Long-acting HIV drugs are on the horizon

HIV treatment has come a long way over the past four decades—from handfuls of pills several times a day to once-daily one-tablet treatments and injections every two months. Daily pills and bimonthly injections also prevent HIV infection. But longer-lasting options are still needed because only about two-thirds of people diagnosed with HIV in the United States have achieved viral suppression, and only one-third of eligible people are on pre-exposure prophylaxis (PrEP).

Long-term treatment and prevention are more convenient, less noticeable and promote good adherence to treatment. Research promises treatments that can be taken even less frequently, and long-term remission is a goal on the horizon.

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

Last December, the Food and Drug Administration approved Sunlenca (lencapavir), the first HIV capsid inhibitor that is given every six months. So far, it’s only available for treatment-experienced people with multidrug-resistant HIV, but it works well for initial treatment and is being studied for PrEP. Sunlenca is the longest-acting antiretroviral drug approved, but it cannot be used alone and lacks an equally durable partner. In an effort to fill this gap, Gilead Sciences is now testing Sunlenca in combination with two broadly neutralizing antibodies in full twice a year.

Long-term TLD

Still in preparation, researchers are investigating other long-acting treatments. A team at the University of Washington in Seattle is testing a long-acting injectable formulation of tenofovir disoproxil fumarate, lamivudine and the integrase inhibitor dolutegravir (sold alone as Tivicay). A daily oral combination of these three drugs—sometimes called TLD—is the most commonly prescribed antiretroviral regimen worldwide.

As described in AIDS magazine, Simone Perazzolo, PhD, and colleagues used a new drug combination nanoparticle technology that allows water-soluble and insoluble substances to be combined to produce antiretroviral drugs that require less frequent administration. Despite the different physical and chemical properties of the drugs, 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.

According to the researchers, unlike some other long-acting drugs that form a “reservoir” that slowly releases the drug over time, TLD-in-DcNPs are rapidly and completely absorbed into the lymph node without significant retention at the injection site. .

When TLD-in-DcNP was administered to monkeys in an early study, all three antiretrovirals had long-acting profiles compared to the same drugs dissolved in liquid but not formulated as nanoparticles. Drug concentrations higher than the predicted effective concentrations remained in the blood plasma for four weeks after a single injection. According to the researchers, drug exposure levels were even higher in the cells than in the plasma, suggesting a cell-targeted drug combination.

Tenofovir and lamivudine are also active against hepatitis B virus (HBV), so this treatment is suitable for people with HIV/HBV co-infection. There are currently no long-acting treatment options for hepatitis B. In addition, the subcutaneous formulation, which is injected under the skin, may allow for self-administration, as opposed to intramuscular injections, which must be administered by a healthcare provider.

The current TLD-in-DcNP formulation would have to be given every month – compared to every other month for Cabenuva – but the drugs reach their maximum concentration in one day, compared to about a week for cabotegravir and rilpivirine. Although injectable treatments can pose logistical challenges, long-acting treatment with familiar, well-tolerated drugs and low production costs can facilitate access to low- and middle-income countries.

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

Lamivudine hydrogel

Another research group from Johns Hopkins University is developing a hydrogel formulation of lamivudine. Hydrogels have unique water-absorbing properties that give them a jelly-like texture. The researchers engineered lamivudine into a polymer, or large chain of molecules, that can either stick together or break apart 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 medicine over six weeks.

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

“Maintaining high drug concentrations in plasma for 42 days is very impressive. But in the future, we hope it will be even longer,” Cui said in a press release. The researchers believe that several months or even longer dosing intervals can be achieved with the optimized formulation.

Cui pointed out that the hydrogel injection consists entirely 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 HIV drugs, and this platform has the advantage that a single polymer can be programmed to deliver multiple different drugs simultaneously,” said study co-author Charles Flexner, MD. “One of the downsides of approved injectable HIV treatments is that none have activity against hepatitis B, a common HIV infection particularly in Asia and Africa. This formulation produces lamivudine, a drug active against both HIV and HBV, but can also be modified to deliver tenofovir, the current standard of care for HBV treatment.

Even longer-lasting technology for HIV treatment and prevention is being developed. As reported at this year’s conference on retroviruses and opportunistic infections, researchers are testing tiny implants placed under the skin that act as long-acting contraception. One group tested a refillable implant containing islatravir, Merck’s experimental nucleoside reverse transcriptase translocation inhibitor, which could last for several years, while another is studying a biodegradable implant. Both implants protected female monkeys from vaginal infection caused by an HIV-like virus, and the refillable implant also protected male monkeys from rectal infection.

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