The Long-Acting Bandwagon: A Top HIV Clinical Development of 2018

Word is getting out that, barring some major setback, long-acting injectable HIV antiretrovirals will soon be coming our way. Patients have come to my clinic asking about it; others muse that they wish there were shots instead of pills, and are heartened when learning that there might well be some in the near future.

The LATTE-2 trial has continued to show the ability of cabotegravir (CAB) and rilpivirine (Edurant, RPV) to maintain viral suppression, and these will be the first injectable antiretrovirals to hit the market. But they will not be alone forever, as others are working to get in on the long-acting game.

Some notable agents under development include MK8591 (EFdA), a non-nucleoside reverse transcriptase translocation inhibitor (NNRTTI) -- note the extra "T" -- that has in vitro activity against HIV, including multidrug resistant strains. The active metabolite of this compound has been shown to have a half-life on the order of 120 hours, leading to options for oral dosing weekly, and perhaps much less frequently if injected.

Another interesting drug with long-acting potential is GS-9131, a nucleoside reverse transcriptase inhibitor that is also potent in vitro and has activity against resistant HIV. Some are thinking beyond pills and needles to implants, tearing a page from the contraception playbook. On a related note, some preliminary work on a tenofovir alafenamide (Vemlidy) implant was recently presented at the 2018 HIV Research for Prevention conference, fanning interest in this potential future option for both prevention and treatment.

The Bottom Line

Channeling Arthur C. Clarke and that guy in The Big Short who bet it all on the crash of 2008, I predict the future of HIV treatment will be long-acting antiretrovirals. It won't be right away, but it will happen.

There are lots of reasons to think otherwise. Pills for HIV nowadays are small and amazingly well tolerated. Shots hurt, and there are plenty of needle-phobes. Plus, at first, injections will have to be given by someone with a white coat, rather than self-administered. Moreover, long-acting injectables go against the grain of some other conditions, such as multiple sclerosis, for which there is a desire for oral meds to take the place of injections. There are also potential concerns around pregnancy.

Despite these challenges, some of which will be engineered out, I believe that freedom from a daily reminder of HIV is a powerful and liberating motivation for people who wish to be like everyone else but can't, because of residual grains of virus slumbering in their cells. The longer the span between doses, the more these folks will want it. Pre-exposure prophylaxis (PrEP) will follow -- or maybe even lead -- and further normalize the use of shots to cover all HIV bases.

This is a long-range vision. Shorter-term, we will need compatible agents to adminster together in an effective regimen. This will require a future in which HIV drug companies play nice with one another.

Top 10 Clinical Developments of 2018
0. Introduction
1. GEMINI and the Rise of Two-Drug HIV Therapy
2. Debate Over Dolutegravir in Early Pregnancy
3. Integrase Inhibitors and Weight Gain
4. PrEP and the Decline in New HIV Diagnoses
5. On-Demand Prevention in France
6. Bictegravir Has Finally Arrived
7. Abacavir, Platelets, and a Cardiovascular Verdict
8. African-American Men and HIV Treatment Outcomes
9. The Long-Acting Bandwagon
10. Designing HIV-Resistant People

David Alain Wohl, M.D., is a professor of medicine in the Division of Infectious Diseases at the University of North Carolina (UNC). He is site leader of the UNC AIDS Clinical Trials Unit at Chapel Hill, director of the North Carolina AIDS Education and Training Center (AETC), and co-director of HIV services for the North Carolina state prison system. In 2014, he became co-director of the UNC-Duke Clinical RM Ebola Response Consortium.