PMID- 34118115
OWN - NLM
STAT- MEDLINE
DCOM- 20211015
LR  - 20240402
IS  - 1758-2652 (Electronic)
IS  - 1758-2652 (Linking)
VI  - 24
IP  - 6
DP  - 2021 Jun
TI  - Phase 1 pharmacokinetics and safety study of extended duration dapivirine vaginal 
      rings in the United States.
PG  - e25747
LID - 10.1002/jia2.25747 [doi]
LID - e25747
AB  - INTRODUCTION: Vaginal rings are a promising approach to provide a woman-centred, 
      long-acting HIV prevention strategy. Prior trials of a 25 mg dapivirine (DPV) 
      ring have shown a favourable safety profile and approximately 30% risk reduction 
      of HIV-1 infection. Extended duration rings replaced every three months may 
      encourage user adherence, improve health service efficiency and reduce cost 
      overall. We evaluated safety, pharmacokinetics, adherence and acceptability of 
      two three-month rings with different DPV dosages, compared with the monthly DPV 
      ring. METHODS: From December 2017 to October 2018, MTN-036/IPM-047 enrolled 49 
      HIV-negative participant in Birmingham, Alabama and San Francisco, California 
      into a phase 1, randomized trial comparing two extended duration (three-month) 
      rings (100 or 200 mg DPV) to a monthly 25 mg DPV ring, each used over 13 weeks, 
      with follow-up completed in January 2019. Safety was assessed by recording 
      adverse events (AEs). DPV concentrations were quantified in plasma, 
      cervicovaginal fluid (CVF) and cervical tissue, at nominal timepoints. Geometric 
      mean ratios (GMRs) relative to the comparator ring were estimated from a 
      regression model. RESULTS: There were no differences in the proportion of 
      participants with grade >/=2 genitourinary AEs or grade >/=3 AEs in the extended 
      duration versus monthly ring arms (p = 1.0). Plasma and CVF DPV concentrations 
      were higher in the extended duration rings compared to the monthly ring. Plasma 
      GMRs were 1.31 to 1.85 and 1.41 to 1.86 and CVF GMRs were 1.45 to 2.87 and 1.74 
      to 2.60 for the 100 and 200 mg ring respectively. Cervical tissue concentrations 
      were consistently higher in the 200 mg ring (GMRs 2.36 to 3.97). The majority of 
      participants (82%) were fully adherent (ring inserted at all times, with no 
      product discontinuations/outages) with no differences between the monthly versus 
      three-month rings. Most participants found the ring acceptable (median = 8 on 
      10-point Likert scale), with a greater proportion of participants reporting high 
      acceptability (9 or 10) in the 25 mg arm (73%) compared with the 100 mg (25%) and 
      200 mg (44%) arms (p = 0.01 and p = 0.15 respectively). CONCLUSIONS: The extended 
      duration DPV rings were well-tolerated and achieved higher DPV concentrations 
      compared with the monthly DPV ring. These findings support further evaluation of 
      three-month DPV rings for HIV prevention.
CI  - (c) 2021 The Authors. Journal of the International AIDS Society published by John 
      Wiley & Sons Ltd on behalf of the 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, CA, USA.
AD  - Department of Medicine, University of California, San Francisco, CA, USA.
FAU - Dominguez Islas, Clara
AU  - Dominguez Islas C
AD  - Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 
      Seattle, WA, USA.
FAU - Gundacker, Holly
AU  - Gundacker H
AD  - Statistical Center for HIV/AIDS Research & Prevention, Fred Hutchinson Cancer 
      Research Center, Seattle, WA, USA.
FAU - Neradilek, Blazej
AU  - Neradilek B
AD  - Statistical Center for HIV/AIDS Research & Prevention, Fred Hutchinson Cancer 
      Research Center, Seattle, WA, USA.
FAU - Hoesley, Craig
AU  - Hoesley C
AD  - University of Alabama at Birmingham, Birmingham, AL, USA.
FAU - van der Straten, Ariane
AU  - van der Straten A
AUID- ORCID: 0000-0001-8536-648X
AD  - Department of Medicine, University of California, San Francisco, CA, USA.
AD  - Women's Global Health Imperative (WGHI), RTI International, Berkeley, CA, USA.
