Researchers Move Toward Once-Yearly Treatment for HIV
Researchers have reformulated an HIV medication into a version they hope can eventually be taken as infrequently as once a year.
The work is only in the early stages, having been studied in lab animals. But the goal is to create an HIV drug that can be injected annually -- offering protection from infection or control of the virus in people who already have it.
The researchers, at the University of Nebraska Medical Center in Omaha, started with a drug that is already in clinical trials, called cabotegravir. It's an injection drug being developed for both HIV prevention and treatment, and designed to be given once every month or two.
The investigators chemically modified cabotegravir to become a "prodrug" -- an inert substance that, once in the body, is converted into an active form. In this case, that conversion happens gradually, with the drug being released for up to a year in lab animals.
The findings, published online April 27 in the journal Nature Materials, are an initial step, and much more work remains.
"We haven't studied this in humans yet," said researcher Dr. Howard Gendelman, who heads the department of pharmacology and experimental neuroscience at the Nebraska center.
And it's hard to predict how long it could take to move ahead, according to Gendelman.
"We're repurposing a medication that other people invented," he said, and there will be "multiple facets" to getting it into human trials.
Cabotegravir is being developed by North Carolina-based ViiV Healthcare. It belongs to a relatively newer class of HIV drugs called integrase inhibitors. They work by blocking an enzyme the virus needs to replicate itself and spread.
A prevention trial is underway to see if cabotegravir injections, every eight weeks, can lower infection rates among people at high risk of HIV. Other trials are testing the drug for maintaining HIV suppression in people who've gotten the virus down to very low levels with standard medication; there it's given in monthly injections along with another drug, called rilpivirine.
The idea is to free people from needing daily pills.
Oral medications for HIV, which came to market in the 1990s, have changed the face of the epidemic. They are no cure, but when people can stick with their medication regimen, the virus can be suppressed for years.
"The main challenge we face today is adherence," said Dr. Melanie Thompson, former chairwoman of the HIV Medicine Association.
Taking pills every day, for life, is "not so easy," noted Thompson, who was not involved in the new study. People can simply forget, she said, or fail to bring their medication on a trip. They can also run out of pills, or have trouble paying for them.
Longer-acting medications could be helpful in that regard. On the other hand, Thompson said, safety becomes an even bigger concern if a drug is going to persist in the body for a long time.
"If you take it and you don't do well, you're stuck with it," she said. "You can't take it away."
Another question, Thompson said, is what happens toward the end of the drug's life in the body. Does it suddenly shut off? Or do levels of the drug wane to where they would no longer be protective, but possibly allow the virus to develop resistance to it?
The safety concerns also include possible drug interactions: What if someone on a long-acting drug develops an infection and needs medication? Or, Thompson said, what if she becomes pregnant?
With a yearly formulation, instead of every two months, those issues loom even larger.
"The idea of moving toward something that's given once a year is exciting," Thompson said. But, she stressed, many unknowns would have to be addressed.
Gendelman said that while the cabotegravir injections currently in trials could free people from daily pills, they would still require frequent doctor visits -- and a regular jab into the buttocks muscle, which can be uncomfortable for days.
That's what led him and colleague Benson Edagwa, an assistant professor, to the current project.
Edagwa, a chemist, designed the modifications necessary to turn cabotegravir into a "nanocrystal." After it's injected, much of that modified substance takes up residence in muscle, some of it in the liver and spleen, Gendelman said. Over time, the body's own enzymes "very slowly" convert it into active drug.
At least that's what happens in lab mice and rhesus macaque monkeys. Results in humans are often different than in animals.
And Thompson said more animal research is needed to evaluate safety. The results of the ongoing prevention trial, where cabotegravir is being given every eight weeks, should be informative, she said.
If a once-a-year version were ever to be used for HIV treatment, it would have to be paired with another long-acting medication -- since, Thompson noted, HIV is never treated with a single drug.
The U.S. Department of Health and Human Services has more on HIV treatment.
SOURCES: Howard Gendelman, M.D., chairman, department of pharmacology and experimental neuroscience, University of Nebraska Medical Center, Omaha; Melanie Thompson, M.D., former chairwoman, HIV Medicine Association, Arlington, Va.; April 27, 2020, Nature Materials, online
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