Two shots a year prevented HIV in 100 percent of women

Investigators of the PURPOSE 1 trial gave lenacapavir every six months to more than 2,000 young women in South Africa and Uganda and recorded zero HIV infections.

A drug aimed at the virus's shell

Every antiretroviral class before lenacapavir attacked an enzyme or a step of entry. Lenacapavir attacks the capsid, the protein shell that packages the viral genome and manages its passage into the nucleus. In 2020, John Link and colleagues at Gilead Sciences described the molecule, then called GS-6207, in Nature. Designed from X-ray crystal structures, it binds a conserved pocket at the interface between capsid protein monomers and disrupts the interactions that the capsid must make at several stages of the replication cycle. It inhibited every HIV-1 subtype tested at picomolar concentrations and showed no cross-resistance with approved drugs.

The property that mattered for prevention was pharmacokinetic. In the phase 1 study reported in the same paper, a single 450 milligram subcutaneous dose in people living with HIV reduced plasma viral load by a mean of 2.2 log10 after 9 days, and plasma concentrations remained at antivirally active levels for more than six months. A drug that could be given twice a year was, for the first time, a chemical fact.

The problem the trial was built to solve

Daily oral pre-exposure prophylaxis prevents HIV when the pills are taken. The PURPOSE 1 investigators, led by Linda-Gail Bekker of the Desmond Tutu HIV Centre at the University of Cape Town, stated the gap in their first sentence: uptake of, adherence to and persistence in daily prevention among cisgender women are all incomplete. The trial was designed to test whether an injection every 26 weeks could close it, in the population where incidence remains among the highest in the world.

How PURPOSE 1 was run

PURPOSE 1 was a phase 3, double-blind, randomised, controlled trial of adolescent girls and young women aged 16 to 25 at 25 sites in South Africa and 3 in Uganda. Participants were assigned 2:2:1 to subcutaneous lenacapavir every 26 weeks, to daily oral emtricitabine-tenofovir alafenamide, or to daily oral emtricitabine-tenofovir disoproxil fumarate, the established pill and the trial's active control. Every participant also received the matching placebo, an injection or a pill, so that no one knew which active product she was on. Because a placebo-only arm would have been unethical, efficacy was judged against the background HIV incidence measured in the 8,094 women screened for the trial, and against the active control.

Zero of 2,134

Among 5,338 participants who were HIV-negative at entry, 55 acquired HIV during the blinded phase. None of them was in the lenacapavir group. Zero infections occurred among 2,134 women given the injection, an incidence of 0 per 100 person-years with a 95 percent confidence interval of 0.00 to 0.19. In the emtricitabine-tenofovir alafenamide group there were 39 infections among 2,136 women, 2.02 per 100 person-years. In the active control group there were 16 among 1,068, 1.69 per 100 person-years. Background incidence in the screened population was 2.41 per 100 person-years. The incidence rate ratio for lenacapavir against background was 0.00, with an upper confidence bound of 0.04, and against the active control 0.00 with an upper bound of 0.10. Both comparisons gave P values below 0.001.

The oral arms told the other half of the story. Adherence to both pills was low, and the newer pill did not separate from background incidence. Injection-site reactions were common with lenacapavir, 68.8 percent against 34.9 percent in the placebo injection groups, but 4 participants, 0.2 percent, stopped the regimen because of them. No safety concern was identified.

On June 20, 2024, Gilead announced that the independent data monitoring committee had recommended stopping the blinded phase and offering open-label lenacapavir to all participants. The result was already beyond doubt. The paper appeared in the New England Journal of Medicine on October 3, 2024.

The second trial

PURPOSE 2, led by Colleen Kelley of Emory University, tested the same injection in cisgender men, transgender women, transgender men and gender-nonbinary people across a wider geography, randomised 2:1 against the daily pill. Among 3,265 participants in the analysis, 2 infections occurred in the lenacapavir group, 0.10 per 100 person-years, against 9 in the pill group, 0.93 per 100 person-years, with a background incidence of 2.37. The incidence rate ratio against background was 0.04 and against the pill 0.11. Of 2,183 people given lenacapavir, 26, or 1.2 percent, discontinued because of injection-site reactions. The paper was published in the New England Journal of Medicine in April 2025. Two infections is not zero, and the second trial is the more realistic estimate of what the drug does across populations.

Breakthrough of the Year, then approval

On December 13, 2024, Science named lenacapavir its Breakthrough of the Year. The editorial by Holden Thorp called it the next, but by no means final, step in the drive against HIV/AIDS. Jon Cohen's accompanying feature carried the headline "The long shot." On June 18, 2025, the U.S. Food and Drug Administration approved the drug under the name Yeztugo for pre-exposure prophylaxis to reduce the risk of sexually acquired HIV-1 in adults and adolescents weighing at least 35 kilograms.

The scale of the problem the drug addresses is recorded by UNAIDS. By the end of 2025, 44.2 million people had died of AIDS-related illnesses since the start of the epidemic, 41.0 million were living with HIV, and 1.2 million acquired the virus in that year alone.

What the story does and does not show

PURPOSE 1 showed that among 2,134 adolescent girls and young women in South Africa and Uganda, two subcutaneous injections of lenacapavir a year produced no HIV infections during the blinded phase of the trial, against an expected 2.41 per 100 person-years, in a double-blind design with an active control. PURPOSE 2 showed 2 infections among 2,183 people in a broader population, a 96 percent reduction against background. Together they are the strongest prevention results yet recorded for HIV.

A trial result of zero is a measurement over a finite follow-up, and its confidence interval, 0 to 0.19 per 100 person-years, is the honest statement of what was observed. The 100 percent figure describes the PURPOSE 1 blinded period, not the drug in general; the second trial recorded breakthrough infections, and real-world use will involve missed appointments that the trial design minimised. The trials measured sexual acquisition and did not study injection drug use. Lenacapavir prevents infection; it does not treat or cure HIV in people who already have it, and the UNAIDS figure of 44.2 million deaths, slightly higher than the 40 million in the slide text, is a measure of what prevention arrived too late for. The story is a number, zero, that was measured in one trial under controlled conditions and then confirmed as very close to zero in a second.

Zero infections. Two injections. One year.