Lenacapavir (YEZTUGO), a Twice-Yearly Injectable Drug To Prevent Sexually Acquired HIV Infection

In June 2025 the Food and Drug Administration (FDA) approved lenacapavir (YEZTUGO) for preexposure prophylaxis (PrEP) to reduce the risk of sexually acquired human immunodeficiency virus (HIV) infection.[1] Lenacapavir is administered subcutaneously (just below the surface of the skin) every six months and is indicated for adults and adolescents weighing at least 35 kilograms (77 pounds) who are at risk of contracting HIV.[2]

The approval of lenacapavir for HIV prevention offers an alternative to daily oral PrEP drugs. Lenacapavir also offers long-lasting protection against HIV, although the drug is not a vaccine in the traditional sense.[3]

The FDA has also approved cabotegravir (APRETUDE), a long-acting injectable form of PrEP for people at risk of contracting HIV through sex.[4],[5] Unlike lenacapavir, however, cabotegravir must be given every other month.

Access to lenacapavir will be limited by insurance coverage and the anticipated list price (approximately $28,000 per year, even as some estimate the drug could be profitably made and distributed for less than $100).[6],[7] Ensuring widespread availability of lenacapavir in low- and middle-income countries will be particularly challenging.[8]

Lenacapavir, the first drug of its type, acts by disrupting the virus’s protective outer covering (capsid), thereby preventing proper assembly of the virus when it reproduces in an infected individual’s cells.[9] The drug was first approved in 2022 for adults with HIV infection who fail to respond to other HIV drugs because of resistance or adverse effects.

Marketed as SUNLECA, lenacapavir is initiated by HIV-infected individuals as either oral tablets or as subcutaneous injections, followed by injections every six months.[10]

In contrast, people who take lenacapavir to prevent HIV infection must be tested for HIV prior to beginning the treatment and before each subsequent injection to confirm that they remain uninfected. The lenacapavir PrEP label has a boxed warning, the most prominent warning that the FDA can require, for the risk of drug resistance with use of the drug for PrEP if a person has undiagnosed HIV infection. PrEP does not protect against other sexually transmitted infections.

Background on HIV

HIV infects cells in the body that are critical for the maintenance of an immune response.[11] Left untreated, HIV infection usually progresses to acquired immunodeficiency syndrome (AIDS).

In 2022 there were approximately 1.2 million HIV-infected individuals in the United States[12] and about 4,200 HIV-related deaths, three-quarters of which occurred in people younger than 65 years.[13] Also in 2022, 67% of the more than 31,000 new HIV infections were attributed to men having sex with men, 22% to heterosexual intercourse, and 7% to injection drug use.

Since HIV was first recognized as a major threat to human health in the 1980s, at least 25 drug treatments have been developed, some of which are very effective.[14] These antiretroviral drugs block different steps critical to HIV proliferation, including one step that involves reverse transcription of messenger RNA (mRNA) to DNA (typically, cells make proteins by converting their DNA code into mRNA). Most HIV treatments must be taken daily and involve combinations of medicines with adverse effects; resistance to the evolving virus frequently develops.

Clinical trials of lenacapavir for HIV prevention

The efficacy and safety of lenacapavir for HIV prevention was evaluated in two phase 3, randomized, double-blind, active-control clinical trials, called PURPOSE 1 and 2.[15] The active control was one of two daily oral PrEP medications, a combination of emtricitabine with either tenofovir disoproxil fumarate (TRUVADA and generics)[16] or with tenofovir alafenamide fumarate (DESCOVY and generics).[17] Placebo injections or pills were used to maintain blinding. The participants were HIV negative before starting treatments and were at increased risk of contracting the virus based on sexual activity with male partners. Results of both trials were published in the New England Journal of Medicine in 2024[18] and 2025.[19]

Participants in PURPOSE 1 were cisgender (identity matches sex at birth) females age 16 to 25 years in South Africa and Uganda. They were randomized to receive either lenacapavir PrEP injections every six months (n=2,134), or placebo injections every six months plus daily oral emtricitabine with tenofovir alafenamide fumarate (n=2,136) or emtricitabine with tenofovir disoproxil fumarate (n=1,068).

Participants in PURPOSE 2 were cisgender and transgender men, transgender women, or nonbinary individuals age 17 to 74 (mean=29) years who lived in Argentina, Brazil, Peru, South Africa, Thailand or the United States. They were randomized to receive either lenacapavir PrEP injections (n=2,179) or placebo injections and daily emtricitabine with tenofovir disoproxil fumarate (n=1,086).

Both trials were stopped early because of significant results favoring lenacapavir PrEP; only half of all participants were followed for at least 52 weeks. PURPOSE 1 found that for every 100 person-years of follow-up there were no (zero) HIV infections in the lenacapavir group, compared with the significantly higher rates of 1.7 and 2.0 infections per 100 person-year of follow-up in the emtricitabine with tenofovir disoproxil fumarate and emtricitabine with tenofovir alafenamide groups, respectively.

PURPOSE 2 found a similar benefit for lenacapavir injections as compared with daily emtricitabine with tenofovir disoproxil fumarate: 0.1 infections and 0.9 infections, respectively, per 100 person-years of follow-up.

Further confirming these results, background HIV incidence in untreated people, calculated using data from the few months leading up to randomization, was higher than for any of the three PrEP regimens: 2.4 per 100 person-years in both PURPOSE 1 and PURPOSE 2.

