Optimum ribavirin exposure overcomes racial disparity in efficacy of peginterferon and ribavirin treatment for hepatitis C genotype 1
Abstract
OBJECTIVES: 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.Description
SUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature.com/ajg. Author affiliations: School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, USA, Duke Clinical Research Institute & Division of Gastroenterology, Duke University , Durham , North Carolina , USA ; 4 Department of Medicine, University of Maryland School of Medicine , Baltimore , Maryland , USA.Citation
Jin, R., Cai, L., McHutchison, J. G., Dowling, T. C., & Howell, C. D. (2012). Optimum ribavirin exposure overcomes racial disparity in efficacy of peginterferon and ribavirin treatment for hepatitis C genotype 1. American Journal of Gastroenterology, 107(11), 1675-1683, DOI: 10.1038/ajg.2012.306.Keyword
African Americans--geneticsAntiviral Agents--administration & dosage
Antiviral Agents--therapeutic use
Chi-Square Distribution
Genotype
Hepatitis C, Chronic--drug therapy
Hepatitis C, Chronic--genetics
Interferon-alpha--administration & dosage
Logistic Models
Polyethylene Glycols--administration & dosage
Recombinant Proteins--administration & dosage
Ribavirin--administration & dosage
Identifier to cite or link to this item
http://hdl.handle.net/10713/2339ae974a485f413a2113503eed53cd6c53
10.1038/ajg.2012.306
Scopus Count
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