For years, the usual way to lower the chance of getting HIV before a possible exposure was a pill you had to take every day. A shot given twice a year can now do that job for many people, and the trial results are unusually strong. Whether someone can actually get the shot still depends on price, a clinic visit, and a negative HIV test first.
A daily pill, then a shot on a longer clock
The idea has a plain name: pre-exposure prophylaxis, or PrEP. It means taking medicine before exposure so a virus has a harder time establishing an infection. The first PrEP pill was approved in the United States in 2012. It works, and a lot of people who could benefit still do not stay on it. Gilead, citing Centers for Disease Control and Prevention figures, said that in 2022 only about 36 percent of people in the United States who met eligibility criteria were prescribed some form of PrEP, and that in 2023 more than 100 people a day were diagnosed with HIV.
A shot was already an option before this one. Cabotegravir, sold as Apretude, is an injection given about every two months. Lenacapavir stretches that gap to twice a year. In the United States the prevention brand is Yeztugo. In the European Union the same prevention use is sold as Yeytuo. It is not a vaccine, and it is not a cure. The Food and Drug Administration label is specifically for reducing the risk of sexually acquired HIV-1 in adults and adolescents who weigh at least 35 kilograms and who test negative first.
What the drug grabs onto
Lenacapavir is a capsid inhibitor. The capsid is the protein shell that packs the virus’s genetic material. Most HIV drugs interrupt one step in the virus’s life cycle. This one is designed to get in the way at several stages, and it is a different class from the older pills, so lab tests have not shown the usual cross-resistance to those classes. That is the scientific reason a new shot was possible at all.
The molecule is not brand new. In December 2022 the FDA approved it, under the name Sunlenca, as a treatment for multi-drug-resistant HIV in adults, and only together with other HIV medicines. Yeztugo is the prevention version. Used alone, it is not a complete treatment. That difference is why the label carries a boxed warning: if someone who already has HIV, including a very new infection, takes only this drug, the virus can develop resistance. Clinics are supposed to confirm a negative result with a test suited to recent infection before the first dose and again before every later injection.
How the visits actually work
The schedule is not “one needle and you are done for the year.” On day 1 a clinician gives two small injections under the skin, 927 milligrams in total, plus tablets. On day 2 there is another oral dose. After that, the injection comes back about every 26 weeks, with a window of roughly two weeks on either side. If a visit will be more than two weeks late, tablets taken once a week can bridge the gap for up to six months. If someone goes past 28 weeks without the shot and without those bridge tablets, the starting doses have to begin again.
The drug also lingers. Measurable amounts can remain for 12 months or longer after the last injection. People who stop, and who are still at risk, are advised to start a different form of PrEP within 28 weeks of that last shot. Some other medicines change how long lenacapavir stays in the body, so the prescriber has to check interactions. None of this replaces condoms if the goal is also to avoid other sexually transmitted infections. The shot does not cover those.
What the two big trials found
The FDA approval on June 18, 2025, rested on two phase 3 trials, PURPOSE 1 and PURPOSE 2, both published in the New England Journal of Medicine and both funded by Gilead. Science magazine named lenacapavir its 2024 Breakthrough of the Year, largely because of these results. Gilead’s summary line is that at least 99.9 percent of participants who received the shot in the two trials remained HIV-negative.
PURPOSE 1 enrolled cisgender women and adolescent girls in South Africa and Uganda. Among 2,134 participants on twice-yearly lenacapavir, the published count of new HIV infections was zero. In the screened population the background rate was 2.41 infections per 100 person-years, a way of saying how many infections you would expect in a group followed over time. The daily-pill arms did not look like that. There were 39 infections among 2,136 people on one daily pill combination and 16 among 1,068 on the older daily pill. Adherence to those pills was low. The fair reading is not that daily pills cannot work. It is that a shot removes the need to remember a tablet, and in this trial many people did not keep taking the tablets.
