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Low and Transient Rectal Dapivirine Levels in 7-Day Rectal Gel Trial
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HIVR4P Virtual, January 27-28 and February 3-4, 2021
Mark Mascolini
A vaginal ring emitting the nonnucleoside dapivirine (DPV) cuts HIV risk about 30% in women [1,2], but DPV rectal gel yielded only transient rectal tissue levels in a placebo-controlled trial [3]. Rectal DPV levels lay well below those seen in vaginal tissues of women wearing the DPV ring.
MTN-026, a Microbicide Trials Network study, is the first to assess the rectal safety, drug concentrations, and acceptability of DPV 0.05% rectal gel [3]. This phase 1 double-blind trial randomized HIV-uninfected men and women in a 2-to-1 ratio to DPV gel or placebo gel. Participants at sites in the United States and Thailand had to be 18 to 45 years old.
Participants received the gel via rectal applicator under direct observation. They got a single dose at visit 3, followed by a 2-week washout, then 7 consecutive daily doses. Researchers collected samples of blood plasma, rectal fluid, rectal tissue, and cervical tissue multiple times after dosing. Rectal samples were challenged with HIV ex vivo.
Nineteen participants randomized to DPV gel averaged 28.5 years in age, while 9 randomized to placebo averaged 34.2 years. Four in the DPV arm (21%) and 5 in the placebo group (56%) were women. At US sites 63% of participants were white, 21% African American, 11% Asian, and 5% Hispanic. Twenty-six participants (93%) attended college, and 6 (21%) were married or living with a partner.
Among 26 people who completed the study, researchers observed all gel applications in the clinic, except for one application done at home for visit 11. Five of 9 evaluable people in the placebo group and 3 of 18 in the DPV group had 1 or more grade 2 or higher adverse event (56% vs 17%, P = 0.072). Among 11 adverse events reported by 6 people receiving DPV, 7 (63%) were grade 1 and 4 (36%) were grade 2. In the DPV group 2 grade 1 adverse events (diarrhea and itching) and 1 grade 2 event (diarrhea) were related to study drug. Fifteen of 17 evaluable participants receiving DPV gel (88%) and 7 of 9 receiving placebo (78%) reported that the gel felt "comfortable" or "very comfortable" (difference not significant).
One person withdrew from the study without receiving a gel application, so the DPV concentration analysis involved 18 people. DPV could be detected for 24 hours in both plasma and rectal fluid after the single administration. But 60% of rectal tissue measurements lay below the limit of detection 120 minutes after the single dose.
DPV could be detected in plasma and rectal fluid after each of the 7 daily doses, but DPV could be measured in rectal tissue only in the hours after dosing. DPV remained undetectable in the female genital tract after single or multiple rectal doses of the drug.
Ex vivo rectal biopsy challenge studies showed about a 10-fold drop in viral replication measured as HIV p24, but only in the 2 hours after DPV dosing.
Although DPV could be detected in blood plasma and rectal fluid after gel use, DPV concentrations in rectal tissue and antiviral effect in rectal biopsies were transient. The MTN-026 investigators concluded that "a long-acting formulation or increased dosing [of DPV gel] will be necessary to provide effective HIV protection during anal sex."
References
1. Nel A, van Niekerk N, Kapiga S, et al. Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women. N Engl J Med. 2016;375:2133-2143. doi: 10.1056/NEJMoa1602046.
2. Baeten JM, Palanee-Phillips T, Brown ER, et al. 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. Hoesley C, Ho K, Dunne E, et al. A randomized, double blind, placebo-controlled, phase 1 safety and pharmacokinetic study of dapivirine gel (0.05%) administered rectally to HIV-1 seronegative adults (MTN-026). HIVR4P (HIV Research for Prevention) Virtual, January 27-28 and February 3-4, 2021. Abstract OA16.05.
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