title: Long-acting rilpivirine as potential pre-exposure prophylaxis for HIV-1 prevention (the MWRI-01 study): an open-label, phase 1, compartmental, pharmacokinetic and pharmacodynamic assessment.
abstract: Long-acting injectable antiretroviral agents are being developed for HIV-1 prevention. The MWRI-01 study was done to characterise the safety, acceptability, and pharmacokinetic and pharmacodynamic profile of long-acting rilpivirine.
  
  
  
  We did a phase 1 open-label study at the University of Pittsburgh. We enrolled healthy individuals (aged 18-45 years) who were seronegative for HIV-1. Participants were assigned alternately one intramuscular dose of either 1200 mg or 600 mg long-acting rilpivirine, beginning with the 1200 mg dose. We obtained plasma specimens, genital and rectal fluids, and tissue samples (rectal, cervical, and vaginal) before and after exposure to long-acting rilpivirine for assessment of pharmacokinetics and ex-vivo biopsy challenge with HIV-1. Our primary objective was to characterise product safety, and the analysis included all enrolled participants. This trial is registered with ClinicalTrials.gov, number NCT01656018.
  
  
  
  36 participants were enrolled into the study, of whom 24 were women and 12 men. 12 women and six men received each dose. 204 adverse events were reported among the 36 participants, of which 200 (98%) were grade 1-2. The most common adverse event was injection site reaction. All grade 3 and 4 adverse events were deemed not related to rilpivirine. Geometric mean (90% CI) concentrations in plasma of rilpivirine at day 28 post dose were 53 ng/mL (38-67) in women and 43 ng/mL (23-63) in men for the 1200 mg dose and 28 ng/mL (19-37) in women and 17 ng/mL (9-24) in men for the 600 mg dose. The tissue-to-plasma ratio for rilpivirine in rectal tissue was about two-fold higher than in vaginal and cervical tissue (1·10-1·53 vs 0·61-0·72 and 0·50-0·71, respectively). Exposure to long-acting rilpivirine suppressed viral replication significantly in rectal tissue (p<0·0001), and this suppression persisted for up to 4 months. By contrast, no viral suppression was seen in cervical or vaginal tissue.
  
  
  
  Ongoing research will characterise longer term safety and acceptability of multiple injections and help ascertain whether long-acting rilpivirine should advance to assessment of efficacy in preventing HIV-1 infection.
  
  
  
  Bill & Melinda Gates Foundation.
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: imcgowan@pitt.edu.
authors.forename: Ian
authors.initials: I
authors.lastname: McGowan
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Magee-Womens Research Institute, Pittsburgh, PA, USA.
authors.forename: Charlene S
authors.initials: CS
authors.lastname: Dezzutti
authors.affiliation: Magee-Womens Research Institute, Pittsburgh, PA, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Siegel
authors.affiliation: Magee-Womens Research Institute, Pittsburgh, PA, USA.
authors.forename: Jarret
authors.initials: J
authors.lastname: Engstrom
authors.affiliation: Magee-Womens Research Institute, Pittsburgh, PA, USA.
authors.forename: Alexiy
authors.initials: A
authors.lastname: Nikiforov
authors.affiliation: Magee-Womens Research Institute, Pittsburgh, PA, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Duffill
authors.affiliation: Magee-Womens Research Institute, Pittsburgh, PA, USA.
authors.forename: Cory
authors.initials: C
authors.lastname: Shetler
authors.affiliation: Alpha StatConsult, Damascus, MD, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Richardson-Harman
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Kaleab
authors.initials: K
authors.lastname: Abebe
authors.affiliation: University of Liverpool, Liverpool, UK.
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.affiliation: University of Liverpool, Liverpool, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Else
authors.affiliation: University of Liverpool, Liverpool, UK.
authors.forename: Deidre
authors.initials: D
authors.lastname: Egan
authors.affiliation: University of Liverpool, Liverpool, UK.
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.affiliation: University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Egan
authors.affiliation: University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Stall
authors.affiliation: Janssen Research and Development, Beerse, Belgium.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Williams
authors.affiliation: Magee-Womens Research Institute, Pittsburgh, PA, USA.
authors.forename: Khaleel K
authors.initials: KK
authors.lastname: Rehman
authors.affiliation: The Translational Science Corp, Los Angeles, CA, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Adler
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Brand
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Chen
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Achilles
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Ross D
authors.initials: RD
authors.lastname: Cranston
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001706:Biopsy; D002584:Cervix Uteri / Q000737:chemistry / Q000821:virology; D003692:Delayed-Action Preparations; D005260:Female; D015658:HIV Infections / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D064368:Healthy Volunteers; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D008875:Middle Aged; D065129:Pre-Exposure Prophylaxis; D012007:Rectum / Q000737:chemistry / Q000821:virology; D000068696:Rilpivirine / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D014621:Vagina / Q000737:chemistry / Q000821:virology; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D003692:Delayed-Action Preparations; D000068696:Rilpivirine