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Steep Dapivirine Drops in Vaginal Fluid
With Cyclic Use of DPV/LNG Vaginal Ring
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Pharmacokinetics, safety, and vaginal bleeding associated with continuous versus cyclic 90-day use of dapivirine and levonorgestrel vaginal rings for multipurpose prevention of HIV and pregnancy
HIVR4P Virtual, January 27-28 and February 3-4, 2021
Mark Mascolini
Vaginal fluid levels of the nonnucleoside antiretroviral dapivirine (DPV) dropped precipitously during cyclic planned removal of a DPV/levonorgestrel (LNG) vaginal ring being studied to prevent both HIV infection and pregnancy [1]. Whether such steep falls in DPV levels will affect HIV prevention remains unknown because research has not determined whether DPV in vaginal fluid, tissues, or plasma is critical for prevention of sexually transmitted HIV.
Researchers from the University of Pittsburgh, the Microbicide Trials Network (MTN), and other groups conducted this phase 1 trial of the DPV/LNG vaginal ring as an open-label extension of a phase 3 DPV ring trial [2]. That double-blind, placebo-controlled trial in 2629 HIV-negative African women found significantly lower HIV incidence in women using the dapivirine ring, which has received World Health Organization prequalification for HIV prevention.
Developed by the International Partnership for Microbicides (IPM), the 90-day vaginal ring used in the phase 1 study combines 200 mg of DPV (about 440 mcg/day released in first month, then about 220 mcg/day) and 320 mg of LNG (about 120 mcg/day released in first month, then about 85 mcg/day). In the first-in-human study presented in 2018 (MTN-030/IPM 041), plasma DPV and LNG concentrations 2 days after ring removal (following 14 days of use) were consistent with those of the 25-mg DPV ring and other LNG-based contraceptives [3]. Because many hormonal contraceptive rings are removed periodically to optimize bleeding patterns, the researchers planned this trial to assess the potential impact of periodic ring removal on HIV prevention with a 200/320-mg DPV/LNG ring.
This phase 1 trial examined a 90-day ring exposure period in 25 women enrolled from July 2018 through May 2019 at the University of Pittsburgh. Researchers randomized them in a 1-to-1 ratio to wear the ring continuously for 90 days or for 3 cycles with 28 days in and 2 days out. They collected vaginal fluid and blood samples 13 times throughout the study period, and women recorded bleeding and both planned and unplanned ring removal by text messaging.
Participants had a median age of 36 years; 20 were white, 3 black, and 2 Asian. Thirteen women had a man as their primary sex partner, 1 had a woman, 1 another gender, and 10 had no primary partner. Median body mass index stood in the overweight range at 27 kg/m2.
Women completed 320 of 355 planned study visits (90%), and per-protocol ring adherence stood at 91%. Nineteen women (76%) had at least 1 partial ring expulsion, and 10 (40%) had at least 1 full expulsion.
As expected, DPV concentrations in blood plasma dropped when women removed the ring on days 28 and 58 then rebounded when they put the ring back in on days 30 and 60. Median declines in DPV concentrations did not dip below the DPV minimum dose target. DPV plasma exposure stayed steady in women who did not remove the ring. Researchers observed similar patterns with LNG concentrations in blood plasma.
Concentrations of both DPV and LNG in vaginal fluid plummeted as soon as women removed the vaginal ring. DPV levels plunged from near 100,000 ng/g to only about 10 ng/g within hours of ring removal. Concentrations of DPV and LNG climbed swiftly back to their ring-in levels days after reinsertion.
The researchers do not believe the transient dips in vaginal fluid LNG should affect contraceptive efficacy. No one knows how the similar fall and rebound of vaginal fluid DPV will affect this antiretroviral's ability to prevent vaginally transmitted HIV infection. But this finding raises concern that cyclical use of a DPV/LNG vaginal ring may let HIV get a foothold when DPV levels nosedive nearly 4 orders of magnitude.
Of the 84 adverse events recorded, 70% were mild and 29% moderate. Study arms did not differ in rates of genitourinary adverse events or grade 2 or higher adverse events. One severe event judged related to study drugs, grade 4 anemia, occurred in a woman in the cyclic group with an enrollment hemoglobin of 10.3 g/dL. At the end of the randomized phase of the trial, during the day-90 visit, this woman reported heavy vaginal bleeding for the past 12 days. And she had unknowingly expelled her vaginal ring. The woman required a blood transfusion with intravenous iron.
Vaginal bleeding did not differ between the continuous and cyclic ring groups. No bleeding occurred in about 60% of study days in both groups, while spotting or light bleeding occurred in about 30% of days in both groups.
The researchers called the high ring expulsion rates "concerning for acceptability of this formulation." The ring was reformulated to address this problem, and a clinical trial to evaluate this new formulation is being planned.
Women will periodically remove vaginal rings during routine use, as happens with many hormonal contraceptives, the researchers noted. They believe contraceptive efficacy of a DPV/LNG ring can tolerate periodic removal of the ring. But whether periodic ring removal will affect HIV prevention efficacy remains to be seen. More will be known when continuing research answers two questions: (1) Which DPV concentrations are critical for HIV prevention efficacy-those in plasma, vaginal fluid, and/or tissue? (2) What are the target genital tract concentrations for HIV prevention?
References
1. Achilles SL, Kelly CW, Blithe DL, et al. Pharmacokinetics, safety, and vaginal bleeding associated with continuous versus cyclic 90-day use of dapivirine and levonorgestrel vaginal rings for multipurpose prevention of HIV and pregnancy. HIVR4P (HIV Research for Prevention) Virtual, January 27-28 and February 3-4, 2021. Abstract OA06.01.
2. Baeten JM, Palanee-Phillips T, Brown ER, et al; MTN-020-ASPIRE Study Team. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med. 2016;375:2121-2132. doi: 10.1056/NEJMoa1506110.
3. MTN. Microbicide Trials Network. MTN-030/IPM 041. https://mtnstopshiv.org/news/mtn-030ipm-041
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