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Achilles heel spotted for promising HIV-prevention drug

People sitting in chairs in a row in a hospital waiting room.

People wait to be seen at a clinic in Johannesburg, South Africa, that offers drugs to treat or prevent HIV infection.Credit: Foto24/Gallo Images/Getty

An injectable drug that was lauded last year for being able to prevent HIV infection looks less perfect today, in light of a new analysis.

Researchers revisited a 4,570-person clinical trial of the drug, examining blood samples collected during the study. They found that four people who contracted HIV despite receiving injections of cabotegravir — which is used to treat HIV as well as prevent it — had been infected for more than a month before standard HIV tests detected the virus. During this time, they developed resistance to cabotegravir and closely related HIV treatments. Although alternatives to these common drugs can treat HIV infections, they are expensive or difficult to obtain in some countries.

The team thinks that cabotegravir suppressed the virus enough to prevent the HIV tests from detecting it during early stages of infection.

The news comes as several other potent drugs to prevent HIV — a type of therapy known as pre-exposure prophylaxis, or PrEP — are entering clinical trials. Raphael Landovitz, an HIV-prevention researcher at the University of California, Los Angeles, who presented the cabotegravir results at the online Conference on Retroviruses and Opportunistic Infections on 9 March, suggests that scientists leading those studies should monitor their participants with more sensitive HIV tests than usual, to avoid a similar situation.

Still, Landovitz and other scientists say that PrEP remains one of the most hopeful tools for curbing a virus that infects approximately 1.7 million additional people each year. Despite the findings from the cabotegravir study, Quarraisha Abdool Karim, associate scientific director at the Centre for the AIDS Programme of Research in South Africa, based in Durban, remains positive about the drug's potential. She wasn’t involved with the trial but is part of the same network developing these therapies. “When people are on PrEP, perhaps we should up the game in what tests we use,” she adds, noting that this will cost more.

Improving compliance

In 2012, the US Food and Drug Administration gave the green light to using daily pills of an HIV medication called Truvada (emtricitabine/tenofovir), developed by Gilead Sciences in Foster City, California, to prevent infection. It proved more than 85% effective when taken on schedule. However, studies revealed that many people who don’t have HIV won’t take a protective pill every day. For example, a clinical trial of women in Kenya, Tanzania and South Africa stopped early because the pills weren’t working. Analyses of drug levels in the blood revealed that many participants weren’t taking them1.

So researchers have developed longer-lasting treatments, such as the cabotegravir injection, to improve compliance. These remain in a person’s system for weeks or months and therefore require less frequent doses. Last year, there was excitement when Landovitz reported that in a clinical trial, a shot of cabotegravir administered every other month proved three times as effective at preventing HIV infection as did daily Truvada pills. The trial compared Truvada with cabotegravir among men who have sex with men and transgender women who have sex with men across seven countries, including the United States, South Africa and Brazil. Cabotegravir proved so successful that an independent monitoring board recommended ‘unblinding’ the trial, so that participants could learn if they were being given Truvada (and a placebo injection), or cabotegravir (and placebo pills) and switch to the more effective drug.

But the research team wanted to understand why some people still got infected. The researchers found that some people didn’t stick to their daily Truvada regimen, and others picked up the virus after the treatments stopped.

They were surprised, however, when they analysed blood samples from four people who had become infected while receiving cabotegravir. Sensitive tests that detect RNA from HIV revealed that the participants had been infected for 6–16 weeks before standard HIV tests, given monthly as part of the trial, spotted the infection. Landovitz suggests that cabotegravir is so potent that it kept the level of virus in these individuals too low to be detected by the standard tests. But that changed when the virus evolved resistance to the drug — then it replicated, causing levels to surge.

“The take-home message here is that we need better diagnostics, and we need to be ready to get people into suppressive treatment as soon as you diagnose the infection,” says Landovitz. He notes that the participants responded well to HIV therapies that are alternatives to cabotegravir and drugs like it.

Possible backlash

Michael Robertson, executive director of Merck Research Laboratories in West Point, Pennsylvania, says that scientists plan to assess blood samples for signs of drug-resistant HIV in two clinical trials of long-acting PrEP treatments launched by Merck in the past few months. One study will test how well a monthly pill of a new HIV drug, islatravir, prevents HIV. Another is examining the performance of a matchstick-sized implant — to be embedded in a person’s upper arm — filled with islatravir. He remains enthusiastic about the treatments, despite the cabotegravir results, saying that a monthly pill or an implant might appeal to people who feel a stigma in taking a drug every day to prevent HIV.

Landovitz agrees. “I take a step back and remember that we’ve seen remarkable results,” he says. “This could be incredible, so let’s just figure out how to minimize the risk to individuals.”

But some of the communities that these researchers are trying hardest to reach because they have high rates of HIV may not react to the news so optimistically. Levi Maxwell, a Black transgender community activist in San Francisco, California, warns that the news on cabotegravir could cause a backlash. “The answer is not to tell people this is better than nothing,” they say. Maxwell explains that many Black and transgender people are wary of government officials and scientists because of a history of harm and discrimination. That mistrust might be exacerbated by a negative effect — even a rare one — caused by a drug meant to prevent HIV.

Maxwell recommends that HIV scientists concentrate on developing new forms of PrEP that don’t cause drug resistance. And they suggest that HIV-prevention researchers push for policy changes to improve the conditions that put Black and transgender people at risk of HIV infection in the first place, such as unaffordable housing and mass incarceration. “Scientists may be well intentioned, but they need to understand that they can’t have tunnel vision if they want to succeed in their goals,” says Maxwell. “This isn’t just a medical issue.”

Nature 591, 357-358 (2021)

doi: https://doi.org/10.1038/d41586-021-00618-7

Updates & Corrections

  • Correction 09 March 2021: This story was updated to correct Michael Robertson’s location. He works at Merck Research Laboratories in West Point, Pennsylvania, not Boston, Massachusetts.

References

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    Van Damme, L. et al. N. Engl. J. Med. 367, 411–422 (2012).

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