Two presentations at the 17th Conference on Retroviruses and Opportunistic Infections (CROI) investigated the use of the CCR5 inhibitor maraviroc (licensed as Celsentri or Selzentry for HIV treatment) as a possible vaginal and rectal microbicide.
In one, maraviroc, introduced vaginally before challenge, protected five out of five rhesus macaques against a high-dose single injected challenge of the human/monkey chimeric virus SHIV-162p3.
In another, measures of maraviroc in the semen of male volunteers were found to be somewhat lower than in blood plasma – contrary to levels seen in vaginal fluid, which were 3.3 times higher – but levels in rectal tissue biopsies were very much higher than in blood, suggesting that maraviroc might be a promising rectal microbicide candidate.
In the first study, the monkeys were fully protected with a 6mg/ml dose of maraviroc and four out of five were protected with a 2mg/ml dose.
Protection tailed off rapidly as the interval between microbicide dose and challenge lengthened, with protection reduced to 50% after a four-hour delay. This was simply due to microbicide leakage.
Some microbicide experiments with tenofovir have shown that animals infected despite microbicide use develop lower viral loads, but this was not the case with maraviroc.
The same test protocol was also used with an SHIV virus using the CXCR4 co-receptor, and as expected maraviroc offered no protection against this, but there were no changes in the viral load of the infected monkeys. This was done to test concerns that using a CCR5 inhibitor microbicide might facilitate infections of particularly aggressive X4-using viruses.
Presenter John Moore of Cornell Medical School commented that a single maraviroc pill containing 300mg of drug retails for about $15 and could in theory protect about 15 women, at the cost of less than a dollar a dose.
He also commented that large microbicide-developing programmes such as IPM (International Partnership for Microbicides) did not plan to conduct animal safety studies, and his institute had had to run their trial using a limited supply of ground-up maraviroc in solution.
Some cautions were expressed about this study in questions, including whether the use of progesterone to thin the vaginal epithelium might expose vaginal tissue to more drug than it would get in typical use. And session chair Ian McGowan commented that a study using human rectal explant tissue presented at last year’s conference had not produced impressive results – see this report.
Moore commented that the exact process of HIV infection via the genital tract was poorly understood, which was why animal-model experiments, especially of a cell entry inhibitor, were necessary.
Maraviroc concentrates at very high levels in rectal tissue
In the other presentation, Kevin Brown of the University of North Carolina presented findings of maraviroc concentration in the semen and rectal tissue of male volunteers after oral dosing.
The study used twelve HIV-negative male volunteers, who took an eight-day course of maraviroc dosed at the treatment level of 300mg twice daily.
Blood and semen drug levels were measured five times in twelve hours after a single dose on days one, seven and eight of the study, and also once on days three to six. Rectal biopsy specimens were collected on days one, seven and eight.
After a single dose, semen and blood plasma levels were initially the same but after six hours semen levels fell off more quickly. Trough levels in semen were 70% of blood levels on days 7/8, and the area under the curve (AUC – total drug exposure) in semen was 60% of that in blood. Levels seen after multiple dosing were similar.
Concentrations in rectal tissue were much higher than in blood, with a mean trough level 91 times higher than in blood and the AUC 28 times higher.
Dr Brown said that the rectal tissue levels appeared promising for the use of maraviroc as a rectal microbicide. Levels might be higher because maraviroc was partially eliminated in the faeces.
He commented that the study proved that drug levels in the male anogenital tract could not be extrapolated from studies conducted in women.
Veazey R et al (presenter Moore J). Protection of rhesus macaques from vaginal infection by maraviroc, an inhibitor of HIV-1 entry via the CCR5 co-receptor. Seventeenth Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 84LB, 2010.
Brown K et al. Antiretrovirals for prevention: maraviroc exposure in the semen and rectal tissue of healthy male volunteers after single and multiple dosing.. Seventeenth Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 85, 2010.