High Diversity of Hepatitis C Viral Quasispecies Is Associated with Early Virological Response in Patients Undergoing Antiviral Therapy Xiaofeng Fan,1,2 Qing Mao,3,4 Donghui Zhou,1,5 Yang Lu,1 Jianwei Xing,1 Yanjuan Xu,1 Stuart C. Ray,3 and Adrian M. Di Bisceglie1,2 Differential response patterns to optimal antiviral therapy, peginterferon alpha plus ribavi-rin, are well documented in patients with chronic hepatitis C virus (HCV) infection. Amongmany factors that may affect therapeutic efficiency, HCV quasispecies (QS) characteristicshave been a major focus of previous studies, yielding conflicting results. To obtain a com-prehensive understanding of the role of HCV QS in antiviral therapy, we performed thelargest-ever HCV QS analysis in 153 patients infected with HCV genotype 1 strains. A totalof 4,314 viral clones spanning hypervarible region 1 were produced from these patientsduring the first 12 weeks of therapy, followed by detailed genetic analyses. Our data show anexponential distribution pattern of intrapatient QS diversity in this study population inwhich most patients (63%) had small QS diversity with genetic distance (d) less than 0.2. Thegroup of patients with genetic distance located in the decay region (d>0.53) had a signifi-cantly higher early virologic response (EVR) rate (89.5%), which contributed substantiallyto the overall association between EVR and increased baseline QS diversity. In addition, EVRwas linked to a clustered evolutionary pattern in terms of QS dynamic changes. Conclusion:EVR is associated with elevated HCV QS diversity and complexity, especially in patients withsignificantly higher HCV genetic heterogeneity.(HEPATOLOGY 2009;50:1765-1772.)