Are We on the Verge of Gene-Based Personalized Treatment for Hepatitis C Virus Infection?

William F. Balistreri, MD
Authors and Disclosures
Posted: 07/14/2010

Question
I've heard that it is now possible to predict which patients with chronic hepatitis C virus infection will respond to treatment -- is this true?

Response from William F. Balistreri, MD
Dorothy M.M. Kersten Professor of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Medical Director, Liver Transplantation Program, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

Yes -- to an extent. As we learn more about the genetic and molecular mechanisms of liver injury and repair, we will be better able to predict response to treatment and therefore tailor the therapeutic strategy. This will be especially relevant to chronic hepatitis C virus (HCV) infection; it will permit us to direct treatment resources to the patients who are most likely to benefit.

Identification of the determinants of clearance and response to treatment in HCV Infection has been a high research priority. Recovery from HCV infection and the response to standard antiviral treatment depends on host factors, viral factors, and treatment (adherence) factors. The viremia in about 30% of people who acquire HCV infection will spontaneously resolve without long-term consequences.

Differences (eg, polymorphisms) in genes encoding cytokines and other immunologic mediators partially explain spontaneous recovery from HCV.[1,2] Similarly, marked differences are possible in the degree to which individuals with chronic HCV infection respond to treatment.[3]

The currently recommended treatment for chronic HCV infection is a 48-week course of pegylated-interferon alpha α alpha-2b) or PegIFN α alpha-2a combined with ribavirin. Like spontaneous clearance, treatment-related resolution of chronic hepatitis C is associated with clearance of viremia and reduction in the risk for long-term consequences of infection.[4] Differences in candidate genes are also found in patients who respond to treatment compared with so-called nonresponders.[5-7] Patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry.

Rauch and colleagues performed a genome-wide association study to screen for host genetic determinants of HCV persistence and response to therapy.[8] They compared the frequency of approximately 500,000 single nucleotide polymorphisms (SNPs) in DNA from patients with spontaneous HCV resolution and patients with persistent infection. The strongest association with spontaneous recovery was detected for rs8099917, a SNP located nearest to interleukin 28B (IL28B), the gene that encodes for IFN lambda-3. Patients who are homozygous for C at rs12979860 have a >2.5-fold increased likelihood of spontaneous resolution of HCV compared with control patients who have persistent HCV infection.[9] The frequency of the minor G allele is over-represented among patients with chronic hepatitis C compared with those with spontaneous recovery; it is also overrepresented in the subset of patients with chronic infection who do not respond to PegIFN and ribavirin compared with those who achieve a sustained virologic response. Other groups have confirmed and expanded these observations.[10-12] The association of the IL28B locus with natural and treatment-associated control of HCV suggests the importance of innate immunity and IFN lambda-3 in the pathogenesis of HCV infection.

Ge and colleagues compared the frequencies of approximately 600,000 SNPs in DNA from patients with persistent HCV infection according to their response to PegIFN and ribavirin.[12] They reported that a genetic polymorphism near the IL28B gene was associated with a 2-fold change in response to treatment, among patients of European ancestry and those of African-American ancestry.[12] The C/C genotype, associated with a better response, is more frequent in European than African populations. This genetic polymorphism also explains much of the difference in response rates between black patients and patients of European ancestry. Patients who were homozygous for the T/T genotype were less likely to respond to treatment. Thus, the global distribution of the protective C/C allele correlates strongly with ethnic differences in spontaneous resolution of HCV and in treatment-related response.[12,13]

What functional mechanism underlies the IL28B response? HCV RNA triggers production of type 1 interferons by hepatocytes; these molecules stimulate transcription of interferon-stimulated genes (ISGs). Exogenous (therapeutic) interferon alpha signals similarly. Given that the polymorphism 3-kb upstream of IL28B appears to be associated with natural clearance as well as treatment response, it seems likely that the gene product is involved in the innate control of HCV. Indeed, IFN lambda has antiviral activity against genotype 1 HCV in vitro and in vivo.

Data presented at Digestive Disease Week 2010 further indicated that we can predict sustained virologic response on the basis of emerging validation of the genetic variation in regulation of the immune response to HCV.[13] The specific IL28B polymorphism (C/C, which occurs in up to 33% of patients) is strongly associated with reduced expression of intrahepatic ISGs and the response rate to PegIFN and ribavirin. Genetic variation in IL28B regulates the innate immune response to HCV in the liver, priming patients for a stronger response to exogenous IFN alpha therapy.[13]

Thus, at least 5 independent studies provide overwhelming genetic evidence for the role of IL-28B in the pathogenesis of HCV infection and in spontaneous and treatment-related recovery from HCV infection. Future studies will link these findings to improved, and perhaps personalized, HCV treatment and prevention worldwide.

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