A new HIV antiretroviral shows promise as a long-acting, oral prophylactic agent, according to a new study by Izzat Raheem, Tracy Diamond and colleagues from Merck & Co., Inc., Rahway, NJ, U.S., published in the open-access journal PLOS Biology.

HIV pre-exposure prophylaxis (PrEP) is a key part of reducing the number of new HIV infections. The most common oral PrEP therapies, consisting of once-daily pills, are highly effective at protecting people from acquiring HIV, but they only work if taken properly.

Currently, the only long-acting PrEP therapies require injection by a health care provider, which isn’t always feasible for people. Long-acting, oral PrEP therapies could facilitate adherence, provide greater privacy and discretion, reduce concerns about stigma, and improve accessibility for more people to initiate and continue on PrEP, ultimately helping to stem the tide of the nearly 1.3 million new HIV infections globally per year.

Researchers from Merck engaged in a lead optimization campaign to develop a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI). NRTTIs are a new class of anti-HIV drugs that have shown potential for long-acting prophylaxis. They inhibit viral replication by more than one mechanism, including blocking translocation of reverse transcriptase on the growing viral DNA chain.

Using a known NRTTI, islatravir, as a starting point, researchers used several medicinal chemistry strategies to modify the structure and optimize it using both in vitro and in vivo assays.

The lead compound, dubbed MK-8527, showed robust antiviral activity in vitro, and pharmacokinetics in animal studies demonstrated that it may be suitable as a long-acting oral therapy.

Studies in humans are underway to assess the safety and tolerability of MK-8527 as a once-monthly oral pill in volunteers at low likelihood of HIV exposure, and at least one completed clinical study shows promising results.