Phase 1 pharmacokinetics and safety study of extended duration dapivirine vaginal rings in the United States

Abstract

Introduction Vaginal rings are a promising approach to provide a woman‐centred, long‐acting HIV prevention strategy. Prior trials of a 25 mg dapivirine (DPV) ring have shown a favourable safety profile and approximately 30% risk reduction of HIV‐1 infection. Extended duration rings replaced every three months may encourage user adherence, improve health service efficiency and reduce cost overall. We evaluated safety, pharmacokinetics, adherence and acceptability of two three‐month rings with different DPV dosages, compared with the monthly DPV ring. Methods From December 2017 to October 2018, MTN‐036/IPM‐047 enrolled 49 HIV‐negative participant in Birmingham, Alabama and San Francisco, California into a phase 1, randomized trial comparing two extended duration (three‐month) rings (100 or 200 mg DPV) to a monthly 25 mg DPV ring, each used over 13 weeks, with follow‐up completed in January 2019. Safety was assessed by recording adverse events (AEs). DPV concentrations were quantified in plasma, cervicovaginal fluid (CVF) and cervical tissue, at nominal timepoints. Geometric mean ratios (GMRs) relative to the comparator ring were estimated from a regression model. Results There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs in the extended duration versus monthly ring arms ( p = 1.0). Plasma and CVF DPV concentrations were higher in the extended duration rings compared to the monthly ring. Plasma GMRs were 1.31 to 1.85 and 1.41 to 1.86 and CVF GMRs were 1.45 to 2.87 and 1.74 to 2.60 for the 100 and 200 mg ring respectively. Cervical tissue concentrations were consistently higher in the 200 mg ring (GMRs 2.36 to 3.97). The majority of participants (82%) were fully adherent (ring inserted at all times, with no product discontinuations/outages) with no differences between the monthly versus three‐month rings. Most participants found the ring acceptable (median = 8 on 10‐point Likert scale), with a greater proportion of participants reporting high acceptability (9 or 10) in the 25 mg arm (73%) compared with the 100 mg (25%) and 200 mg (44%) arms ( p = 0.01 and p = 0.15 respectively). Conclusions The extended duration DPV rings were well‐tolerated and achieved higher DPV concentrations compared with the monthly DPV ring. These findings support further evaluation of three‐month DPV rings for HIV prevention.

Acceptability and Preference for 3-Month Versus 1-Month Vaginal Rings for HIV-1 Risk Reduction Among Participants in a Phase 1 Trial

“…However, the 1-month ring had consistently higher ratings throughout the study. Although there were no safety concerns identified, and no differences in grade ≥2 genitourinary adverse events between arms, 14 participants using the 3-month ring reported more changes to the vaginal environment, and they expressed concerns about the hygiene and safety of a ring left in place for so long.…”

“…However, for the 1-month ring, acceptability findings from phase 1 and 2 studies with lower risk women 18 , 24 , 40 largely predicted those from larger studies among higher risk women, 20 , 22 , 41 and participants in the current study reported that they would be highly likely to use the ring if it were found effective. 14 …”

“…The design, procedures, and primary findings have been previously published. 14 Briefly, 49 participants were enrolled and randomized (1:1:1) to receive a silicone elastomer vaginal ring containing either 25, 100, or 200 mg DPV, all visually identical. Eligibility criteria included being born female, aged 18–45 years, HIV-uninfected, and generally healthy; willing to refrain from inserting any non-study vaginal products or objects (except tampons) into the vagina for the duration of study participation; not pregnant or breastfeeding; and having regular menstrual cycles or using a method of contraception for which the absence of regular menstrual cycles is an expected, normal consequence ( i.e., a progestin-only method or continuous combination oral contraceptive pills).…”

“… 11–13 In a recent phase 1 study conducted in the United States, two extended duration DPV vaginal rings, used over 13 weeks, were found to be well tolerated and to have a similar safety profile as the monthly ring. 14 In this article, we compare acceptability of and stated preference for the 3-month versus 1-month rings in that study.…”

HIV prevention: better choice for better coverage

“…The ring remains in‐situ until it is removed at the end of the month. A 90‐day ring has additionally been evaluated in a phase 1 study [ 36 ]. Two RCTs with the DVR ring indicated an overall efficacy of 30%, and effectiveness improved to 50% when the trial was converted to open label and adherence was improved [ 37 , 38 ].…”