Predictors of Response to Chronic Hepatitis C Treatment

Ezequiel Ridruejo

Disclosures

Future Virology. 2012;7(11):1089-1101. 

In This Article

Abstract and Introduction

Abstract

Chronic hepatitis C is a growing health problem worldwide that has attracted increased attention in recent years. Treatment with peginterferon and ribavirin combination had previously been the standard of care. In 2011, a new treatment with protease inhibitors, telaprevir and boceprevir was approved, and a new standard of care was defined. Previous predictors of response have been redefined, and while IL28B, fibrosis stage and hepatitis C virus viral load testing continue to have their value, viral kinetics during treatment defining viral response have emerged as the strongest predictor for achieving sustained virologic response with the new treatment. New therapies are expected in the near future, and current treatment predictors of response may soon change.

Introduction

Chronic hepatitis C is a growing health problem worldwide that has attracted increased attention in recent years. Approximately 3% of the world's population (130–170 million people) is chronically infected with HCV.[1,2] HCV is one of the most prevalent blood-borne infections, with a higher prevalence than HIV (~1.1 million infected) and HBV (0.8–1.4 million infected) in western countries.[3] Chronic HCV infection progresses asymptomatically, and almost 75% of patients are unaware of the diagnosis when they present with complications of cirrhosis, portal hypertension or develop a hepatocellular carcinoma (HCC) many years later.[4] In western countries HCV infection is one of the most frequent causes of death from end-stage liver diseases and HCC.[5] In the last decade, HCV-related morbidity doubled, and HCC related to HCV increased almost threefold.[6] Its impact on liver-related morbidity and mortality is expected to reach its peak in the next decade.[7]

The objective with antiviral therapy is to obtain a sustained virologic response (SVR), defined as undetectable HCV RNA 24 weeks after the end of treatment. In the last decade, treatment with pegylated interferon 2a or 2b (pegIFN) combined with weight-based ribavirin (RBV) for 48 weeks (genotypes 1, 4, 5 and 6) or 24 weeks (genotypes 2 and 3), has been considered the standard of care (SOC) for HCV treatment. With pegIFN/RBV treatment, SVR rates were 40–50% in genotype 1 and 70–80% in genotypes 2/3-infected patients in western countries.[8] Some studies showed that prolonging treatment up to 72 weeks in genotype 1 slow responders (HCV RNA detectable at week 12 but undetectable at week 24), can increase SVR rates.[9–12] But, prolonged treatment is associated with higher costs, increases in adverse events, and cannot be used in treatment-intolerant patients.

Many viral and host factors affect treatment response, and not achieving a SVR might be related to a combination of them. HCV genotype and IL28B host genotype are the strongest predictors of pegIFN/RBV therapy outcome.[13]IL28B designates single-nucleotide polymorphisms (SNPs) in the interferon λ gene region in chromosome 19, and it is related to interferon responsiveness. Other factors such as high viral load, older age, black race and advanced fibrosis or cirrhosis negatively influence SVR rates.[14,15]

In 2011 the US FDA and the EMA approved telaprevir (TVR) (Incivek/Incivo™, Vertex) and boceprevir (BOC) (Vitrelis™, Merck) for its use in HCV genotype 1 infected patients. These two NS3/4A serine protease inhibitors (PIs) are the first generation of direct-acting antiviral (DAA) drugs to be approved for its use in clinical practice. Used in combination with pegIFN/RBV, PIs increased SVR rates up to 68–75% in naive patients and to 41–52% in previous nonresponders.[16–19] With the new treatment regime of PI-based triple therapy, some of the predictors of response to dual pegIFN/RBV-based therapy are less important. In fact, some host factors are used differently. Nonetheless, baseline host and viral factors and early viral kinetics are still important determinants for patient counseling and management using BOC or TVR combination treatment.

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