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Long-acting drug acts like a short-term AIDS vaccine (Cabotegravir injectable long-acting HPTN-083 study)
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Jon Cohen
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Science 22 May 2020
Long-acting injectable drug prevents HIV infections - (05/18/20)
Global HIV prevention study to stop early after ViiV Healthcare's long-acting injectable formulation of cabotegravir dosed every two months shows higher efficacy than daily oral PrEP - (05/18/20)
Long-acting injectable cabotegravir is highly effective for the prevention of HIV infection in cisgender men and transgender women who have sex with men - (05/18/20)
It's not an AIDS vaccine, but it may be the closest thing to one so far. A long-acting antiretroviral drug given as an injection every 2 months powerfully protected uninfected people from HIV in a large-scale clinical trial. Although it was cut short by the COVID-19 pandemic and has not been published in a peer-reviewed journal or presented at a meeting, the study holds out hope of preventing HIV infections in high-risk groups without the need to take pills every day, which many people find difficult.
The trial compared the experimental drug cabotegravir with Truvada, a daily pill combining two antiretroviral compounds that is the standard regimen for pre-exposure prophylaxis (PrEP), as the strategy of preventing infection with drugs is known. Sponsored by the U.S. National Institute of Allergy and Infectious Diseases (NIAID), the trial began in December 2016 and enrolled more than 4500 men who have sex with men and transgender women. Participants were randomly assigned to Truvada, intramuscular injections of cabotegravir, placebo pills, or dummy injections. As of late April, 12 infections occurred in the cabotegravir group versus 38 in the equally sized group that received Truvada: a 0.38% incidence in the cabotegravir arm versus 1.21% in the Truvada one. This overall result, reported by press releases on 18 May, indicates cabotegravir works just as well as Truvada, and perhaps better, though the trial saw too few infections for that conclusion to reach statistical significance.
"It's really exciting," says Jared Baeten, an epidemiologist at the University of Washington, Seattle, who conducted a landmark PrEP study of anti-HIV pills-including Truvada-in Kenya and Uganda. "It gives another option for people who can't or don't want to take daily pills." That may get more people to try PrEP, Baeten adds, noting that more women began to use contraception as options increased. Epidemiologist Kevin De Cock, who heads the Kenya program for the U.S. Centers for Disease Control and Prevention, says, "A new vista of HIV prevention has been opened."
Several PrEP studies with Truvada have shown that, by and large, people who became infected with HIV did not take the daily pills. (Blood measurements can reveal levels of the drugs.) To address that problem, "People are looking aggressively for long-acting agents," says Myron Cohen, a microbiologist at the University of North Carolina School of Medicine, who is co–principal investigator of the NIAID HIV Prevention Trials Network. Cabotegravir, which has worked well as a treatment in clinical trials, is further along in development than other long-acting drugs. Made by ViiV Healthcare, a joint venture of GlaxoSmithKline, Pfizer, and Shionogi that focuses on AIDS drugs, the compound targets integrase, an HIV protein that is essential to its replication.
COVID-19 shut down 11 of the trial's 43 sites in seven countries, and participants at others increasingly had trouble attending appointments, says Raphael Landovitz of the University of California, Los Angeles, the study's protocol chair. The investigators told the study's independent data and safety monitoring board (DSMB) about this problem in early April and asked that the endpoint of the trial be changed to make sure the study had an "undisrupted data set." Instead of evaluating whether the injections were superior to the Truvada pills-the original goal-they decided to assess a lower standard of "noninferiority."
On 14 May, the DSMB members took a scheduled interim peek at the data. They found that the cabotegravir arm met that threshold and that the injections appeared safe and mostly well-tolerated. Study organizers now plan to offer the injections to all participants. "With cabotegravir lasting at least a couple of months we're moving in the direction of providing people with some of the benefits of a vaccine," Cohen says.
Landovitz says ongoing analyses should reveal why people who received shots of the drug became infected. Earlier studies found that men and transgender women who are underweight more rapidly eliminate the drug from their blood. Another possibility is that participants who got infected may have missed some doses of the cabotegravir pills they had to take for 5 weeks-for safety reasons-before starting the injections. Or someone could have been infected with an HIV variant that is resistant to cabotegravir.
Injected cabotegravir is also being tested in a large study of heterosexual women, which could have clear data as early as November. ViiV said in a statement it is "actively working with global health partners" to make sure that people in resource-limited countries have access to cabotegravir injections, but it did not reveal any information about pricing. Cohen says the addition of long-acting cabotegravir as PrEP provides a powerful new HIV prevention weapon. "This agent really could contribute to the goal of ending AIDS by 2030."
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