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 study that was disrupted by the COVID-19 pandemic. The apparent success—the study has not been published in a peer-reviewed journal or presented to HIV researchers at a meeting—offers a potentially easier alternative to taking daily pills of other antiretrovirals, which has proved difficult for many people.
The strategy of uninfected people taking drugs to ward off HIV, known as pre-exposure prophylaxis (PrEP), earned the U.S. Food and Drug Administration’s blessing in 2012 when the agency approved a daily pill combining two drugs that cripple the virus. In the new study, this combo marketed as Truvada was tested against intramuscular injections of the experimental drug cabotegravir or placebos in men who have sex with men and transgender women. The trial, sponsored by the U.S. National Institute of Allergy and Infectious Diseases (NIAID), began in December 2016 and enrolled more than 4500 participants worldwide, who were randomly assigned to Truvada, cabotegravir, placebo pills, or placebo injections. As of late April, 12 infections occurred in the cabotegravir group versus 38 in the equally sized group that received Truvada. This represents a 0.38% incidence in the cabotegravir arm versus 1.21% in the Truvada one, a 69% difference in new infection rates.
“It’s really exciting,” says Jared Baeten, an epidemiologist at the University of Washington, Seattle, who was not involved in the NIAID trial but conducted a landmark PrEP study of anti-HIV pills (one was Truvada) in Kenya and Uganda. “It gives another option for people who can’t or don’t want to take daily pills.” The new study did not, on a statistical level, demonstrate cabotegravir’s superiority over Truvada, but the data clearly showed it worked just as well. Having options may get more people to try PrEP, Baeten says, comparing the situation to women who now have several forms of contraception from which to choose.
The cabotegravir study is one of many PrEP strategies being tested by NIAID’s HIV Prevention Trials Network (HPTN), which evaluates a wide range of nonvaccine interventions. “People are looking aggressively for long-acting agents,” against HIV, says HPTN’s co–principal investigator Myron Cohen of the University of North Carolina School of Medicine. “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.”
HPTN 083, the name of the cabotegravir study, has 43 sites in the United States, South Africa, Argentina, Brazil, Peru, Vietnam, and Thailand. COVID-19 forced 11 of the sites to close, and others struggled to continue because participants increasingly had difficulty attending appointments, explains Raphael Landovitz of the University of California, Los Angeles, protocol chair of the study. The investigators informed the study’s independent data and safety monitoring board (DSMB) of 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 the original goal of proving the injections were superior to the Truvada pills, they decided to assess a lower standard of “noninferiority.”
On 14 May, DSMB member took a scheduled interim peek at the data and found the cabotegravir arm met that threshold. The Truvada pills and cabotegravir injections were deemed safe and well tolerated, with reactions at the injection site in the buttocks being a primary “adverse event” in the latter group.
Based on the data, they recommended that all participants, including those receiving placebos, be offered the injections, which should happen this week. HPTN 083 leaders decided to release the study’s results at 7 a.m. U.K. time because of the potential impact they could have on the stock prices of several companies. Cabotegravir is made by ViiV Healthcare, a joint venture of GlaxoSmithKline, Pfizer, and Shionogi that focuses on anti-HIV drugs. Truvada is made by Gilead Sciences.
Several studies with Truvada as PrEP have shown that, by and large, people who became infected did not take the daily pills. (Blood measurements can reveal levels of the drugs.) The hope was that injections of an antiretroviral would eliminate this adherence issue. Cabotegravir targets an HIV enzyme called integrase that is essential to its replication.
So why did a dozen people who got shots of the drug still get infected? “One of our most pressing analytic tasks at this point is to examine these 12 cases of HIV that were acquired after being exposed to cabotegravir,” Landovitz says. A person’s weight could be an explanation. Earlier studies have shown that men and transgender women who were designated male at birth with a lower body mass index more rapidly eliminate the drug from their blood. Another possibility is those who got infections did so very early in the study. Because of safety concerns about cabotegravir, the study required people in the injection group to first take pills of the drug for 5 weeks; the infected participants may have failed to take some of those doses during that period. Or someone could have been infected with an HIV variant that is resistant to cabotegravir.
It’s unclear whether injected cabotegravir will work in other populations. HPTN 084, a sister study, is staging the same comparison in heterosexual women and could have clear data as early as November. As for HPTN 083, a close examination of infections in penetrative partners, instead of receptive partners, may clarify whether the injections are likely to work in heterosexual men. Long-acting cabotegravir has shown promise as a treatment, too, but has yet to receive regulatory approval. Other long-acting anti-HIV PrEP treatments are in the works, too. Landovitz says ViiV is planning for “global scale-up” of the injections and to have them accessible in low-resource settings, but nothing has been made public 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.”