Long-acting drugs may revolutionize HIV health care
A pill taken once a week. A shot administered at home once a month. Even a jab given at a clinic every six months.
In the next five to 10 years, these options may be available to prevent or treat HIV. Instead of drugs that must be taken daily, scientists are closing in on longer-acting alternatives — perhaps even a future in which HIV may require attention just twice a year, inconceivable in the darkest decades of the epidemic.
“This period is the next wave of innovation, newer products meeting the needs of people, particularly in prevention, in ways that we didn’t ever have before,” said Mitchell Warren, the executive director of the HIV prevention organization AVAC.
Long-acting therapies may obviate the need to remember to take a daily pill to prevent or treat HIV. And for some patients, the new drugs may ease the stigma of the disease, itself an obstacle to treatment.
“To not have to remember that every morning is earth-changing for them,” said Dr. Rachel Bender Ignacio, the director of University of Washington’s UW Positive, a clinical research site focusing on HIV. “That stigma, that internalized stigma of taking that pill every morning, is what prevents them from taking it.”
Long-acting drugs are likely to be an even greater boon in populations that have long been hard to reach: patients who have spotty access to health services, or who have trouble taking daily pills because they have unstable housing or transportation, are struggling with substance use, are mentally ill or face discrimination and stigma.
In 2022, nearly 30 years after the advent of combination antiretroviral therapy, more than 9 million of the 39 million people living with HIV worldwide were not receiving treatment. About 630,000 died from AIDS-related illnesses that year.
Even in the United States, about one-third of those diagnosed with HIV are not keeping the virus in check. “We still haven’t addressed these sort of underlying issues around access,” said Gregg Gonsalves, a longtime HIV activist and an epidemiologist at the Yale School of Public Health.
“We can be elated about the science and the clinical implications” of long-lasting drugs, he added. “But for many people, it’s going to be a distant dream.”
One barometer of the excitement about longacting regimens was their prominence at the Conference on Retroviruses and Opportunistic Infections in Denver in March. The annual meeting has served as the backdrop to many HIV milestones, including the electric moment in
1996 when researchers showed that a combination of drugs could suppress the virus.
Dozens of studies of long-acting regimens were presented at the conference this year. (While most such drugs are tantalizingly close for HIV prevention and treatment, similar options for tuberculosis, hepatitis B and hepatitis C are not far behind.)
One long-acting treatment — Cabenuva, two shots given every other month — has been available for nearly three years. It costs more than $39,000 annually in the United States, although few patients pay that price. Even with a steep discount, however, the treatment is out of reach for many patients in low-income countries.
Still, many researchers at the conference were excited about the results from one study showing that Cabenuva was more effective than daily pills at controlling HIV even in groups that typically have trouble adhering to treatment.
“When you think about how hard it is for some folks, giving them new tools that might be able to get them to be suppressed is a big deal,” said Dr. Kimberly Smith, who leads research and development at ViiV Healthcare, which makes one of the component drugs in Cabenuva.
Long-acting drugs might be useful even for children living with HIV. Worldwide, only about half of children diagnosed with HIV are receiving treatment.
That’s in part because of the lack of drug versions made for children, Dr. Charles Flexner, an HIV expert at Johns Hopkins University, said in a presentation at the Denver conference.
“With long-acting formulations, that will no longer be the case,” Flexner said. “Children will be able to use the same formulation as adults, just at a different dose.”
Most long-acting shots contain nanocrystals of drug suspended in liquid. While oral pills must pass through the stomach and the intestinal tract before they enter the circulation, so-called depot shots deliver the drugs directly into the bloodstream. But they are released extremely slowly, over the course of weeks or months.
Some depot antipsychotics are given every two to eight weeks, and the contraceptive Depo-Provera is administered once every three months. Cabenuva — a combination of cabotegravir, made by Viiv Healthcare (majority owned by GSK), and Janssen’s rilpivirine — is injected into gluteal muscles every two months to treat HIV.
Cabotegravir given under the skin of the stomach produced more bruising and rashes than in the buttocks, and some people developed nodules that lingered for weeks or even months. But with gluteal injections, “there’s nothing that you see,” Smith said. “You feel pain for a couple of days and then you go on with your life.”
Viiv is trying to develop a version of cabotegravir to be given every four months and, ultimately, one every six months. The company aims to bring the fourmonth version to market for preventing HIV in 2026, and for treatment in 2027.
But injecting drugs into muscle is challenging for people who have significant body fat or who have silicone implants in the buttocks, as some trans women do. Some newer shots under development are administered under the skin, circumventing the problem.
Gilead’s lenacapavir can be given as a subcutaneous injection in the stomach once every six months, but it is so far approved only for people with HIV who are resistant to other drugs.
The drug is in multiple late-stage trials as a longacting HIV preventive in various groups, including cisgender women.
Lenacapavir is also being tested as a treatment in the form of a once-weekly pill in combination with another drug, islatravir, made by Merck. Having multiple long-acting treatments is ideal, “so people can really make the choice among the options that are going to work best for them,” said Dr. Jared Baeten, a vice president at Gilead.
To make it truly accessible for everyone, including those who may live far from a health care center, researchers must also come up with a long-acting injection that can be selfadministered, some experts noted.
One team is developing exactly that and, with backing from the global health initiative Unitaid, planning to make it available in lowand middle-income nations.
“The really exciting thing about this is that the way that it’s being developed, it ideally will bypass the trickle-down effect to get into the people who need it most,” said Dr. Bender Ignacio, referring to the tendency of rich countries to gain access to new therapies first. She is leading the study.
Because the component drugs have each been independently approved, Bender Ignacio estimated the shots could be available to treat HIV in less than five years.
Many of the products, including those in Bender Ignacio’s study, can be adjusted to prevent HIV. There are currently only three options for that: two types of daily pills, and Viiv’s cabotegravir, which is injected into the buttocks once every two months.
“It’s been prevention where we have been lagging the greatest in the AIDS response over the last decade,” said Warren, of AVAC.