapavir for HIV prevention in men and gender-diverse persons. N Engl J Med. 2025;392:1261-1276 doi:10.1056/NEJMoa2411858

6. Steenhuysen J, Beasley D. Gilead commits to HIV prevention rollout for low-income countries despite funding uncertainty. Reuters. May 30, 2025. Accessed June 13, 2025. https://www.reuters.com/business/healthcare-pharmaceuticals/gilead-commits-hiv-prevention-rollout-low-income-countries-despite-funding-2025-05-30/