Forty years after HIV became a global pandemic, there are now more than 30 drugs approved to treat it. The National Institute of Allergy and Infectious Diseases’ director, Anthony Fauci, and clinical director, Clifford Lane, opined in the July 2, 2020, issue of The New England Journal of Medicine that “considering the spectacular scientific advances that have been made over nearly four decades, it is conceivable that with optimal implementation of available prevention strategies and treatments, the end of HIV/AIDS as a global pandemic will be attainable.”

But “even in this era…. new agents will always be needed,” James McMahon, infectious diseases physician and head of clinical research at Monash University’s Alfred Hospital, told the audience in a symposium on “State of the ART: the latest in HIV treatment” at the 23rd International AIDS Conference (AIDS 2020: Virtual).

At the session, Claudia Cortes, associate professor at the University of Chile, gave an overview of the most interesting new agents coming down the pike. Notably, those agents included not just new agents against old targets, but also experimental drugs with three new mechanisms of action – capsid-targeting agents, maturation inhibitors and Rev inhibitors.

Furthest along among the three is lenacapavir (GS-6207, Gilead Sciences Inc.) which is in a phase II/III trial in combination with optimized background treatment for heavily pretreated patients with multidrug-resistant HIV. The drug has the FDA’s breakthrough designation.

Lenacapavir targets the capsid protein, which makes up an inner viral shell just inside the outer membrane that is an additional protection for the virus’ core proteins and RNA genome. Interfering with the capsid can catch HIV both coming and going; by interacting with different host factors, it supports multiple different steps in the viral life cycle, from infectivity through reverse transcription to packing up new virions to start the process anew in the next infected cell.

Targeting capsid protein has been challenging both because it does not have a deep binding pocket to stick a small molecule into, and because the sheer amount of capsid protein in virions overwhelmed inhibitors. In the July 2, 2020, issue of Nature, researchers from Gilead reported that lenacapavir acted by another mechanism – it accelerated the assembly of capsids, ultimately producing malformed capsids.

In a poster presented at AIDS2020: Virtual, as well as in the paper, the team also reported that in the phase I trial of the drug, a single subcutaneous injection of lenacapavir was able to keep therapeutic concentrations of the drug in the bloodstream for six months.

Long-acting drugs are a frontier in HIV medicines, and could improve both treatment and prevention. A treatment that needs to be given only twice a year would make it much easier for patients to adhere to the drug regimen, thus slowing down the emergence of resistance.

And HIV treatment can be used for prevention, the so-called pre-exposure prophylaxis (PrEP) approach. Here, too, less frequent dosing makes adherence easier, via two mechanisms.

A drug that does not need to be taken daily does not have a daily risk of not being taken. And individuals who live in societies or situations where HIV, sexual activity or both are stigmatized are sometimes hesitant to have pills around, especially if there is also a lack of privacy, because they fear being branded as either HIV-positive or promiscuous.

At the meeting, researchers reported new subgroup analyses from the HPTN083 trial, which compared PrEP using long-acting cabotegravir injections to daily oral Truvada (emtricitabine/tenofovir, Gilead Sciences Inc.). That trial was stopped early in May 2020, after an interim analysis demonstrated that a cabotegravir injection every two months was 69% more effective than daily oral Truvada at preventing HIV acquisition in cisgender men and transgender women who have sex with men. HPTN084, a companion study in African cisgender women who have sex with men, is ongoing.

In their paper, the Gilead team wrote that “the infrequent subcutaneous dosing renders GS-6207 an attractive candidate for the simplified prevention of the acquisition of HIV in at-risk populations – making this drug a potentially transformative tool in efforts to end the global HIV epidemic.”

Long-acting regimens that could greatly extend treatment intervals are being pursued by several companies.

Treatment: Half-empty glass

While prophylaxis could likely be achieved with one drug, treatment takes a combination regimen – and for a long-acting regimen to have an advantage, all drugs in the regimen have to be long-acting.

To date, the longest-acting combination with demonstrated clinical success is an every-other-month dose of cabotegravir (Viiv Healthcare Ltd.) and rilpivirine (Janssen Pharmaceutical Co.). Results from the ATLAS2M trial demonstrating that treatment with the combination every other month was as good as monthly treatments were presented at the virtual 2020 Conference on Retroviruses and Opportunistic Infections (CROI) in March.

Under the trade name Cabenuva, the combination is approved for monthly treatments in Canada, but it received a complete response letter from the FDA in December 2019 over a manufacturing issue.

A Gilead spokesperson told BioWorld, “We are already conducting clinical trials in people living with HIV using lenacapavir in combination with other ARV agents (in heavily treatment experienced and treatment naïve). None of the agents we are combining lenacapavir with are long acting; however, we are making efforts to develop a suitable long-acting partner agent.”

At the 2019 meeting on HIV science, Merck Sharp & Dohme had reported modeling studies indicating that its nucleoside reverse transcriptase translocation inhibitor (NRTTI) islatravir could be effective for up to a year, as well as patient data showing that drug levels remained sufficient for effective PrEP for three months when they were delivered via an implant.

Michael Robertson, executive director of clinical research at Merck, told BioWorld that according to the modeling data, “a year duration with the implant is very feasible.” Oral islatravir, which is in a phase III trial in combination with doravirine, could also be used in regimens with less frequent dosing.

“For islatravir orally, we believe that you could administer it once a month, and we believe that that could be very important for PrEP,” he said.

In the treatment realm, Merck is evaluating combination possibilities and has an active internal research program to identify good islatravir partners.

Scientifically, other existing long-acting drugs could be combined with islatravir. Some combinations “may be better suited than others… because of their route of administration, or if you wanted to have a synchronized schedule,” Robertson said.

“We and others are doing surveys and getting focus groups to ask them what their preference would be,” he said, adding that “the longer the interval, the less it matters” whether schedules are synchronized or not. “But different people have different preferences.”

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