Amy Maxmen

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

An injectable drug that was lauded one year ago for being able to prevent HIV 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, and found that four people who contracted HIV despite receiving injections of the medication, called cabotegravir, had been infected for more than a month before ordinary HIV tests detected the virus. During this time, they developed resistance to cabotegravir and closely-related therapies that are used to treat HIV infections. Although alternatives to these common drugs can treat HIV infections, they can be expensive or difficult to obtain in some countries.

Monthly HIV injection could free patients from gruelling drug regimen

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

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

Still, Landovitz and other scientists say this type of HIV preventative therapy, called pre-exposure prophylaxis, or PrEP, remains one of the most hopeful tools for curbing a virus that infects approximately 1.7 million additional people each year, according to the most recent data available. Despite the news, PrEP remains a powerful tool, says Quarraisha Abdool Karim, an HIV researcher at the Centre for the AIDS Programme of Research in South Africa, based in Durban, who wasn’t involved with the trial but is part of the 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 greenlight to daily pills of an HIV medication called Truvada, made by Gilead Sciences in Foster City, California, that proved more than 85% effective when taken on schedule. Soon after, though, studies revealed that most people who don’t have HIV won’t take a protective pill every day. For example, a clinical trial in Kenya, Tanzania and South Africa stopped early because the pills weren’t working. Drug-level analyses revealed that many women weren’t taking them1. 

So researchers have developed longer-lasting treatments, like the cabotegravir shot, that they hope will improve compliance because the drugs remain in a person’s system for weeks or months and therefore require fewer doses. Last year, there was excitement when Landovitz reported that a shot of cabotegravir administered every other month proved three times as effective as daily Truvada pills in a clinical trial. The trial compared the medications head-to-head among men and transgender women who have sex with men across seven countries, including the United States, South Africa and Brazil. The trial was so successful for cabotegravir that an independent monitoring board recommended ‘unblinding’ it, 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.

Promising HIV vaccines could stall without coordinated research

But the research team wanted to better 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.

The researchers were surprised, however, when they analysed blood samples from four individuals who had gotten infected while on cabotegravir. Sensitive tests that measure RNA from HIV revealed that the participants had been infected for 6 to 16 weeks before regular, monthly HIV diagnostics 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 and 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 resistance in two clinical trials Merck recently launched to test long-acting PrEP treatments. 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.”

Alarming surge in drug-resistant HIV uncovered

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, warns that the news on cabotegravir may 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. So a negative — albeit rare — effect that occurs when taking a drug to ostensibly prevent HIV might seem to corroborate and exacerbate existing mistrust in medical institutions.

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 that 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.”