Background: Unprotected receptive anal intercourse (RAI) is also practiced by women, providing strong rationale for the development of an HIV microbicide gel that is suitable for both rectal and vaginal applications. This would remove the need for separate products and dosages for women who engage in RAI and vaginal intercourse, thereby helping to increase user adherence and potentially cutting costs associated with separate products. A DuoGel™ product containing 1% wt/vol IQP-0528, which has non-nucleoside reverse transcriptase and entry inhibitory activities, was developed and first evaluated vaginally in pigtailed (PM) and rhesus (RM) macaques.
Methods: DuoGel™ formulation was optimized for dual compartment application. A 1.5 ml volume of 1% IQP-0528 DuoGel™ was applied vaginally to 6 SHIV+ female RM and 6 naïve female PM. Blood, vaginal pH measurements, cervicovaginal lavage, and vaginal and rectal spears were collected before, and up to 24 hours after gel application. Vaginal and rectal biopsies were also collected from PM at 24 hours. The RM were euthanized at 4 hours, and vaginal, cervical, rectal, and regional lymph node tissues were harvested for drug analysis. Anti-viral activity was tested ex vivo by co-culturing RM vaginal tissues with activated human peripheral blood mononuclear cells (PBMC), and measuring p24 levels up to 10 days after challenge with HIV-1Ba-L. Drug levels in plasma, vaginal fluids, and tissues were determined using LC-MS.
Results: In RM, median levels of IQP-0528 were between 104-105 ng/g in vaginal and cervical tissue, and 105-107 ng/ml in vaginal fluids for 4 hours after gel application. Bi-directional dosing was shown by median IQP-0528 levels being between 103-104 ng/g in rectal tissues. Similar levels were observed in PM vaginal fluids for 4 hours post gel application, but IQP-0528 was not detected in the rectum. Vaginal pH remained within normal range for both species (6.5-9). Vaginal tissues obtained from RM at necropsy protected co-cultured PBMC from HIV-1 infection ex vivo, with a viral inhibition range of 90-100%. Anti-viral activity was observed in vaginal tissues that were proximal, medial, and distal relative to the cervix. Viral inhibition was not detected in baseline tissue samples.
Conclusions: These data suggest that 1.5 ml of DuoGel™ delivers IQP-0528 throughout the macaque vaginal compartment at levels that are highly inhibitory to HIV-1 infection. Rectal PK studies are underway.