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 (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.

Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin

“…121 Higher platelet-derived growth factor receptor expression, a major driver of GB 121 Usual plasma levels during HCV treatment are 2500 ng/mL (~10 µM). 123 Neutropenia is the most frequent side effect of treatment with ribavirin. Liu et al 124 found that HCV patients treated with ribavirin have lower serum levels of G-CSF and GM-CSF.…”

Interferon (IFN) Based Treatment of African Americans with Chronic Hepatitis C (CHC) in an Urban Clinic: Improving Response with Advances in Therapy

“…Response to therapy was evaluated for both the overall and the racial sub groups since studies have suggested that AA were less likely to respond than Cau for both dual and triple therapy [10,15,16] .…”

“…African Americans (AA) are twice as likely to be infected with HCV compared to the non-Hispanicwhite US population (Cau) and in addition, have a lower response rate to approved IFN based therapies [7][8][9][10][11][12] . Studies focusing on this population provide useful information with respect to the efficacy of new therapies and decisions to treat this historically low response rate group.…”

Hepatitis C Pharmacogenetics: Possible Solutions for an Existing Problem

“…In addition, patient genetic ancestry plays a significant role in treatment outcome. For examples, African American (AA) patients with chronic HCV infection have about 50% reduction in SVR rates with PEG+RBV treatment compared with non-Hispanic patients of European ancestry [3,4]. This difference is not explained by sociodemographic characteristics or compliance to treatment.…”