PMID- 38444118 OWN - NLM STAT- MEDLINE DCOM- 20240307 LR - 20240315 IS - 1758-2652 (Electronic) IS - 1758-2652 (Linking) VI - 27 IP - 3 DP - 2024 Mar TI - Phase 1 randomized pharmacokinetic and safety study of a 90-day tenofovir vaginal ring in the United States. PG - e26223 LID - 10.1002/jia2.26223 [doi] LID - e26223 AB - INTRODUCTION: Tenofovir-based oral pre-exposure prophylaxis is currently approved for HIV prevention; however, adherence in women has been low. A vaginal gel containing tenofovir (TFV) demonstrated partial protection to HIV but protection was not confirmed in additional studies. Vaginal rings offer user-controlled long-acting HIV prevention that could overcome adherence and protection challenges. TFV may also help prevent herpes simplex virus type 2 acquisition when delivered intravaginally. We evaluated the pharmacokinetics, safety, adherence and acceptability of a 90-day TFV ring. METHODS: Between January and June 2019, Microbicide Trials Network (MTN)-038 enrolled 49 HIV-negative participants into a phase 1, randomized (2:1) trial comparing a 90-day ring containing 1.4 grams (g) TFV to a placebo ring. TFV concentrations were quantified in plasma, cervicovaginal fluid (CVF), rectal fluid and cervical tissue, and TFV-diphosphate (TFV-DP) in cervical tissue. Used rings were analysed for residual TFV. Safety was assessed by adverse events (AEs); acceptability and adherence by self-report. RESULTS: Mean age was 29.5; 46 identified as cisgender-female and three gender non-conforming. There were no differences in the proportion of participants with grade >/=2 genitourinary AEs in the TFV versus placebo arms (p = 0.41); no grade >/=3 AEs were reported. Geometric mean TFV concentrations increased through day 34 in CVF/rectal fluid and day 59 in plasma, but declined across compartments by day 91. Geometric mean TFV-DP tissue concentrations exceeded the 1000 fmol/mg target through day 56, but fell to 456 fmol/mg at day 91. Among 32 rings returned at the end of the study, 13 had no or low (<0.1 g) residual TFV. Residual TFV did not differ by socio-demographics, sexual activity, Nugent Score or vaginal microbiota. Most participants reported being fully adherent to ring use: 85% and 81% in the TFV and placebo arms, respectively (p = 1.00). A majority of participants reported liking the ring (median 8 on a 10-point Likert scale) and reported a high likelihood of using the ring in the future, if effective (median 9). CONCLUSIONS: The 90-day TFV ring was well-tolerated, acceptable and exceeded target cervical tissue concentrations through day 56, but declined thereafter. Additional studies are needed to characterize the higher release from TFV rings in some participants and the optimal duration of use. CI - (c) 2024 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society. FAU - Liu, Albert Y AU - Liu AY AUID- ORCID: 0000-0003-0320-823X AD - Bridge HIV, San Francisco Department of Public Health, San Francisco, California, USA. AD - Department of Medicine, University of California, San Francisco, San Francisco, California, USA. FAU - Gundacker, Holly AU - Gundacker H AD - Statistical Center for HIV/AIDS Research & Prevention, Fred Hutchinson Cancer Center, Seattle, Washington, USA. FAU - Richardson, Barbra AU - Richardson B AD - Departments of Biostatistics and Global Health, University of Washington, Seattle, Washington, USA. AD - Vaccine and Infectious Disease and Public Health Sciences Divisions, Fred Hutchinson Cancer Center, Seattle, Washington, USA. FAU - Chen, Beatrice A AU - Chen BA AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. AD - Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA. FAU - Hoesley, Craig AU - Hoesley C AD - University of Alabama at Birmingham, Birmingham, Alabama, USA. FAU - van der Straten, Ariane AU - van der Straten A AD - Department of Medicine, University of California, San Francisco, San Francisco, California, USA. AD - ASTRA Consulting, Kensington, California, USA. FAU - Brown, Amanda AU - Brown A AD - Statistical Center for HIV/AIDS Research & Prevention, Fred Hutchinson Cancer Center, Seattle, Washington, USA. FAU - Beamer, May AU - Beamer M AUID- ORCID: 0000-0001-6265-100X AD - Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA. FAU - Robinson, Jennifer AU - Robinson J AD - Division of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. FAU - Jacobson, Cindy E AU - Jacobson CE AD - Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA. FAU - Scheckter, Rachel AU - Scheckter R AD - FHI 360, Durham, North Carolina, USA. FAU - Bunge, Katherine AU - Bunge K AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. FAU - Schwartz, Jill AU - Schwartz J AD - CONRAD, Eastern Virginia Medical School, Norfolk, Virginia, USA. FAU - Thurman, Andrea AU - Thurman A AD - CONRAD, Eastern Virginia Medical School, Norfolk, Virginia, USA. FAU - Piper, Jeanna M AU - Piper JM AD - Division of AIDS, National Institutes of Health, Bethesda, Maryland, USA. FAU - Marzinke, Mark A AU - Marzinke MA AUID- ORCID: 0000-0003-1670-8786 AD - Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. AD - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. CN - MTN-038 Protocol Team for the Microbicide Trials Network LA - eng GR - UM1 AI106707/AI/NIAID NIH HHS/United States GR - PEPFAR/PEPFAR/United States GR - MH/NIMH NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PL - Switzerland TA - J Int AIDS Soc JT - Journal of the International AIDS Society JID - 101478566 RN - JAC85A2161 (Adenine) RN - 99YXE507IL (Tenofovir) SB - IM MH - Adult MH - Female MH - Humans MH - Adenine MH - Herpesvirus 2, Human MH - *HIV Infections/drug therapy/prevention & control MH - Microbiota MH - *Tenofovir/adverse effects/pharmacokinetics MH - United States PMC - PMC10935712 OTO - NOTNLM OT - microbicide OT - pharmacokinetics OT - pre-exposure prophylaxis OT - safety OT - tenofovir OT - vaginal ring COIS- AYL has received funding for investigator-sponsored research grants from Gilead Sciences and Viiv Healthcare, and has led studies in which Gilead Sciences has donated study drugs. MAM has received research support from Viiv Healthcare, Gilead Sciences, Merck Inc. and Ridgeback Therapeutics. HG, BR, BAC, CH, AVDS, AB, MB, JR, CEJ, RS, KB, JS, AT, JMP and MAM declare that they have no competing interests. EDAT- 2024/03/06 06:43 MHDA- 2024/03/07 06:42 PMCR- 2024/03/05 CRDT- 2024/03/06 00:43 PHST- 2023/05/19 00:00 [received] PHST- 2024/02/05 00:00 [accepted] PHST- 2024/03/07 06:42 [medline] PHST- 2024/03/06 06:43 [pubmed] PHST- 2024/03/06 00:43 [entrez] PHST- 2024/03/05 00:00 [pmc-release] AID - JIA226223 [pii] AID - 10.1002/jia2.26223 [doi] PST - ppublish SO - J Int AIDS Soc. 2024 Mar;27(3):e26223. doi: 10.1002/jia2.26223.