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.

Figure 1

Ribavirin (RBV) plasma concentrations in African Americans (AA) and Caucasian Americans (CA) during peginterferon alfa-2a and ribavirin treatment. Ribavirin concentrations were measured by LC-MS/MS as described in Methods. Results at each time were compared by t-tests. s.e.m., standard error of mean.

Figure 2

Ribavirin (RBV) plasma concentrations and WK24VR (a, b) and sustained virologic response (SVR) (c, d) in African Americans (AA) and Caucasian Americans (CA). Ribavirin concentrations were measured as described in Methods and Figure 1. Results within racial groups at each time were compared between responders and nonresponders by t-tests.

Figure 3

Ribavirin (RBV) area under concentration vs. time curve (AUC)_0-7 threshold (≥4095 ng/ml × day) predict WK24VR. WK24VR for the total sample (a) and patients with interleukin-28B (IL28B) single-nucleotide polymorphism (SNP) CC (b) and non-CC (c) genotypes categorized by AUC_0-7 and race. Response rates between ribavirin exposure categories were compared using the χ²tests.

Figure 4

Ribavirin (RBV) area under concentration vs. time curve (AUC)_0-7 threshold (≥4480 ng/ml × day) predict sustained virologic response (SVR). SVR for total sample (a) and patients with interleukin-28B (IL28B) single-nucleotide polymorphism (SNP) CC (b) and non-CC (c) genotypes stratified by AUC_0-7 category and race. Response rates between ribavirin exposure categories were compared using the χ² tests.

Figure 5

Hepatitis C virus (HCV) RNA kinetics day 0–28. Serum HCV RNA concentrations were measured with the Roche Amplicor Monitor Assay, version 2. Results are shown by race (a), race and ribavirin area under concentration vs. time curve (AUC)_0-7 (b), and interleukin-28B (IL28) single-nucleotide polymorphism (SNP) genotype and ribavirin (RBV) AUC_0-7 (c, d) in AA. Differences in HCV RNA log10 IU/ml relative to day 0 at each time point were compared between using t-tests (a, c, d) and analysis of variance (ANOVA) (b). AA, African Americans; CA, Caucasian Americans. Threshold ≥4095 ng/ml × day.