title: Optimum ribavirin exposure overcomes racial disparity in efficacy of peginterferon and ribavirin treatment for hepatitis C genotype 1.
abstract: OBJECTIVE
  Peginterferon and ribavirin treatment is less effective for hepatitis C virus (HCV) genotype 1 infections in African Americans (AA) compared with Caucasian Americans (CA). Host genetic variability near the interleukin-28B (IL28B) gene locus is partly responsible. We investigated the relationship between ribavirin drug exposure and week 24 and 72 (sustained virologic response, SVR) responses (undetected serum HCV RNA) in 71 AA and 74 CA with HCV genotype 1 who received >90% of the prescribed peginterferon and weight-based ribavirin (1,000 or 1,200 mg per day) from week 1 to 24.
  
  
  METHODS
  Ribavirin plasma levels were measured at weeks 1, 2, 4, 8, 12 and 24; ribavirin area under the concentration vs. time curve (AUC) was calculated using the linear trapezoidal rule.
  
  
  RESULTS
  Compared with CA, AA had lower week 24 (WK24VR) (57.8 vs. 78.1; P<0.05) and week 72 (SVR) (36.6% vs 54.8%; P<0.05) response rates. AA also had significantly lower ribavirin exposure (AUC) from week 1 to 12 (P<0.05). Ribavirin exposures ≥4,065 and ≥4,480 ng/ml/day in the first week (AUC(0-7)) were thresholds for WK24VR and SVR in receiver-operating characteristic curve analyses. AA were less likely to have a threshold ribavirin AUC(0-7) level than CA (P<0.05). There were no significant racial differences in WK24VR (AA: 77 vs. CA: 84%) and SVR (AA: 52 vs. CA: 60%) rates in patients who met the ribavirin AUC(0-7) thresholds. Ribavirin AUC(0-7) predicted WK24VR and SVR independently of IL28B single-nucleotide polymorphism rs12979860 genotype. Yet, achieving threshold AUC(0-7) levels increased response rates primarily in AA with the less favorable non-C/C genotypes.
  
  
  CONCLUSIONS
  Standard weight-based dosing leads to suboptimal ribavirin exposure in AA and contributes to the racial disparity in peginterferon and ribavirin treatment efficacy for HCV genotype 1.
authors.affiliation: School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, USA.
authors.forename: Runyan
authors.initials: R
authors.lastname: Jin
authors.forename: Ling
authors.initials: L
authors.lastname: Cai
authors.forename: Ming
authors.initials: M
authors.lastname: Tan
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Dowling
authors.forename: Charles D
authors.initials: CD
authors.lastname: Howell
mesh_terms: D001741:Black or African American / Q000235:genetics*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D019540:Area Under Curve; D001835:Body Weight; D016009:Chi-Square Distribution; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012254:Ribavirin / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D044465:White People / Q000235:genetics*; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C100416:peginterferon alfa-2a