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Early Data Hint Once-Monthly Oral PrEP Feasible With Novel Antiretroviral
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HIVR4P Virtual, January 27-28 and February 3-4, 2021
Mark Mascolini
Interim results from a phase 2a placebo-controlled trial of islatravir suggest this novel antiretroviral may reach and maintain HIV-preventing levels with a single monthly pill [1]. Two phase 3 trials of preexposure prophylaxis (PrEP) with this first nucleoside reverse transcriptase translocation inhibitor are in the planning stage.
Once-daily oral tenofovir (TDF or TAF)/emtricitabine remains the standard strategy for HIV PrEP, although studies show that taking that pill "on demand" just before and after sex offers similar protection from HIV. An ever-growing array of long-term injections, patches, and implants promises to simplify PrEP further. Islatravir (also called MK-8591) is the first PrEP agent tested as a once-monthly pill, and researchers are mulling a once-yearly subdermal implant.
Islatravir inhibits HIV reverse transcriptase by two mechanisms. The body swiftly converts islatravir to its active form, islatravir-triphosphate (ISL-TP), in target cells; then the drug settles in for a long stay. Estimated half-life in peripheral blood mononuclear cells after oral administration reaches about 190 hours in adults without HIV.
The phase 2a double-blind, placebo-controlled, multinational trial enrolled 18- to 65-year-old HIV-negative adults with a low risk of HIV infection. The study has reached full enrollment of 242 people with randomization in a 2:2:1 ratio to 60 mg of islatravir monthly, 120 mg monthly, or placebo. Participants take their assigned agent monthly for 24 weeks, then blinded observation continues for another 12 weeks.
This interim analysis considered 192 people (79% of 242) who range in age from 19 to 58 (median 32). So far one third are men and two thirds women. Almost two thirds of participants are white, 30% black, and 16% Hispanic.
While 53% of participants have had 1 or more adverse events, no one has had a serious adverse event and no one died. Two people (1%) dropped out of the study because of an adverse event: a mild sensation of a foreign body in the throat, and moderate rash and itchiness.
Using data from a study in monkeys and an early study in humans, researchers chose trial doses to maintain islatravir exposure above 0.05 pmol/million cells, which is about 5 times the 50% inhibitory concentration (IC50) in cell studies. With either 60 or 120 mg of islatravir monthly, average trough concentrations of ISL-TP stayed well above the 0.05-pmol target in peripheral blood mononuclear cells. A gradual decline in ISL-TP levels in the weeks after dosing stopped suggests that a missed dose will not quickly compromise islatravir's protective efficacy.
Preliminary analysis of islatravir levels in rectal, cervical, or vaginal tissue suggests "rapid, sustained, and adequate distribution" of the drug to these important sites. But the investigators did not show data on tissue penetration.
The researchers concluded that these findings indicate that 60 or 120 mg of oral islatravir monthly hit prespecified PrEP efficacy targets, and that these doses are tolerable. Phase 3 trials will compare 60 mg of islatravir monthly with TDF or TAF plus FTC in two groups: cisgender women at high risk for HIV infection (ClinicalTrials.gov NCT04644029) and men and transgender women who have sex with men and run a high risk of HIV infection (ClinicalTrials.gov NCT04652700). Neither trial is recruiting participants yet.
Reference
1. Hillier S, Bekker LG, Badal-Faesen S, et al. Trial design, enrollment status, demographics, and pharmacokinetics (PK) data from a blinded interim analysis from a phase 2a trial of islatravir once monthly (QM) for HIV pre-exposure prophylaxis (PrEP). HIVR4P (HIV Research for Prevention) Virtual, January 27-28 and February 3-4, 2021. Abstract OA04.05.
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