Lenacapavir HIV PrEP: Not an AIDS Vaccine, but Vaccine Adjacent

The 40-year quest for a safe and effective AIDS vaccine remains unfulfilled, but hopes for a preventive intervention that could largely end HIV transmission have brightened because of injectable long-acting antiviral medications administered on a preventive basis.

Today’s announcement that the FDA had approved Gilead’s Yeztugo (lenacapavir), while expected, was a milestone in the development of HIV preexposure prophylaxis (PrEP), moving PrEP from a regimen of daily pills that many people have difficulty following to twice-a-year subcutaneous injections in the abdomen.

Peter Ehrenkranz, M.D., M.P.H.

“If you can figure out a way to identify the people who need it and encourage them to come in twice a year, you’ve basically got a vaccine for those folks,” said Peter Ehrenkranz, M.D., M.P.H., deputy director, HIV, at the Gates Foundation.

But Yeztugo’s approval is also coming at a time when the future of domestic and international HIV prevention programs is clouded by funding and staffing cuts by the Trump administration. Moreover, the number of people in the United States disconnected from the healthcare system seems likely to climb if the Medicaid and ACA cuts that Congress is considering make it into the final version of the reconciliation spending package. Ehrenkranz said that prevention programs have borne the brunt of the administration’s uneven handling of funding for the U.S. President’s Emergency Plan for AIDS Relief, better known by its acronym, PEPFAR.

“Recent actions by the Trump administration to decimate HIV prevention jeopardize access to preventive measures such as PrEP,” Carl Schmid, executive director of the HIV+Hepatitis Policy Institute, said in a prepared statement. Schmid said a weakened public health infrastructure will mean less HIV testing, a requirement before starting PrEP.

Jonathan Z. Li, an associate professor at Harvard Medical School and a member of the AIDS Clinical Trials Group (ACTG) Executive Committee, called the twice-a-year version of lenacapavir “a big step forward but also expressed concern about the consequences of Gilead’s pricing. “I think the price point is going to make a big difference,” he said, adding that a high price could put the Yeztugo out of reach of the neediest and highest-risk patients.

The price

Jessica Smith, M.A., a Gilead spokesperson, said in an email today that the company has set Yeztugo’s annual list price in the U.S. at $28,218. That price lines up with other branded PrEP drugs, she said, noting also that the company has seen high health insurance coverage for PrEP. The majority of consumers have zero-dollar copays for the PrEP version of Gilead’s Descovy (emtricitabine and tenofovir alafenamide), she said.

Smith said Gilead’s international strategy includes voluntary licensing for generics and providing its product at no profit until generics are available in 120 high-need countries.

Ehrenkranz sang the praises of lenacapavir as a “really well-tolerated product, incredibly efficacious” that does not require refrigeration. But he also cautioned that “it has to make its way into the right people’s bodies.” He said, “It’s got to be appropriately targeted and accessed by the people who need it the most. And they have to come back when they're at risk.” Ehrenkranz said people may move in and out of the groups and behaviors commonly identified as increasing the risk of becoming infected with HIV. He cited women at the “edge of sex work” as an example who don’t see themselves as sex workers, but “circumstances have required them to do things that they wouldn't normally do.”

Jonathan Z. Li

Li was also enthusiastic about Yeztugo, but he also cast it as a stepping stone to the formulation of lenacapavir for PrEP that would require a single injection per year. Gilead presented pharmacokinetic data from a Phase 1 trial of the annual shot at the 2025 Conference on Retroviruses and Opportunistic Infections meeting in March. The results showed that the lenacapavir concentrations from two different formulations of a once-yearly version of lenacapavir exceeded the concentrations associated with HIV protection in the phase 3 trials that supported Yeztugo’s application for approval by the FDA. Gilead said in a press release that it plans to start a Phase 3 study of the once-a-year formulation of lenacapavir in the second half of 2025.

“Once a year is akin to a vaccine,” Li said. Twice-a-year dosing can still be challenging, said Li, who expressed concern about people taking risks as the concentrations of lenacapavir wane because of a missed or delayed injection.

Still, Li contrasted the twice-a-year injections to daily pills for PrEP. “The biggest problem with preventing HIV with the tools that we have is that it is not easy for people who don't have HIV to take medications against HIV every day to prevent infection. These are generally young, healthy individuals, and as you can imagine, it's hard for them to get them to do anything every single day for their health, let alone something that is a theoretical kind of preventative therapy. Any way that we can give them long-acting prevention options is a huge win,” he said.

Ehrenkranz echoed Li, noting that “preventing HIV is not the highest thing on everybody’s radar.” Daily oral PrEP has been very effective in some populations, he noted, but it has been less effective in southern East Africa.

The Purpose trials

The FDA approval of Yeztugo was not a surprise. Gilead has reported a steady stream of positive results from two sizable phase 3 trials, Purpose 1 and Purpose 2, that it sponsored and used to support its application for approval. Researchers enrolled 5,338 cisgender adolescent girls and young women in South Africa and Uganda in the Purpose 1 trial. The results, as reported in the New England Journal of Medicine, showed zero infections among 2,134 participants that had been randomly assigned to the lenacapavir. Purpose 2 included cisgender gay, bisexual, and other men; transgender women; transgender men; and gender-nonbinary persons enrolled at 92 trial sites, most (61) of them in the U.S. but also at sites in Brazil, Thailand, South Africa, Peru, Argentina, and Mexico. The results, which were also published in New England Journal of Medicine, showed two HIV infections among the 2,179 study participants that the researchers had randomly assigned to twice-a-year lenacapavir for PrEP and nine infections among 1,086 randomly assigned to daily oral pills containing emtricitabine and tenofovir disoproxil fumarate, a PrEP formulation sold under name Truvada in the U.S.

Li noted the PURPOSE trials are a prime example of how international trials can benefit Americans. The researchers were able to enroll people in the trials and generate data much faster and at a lower cost because the studies were international, he said.