No safety concerns were identified in either trial. However, acute injection-site reactions (nodules) were markedly more common with lenacapavir than placebo injections; in PURPOSE 1, such reactions led to discontinuation of lenacapavir injections in about 1% of participants.

The other common adverse effects associated with lenacapavir were headache and nausea; these occurred in 4.7% of the PURPOSE 1 or 2 participants, although they were less likely with lenacapavir than emtricitabine with tenofovir disoproxil fumarate. As lenacapavir has only been marketed since 2022, information about potential longer-term adverse effects is not yet available.

The drug label for lenacapavir PrEP notes that risk estimates regarding pregnancy effects are uncertain owing to small sample sizes. So far, no drug-associated risks for miscarriage or adverse fetal outcomes have been identified when the drug is compared with other PrEP medications. Studies in pregnant rabbits and rats have revealed “no significant toxicological effects” on embryos, fetuses or newborns. Surveillance of pregnancy effects is ongoing through a registry.

People who use either lenacapavir PrEP or other PrEP medications remain at high risk of other sexually transmitted diseases, such as chlamydia, gonorrhea and syphilis. In PURPOSE 2, post-treatment data showed that over 10% of lenacapavir or emtricitabine with tenofovir disoproxil fumarate users experienced a chlamydia or gonorrhea infection. In PURPOSE 1 (cisgender women), chlamydia infection rates across all three PrEP regimens were 12-15% and gonorrhea rates were approximately 7%.

What You Can Do

If you are concerned that you are at high risk of contracting HIV because of your sexual activity or drug-use behavior, or because your partner is infected with the virus, discuss your PrEP options with a clinician. Daily oral PrEP is only effective if medications are taken every day as prescribed.

Lenacapavir is administered once every six months; at present it is highly effective and has not raised safety concerns. Be aware that PrEP does not prevent other sexually transmitted diseases, so condom use and regular medical visits are important.
 

References

[1] Cohen J. Always ‘one atom away’: The long, rocky journey to an HIV prevention breakthrough. Science. June 20, 2025. https://www.science.org/content/article/always-one-atom-away-long-rocky-journey-hiv-prevention-breakthrough. Accessed July 4, 2025.

[2] Gilead Sciences. Label: lenacapavir (YEZTUGO). June 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/220018s000lbl.pdf. Accessed July 4, 2025.

[3] Pao W. The decades-long journey to Gilead’s twice-a-year HIV prevention drug lenacapavir. STAT. June 23, 2025. https://www.statnews.com/2025/06/23/fda-approval-lenacapavir-yeztugo-gilead-history-development-breakthrough-william-pao/. Accessed July 4, 2025.

[4] ViiC Healthcare. Label: cabotegreavir (ARETUDE). April 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/215499s009lbl.pdf. Accessed July 21, 2025.

[5] HIV.gov. Pre-exposure prophylaxis. July 9, 2025. https://www.hiv.gov/hiv-basics/hiv-prevention/using-hiv-medication-to-reduce-risk/pre-exposure-prophylaxis. Accessed July 21, 2025.

[6] Mandavilli A. Regulators approve a twice-yearly shot to prevent H.I.V. infection. New York Times. June 18, 2025.

[7] Gray GE, Venter WDF. Working at Cross-PURPOSEs to Ending HIV. N Engl J Med. 2025 Apr 3;392(13):1344-1345.

[8] Public Citizen. Lenacapavir campaign. https://www.citizen.org/article/lenacapavir-campaign/. Accessed July 21, 2025.

[9] Pao W. The decades-long journey to Gilead’s twice-a-year HIV prevention drug lenacapavir. STAT. June 23, 2025. https://www.statnews.com/2025/06/23/fda-approval-lenacapavir-yeztugo-gilead-history-development-breakthrough-william-pao/. Accessed July 4, 2025.

[10] Gilead Sciences. Label: lenacapavir (SUNLENCA). November 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/215973s006,215974s008lbl.pdf. Accessed July 4, 2025.

[11] HIV.gov. What are HIV and AIDS? July 26, 2023. https://www.hiv.gov/hiv-basics/overview/about-hiv-and-aids/what-are-hiv-and-aids. Accessed July 4, 2025.

[12] HIV.gov. U.S. statistics. February 21, 2025. https://www.hiv.gov/hiv-basics/overview/data-and-trends/statistics. Accessed July 4, 2025.

[13] Centers for Disease Control and Prevention. Diagnoses, deaths, and prevalence of HIV in the United States and 6 territories and freely associated states, 2022. HIV Surveillance Report, 2022. May 2024. https://stacks.cdc.gov/view/cdc/112160. Accessed July 4, 2025.

[14] Fletcher CV. Overview of antiretroviral agents used to treat HIV. UpToDate. May 2025.

[15] Gilead Sciences. Label: lenacapavir (YEZTUGO). June 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/220018s000lbl.pdf. Accessed July 4, 2025.

[16] Gilead Sciences. Label: emtricitabine and tenofovir disoproxil fumarate (TRUVADA). April 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/021752s064lbl.pdf. Accessed July 4, 2025.

[17] Gilead Sciences. Label: emtricitabine and tenofovir alafenamide (DESCOVY). https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/208215s023s025lbl.pdf. June 2025.

[18] Bekker LG, Das M, Abdool Karim Q, et al. Twice-Yearly lenacapavir or daily F/TAF for HIV prevention in cisgender women. N Engl J Med. 2024;391(13):1179-1192.

[19] 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(13):1261-1276.