FDA Approves a Twice-Yearly Shot to Prevent HIV

On June 18, the U.S. Food and Drug Administration (FDA) approved the first medicine to prevent HIV that only has to be taken twice a year. People who are at high risk for HIV can now take the injection—called lenacapavir and sold as Yeztugo—just once every six months.

The approval is a milestone in the fight against HIV and could transform the epidemic. While anti-HIV drug treatments have helped millions of people suppress the virus to undetectable levels so that they don’t spread it to others—and have also allowed people who are HIV-negative to maintain their status when used to prevent infection—a regimen of daily pills means that compliance, and therefore effectiveness, is often not as strong as it should be.

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In two studies, scientists at Gilead, which developed lenacapavir, showed that the drug was 96% effective at protecting cisgender women from becoming HIV positive as compared to daily oral pills (called PrEP, short for pre-exposure prophylaxis). In men who have sex with men and gender-diverse people, the drug was 100% effective.

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“Lenacapavir used by itself for prevention is a huge breakthrough,” says Dr. David Ho, professor of microbiology, immunology, and medicine at Columbia University who pioneered combining anti-HIV drugs to suppress the virus and its ability to mutate to become resistant to treatment. “Its potential is great in curtailing the epidemic.”

But advocacy groups and global AIDS organizations raise concerns about whether that potential will be fully realized, given recent cuts to U.S.-supported programs for HIV treatment and prevention around the world.

From treatment to prevention

Lenacapavir was approved by the FDA in 2022 to treat people with HIV whose virus has become resistant to other antiviral drugs. As they were developing that treatment, Gilead’s scientists noticed that lenacapavir had two important properties that could make it potentially useful in preventing HIV as well: its ability to remain in the body for a longer time than other antiviral drugs, and its power to interfere with several steps in the process that the virus uses to make copies of itself.

“We observed a fantastic effect after a single injection,” says Tomas Cihlar, senior vice president of virology at Gilead. “Basically, it protected non-human primates from acquiring HIV. That’s when we realized we really needed to get full speed and full force behind the prevention idea.”

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But because people taking a drug to prevent infection are HIV negative, “the bar for safety for people who don’t have the disease is quite high,” says Jared Baeten, vice president of HIV development at Gilead. “Still, based on all the pharmacology, science, and demonstrated antiviral activity and safety in the HIV treatment sphere, by the end of 2020 we made the decision to move lenacapavir into prevention,” he says.

While it’s the same drug, when doctors use lenacapavir to treat HIV, they often combine it with other drugs to limit HIV’s potential for developing resistance. But to prevent disease in people who are HIV negative, lenacapavir can be used alone, since there isn’t already an actively reproducing population of virus in the body.

How lenacapavir could quash HIV vaccine efforts

Lenacapavir is not an HIV vaccine, but its effect in preventing infection is similar to one. Vaccines enlist and train the immune system to recognize and target pathogens like viruses, so the body becomes a factory for generating the appropriate defenses to fight infections. Lenacapavir’s ability to fend off infection comes from having circulating levels of the drug in the body to fight off any virus that might enter.

Whether it’s the immune system or the drug, the effect is very similar—which is a huge advance. In the more than 40 years since HIV was discovered, scientists have not been able to develop a vaccine against it. “So far the candidate vaccines do not show this kind of promise for preventing HIV infection,” says Ho. “We’re nowhere close to an efficacious vaccine.”

With lenacapavir approved to prevent HIV, the bar for developing a vaccine becomes even higher. It could be ethically difficult to justify asking people to take a placebo to establish the effects of a vaccine, since both oral PrEP and now lenacapavir as PrEP are so effective in protecting against HIV infection. Depriving those in a vaccine trial from taking lenacapavir by assigning them to receive a placebo would be problematic. “This might take a bit of the wind out of the sails of vaccine research, because there is something so effective at preventing HIV infection,” says Ho.

The future of HIV treatment and prevention

The long-acting nature of lenacapavir represents a new direction for anti-HIV drugs that could make preventing infections more tenable and accessible to more people, says Hui Yang, head of supply operations of the Global Fund to Fight HIV, TB, and Malaria. “We learned from decades-long experience that in prevention programs, adherence is a big issue. And that is an aspect we are hoping to address with the introduction of lenacapavir for PrEP.” The Global Fund’s goal is to get two million more people in prevention programs over the next three years, and lenacapavir could accelerate reaching that target.

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But the shot still must be administered by a health care provider, and people need to test negative for HIV before receiving each shot. Those are hurdles for many of the most vulnerable populations in low- and middle-income countries, many of whom are young adults. To further increase access, Yang says, a form of lenacapavir that people could inject themselves with twice a year would be even more appropriate for such settings. “It could become something like an insulin injection that people can do themselves,” she says.

Gilead is working on a once-a-year version of lenacapavir that would cut down on the need for multiple clinic visits.

The unrealized potential of lenacapavir

While the advance is scientifically exciting, the drug may take years or even decades to significantly curb the global HIV epidemic. “We just built the best plane in the world, but unfortunately tore up all the runways,” says Kevin Frost, CEO of amfAR, the Foundation for AIDS Research. “Lenacapavir is coming at the worst moment in the last 30 years of the AIDS epidemic. We are seeing ourselves time traveling back decades because of the dismantling of the infrastructure around the treatment and prevention of HIV.” Cuts to USAID, PEPFAR, and the National Institutes of Health “mean lenacapavir will never have a shot coming out of the gate. The very architecture that could deliver lenacapavir on a global scale to be transformative is being dismantled.”

While Gilead would not specify a price for lenacapavir, a company spokesperson said it would likely be “in line with existing branded PrEP options.” Still, that could be out of reach for those in lower income countries who could benefit the most, says Frost.

Addressing cost and other issues related to access will be critical to realizing the full potential of the drug. In the U.S., states that offer and cover PrEP options have reported a 38% decrease in new infections, whereas states that don’t make PrEP as available saw a 27% increase in infections from 2012 to 2022, according to a recent report published in the Lancet HIV. Gilead has negotiated royalty-free licensing deals with six generic manufacturers to manufacture lenacapavir for prevention for 120 low- and middle-income countries.

“Hopefully in those places where they have that kind of manufacturing capacity, we will see cheap, inexpensive lenacapavir,” says Frost—but given that the normal distribution channels are newly gutted programs like USAID and PEPFAR, “I still expect access will be extraordinarily limited.”