Sustained Virologic Response to Hepatitis C Virus Therapy and Spontaneous Viral Clearance Found Linked to Genotype

Abstract

A pair of papers in the journal Nature offer strong evidence that genotype dictates sustained virologic response (SVR) to hepatitis C therapy and is also associated with spontaneous viral clearance. A paper published is September 2009 involved a genome-wide association study of >1600 individuals chronically infected with hepatitis C participating in the IDEAL clinical treatment trial. The study compared the effectiveness of three treatment regimens involving pegylated interferon (PegIFN)-a-2b or PegIFN-a-2a combined with ribavirin (RBV). Patients received 48 weeks of treatment and 24 weeks of follow-up.The study team from Duke University, Johns Hopkins University, and Schering Plough Research Institute, identified a single nucleotide polymorphism, rs12979860, on chromosome 19q13. This single nucleotide polymorphism was strongly associated with SVR.The variant is near the gene for interferon-λ3 (IL-28B), which encodes the type III interferon IFN-λ3. The study team led by David Goldstein, PhD, of Duke University, states the C/C genotype doubles the chance of successful HCV treatments. The variant is a cytosine for thymine switch on chromosome 19 and is the first genetic marker that predicts response to treatment for HCV genotype 1, the authors say.The polymorphism is also more common among people of European ancestry than those of African background, which may explain much of the difference in treatment response between these 2 ethnic groups. Genome-wide association studies were performed, correlating their SVRs with a large number of polymorphisms. Across all ethnic groups, the genetic variation in IL-28B was significantly associated (at P = 1.37 × 10−28) with SVR, defined as the absence of detectable virus at the end of follow-up.In patients of European ancestry who carry 2 copies of the C variant, the genotype was associated with a 2-fold greater rate of SVR than the TT genotype. The ratios of SVR in those with CC genotype were similar in both the African-American and the Hispanic populations in the study—3-fold and 2-fold, respectively, the researchers said. African-Americans with 2 copies of the C allele had a 53.3% SVR rate, significantly higher (P < .05) than the 33.3% seen in Europeans with 2 copies of the T allele. “It seems likely … that advance knowledge of host genotype of patients infected with HCV could in the future become an important component of the clinical decision to initiate treatment with PegIFN and RBV,” the authors state.In the second Nature study published in October 2009, researchers directed by David Thomas, MD, from The Johns Hopkins University, sought to determine the potential effect of the rs12979860 variation on spontaneous clearance of HCV infection. The variant was genotyped in HCV cohorts comprised of individuals who spontaneously cleared the virus (n = 388) or had persistent infection (n = 620). The study found that the C/C genotype “strongly enhances resolution of HCV infection among individuals of both European and African ancestry,” the authors write. “To our knowledge, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection,” the authors write.In their analysis of genotype frequencies, patients with the C/C genotype were 3 times more likely to clear HCV infection relative to patients with the C/T and T/T genotypes combined (odds ratio, 0.33; 95% confidence interval, 0.25–0.45; P = 3 × 10−13). Stratification of this analysis by ethnicity indicated that the strength of the protective C/C effect was similar in individuals of African and European ancestry. “However, a comparison of the C/C to the T/T group alone suggested stronger protection conferred by C/C in individuals of African ancestry relative to that in individuals of European ancestry, although our power to detect a true difference is limited owing to small sample sizes in some groups.”The authors state that the rs12979860 polymorphism upstream of IL-28B, “which was previously associated with HCV treatment response also has a marked impact on natural clearance of HCV and may have been under selection in human history. It is now a priority to determine the mechanisms through which IL28B promotes viral defense and the full range of viruses affected by these mechanisms.”See: Nature Vol. 461, 17 September 2009 and 8 October 2009. A pair of papers in the journal Nature offer strong evidence that genotype dictates sustained virologic response (SVR) to hepatitis C therapy and is also associated with spontaneous viral clearance. A paper published is September 2009 involved a genome-wide association study of >1600 individuals chronically infected with hepatitis C participating in the IDEAL clinical treatment trial. The study compared the effectiveness of three treatment regimens involving pegylated interferon (PegIFN)-a-2b or PegIFN-a-2a combined with ribavirin (RBV). Patients received 48 weeks of treatment and 24 weeks of follow-up. The study team from Duke University, Johns Hopkins University, and Schering Plough Research Institute, identified a single nucleotide polymorphism, rs12979860, on chromosome 19q13. This single nucleotide polymorphism was strongly associated with SVR. The variant is near the gene for interferon-λ3 (IL-28B), which encodes the type III interferon IFN-λ3. The study team led by David Goldstein, PhD, of Duke University, states the C/C genotype doubles the chance of successful HCV treatments. The variant is a cytosine for thymine switch on chromosome 19 and is the first genetic marker that predicts response to treatment for HCV genotype 1, the authors say. The polymorphism is also more common among people of European ancestry than those of African background, which may explain much of the difference in treatment response between these 2 ethnic groups. Genome-wide association studies were performed, correlating their SVRs with a large number of polymorphisms. Across all ethnic groups, the genetic variation in IL-28B was significantly associated (at P = 1.37 × 10−28) with SVR, defined as the absence of detectable virus at the end of follow-up. In patients of European ancestry who carry 2 copies of the C variant, the genotype was associated with a 2-fold greater rate of SVR than the TT genotype. The ratios of SVR in those with CC genotype were similar in both the African-American and the Hispanic populations in the study—3-fold and 2-fold, respectively, the researchers said. African-Americans with 2 copies of the C allele had a 53.3% SVR rate, significantly higher (P < .05) than the 33.3% seen in Europeans with 2 copies of the T allele. “It seems likely … that advance knowledge of host genotype of patients infected with HCV could in the future become an important component of the clinical decision to initiate treatment with PegIFN and RBV,” the authors state. In the second Nature study published in October 2009, researchers directed by David Thomas, MD, from The Johns Hopkins University, sought to determine the potential effect of the rs12979860 variation on spontaneous clearance of HCV infection. The variant was genotyped in HCV cohorts comprised of individuals who spontaneously cleared the virus (n = 388) or had persistent infection (n = 620). The study found that the C/C genotype “strongly enhances resolution of HCV infection among individuals of both European and African ancestry,” the authors write. “To our knowledge, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection,” the authors write. In their analysis of genotype frequencies, patients with the C/C genotype were 3 times more likely to clear HCV infection relative to patients with the C/T and T/T genotypes combined (odds ratio, 0.33; 95% confidence interval, 0.25–0.45; P = 3 × 10−13). Stratification of this analysis by ethnicity indicated that the strength of the protective C/C effect was similar in individuals of African and European ancestry. “However, a comparison of the C/C to the T/T group alone suggested stronger protection conferred by C/C in individuals of African ancestry relative to that in individuals of European ancestry, although our power to detect a true difference is limited owing to small sample sizes in some groups.” The authors state that the rs12979860 polymorphism upstream of IL-28B, “which was previously associated with HCV treatment response also has a marked impact on natural clearance of HCV and may have been under selection in human history. It is now a priority to determine the mechanisms through which IL28B promotes viral defense and the full range of viruses affected by these mechanisms.” See: Nature Vol. 461, 17 September 2009 and 8 October 2009.