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  International AIDS Conference
Durban, South Africa
July 18-22 2016
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Rilpivirine in Genital Tract 18 Months After One Long-Acting Injection
  21st International AIDS Conference (AIDS 2016), July 18-22, 2016, Durban, South Africa
Mark Mascolini
Rilpivirine given in a long-acting injectable formulation remained detectable in female genital tract fluids more than 18 months after a single intramuscular dose [1]. The finding is relevant to possible emergence of rilpivirine-resistant virus if a person becomes infected with HIV after taking rilpivirine for preexposure prophylaxis (PrEP).
Long-activing cabotegravir/rilpivirine is entering phase 3 trials as maintenance therapy for people who attain viral suppression on a standard oral regimen [2]. Both antiretrovirals are also candidates for long-acting PrEP injection. University of Pittsburgh researchers who conducted the rilpivirine study noted that the extended half-lives of long-acting injected antiretrovirals are not well understood. But persistent low levels of injected antiretrovirals could raise the risk of resistance in people who get infected with HIV while taking long-acting PrEP.
Previous research found detectable rilpivirine concentrations in plasma and tissues more than 120 days after a single 1200-mg injection of this nonnucleoside reverse transcriptase inhibitor. Researchers have reported one case of emergence of the K101E mutation in a person who picked up HIV after taking a single 300-mg dose of long-activing rilpivirine PrEP [3]. "This case," the researchers wrote, "is a unique instance of infection with wild-type [nonmutant] HIV-1 and subsequent selection of resistant virus by persistent exposure to long-acting PrEP."
The analysis presented at AIDS 2016 involved participants in a phase 1 study of long-acting rilpivirine first given to men and women in a single 600- or 1200-mg dose. In a multiple-dose phase of the trial, participants receive 1200 mg of long-acting rilpivirine. A secondary objective of this trial is to determine plasma, cervical, vaginal, and rectal tissue secretion pharmacokinetics after single and multiple intramuscular rilpivirine injections. Assays used to detect rilpivirine had lower quantitation limits of 0.5 ng/mL in plasma, 0.025 ng/sample in fluids, and 0.05 ng/sample in tissue.
The investigators had baseline samples from 9 participants--5 women and 2 men who received 1200 mg of rilpivirine and 2 men who received 600 mg. They detected rilpivirine in 7 of 7 plasma samples collected an average 541 days after a single 1200-mg long-acting dose. Rilpivirine could also be detected in endocervical and vaginal fluid but not in cervical, vaginal, or rectal tissue or cervicovaginal lavage samples. Protein-adjusted rilpivirine 90% effective concentration was 12 ng/mL.
The Pittsburgh team concluded that "quantifiable rilpivirine [at an average level of 3.7 ng/mL] was found in plasma and female genital tract fluids [more than] 18 months after single-dose administration" of long-acting rilpivirine. They noted that characterization of the extended rilpivirine pharmacokinetic [PK] profile "will be critical to better inform management of the PK tail to avoid the potential for antiretroviral resistance."
1. McGowan I, Siegel A, Engstrom J, et al. Persistence of rilpivirine following single dose of long-acting injection. 21st International AIDS Conference (AIDS 2016). July 18-22, 2016. Durban, South Africa. Abstract TUAC0103.
2. Spreen W. Cabotegravir long-acting (LA) injectable nanosuspension. 17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, 8-10 June, 2016, Washington DC. Invited lecture. http://www.natap.org/2016/Pharm/Pharm_39.htm
3. Penrose KJ, Parikh UM, Hamanishi KA, et al. Selection of rilpivirine-resistant HIV-1 in a seroconverter from the SSAT 040 trial who received the 300-mg dose of long-acting rilpivirine (TMC278LA). J Infect Dis. 2016;213:1013-1317.
Persistence of Rilpivirine Following Single Dose of Long-Acting Injection
WEBCAST: https://www.youtube.com/watch?v=Wvb1sSZJCFU
Ian McGowan MD DPhil FRCP
Reported by Jules Levin
Durban 2016 July 18-22