Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings

Abstract

Background Variable adherence limits effectiveness of daily oral and intravaginal tenofovir-containing pre-exposure prophylaxis. Monthly vaginal antiretroviral rings are one approach to improve adherence and drug delivery. Methods MTN-013/IPM 026, a multi-site, double-blind, randomized, placebo-controlled trial in 48 HIV-negative U.S. women, evaluated vaginal rings containing dapivirine (25 mg) and maraviroc (100 mg), dapivirine-only, maraviroc-only, and placebo used continuously for 28 days. Safety was assessed by adverse events. Drug concentrations were quantified in plasma, cervicovaginal fluid (CVF), and cervical tissue. Cervical biopsy explants were challenged with HIV ex vivo to evaluate pharmacodynamics. Results There was no difference in related genitourinary adverse events between treatment arms compared to placebo. Dapivirine and maraviroc concentrations rose higher initially before falling more rapidly with the combination ring compared to relatively stable concentrations with the single drug rings. Dapivirine concentrations in CVF were 1 and 5 log10 greater than cervical tissue and plasma for both rings. Maraviroc was consistently detected only in CVF. Dapivirine and maraviroc CVF and dapivirine tissue concentrations dropped rapidly after ring removal. Cervical tissue showed a significant inverse linear relationship between HIV replication and dapivirine levels. Conclusions In this first study of a combination microbicide vaginal ring, all four rings were safe and well tolerated. Tissue dapivirine concentrations were 1,000 times greater than plasma concentrations and single drug rings had more stable pharmacokinetics. Dapivirine, but not maraviroc, demonstrated concentration-dependent inhibition of HIV-1 infection in cervical tissue. Since maraviroc concentrations were consistently detectable only in CVF and not in plasma, improved drug release of maraviroc rings is needed.

Frequent Cross-Resistance to Dapivirine in HIV-1 Subtype C-Infected Individuals after First-Line Antiretroviral Therapy Failure in South Africa

“…The lowest IC 90 (1.74 ng/ml) of the 100 viruses tested was 6-fold higher than the mean plasma C max (0.29 ng/ml), indicating that plasma DPV concentrations were insufficient to block viral replication. In contrast, reported vaginal fluid concentration on day 28 of DPV ring use (prior to ring removal) of 14,900 to 65,000 ng/ml (15,16) exceeded the adjusted IC 90 of 75% of samples by a minimum of 15-fold. The exact IC 90 could not be determined for 25 samples that displayed Ͼ500-FC DPV resistance (Fig.…”

“…Clearance of DPV occurs relatively rapidly, with cervicovaginal fluid concentrations falling to undetectable in 11 of 12 participants within 1 week of ring removal and cervical tissue levels falling below the lower limit of quantification within 3 days of ring removal (16). The concentration of DPV needed in the vaginal fluid and tissue for full protection against wild-type and NNRTI-resistant HIV-1 infection is not known.…”

“…It is unknown whether in vivo cell or tissue concentrations of DPV would be sufficient to inhibit these resistant viruses. Assessment of DPV levels in the genital tract has been imperfect, due to limited sampling from vaginal or cervical biopsy specimens (15,16). Evaluating the susceptibility to DPV in tissue explant models that can achieve higher DPV levels will add critical data on the risk of breakthrough infection with NNRTI-resistant virus.…”

“…Risk of breakthrough HIV-1 infection based on plasma and vaginal fluid DPV concentrations during ring use and after ring removal. Adjusted DPV IC 90 of the first-line ART failure viruses were compared to published mean concentrations of DPV found in plasma and vaginal fluid in the cervix, introitus, and area near the ring from two studies (15,16). The lowest IC 90 (1.74 ng/ml) of the 100 viruses tested was 6-fold higher than the mean plasma C max (0.29 ng/ml), indicating that plasma DPV concentrations were insufficient to block viral replication.…”

Distinct Pharmacodynamic Activity of Rilpivirine in Ectocervical and Colonic Explant Tissue

“…HIV-1 BaL (Advanced Biotechnologies Inc., Eldersburg, MD) was used for the efficacy testing, as it represents a virus that uses CCR5 and it readily infects the mucosal tissue utilized for preclinical testing algorithms (22)(23)(24) as well as for the ex vivo challenge assay (6,25,26). The 50% tissue culture infectious dose (TCID 50 ) in peripheral blood mononuclear cells was determined using the Reed and Muench method (27).…”