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Background: Dapivirine Vaginal Ring (DVR), containing 25mg dapivirine, has been shown to be safe and efficacious in two Phase III clinical trials. This trial investigated the effect of menses and tampon use on local and systemic pharmacokinetics of dapivirine delivered by DVR.
Methods: An open-label, randomised, cross-over trial was conducted among 22 healthy, HIV-negative women, aged 18-40 years. Participants received 3 treatments, separated by washout periods of 28 days, according to a randomly assigned treatment sequence: DVR with menses, without tampon use; DVR with menses, with tampon use; DVR with no menses. Oral contraceptives were used to regulate onset or absence of menses between Days 14 and 19 post-ring insertion. Dapivirine concentrations were determined in plasma and vaginal fluid (VF), and residual dapivirine was assessed in used rings.
Results: Both plasma and VF concentrations decreased after onset of menses. For plasma, AUC11-21days was 6% lower during menses with or without tampon use, relative to no menses (ratio: 0.94; 90% CI: 0.88-1.00). At the end of menses, concentrations increased to levels associated with no menses by Day 28. Menses and tampon use had a greater impact on VF concentrations: AUC11-21days was reduced by 35% during menses without tampon use (ratio “menses/no menses”: 0.65; 90% CI: 0.53-0.80), and by 48% during menses with tampon use (ratio “menses/no menses”: 0.52; 90% CI: 0.42-0.65). The lowest mean VF concentrations occurred on Day 15: 4797 and 7701ng/g for menses with and without tampon use, compared to 38350ng/g (no menses), but were well above the in vitro IC99 in cervical tissue (3.3ng/mL). VF concentrations subsequently increased to levels associated with no menses by Day 21. Ring residual levels seemed unaffected by menses and tampon use, with mean values of 20.3, 20.7 and 20.2mg following menses without tampon use, menses with tampon use, and no menses, respectively.
Conclusions: Plasma dapivirine concentrations were marginally lower during menses. VF concentrations were markedly reduced during the first 2 days of menses; at the end of menses, levels rapidly increased to pre-menses concentrations. A greater reduction in VF concentration was observed with tampon use; however, the lowest mean value was >1400 times above IC99.