Long-acting drugs can revolutionize HIV prevention and treatment

A pill to be taken once a week. An injection given at home once a month. Also a vaccination administered in a clinic every six months.

In the next 5 to 10 years, these options may be available to prevent or treat HIV. Instead of drugs that must be taken daily, scientists are moving towards longer-acting alternatives – perhaps even a future where HIV might require attention only twice a day. year, inconceivable in the darkest decades of the epidemic.

“This period represents the next wave of innovation, new products are meeting people's needs, particularly in prevention, in ways we've never had before,” said Mitchell Warren, executive director of the HIV prevention organization AVAC .

Long-acting therapies can obviate the need to remember to take a daily pill to prevent or treat HIV. And for some patients, new drugs can ease the stigma of the disease, which in itself is a barrier to treatment.

“Not having to remember that every morning is earth-changing for them,” said Dr. Rachel Bender Ignacio, an infectious disease physician and researcher at the Fred Hutch Cancer Center in Seattle. “That stigma, that internalized stigma of taking that pill every morning, is what keeps them from taking it.”

Long-acting drugs are likely to be an even greater benefit in populations that have long been difficult to reach: patients who have patchy access to health services, or who have difficulty taking daily pills because they have housing or unstable transportation, are struggling with the substance. use, are mentally ill or suffer discrimination and stigmatization.

In 2022, nearly 30 years after the advent of combination antiretroviral therapy, more than nine million of the 39 million people living with HIV worldwide were not receiving treatment. About 630,000 people died from AIDS-related illnesses that year.

Even in the United States, about a third of people diagnosed with HIV fail to keep the virus under control. “We haven't addressed these kinds of underlying issues around access yet,” said Gregg Gonsalves, a longtime HIV activist and epidemiologist at the Yale School of Public Health.

“We can get excited about the science and clinical implications” of long-acting drugs, he added. “But for many people it will be a distant dream.”

One barometer of enthusiasm for long-acting regimens was their prominence at the Conference on Retroviruses and Opportunistic Infections in Denver in March. The annual meeting has been the backdrop to many HIV milestones, including the electrifying moment in 1996, when researchers demonstrated that a combination of drugs could suppress the virus.

This year, dozens of studies on long-acting regimens were presented at the conference. (While most of these drugs are surprisingly close to preventing and treating HIV, similar options for tuberculosis, hepatitis B, and hepatitis C are not far behind.)

A long-acting treatment – ​​Cabenuva, two injections given every two months – has been available for almost three years. In the United States it costs more than $39,000 a year, 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.

However, many researchers at the conference were excited by the results of a study showing that Cabenuva was more effective than daily pills at controlling HIV even in groups that typically have difficulty adhering to treatment.

“When you think about how difficult it is for some people, giving them new tools that might be able to put them down is a big deal,” said Dr. Kimberly Smith, who leads research and development at ViiV Healthcare, which makes one of the component drugs of Cabenuva.

Long-acting drugs could also be helpful for children with HIV Worldwide, only about half of children diagnosed with HIV receive treatment.

That's partly due to the lack of drug versions intended for children, said Dr. Charles Flexner, an HIV expert at Johns Hopkins University, in a presentation at the Denver conference.

“With long-acting formulations, this will no longer be the case,” Dr. Flexner said. “Children will be able to use the same formulation as adults, just at a different dose.”

Most long-acting injections contain drug nanocrystals suspended in a liquid. While oral pills must pass through the stomach and intestinal tract before entering the circulation, so-called storage depots carry the drugs directly into the bloodstream. But they are released very slowly, over weeks or months.

Some depot antipsychotics are given every two to eight weeks, and the contraceptive Depo-Provera is given once every three months. Cabenuva – a combination of cabotegravir, made by Viiv Healthcare (majority-owned by GSK) and Janssen's rilpivirine – is injected into the 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 lumps that persisted for weeks or even months. But with injections into the buttocks, “there's nothing that you see,” Dr. Smith said. “You feel pain for a couple of days and then you move on with your life.”

Viiv is trying to develop a version of cabotegravir to be given every four months and eventually one every six months. The company aims to bring the quarterly version to market for HIV prevention in 2026 and for treatment in 2027.

But injecting drugs into muscles is a challenge for people who have significant body fat or who have silicone implants in their buttocks, as some trans women do. Some new vaccines in development are administered under the skin, getting around the problem.

Gilead's lenacapavir can be given via subcutaneous injection into the stomach once every six months, but so far it is only approved for people with HIV who are resistant to other drugs. The drug is in several late-stage trials as a long-acting HIV preventative in various groups, including cisgender women.

Lenacapavir is also being tested as a weekly pill treatment in combination with another drug, islatravir, made by Merck. Having multiple long-acting treatments is ideal, “so people can really make the choice between the options that will work best for them,” said Dr. Jared Baeten, a vice president at Gilead.

Santos Rodriguez, 28, was diagnosed with HIV in 2016 and has been taking a daily pill to suppress the virus ever since. Mr Rodriguez, who works on artificial intelligence at the Mayo Clinic in Florida, said having to take just one pill a week would be “definitely revolutionary for me and my membership”.

He said he was put off by the bimonthly clinic visits required for Cabenuva injections and by reports that injections into the buttocks are painful. A shot every four or six months would be much more attractive, he added.

To make it truly accessible to everyone, including those who live far from a health center, researchers also need to invent a long-acting shot that can be self-administered, some experts noted.

A team is developing exactly that and, with support from the global health initiative Unitaid, plans to make it available in low- and middle-income nations.

“What's really interesting is that the way it's being developed, ideally, will eliminate the trickle-down effect of reaching the people who need it most,” said Dr. Bender Ignacio, referring to the tendency of rich countries to get access first. access to new therapies. She is leading the study.

The product uses a lipid base to suspend three anti-HIV drugs, two water-soluble and one fat-soluble. Unlike depot injections, which release drugs slowly, this so-called nanolozenge is absorbed by immune cells and lymph nodes soon after being administered under the skin of the stomach.

Because of this effectiveness, the injections can deliver smaller doses of medications and can also be easily adapted to children and adolescents, said Dr. Bender Ignacio. A single injection maintains levels of the three drugs in the body for more than a month, replacing 150 pills.

So far, the self-administered long-acting shot has been tested on just 11 people, including Kenneth Davis, 58, a resident of Auburn, Washington. Mr Davis, who lost two family members to AIDS, compared the injection to a bee. jab: fleeting and less painful than Covid vaccines.

Because each of the component drugs has been independently approved, Dr. Bender Ignacio estimated that the shots could be available to cure HIV in less than five years.

Many of the products, including those from Dr. Bender Ignacio's office, can be adapted to prevent HIV. There are currently only three options for this: two types of daily pills and Viiv's cabotegravir, which is injected into the buttocks once every two months.

“Prevention is where we have fallen furthest behind in the response to AIDS over the past decade,” said AVAC's Warren.

A study presented at the Denver conference showed that when people were offered a choice of prevention methods, most chose long-acting cabotegravir. But the percentage who opted for the daily pill also increased.

“The fact that we've seen protection increase through a number of methods – that to me is the most important thing,” Warren said. The study, he added, “really shows that there is now evidence behind the choice, not just the defense.”

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