Long-acting rilpivirine (RPV) preexposure prophylaxis does not inhibit vaginal transmission of RPV-resistant HIV-1 or select for high-frequency drug resistance in humanized mice

Kevin Melody, Chandra N. Roy, Christopher Kline, Mackenzie L. Cottrell, Dwayne Evans, Kathleen Shutt, Pleuni S. Pennings, Brandon F. Keele, Moses Bility, Angela D.M. Kashuba, Zandrea Ambrose

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1 Scopus citations

Abstract

As a long-acting formulation of the nonnucleoside reverse transcriptase inhibitor rilpivirine (RPV LA) has been proposed for use as preexposure prophylaxis (PrEP) and the prevalence of transmitted RPV-resistant viruses can be relatively high, we evaluated the efficacy of RPV LA to inhibit vaginal transmission of RPV-resistant HIV-1 in humanized mice. Vaginal challenges of wild-type (WT), Y181C, and Y181V HIV-1 were performed in mice left untreated or after RPV PrEP. Plasma viremia was measured for 7 to 10 weeks, and single-genome sequencing was performed on plasma HIV-1 RNA in mice infected during PrEP. RPV LA significantly prevented vaginal transmission of WT HIV-1 and Y181C HIV-1, which is 3-fold resistant to RPV. However, it did not prevent transmission of Y181V HIV-1, which has 30-fold RPV resistance in the viruses used for this study. RPV LA did delay WT HIV-1 dissemination in infected animals until genital and plasma RPV concentrations waned. Animals that became infected despite RPV LA PrEP did not acquire new RPV-resistant mutations above frequencies in untreated mice or untreated people living with HIV-1, and the mutations detected conferred low-level resistance. These data suggest that high, sustained concentrations of RPV were required to inhibit vaginal transmission of HIV-1 with little or no resistance to RPV but could not inhibit virus with high resistance. HIV-1 did not develop high-level or high-frequency RPV resistance in the majority of mice infected after RPV LA treatment. However, the impact of low-frequency RPV resistance on virologic outcome during subsequent antiretroviral therapy still is unclear. IMPORTANCE The antiretroviral drug rilpivirine was developed into a long-acting formulation (RPV LA) to improve adherence for preexposure prophylaxis (PrEP) to prevent HIV-1 transmission. A concern is that RPV LA will not inhibit transmission of drug-resistant HIV-1 and may select for drug-resistant virus. In female humanized mice, we found that RPV LA inhibited vaginal transmission of WT or 3-fold RPV-resistant HIV-1 but not virus with 30-fold RPV resistance. In animals that became infected despite RPV LA PrEP, WT HIV-1 dissemination was delayed until genital and plasma RPV concentrations waned. RPV resistance was detected at similar low frequencies in untreated and PrEP-treated mice that became infected. These results indicate the importance of maintaining RPV at a sustained threshold after virus exposure to prevent dissemination of HIV-1 after vaginal infection and low-frequency resistance mutations conferred low-level resistance, suggesting that RPV resistance is difficult to develop after HIV-1 infection during RPV LA PrEP.

Original languageEnglish (US)
Article numbere01912-19
JournalJournal of virology
Volume94
Issue number8
DOIs
StatePublished - Mar 1 2020
Externally publishedYes

Keywords

  • Animal model
  • Drug resistance
  • HIV-1
  • Humanized mice
  • NNRTI
  • Preexposure prophylaxis
  • PrEP
  • Rilpivirine
  • Vaginal transmission

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Melody, K., Roy, C. N., Kline, C., Cottrell, M. L., Evans, D., Shutt, K., Pennings, P. S., Keele, B. F., Bility, M., Kashuba, A. D. M., & Ambrose, Z. (2020). Long-acting rilpivirine (RPV) preexposure prophylaxis does not inhibit vaginal transmission of RPV-resistant HIV-1 or select for high-frequency drug resistance in humanized mice. Journal of virology, 94(8), [e01912-19]. https://doi.org/10.1128/JVI.01912-19