Liver

Subject Category: Liver

Am J Gastroenterol 2012; 107:1675–1683; doi:10.1038/ajg.2012.306; published online 23 October 2012

Optimum Ribavirin Exposure Overcomes Racial Disparity in Efficacy of Peginterferon and Ribavirin Treatment for Hepatitis C Genotype 1

Runyan Jin PhD1, Ling Cai2, Ming Tan PhD2, John G McHutchison MD3, Thomas C Dowling PhD1 and Charles D Howell MD4

  1. 1School of Pharmacy, University of Maryland, Baltimore, Maryland, USA
  2. 2Department of Epidemiology and Public Health, University of Maryland, Baltimore, Maryland, USA
  3. 3Duke Clinical Research Institute & Division of Gastroenterology, Duke University, Durham, North Carolina, USA
  4. 4Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA

Correspondence: Charles D. Howell, Department of Medicine, University of Maryland School of Medicine, 22 South Greene, Street N3W50, Baltimore, Maryland 21201, USA. E-mail: chowell102@verizon.net

Received 6 April 2012; Accepted 7 August 2012
Advance online publication 23 October 2012

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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 1,200mg 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 ≥4,480ng/ml/day in the first week (AUC0–7) were thresholds for WK24VR and SVR in receiver-operating characteristic curve analyses. AA were less likely to have a threshold ribavirin AUC0−7 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 AUC0−7 thresholds. Ribavirin AUC0−7 predicted WK24VR and SVR independently of IL28B single-nucleotide polymorphism rs12979860 genotype. Yet, achieving threshold AUC0−7 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.