A randomized, double blind, placebo-controlled, phase 1 safety and pharmacokinetic study of dapivirine gel (0.05%) administered rectally to HIV-1 seronegative adults (MTN-026)


BACKGROUND: HIV prevention needs persist, in part, because of daily oral PrEP challenges, hence, interest in on demand topical options. The dapivirine vaginal ring demonstrated 30% risk reduction in HIV-1 infections, but has not been evaluated for rectal use. We evaluated rectal safety, pharmacokinetics (PK) and pharmacodynamics (PD) of a dapivirine gel formulation.
METHODS: We enrolled HIV-uninfected men and women, 18-45 years of age, at Thailand and United States sites. We randomized eligible participants 2:1 to receive blinded dapivirine (0.05%) or placebo gel via rectal applicator. A single dose phase was followed by observed daily dosing for seven days. Plasma, and fluid and tissue from both rectum and cervix were collected at baseline and 5 times over 72 hours after each dose for PK, ex vivo HIV-1 biopsy challenge (PD), tissue histology, and flow cytometry.
RESULTS: We randomized 28 participants; two terminated early. Nine participants were female and 19 male (sex at birth); 12 were white, 11 Asian, 4 black, 1 other race/ethnicity. Mean years of age were 28.5 and 34.2 in the dapivirine and placebo arms, respectively.
Thirty adverse events occurred (Grade 1 or 2, except one unrelated Grade 3) without study arm differences or any drug related discontinuation.Dapivirine rectal tissue concentrations (median [interquartile range]) 0.5-1 and 2, hours after a single dose were 256 ng/gm (below limit of quantitation [BLQ], 666) and BLQ (BLQ, 600), respectively, then BLQ (BLQ, BLQ) from 24-72 hours; multiple dose concentrations were similar. Peak dapivirine plasma concentrations were 0.33 ng/mL (0.15, 0.48) after one dose and 0.40 (0.33, 0.49) after seven doses. Cervical tissue and fluid concentrations were all BLQ. Flow cytometry indicated no changes or study arm differences. Ex vivo biopsy challenge showed ~10-fold reduction in viral replication, but only through 2 hours after dosing.
CONCLUSIONS: Dapivirine gel was well-tolerated with dapivirine plasma concentrations similar to those of the dapivirine vaginal ring observed in clinical trials. However, the rectal ex vivo antiviral effect and tissue concentrations were only transient and well below vaginal tissue results with the dapivirine vaginal ring. A long-acting reformulation or higher dose is likely needed to provide protection from anal sex.