Rilpivirine (Edurant) remained detectable in plasma and female genital tract fluids for 18 months or more after a single injection of a long-acting non-nucleoside for HIV pre-exposure prophylaxis (PrEP). The findings in this nine-person analysis stoke concern about emergence of resistant virus if a person with subtherapeutic antiretroviral PrEP levels becomes infected. The study was presented at AIDS 2016, in Durban, South Africa.
A long-acting injectable formulation of the non-nucleoside reverse transcriptase inhibitor rilpivirine is being studied for HIV PrEP and -- with the integrase inhibitor cabotegravir -- for long-term maintenance therapy. Possible emergence of resistant virus during the long pharmacokinetic tail following administration of long-acting antiretrovirals is more than hypothetical. The non-nucleoside-specific K101E mutation evolved in a person who became infected with HIV after taking a single 300-mg PrEP dose of long-acting rilpivirine. "This case is a unique instance of infection with wild-type HIV-1 and subsequent selection of resistant virus by persistent exposure to long-acting PrEP," the researchers wrote.
MWRI-01 is a phase 1 study of the safety, acceptability, pharmacokinetics and pharmacodynamics of long-acting rilpivirine in HIV-negative people. In a single-dose phase of the trial, men and women were randomized to receive a single 600- or 1200-mg injection of long-acting rilpivirine. Participants in the single-dose phase could enter a multiple-dose phase of 1200-mg long-acting rilpivirine.
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Evaluation of participants upon entering the multiple-dose phase afforded the opportunity to assess persistence of rilpivirine concentrations after one intramuscular dose in the single-dose phase. The assays used had a 0.5-ng/mL lower limit of quantitation in plasma, a 0.025-ng/sample lower limit in fluids and a 0.05-ng/sample lower limit in tissue.
At the start of the multiple-dose phase, researchers collected baseline samples from nine participants initially enrolled in the single-dose phase: five women and two men who received a single 1200-mg injection of rilpivirine and two men who received a single 600-mg injection. The plasma assay detected rilpivirine in seven of seven samples from participants who had received 1200 mg of rilpivirine an average 541 days (18 months) earlier. Rilpivirine could also be detected in endocervical and vaginal fluids of the five women who received 1200 mg of rilpivirine an average 541 days earlier. Rilpivirine could not be detected in cervical, vaginal or rectal tissue or in cervicovaginal lavage samples of any participants.
Concentrations of rilpivirine in plasma and female genital tract fluids averaged 3.7 ng/mL. The protein-adjusted 90% effective concentration for rilpivirine is 12 ng/mL. Thus, the rilpivirine that persisted in these samples might have failed to suppress HIV replication if one of these participants had become infected.
The investigators called for further study of long-acting PrEP agents "to better inform management of the [pharmacokinetic] tail to avoid the potential for [antiretroviral] resistance." They noted that the HPTN-083 phase 2b/3 trial of cabotegravir long-acting PrEP may offer study participants 12 months of oral PrEP to cover the tail of injected cabotegravir.