Abstract
BackgroundPegylated interferon plus ribavirin therapy for hepatitis C virus (HCV) fails in approximately half of genotype 1 patients. Treatment failure occurs either by nonresponse (minimal declines in viral titer) or relapse (robust initial responses followed by rebounds of viral titers during or after therapy). HCV is highly variable genetically. To determine if viral genetic differences contribute to the difference between response and relapse, we examined the inter-patient genetic diversity and mutation pattern in the full open reading frame HCV genotype 1a consensus sequences.Methodology/Principal FindingsPre- and post-therapy sequences were analyzed for 10 nonresponders and 10 relapsers from the Virahep-C clinical study. Pre-therapy interpatient diversity among the relapsers was higher than in the nonresponders in the viral NS2 and NS3 genes, and post-therapy diversity was higher in the relapsers for most of HCV's ten genes. Pre-therapy diversity among the relapsers was intermediate between that of the non-responders and responders to therapy. The average mutation rate was just 0.9% at the amino acid level and similar numbers of mutations occurred in the nonresponder and relapser sequences, but the mutations in NS2 of relapsers were less conservative than in nonresponders. Finally, the number and distribution of regions under positive selection was similar between the two groups, although the nonresponders had more foci of positive selection in E2.Conclusions/SignificanceThe HCV sequences were unexpectedly stable during failed antiviral therapy, both nonresponder and relapser sequences were under selective pressure during therapy, and variation in NS2 may have contributed to the difference in response between the nonresponder and relapser groups. These data support a role for viral genetic variability in determining the outcome of anti-HCV therapy, with those sequences that are more distant from an optimal sequence being less able to resist the pressures of interferon-based therapy.Trial registrationClinicalTrials.gov NCT00038974
Highlights
Hepatitis C Virus (HCV) infects over 170 million people worldwide and more than 4 million in the USA [1,2,3]
Inter-patient genetic diversity among the nonresponder and relapser sequences Since there were no amino acid positions at which genetic differences strongly correlated with nonresponse or relapse, we examined the groups of sequences to determine if there were differences in inter-patient diversity between the nonresponders and relapsers that correlated with the response pattern
Failure of interferon plus ribavirin therapy for hepatitis C virus (HCV) can occur in two different patterns: nonresponse and relapse
Summary
Hepatitis C Virus (HCV) infects over 170 million people worldwide and more than 4 million in the USA [1,2,3]. Current therapy for HCV employs pegylated interferon a and ribavirin, but treatment clears the infection in only about half of patients infected with genotype 1, the most common genotype in the USA [5,6,7]. The reasons for failure of treatment are not fully understood, but host, virus, and immune response variables all correlate with response to therapy [5,8]. Pegylated interferon plus ribavirin therapy for hepatitis C virus (HCV) fails in approximately half of genotype 1 patients. To determine if viral genetic differences contribute to the difference between response and relapse, we examined the inter-patient genetic diversity and mutation pattern in the full open reading frame HCV genotype 1a consensus sequences
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