AD  - ASTRA Consulting, Kensington, CA, USA.
FAU - Hendrix, Craig W
AU  - Hendrix CW
AUID- ORCID: 0000-0002-5696-8665
AD  - Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins 
      University School of Medicine, Baltimore, MD, USA.
FAU - Beamer, May
AU  - Beamer M
AUID- ORCID: 0000-0001-6265-100X
AD  - Magee-Womens Research Institute, Pittsburgh, PA, USA.
FAU - Jacobson, Cindy E
AU  - Jacobson CE
AD  - Magee-Womens Research Institute, Pittsburgh, PA, USA.
FAU - McClure, Tara
AU  - McClure T
AD  - FHI 360, Durham, NC, USA.
FAU - Harrell, Tanya
AU  - Harrell T
AD  - Statistical Center for HIV/AIDS Research & Prevention, Fred Hutchinson Cancer 
      Research Center, Seattle, WA, USA.
FAU - Bunge, Katherine
AU  - Bunge K
AUID- ORCID: 0000-0003-3940-8102
AD  - Magee-Womens Research Institute, Pittsburgh, PA, USA.
AD  - Department of Obstetrics, Gynecology, and Reproductive Sciences, University of 
      Pittsburgh, Pittsburgh, PA, USA.
FAU - Devlin, Brid
AU  - Devlin B
AD  - International Partnership for Microbicides, Silver Spring, MD, USA.
FAU - Nuttall, Jeremy
AU  - Nuttall J
AD  - International Partnership for Microbicides, Silver Spring, MD, USA.
FAU - Spence, Patrick
AU  - Spence P
AD  - International Partnership for Microbicides, Silver Spring, MD, USA.
FAU - Steytler, John
AU  - Steytler J
AD  - International Partnership for Microbicides, Silver Spring, MD, USA.
FAU - Piper, Jeanna M
AU  - Piper JM
AD  - Division of AIDS, National Institutes of Health, Bethesda, MD, USA.
FAU - Marzinke, Mark A
AU  - Marzinke MA
AD  - Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins 
      University School of Medicine, Baltimore, MD, USA.
CN  - MTN-036/IPM 047 Protocol Team for the Microbicide Trials Network
LA  - eng
SI  - ClinicalTrials.gov/NCT03234400
GR  - P30 MH062246/MH/NIMH NIH HHS/United States
GR  - UM1 AI068633/AI/NIAID NIH HHS/United States
GR  - UM1 AI068615/AI/NIAID NIH HHS/United States
GR  - UM1 AI106707/AI/NIAID NIH HHS/United States
GR  - UM1 AI069496/AI/NIAID NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
PL  - Switzerland
TA  - J Int AIDS Soc
JT  - Journal of the International AIDS Society
JID - 101478566
RN  - 0 (Anti-HIV Agents)
RN  - 0 (Pyrimidines)
RN  - TCN4MG2VXS (Dapivirine)
SB  - IM
MH  - *Anti-HIV Agents/adverse effects
MH  - *Contraceptive Devices, Female/adverse effects
MH  - Female
MH  - *HIV Infections/drug therapy
MH  - Humans
MH  - Pyrimidines/adverse effects
MH  - United States
PMC - PMC8196716
OTO - NOTNLM
OT  - dapivirine
OT  - microbicide
OT  - pharmacokinetics
OT  - pre-exposure prophylaxis
OT  - safety
OT  - vaginal ring
EDAT- 2021/06/13 06:00
MHDA- 2021/10/16 06:00
PMCR- 2021/06/12
CRDT- 2021/06/12 12:16
PHST- 2021/04/27 00:00 [revised]
PHST- 2020/12/05 00:00 [received]
PHST- 2021/04/30 00:00 [accepted]
PHST- 2021/06/12 12:16 [entrez]
PHST- 2021/06/13 06:00 [pubmed]
PHST- 2021/10/16 06:00 [medline]
PHST- 2021/06/12 00:00 [pmc-release]
AID - JIA225747 [pii]
AID - 10.1002/jia2.25747 [doi]
PST - ppublish
SO  - J Int AIDS Soc. 2021 Jun;24(6):e25747. doi: 10.1002/jia2.25747.