Epidemic spread of hepatitis C virus genotype 3a and relation to high incidence of hepatocellular carcinoma in Pakistan.

Studies conducted in different populations worldwide revealed an association between HCV genotype 1 and the development of hepatocellular carcinoma (HCC) than in infection with other HCV genotypes. There are reports which reveal the association of HCV genotype 3a (HCV-3a) with hepatic steatosis and fibrosis but its relation with the development of HCC has not been investigated. In Pakistan, where the incidence of HCC is increasing, 189 patients with chronic liver disease including 82 with HCC were enrolled. HCV genotypes were determined by phylogeny in the NS5B region and the epidemic history of HCV-3a was examined using coalescent theory based methods. HCV-3a was the predominant genotype (81.4%) in the cohort studied, followed by 3b (9.3%), 3k (2.3%), 1a (1.5%), 1c (1.5%), 1b (0.8%), and 2a (0.8%) where 76% of HCC and 86% of non-HCC were infected with HCV-3a. The significant factors associated with HCC were older age (mean +/- SD) 55.8 (+/-9.9) (P < 0.0001), and male gender (P < 0.001). HCV RNA was significantly higher in patients with HCC and chronic hepatitis than in liver cirrhosis (P < 0.0001). Molecular evolutionary analysis revealed a distinct phylogenetic cluster of HCV-3a in Pakistan and an estimation of the effective number of HCV infections indicated the appearance of HCV-3a in this region around 1920s and a rapid exponential growth in the 1950s. This indicates that the epidemic spread of HCV-3a occurred earlier in Pakistan than in other countries in which this genotype has been reported. HCV-3a which spread earlier in Pakistan may be associated with an increasing incidence of HCC.