FDA approves a twice-yearly injection for HIV prevention

The US Food and Drug Administration has approved lenacapavir, sold as Yeztugo, for pre-exposure prophylaxis to reduce the risk of sexually acquired HIV-1 in adults and adolescents weighing at least 35 kg who are at risk of acquiring the virus [s1]. The application was received on 19 December 2024 and approved on 18 June 2025 [s1].

The significance is the dosing interval. Every previously available oral prophylaxis regimen has to be taken daily. Lenacapavir is given by subcutaneous injection twice a year.

What the two trials found

Approval rests on two phase 3 trials, PURPOSE 1 and PURPOSE 2, both published in the New England Journal of Medicine before the approval.

PURPOSE 1 enrolled adolescent girls and young women in South Africa and Uganda [s2]. Participants were assigned in a 2:2:1 ratio to subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine-tenofovir alafenamide (F/TAF), or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF) as active control, with everyone also receiving the alternate placebo [s2]. Among 5,338 participants who were HIV-negative at the outset, 55 incident infections occurred: none among the 2,134 participants assigned to lenacapavir, 39 among 2,136 on F/TAF (2.02 per 100 person-years, 95% CI 1.44 to 2.76), and 16 among 1,068 on F/TDF (1.69 per 100 person-years, 95% CI 0.96 to 2.74) [s2]. Background incidence in the screened population of 8,094 was 2.41 per 100 person-years (95% CI 1.82 to 3.19) [s2].

Adherence to both oral regimens was low, which the trial reports plainly [s2]. That matters for interpreting the comparison: the daily pills were not failing pharmacologically so much as failing to be taken.

PURPOSE 2 enrolled cisgender men, transgender women, transgender men and gender-nonbinary people, randomised 2:1 to lenacapavir every 26 weeks or daily oral F/TDF [s3]. Among 3,265 participants in the modified intention-to-treat analysis, two infections occurred in the lenacapavir group (0.10 per 100 person-years, 95% CI 0.01 to 0.37) and nine in the F/TDF group (0.93 per 100 person-years, 95% CI 0.43 to 1.77), against a background incidence of 2.37 per 100 person-years in the 4,634 screened (95% CI 1.65 to 3.42) [s3]. The incidence rate ratio against background was 0.04 (95% CI 0.01 to 0.18; P<0.001) [s3].

What the trials did not settle

Neither trial was a conventional superiority test against a fully adherent comparator, because the comparator was not fully adherent. Both used background incidence in the screened population as the primary reference — a design choice that is defensible when a placebo arm would be unethical, but which produces an efficacy estimate anchored to an estimate rather than to a randomised control [s2][s3].

Tolerability was dominated by injection-site reactions. In PURPOSE 1 these occurred in 68.8% of the lenacapavir group against 34.9% of the pooled placebo-injection group, and four participants (0.2%) stopped the regimen because of them [s2]. In PURPOSE 2, 26 of 2,183 participants (1.2%) in the lenacapavir group discontinued for injection-site reactions, against 3 of 1,088 (0.3%) on F/TDF [s3]. Neither trial identified other safety concerns [s2][s3].

The FDA waived the paediatric study requirement for ages from birth to under 16, on the grounds that trials of sexually transmitted infection prophylaxis in a population that is not sexually mature would be impracticable [s1]. The approved population therefore begins at adolescents weighing at least 35 kg [s1].

The testing problem

The indication itself carries a condition: individuals must have a negative HIV-1 test before starting [s1]. This is not a formality. A drug given twice a year to someone with undiagnosed infection amounts to prolonged exposure to a single agent, which is the standard route to resistance. The trials do not answer how reliably repeat testing will happen in routine practice as opposed to trial conditions, where testing was protocolised.

That gap between trial conditions and delivery conditions is where the interesting questions now sit. A six-month injection removes the daily adherence problem and replaces it with a twice-yearly attendance problem — easier in most respects, but not free, and dependent on a health system that can find the same person again half a year later.

A second HIV prevention decision the same week

Regulators on the other side of the Atlantic acted on a different prophylaxis product in the same period. At its 16-19 June meeting, the European Medicines Agency's human medicines committee recommended extending the indication of the Dapivirine Vaginal Ring 25 mg — a ring first approved in July 2020 to reduce the risk of HIV-1 acquisition through vaginal intercourse in women aged 18 and over — to include women from 16 years of age [s4]. That opinion was adopted under EU-Medicines for all, the procedure by which the agency assesses medicines intended for use outside the European Union [s4].

The two decisions point in the same direction: prevention products that do not depend on a daily pill, and populations younger than the ones originally studied.

What to watch

Whether lenacapavir prophylaxis reaches the settings where PURPOSE 1 recruited. The trial that produced the zero-infection result was conducted in South Africa and Uganda; the approval announced this month is a United States marketing authorisation [s1][s2]. Access outside high-income markets depends on pricing, registration in each country and supply, none of which the FDA decision addresses.

Also worth watching: how HIV testing before each injection is implemented, given that the approved indication makes a documented negative test a precondition rather than a recommendation [s1].

Sources

• [s1] NDA 220018 approval letter — Yeztugo (lenacapavir) injection, for subcutaneous use. US Food and Drug Administration, 18 June 2025. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2025/220018Orig1s000ltr.pdf
• [s2] Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women. New England Journal of Medicine, 24 July 2024. https://doi.org/10.1056/NEJMoa2407001
• [s3] Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons. New England Journal of Medicine, 27 November 2024. https://doi.org/10.1056/NEJMoa2411858
• [s4] Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 16-19 June 2025. European Medicines Agency, 20 June 2025. https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-16-19-june-2025