PURPOSE 2 studied cisgender men and gender-diverse people in several countries, including the United States. The journal reported 2 infections in the lenacapavir group, a rate of 0.10 per 100 person-years, against a background rate of 2.37 in the screened population. The daily-pill group had 9 infections, a rate of 0.93. Gilead described the 2 lenacapavir infections as occurring among 2,179 people who received the shot. Two infections is not zero. It is still a large drop compared with both the background rate and the daily pill in that study.
Injection-site reactions were common, which is the expected trade for a medicine that sits under the skin. In PURPOSE 1 they were reported in 68.8 percent of the lenacapavir group, versus 34.9 percent among people who got placebo injections while taking pills. Four people, 0.2 percent, stopped the shot because of those reactions. In PURPOSE 2, about 1.2 percent stopped for the same reason. The most common side effects across the trials, at or above 5 percent, were injection-site reactions, headache, and nausea. The papers did not flag a new major safety problem beyond that.
Who is still left out of the evidence
The trials do not answer every use. A World Health Organization review of the evidence found no prevention studies yet in people who inject drugs. A separate trial, PURPOSE 4, is underway for that group. Until those results exist, it is not honest to talk about the shot as if it had been proven for every route of transmission. The approved United States use is sexual acquisition.
There is also a testing burden that daily pills do not impose in quite the same way. Because the drug lasts so long, a missed diagnosis at the moment of an injection is a bigger problem. Someone with undiagnosed HIV who receives only lenacapavir can grow a resistant virus and then have fewer treatment options. The boxed warning exists for that reason. A fast, cheap test that misses a very recent infection is the wrong tool on injection day.
Approval is ahead of access
Regulators have moved faster than pharmacies. The FDA cleared Yeztugo on June 18, 2025. The European Commission authorized Yeytuo on August 26, 2025. South Africa’s regulator, SAHPRA, registered lenacapavir for PrEP on October 27, 2025, using a pathway tied to the European review. On July 14, 2025, WHO recommended twice-yearly injectable lenacapavir as an additional PrEP option, alongside daily pills, cabotegravir injections, and the dapivirine vaginal ring. WHO also noted 1.3 million new HIV infections worldwide in 2024, and said access to lenacapavir outside trials was still limited at the time of that recommendation.
Price is the blunt part. UNAIDS reported that Gilead had announced a United States list price of 28,218 dollars per person per year. Gilead says eligible people with commercial insurance can use a copay program that brings out-of-pocket cost down to as little as zero, and that eligible uninsured people in the United States can receive the drug free through its medication-assistance program. List price and what a person actually pays are not the same number. List price still shapes whether insurers, health departments, and clinics stock it.
Outside high-income markets, Gilead has said it signed royalty-free voluntary licenses so generic manufacturers can supply 120 high-incidence, mostly low- and lower-middle-income countries, and that it finalized a Global Fund agreement to provide the prevention drug at no profit for up to two million people in those countries until generics can meet demand. UNAIDS also pointed to a Lancet HIV analysis that estimated generic production could cost about 35 to 46 dollars per person per year, and might fall to about 25 dollars. That is a factory-cost model, not a sticker price in a clinic today.
A once-weekly pill version is not available. In 2026 the FDA accepted Gilead’s application for an oral Yeztugo tablet taken once a week. The agency’s decision date is February 2, 2027. Until that decision, the weekly pill is investigational. The approved prevention schedule remains the twice-yearly injection, with the short course of starting tablets.
The bottom line
A medicine that prevented almost every HIV infection in two large trials, and that asks for two injection visits a year instead of a daily pill, is a real change in how prevention can fit a life. It does not end the epidemic by sitting on a shelf. It works only for people who can be tested properly, dosed on time, and kept in care without a five-figure bill deciding the question first. The science cleared a high bar. Access is the part still being negotiated.
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Further reading
And the Band Played On — Randy Shilts’s history of the early AIDS epidemic: the politics, the people, and the years before prevention medicine like PrEP existed.
How to Survive a Plague — David France on the activists and scientists who pushed HIV from a death sentence toward treatable, and later preventable, infection.