Ribavirin Rather than PEG-interferon Pharmacodynamics Predict Nonresponse to Antiviral Therapy in Naive Chronic Hepatitis C Patients

L. G. van Vlerken; E. J. Huisman; H. van Soest; G. J. Boland; J. P. H. Drenth; P. D. Siersema; D. M. Burger; K. J. van Erpecum

Disclosures

J Viral Hepat. 2012;19(1):39-46. 

In This Article

Abstract and Introduction

Abstract

Twenty to fifty per cent of patients with chronic hepatitis C (CHC) experience nonresponse to current antiviral therapy, which may relate in part to ribavirin or PEG-interferon pharmacodynamics. We evaluated potential relevance of various factors for nonresponse. Two hundred forty-two naive CHC patients who received in a previous trial at least 24 weeks of antiviral therapy, including PEG-interferon alfa-2b and ribavirin, were analysed. Of them, 53% were infected with hepatitis C virus (HCV) genotype 1–4, 71% exhibited high viral load and 32% had severe fibrosis/cirrhosis. After 24 weeks of treatment, 39 patients (16%) were nonresponders. In multivariate analysis, lower serum ribavirin concentrations, HCV genotype 1–4 and higher baseline γ-GT predicted nonresponse. Week-24 ribavirin concentrations (2.2 vs 2.8 mg/L, P < 0.001), average ribavirin doses (14.5 vs 15.2 mg/kg per day, P = 0.03) and week-24 haemoglobin decreases (1.7 vs 2.0 mm, P = 0.02) were lower in nonresponders. Nonresponse rates increased progressively at decreasing ribavirin concentrations: 4%, 11%, 13% and 36% in case of serum ribavirin concentrations ≥4, 3–4, 2–3 and ≤2 mg/L, respectively (P = 0.001). Ribavirin concentrations correlated with both week-24 haemoglobin decreases (r = 0.42, P < 0.001) and ribavirin doses (r = 0.17, P = 0.01). Subgroup analysis in HCV genotype 1–4 patients revealed essentially the same results. Nonresponse was exceptional in HCV genotype 2–3 patients and associated with ribavirin concentrations <2 mg/L. Presumed interferon-related factors (average PEG-interferon doses and decreases in leucocytes, granulocytes, platelets and body weight) did not differ between nonresponders and responders. In conclusion, ribavirin- rather than PEG-interferon-related factors are independent and potentially modifiable predictors of nonresponse in treatment-naive CHC patients.

Introduction

Current treatment for chronic hepatitis C (CHC), consisting of PEG-interferon and ribavirin, is not effective in 20–50% of cases.[1,2] Several baseline patient and viral characteristics have been described as predictive factors for nonresponse to PEG-interferon and ribavirin treatment in previous studies, such as hepatitis C virus (HCV) genotype, viral load, patient weight, presence of cirrhosis and African American race.[3] It is important to explore which modifiable on-treatment factors affect nonresponse rates, in order to develop effective strategies to improve outcome of antiviral treatment. Adherence to at least 80% of the prescribed (PEG) interferon and ribavirin doses has been associated with better response rates, especially in HCV genotype 1 patients.[4] Inter-individual variability in plasma concentrations of ribavirin during treatment is high,[5,6] and low plasma concentrations of ribavirin could be important predictors of nonresponse.[5,7–10] Interferon-related factors could also be relevant: in a recent post hoc analysis of the HALT-C trial in previous nonresponders with advanced fibrosis or cirrhosis undergoing PEG-interferon and ribavirin re-treatment, presumed interferon-related factors (less pronounced reductions in body weight, leucocytes or platelets) were significantly associated with null response (≤1 log decrease in HCV RNA at week 24) in multivariate analysis.[11] The underlying mechanism could be systemic interferon resistance. The aim of the current study was therefore to evaluate the influence of various baseline and on-treatment factors, including serum ribavirin concentrations, on nonresponse in treatment-naive CHC patients.

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