Longer HIV Meds are on the Horizon

HIV treatment has come a long way in the past four decades—from a handful of pills taken several times a day to a once-daily single-tablet regimen and injections every two months. Daily pills and every-other-month injections also prevent HIV. But longer-term options are still needed, as only about two-thirds of people diagnosed with HIV in the United States achieve viral suppression, and only one-third of eligible individuals are on pre-exposure prophylaxis (PrEP).

Long-term treatment and prevention is more convenient, more careful and encourages good compliance. Research holds promise for therapies that can be done even more often, and long-term remission is a goal on the horizon.

Currently, the longest-acting complete HIV treatment regimen is Cabenuva (injectable cabotegravir and rilpivirine), administered by a health care provider every one to two months. It’s only approved for people with an undetectable viral load who want to switch to a new regimen, but recent pilot studies show it can work well for people without viral suppression, too. For HIV prevention, Apretude (injectable cabotegravir alone) works better than the PrEP pill.

Last December, the Food and Drug Administration approved Sunlenca (lenacapavir), the first HIV capsid inhibitor, given every six months. Right now, it’s only available for treatment-experienced people with multidrug-resistant HIV, but it also works well for initial treatment, and it’s being studied for PrEP. Sunlenca is the longest-acting approved antiretroviral, but it cannot be used alone, and it does not have a consistent partner. In an effort to fill that gap, Gilead Sciences is now testing Sunlenca with two broadly neutralizing antibodies as a complete twice-yearly regimen.

Long-Acting TLD

Further back in the pipeline, researchers are exploring other long-acting therapies. A team at the University of Washington in Seattle is testing an extended-release injectable formulation of tenofovir disoproxil fumarate, lamivudine and the integrase inhibitor dolutegravir (sold alone as Tivicay). This daily oral combination of three drugs—sometimes called TLD—is the most widely prescribed antiretroviral regimen worldwide.

As described in the journal AIDS, Simone Perazzolo, PhD, and colleagues used novel drug combination nanoparticle technology, which makes it possible to combine water-soluble and insoluble agents, to produce antiretrovirals that require more frequent administration. Despite the drugs’ different physical and chemical properties, the researchers were able to stabilize and assemble tenofovir, lamivudine and dolutegravir into a formulation suitable for subcutaneous injection, which they called TLD-in-DcNP.

Unlike some other long-acting drugs that form a “depot” that releases drugs slowly over time, TLD-in-DcNP agents are rapidly and completely absorbed by the lymphatics. system, with no significant retention at the injection site, according to the researchers. .

When TLD-in-DcNP was given to monkeys in an early study, all three antiretrovirals showed long-acting profiles, compared to the same drugs dissolved in liquid but not formulated into nanoparticles. Drug levels above predicted effective concentrations are maintained in blood plasma for four weeks after an injection. Drug exposure levels were even higher in cells than in plasma, suggesting cell-targeted delivery of the drug combination, according to the researchers.

Tenofovir and lamivudine are also active against hepatitis B virus (HBV), making this regimen suitable for people with HIV/HBV coinfection. There are currently no long-term treatment options for hepatitis B. Furthermore, the subcutaneous formulation, which is injected under the skin, may allow for self-administration, as opposed to intramuscular injections that must be administered by a healthcare provider. care providers.

The current TLD-in-DcNP formulation has to be given every month—compared to every other month for Cabenuva—but the drugs reach their peak concentrations within a day, compared to nearly a week for cabotegravir and rilpivirine. Although injectable therapies may present logistical challenges, a long-acting regimen of familiar, well-tolerated drugs with low production costs may facilitate access in low-income countries. and the income is in the middle.

“The successful conversion of short-acting to long-acting TLD-in-DcNP may provide an all-in-one long-acting first-line complete HIV treatment,” the study authors concluded. “With dose adjustments, this novel all-in-one three HIV drug formulation opens up new possibilities for long-acting HIV therapy, potentially changing the lives of people living with HIV and HIV / HBV.”

Lamivudine Hydrogel

Another research group, at Johns Hopkins University, is developing a hydrogel formulation of lamivudine. Hydrogels have unique water-absorbing properties that give them a jelly-like consistency. The scientists tweaked lamivudine into a polymer, or large chain of molecules that can stick together or separate, depending on temperature, pH and other conditions. After the injection, the solution self-assembles into a gel that stays close to the injection site and slowly releases the drug over six weeks.

As described in the Journal of the American Chemical Society, Honggang Cui, PhD, and colleagues injected lamivudine hydrogel into the backs of mice. A single injection maintains effective drug concentrations for 42 days in plasma—and even longer in tissues such as lymph nodes, liver and kidney—while lamivudine injection without the hydrogel was not detected internally. for three days.

“Maintaining high levels of the drug in plasma for 42 days is very impressive. But in the future, we hope it will be even longer,” Cui said in a news release. The researchers think that the an optimized formulation can achieve dosing intervals of several months or longer.

Cui noted that the hydrogel injection is entirely composed of the therapeutic agent itself, which could streamline regulatory approval. His team plans to test the technology with other drugs, and it may be suitable for PrEP as well as HIV and hepatitis B treatment.

“This is a new way to deliver anti-HIV drugs, and this platform has the advantage that a polymer can be programmed to deliver many different drugs simultaneously,” said by study co-author Charles Flexner, MD. “One of the drawbacks of the approved injectable HIV treatment is that it has no activity against the hepatitis B virus, which is a common coinfection with HIV, especially in Asia and Africa. This formulation delivers lamivudine, a drug active against HIV and HBV, but can also be modified to deliver tenofovir, which is the current standard of care for HBV treatment.

Even long-term technologies for HIV treatment and prevention are in development. As reported at this year’s Conference on Retroviruses and Opportunistic Infections, researchers are testing tiny implants inserted under the skin that work like long-acting contraception. One team tested a refillable implant containing islatravir, Merck’s experimental nucleoside reverse transcriptase translocation inhibitor, which could last several years, while another tested a biodegradable implant. Both implants protected female monkeys against vaginal infection with a virus like HIV, and the refillable implant also protected male monkeys from rectal infection.

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