Pharmacokinetics of Cabotegravir for HIV PrEP

The world’s collective focus rests with another infectious disease at the moment—but preventing HIV remains a priority.

Which is why the relatively low uptake of the 2 currently available preexposure prophylaxis (PrEP) regimens—about 225,000 of the roughly 1.2 million considered at high risk for HIV are taking them, according to the US Centers for Disease Control and Prevention—is such a cause for concern. Of course, among the barriers for many in starting PrEP has been the cost—hence, guidance issued July 20th by the US Centers for Medicare and Medicaid Services recommending that it be free for all with (public and private) health insurance.

Although that’s sure to help, another positive development would be an expansion of the PrEP armamentarium. Enter long-acting cabotegravir. The integrase inhibitor has already been approved by the US Food and Drug Administration as part of a combination regimen with the antiviral rilpivirine for long-acting antiretroviral therapy (ART). The regimen is marketed as Cabenuva (ViiV Healthcare).

In an analysis published on July 8 by the British Journal of Clinical Pharmacology, researchers found that 16 patients given a 600 mg injection of cabotegravir still had detectable levels of the drug in plasma, as well as all tissues and fluids, 12 weeks later. In addition, median plasma cabotegravir concentrations exceeded the in vitro protein-adjusted 90% maximal inhibitory concentration over the same period, with median tissue- and fluid-to-plasma concentration ratios across all visits measuring at 0.32 for rectal fluid and 0.08 to 0.16 for other tissues and fluids.

These findings suggest that the drug, again in its long-acting form, may be a viable candidate for PrEP, the researchers said.

“After a single intramuscular injection in healthy volunteers, the long-acting integrase inhibitor cabotegravir distributes into tissues and mucosa that are relevant for the prevention of sexually-acquired HIV, including vagina, cervix, and rectal tissue and associated fluids,” study co-author Ethel D. Weld, MD, PhD, Assistant Professor of Medicine, Pharmacology, and Molecular Sciences at Johns Hopkins University School of Medicine in Baltimore, told Contagion. “Overall, cabotegravir concentrations in tissues were about a tenth of what they were in plasma and were highly correlated with concentrations in plasma.”

Injection-site reactions were by far the most common adverse events reported, among 14 of 16 patients, though 82% were grade 1 in severity, according to the researchers. Adverse events associated with currently available PrEP regimens include diarrhea, nausea, headache, fatigue, and stomach pain—none of which were reported by patients given cabotegravir.

Media reports indicate the manufacturer submitted a new drug application to the FDA in May, which means cabotegravir could be approved for use in PrEP within a year or so, according to Dr. Weld.

“Some of the characteristics that I hope will make long-acting cabotegravir an attractive option for PrEP to people whose lives may put them at risk of HIV acquisition include [that] it does not require daily or peri-coital action from people,” she said. In addition, there is good data from the HPTN 083 and 084 trials that long-acting cabotegravir is superior at preventing HIV to a daily oral PrEP option—and that that superiority boils down to an adherence advantage, rather than a molecule-for-molecule advantage.”

And improved adherence likely means enhanced uptake.