March 4, 2014
Macaques vaginally exposed to simian-human immunodeficiency virus (SHIV) appeared to be completely protected from infection by monthly injections of the integrase inhibitor GSK1265744 (a.k.a. "744"), according to study results presented at CROI 2014.
Pre-exposure prophylaxis (PrEP) use remains relatively little-used among HIV-negative people in the U.S., despite being approved by the Food and Drug Administration in 2012. Why this is remains a matter of intense discussion, but one prominent view centers around concerns that many find it difficult to commit to adhering to a once-daily oral prevention pill.
Enter 744, an experimental integrase inhibitor being developed as a long-acting antiretroviral. Early data suggest promise for the drug as an HIV treatment option with monthly -- or even quarterly -- dosing, but integrase inhibitors have also shown potential as PrEP possibilities.
At CROI 2014, J. Gerardo Garcia-Lerma, Ph.D., of the U.S. Centers for Disease Control and Prevention, presented a proof-of-concept study exploring the ability of long-acting 744 to prevent vaginal HIV infection. The study was conducted on 12 female pigtail macaques divided into two age- and weight-matched groups.
Six macaques received intramuscular injections of 744 (in the form of two shots in the quadriceps) at a dose of 50 mg/kg; after four weeks, they received another round of injections; and after eight weeks, they received one additional round. The other six macaques received placebo injections at the same interval.
Twice each week from weeks 1 through 12 of the study, the macaques' vaginas were directly exposed to low levels of SHIV, a modified version of HIV designed to function in simians. SHIV status and drug concentrations of 744 were tested weekly.
None of the six 744-treated macaques contracted SHIV, and they remained virus-free (according to viral DNA testing) through 28 weeks. By contrast, the macaques who received placebo injections became SHIV infected within an average of two to four exposures.
A separate pharmacokinetic analysis of 744 levels in six female pigtail macaques found that concentrations of the drug in plasma were "within the same range" of that seen in humans who have received injections of 744 dosed at 800 mg, and vaginal concentrations of the drug were roughly 16% to 26% of that found in the blood -- a finding that Garcia-Lerma suggested may inform further development of the drug as an HIV treatment option in humans.
These findings dovetail with previous early study results presented at last year's CROI that found 744 protected rhesus macaques against rectal SHIV exposure, and support further exploration of the drug as a PrEP option. Garcia-Lerma's presentation also immediately followed a presentation by Chasity Andrews of the Aaron Diamond Research Center, who shared evidence regarding just how long-acting 744 may be in humans; her team's data suggest that an 800-mg dose may be enough to "readily achieve" fully protective levels of the drug for three months at a time.
Left unanswered, for the time being, are questions regarding 1.) the drug's potential cost if it should eventually make it through the development process and 2.) the extent to which HIV-negative people at risk would be more or less willing to receive a periodic intramuscular injection to keep them HIV free than they would be to take a daily oral pill. (Or to use a gel, film or vaginal ring, which are some of the other forms of PrEP being discussed at this and other research meetings.)
The day we begin to answer those questions is clearly drawing closer, however; as Andrews noted in her presentation, this spring (in the Northern Hemisphere) will bring with it new Phase 2 studies examining the safety and tolerability of 744 as PrEP in high-risk men who have sex with men.
Myles Helfand is the editorial director of TheBody.com and TheBodyPRO.com.
Follow Myles on Twitter: @MylesatTheBody.