title: Drug Interactions With Direct-Acting Antivirals for Hepatitis C: Implications for HIV and Transplant Patients.
abstract: OBJECTIVE
  Review pharmacokinetics of new direct-acting antivirals (DAAs) for hepatitis C (HCV) infection and interactions with concomitant immunosuppressant and antiretroviral therapies (ART).
  
  
  METHODS
  MEDLINE (1948-January 2015), EMBASE (1964-January 2015), International Pharmaceutical Abstracts (1970-January 2015), Google, and Google Scholar were searched combining the terms simeprevir, sofosbuvir, ledipasvir, daclatasvir, paritaprevir, ABT-450, ombitasvir, dasabuvir, pharmacokinetics, drug interaction, drug metabolism, HIV, antiretroviral, immunosuppressant, transplant. Articles, conference proceedings, abstracts, and product monographs were reviewed.
  
  
  METHODS
  Literature on pharmacokinetic or pharmacodynamic interactions with DAAs and immunosuppressants or ART was considered for inclusion. Pertinent information was extracted and summarized in the review. In the absence of data, pharmacokinetic and pharmacodynamic principles were used to predict the likelihood of interactions.
  
  
  RESULTS
  DAA pharmacokinetics are reviewed and drug interaction data are presented with provision of management strategies. Fixed-dose combination paritaprevir/ritonavir/ombitasvir plus dasabuvir is most susceptible to drug interactions with immunosuppressants and ART mainly due to the influence of ritonavir on multiple enzymes. Simeprevir is also prone to drug interactions because of cytochrome P450(CYP) 3A4, CYP1A2, P-glycoprotein, and OATP1 involvement and is not recommended for use in combination with several HIV antiretrovirals (ARVs). Close therapeutic drug monitoring of calcineurin inhibitors is required with concomitant simeprevir. Few clinically significant interactions are expected with sofosbuvir or ledipasvir. Limited data suggest that daclatasvir may be coadministered with immunosuppressants but requires dose adjustments with certain ARVs.
  
  
  CONCLUSIONS
  None of the DAAs are completely free of drug interactions. Awareness and management of drug interactions is critical to optimize outcomes and minimize adverse effects in these patient populations.
authors.affiliation: University of British Columbia, Vancouver, BC, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Burgess
authors.affiliation: University of British Columbia, Vancouver, BC, Canada Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: Nilufar
authors.initials: N
authors.lastname: Partovi
authors.affiliation: University of British Columbia, Vancouver, BC, Canada Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Yoshida
authors.affiliation: University of British Columbia, Vancouver, BC, Canada Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: Siegfried R
authors.initials: SR
authors.lastname: Erb
authors.affiliation: University of British Columbia, Vancouver, BC, Canada Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: Vladimir Marquez
authors.initials: VM
authors.lastname: Azalgara
authors.affiliation: University of British Columbia, Vancouver, BC, Canada Vancouver General Hospital, Vancouver, BC, Canada trana.hussaini@vch.ca.
authors.forename: Trana
authors.initials: T
authors.lastname: Hussaini
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions; D015658:HIV Infections / Q000188:drug therapy*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D007166:Immunosuppressive Agents
keywords: HIV; antiretroviral; direct-acting antivirals; drug interaction; hepatitis; hepatitis C; immunosuppressant; infectious diseases; pharmacokinetics; transplant