A subcutaneous implant of tenofovir alafenamide fumarate causes local inflammation and tissue necrosis in rabbits and macaques

Jonathan T. Su, Solange M. Simpson, Samuel Sung, Ewa Bryndza Tfaily, Ronald Veazey, Mark Marzinke, Jiang Qiu, David Watrous, Lakmini Widanapathirana, Elizabeth Pearson, M. Melissa Peet, Dipu Karunakaran, Brooke Grasperge, Georgina Dobek, Charlette M. Cain, Thomas Hope, Patrick F. Kiser

Research output: Contribution to journalArticle

Abstract

We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo. We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbit and rhesus macaque models. A dose-ranging study in rabbits demonstrated dose-dependent pharmacokinetics and local inflammation up to severe necrosis around the active implants. The matched placebos showed normal wound healing and fibrous tissue encapsulation of the implant. We designed a second implant with a lower release rate and flux of TAF and achieved a median cellular level of tenofovir diphosphate of 42 fmol per 106 rhesus macaque peripheral blood mononuclear cells at a TAF dose of 10 μg/kg/day. This dose and flux of TAF also resulted in adverse local inflammation and necrosis near the implant in rhesus macaques. The level of inflammation in the primates was markedly lower in the placebo group than in the active-implant group. The histological inflammatory response to the TAF implant at 4 and 12 weeks in primates was graded as a severe reaction. Thus, while we were able to achieve a sustained target dose, we observed an unacceptable inflammatory response locally at the implant tissue interface.

Original languageEnglish (US)
Article numbere01893
JournalAntimicrobial agents and chemotherapy
Volume64
Issue number3
DOIs
StatePublished - Jan 1 2020

Keywords

  • Antiretroviral agents
  • Histopathology
  • Implant
  • Preexposure prophylaxis

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Su, J. T., Simpson, S. M., Sung, S., Tfaily, E. B., Veazey, R., Marzinke, M., Qiu, J., Watrous, D., Widanapathirana, L., Pearson, E., Peet, M. M., Karunakaran, D., Grasperge, B., Dobek, G., Cain, C. M., Hope, T., & Kiser, P. F. (2020). A subcutaneous implant of tenofovir alafenamide fumarate causes local inflammation and tissue necrosis in rabbits and macaques. Antimicrobial agents and chemotherapy, 64(3), [e01893]. https://doi.org/10.1128/AAC.01893-19