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Three-Month Vaginal Ring Yields
Higher Dapivirine Levels in US Study
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CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021
Mark Mascolini
Compared with the current 1-month dapivirine (DPV) vaginal ring, 3-month rings provided higher DPV concentrations, which the researchers believe should translate into at least equal efficacy [1]. Adverse event rates were similar with the 3-month and 1-month rings in this US study, and adherence to ring use was high.
Vaginal rings put women in charge of HIV prevention with a long-lasting reversible strategy. Two phase 3 clinical trials found monthly 25-mg DPV rings safe and effective, and in 2021 the World Health Organization endorsed these DPV rings as an additional choice in planning combination prevention. Longer-lasting rings, the researchers proposed, could reduce cost, streamline follow-up, and promote adherence.
To compare 3-month DPV rings with the 1-month ring, researchers conducted MTN-036/IPM 047, a phase 1 randomized trial of ring safety, acceptability, and pharmacokinetics. The study randomized HIV-negative women in a 1-1-1 ratio to a 25-mg 1-month DPV ring, a 100-mg 3-month DPV ring, or a 200-mg 3-month DPV ring. Women in the 1-month group replaced their ring every 4 weeks for 8 weeks and wore the third ring for 5 weeks. Women in the other two groups wore their ring continuously for 13 weeks.
The trial recruited 49 healthy HIV-negative women assigned female sex at birth and between 18 and 45 years old. Study sites were the University of Alabama at Birmingham and the San Francisco Department of Public Health. Seventeen women were randomized to the 25-mg arm, 16 to the 100-mg arm, and 16 to the 200-mg arm. Across the 3 arms age averaged 30 years, 41% of participants were black, 39% white, 8% Asian, and 12% of other races or ethnicities. Trial retention stood at 94% through day 91.
Rates of grade 2 or higher genitourinary adverse events did not differ significantly between the three study arms: 12% with 25 mg, 6% with 100 mg, and 6% with 200 mg (P = 1.00). The same proved true for grade 3 or higher adverse events. Three quarters of adverse events (76%) were not related to study device or drug, 79% were mild, and 21% were moderate.
Geometric mean ratios (GMR) showed that DPV concentrations were nearly always higher with the 100- and 200-mg rings than with the 25-mg ring. Plasma concentrations at days 28, 56, and 91 were 1.3-fold to 1.9-fold higher with the 3-month rings than the 1-month rings, and cervicovaginal fluid concentrations at those three points were 1.5-fold to 2.9-fold higher with the 3-month rings. In cervical tissue at day 28, DPV concentration were virtually equivalent with the 100-mg ring and the 25-mg ring (GMR 0.99, confidence interval [CI] 0.29 to 3.37). DPV concentrations were higher with the 200-mg ring than the 25-mg ring at day 28 (GMR 2.36, CI 1.13 to 4.91) and day 91 (GMR 3.97, CI 1.15 to 13.76), and nonsignificantly higher with the 100-mg ring than the 25-mg ring at day 91 (GMR 3.04, CI 0.80 to 11.54).
DPV maximum concentration and area under the concentration-time curve (AUC) were always higher (and usually significantly higher) with the higher-dose extended-release rings than with the lower-dose 4-week ring in plasma and cervicovaginal fluid.
Forty of 49 women (82%) said they remained fully adherent to ring use during the study, and this adherence rate did not vary from study arm to arm. Women removed the ring 9 times during the trial, usually because of discomfort or minor genitourinary symptoms (3 times), because they did not want their partner to know or their partner complained (2 times), or for sex or a pelvic exam (2 times). Women reported 2 ring expulsions, 1 for tampon removal and 1 related to sex.
Checking how much DPV remained in rings collected after use, the researchers estimated average total DPV release over 13 week at 11.2 mg for the 25-mg rings, 14.2 mg for the 100-mg rings, and 22.8 mg for the 200-mg rings.
When asked how much they liked the ring overall, on a 10-point scale participants gave the ring a median score of 8 (IQR 6 to 10). And when asked if they were likely to use the ring if research proved it effective, women showed even more enthusiasm with a median score of 9 (IQR 7 to 10).
The researchers suggested that "future approval of extended duration rings, if shown effective, could provide more long-acting options and increase access and equity to HIV prevention in women."
Reference
1. Liu A, Islas CD, Gundacker H, et al. Phase 1 PK, safety, and acceptability of 3-month dapivirine vaginal rings. CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021. Abstract 147.
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