HBV genotype C is found throughout the eastern and southeastern portions of Asia and the Pacific islands (Micronesia, Melanesia, and Polynesia), as well as in immigrants from these areas in the United States, Europe, Australia, and New Zealand [6
]. More studies have been published about genotype C than any other HBV genotype. The majority of the studies compare the disease manifestations in persons infected with genotype C in comparison with those found in persons infected with genotype B [28
]. Most of the published studies are cross-sectional and clinic-based. These studies can suffer from referral bias, since a higher proportion of patients with advanced disease are seen in hepatology clinics, and selection bias, a problem with all studies that are not population-based share. However, a few important population-based prospective studies have been published. Multiple cross-sectional studies have almost universally shown that patients with genotype C experience HBeAg seroconversion at an older age and are more likely to be HBeAg positive at any given age than HBV genotype B [30
]. In most cross-sectional studies, HBV genotype C is associated with an increase risk of liver inflammation, flares of hepatitis, liver fibrosis, and cirrhosis [30
Several cross-sectional studies have been conducted examining the association of genotypes C and B with HCC. In most of the studies, genotype C has been associated with an increased risk of HCC [34
]. In two of these studies, genotype C-associated HCC occurred in significantly younger persons (<50 years) and genotype B HCC was found primarily in persons older than 60 years [35
]. In one of these cross-sectional studies, the overall risk of HCC was not shown to be different between HBV genotypes B and C, but risk of HCC in genotype C occurred at a younger age [36
]. The BCP mutation was found to be independently associated with presence of HCC [21
] and occurred more frequently in HBV genotype C [33
]. In patients infected with HBV genotype B or C, the relationship between PC and HCC was less clear [21
Fortunately, several prospective studies compared the outcome in those infected with genotypes B and C and bolster the findings of the cross-sectional studies. These studies included between 90 and 4,841 patients followed up for up to 14 years [33
]. They confirmed that HBeAg seroconversion occurred at a significantly younger age for those infected with genotype B than genotype C [15
] and that increased risk of fibrosis was associated with genotype C [39
]. The two largest studies, consisting of 426 and 4,841 patients followed up for a mean of 4.8 and 14 years, respectively, showed a significant increase in risk for HCC in genotype C in comparison with genotype B [33
]. Two smaller studies did not find any difference [39
]. Taken together, the majority of the cross-sectional and the largest prospective studies with the longest follow-up show that persons infected with HBV genotype C seroconvert from HBeAg later in life and have an increased risk of liver inflammation, liver fibrosis, and HCC.
Increased HBV viral level in several prospective studies in Asia has been shown to be associated with an increased risk of both cirrhosis and HCC [43
]. In one of these studies, infection with genotype C was also found to be an independent risk factor for the development of HCC [45
]. These studies suggest that genotype C might be the most deadly of the HBV genotypes, and there are two possible explanations for this finding. First, persons infected with HBV genotype C clearly have higher levels of HBV DNA, as evidenced by prolonged HBeAg positivity, than those infected with genotypes A1, A2, B1–6, D, and F1. Those infected with genotype C experience prolonged viremia throughout much of their lives, which means more time for HBV integration to occur and more opportunity for liver inflammation and fibrosis. Second, certain mutations such as the BCP mutation, which independently may be associated with higher risk of HCC, appear to occur more frequently in those infected with genotype C.
Within HBV genotype C, there is not much information regarding differences between subgenotypes and disease outcome. However, a recent prospective study from Hong Kong of 1,006 patients with chronic HBV infection followed up for a median of 7.7 years showed that the highest risk of developing HCC was in persons infected with HBV genotype C2 (Ce) and the next highest in C1 (Cs) than those infected with genotype B (presumably Ba) [45
]. However, more studies comparing the risk of HCC among HBV subtypes of genotype C are needed (Table ).
Liver disease associated with HBV genotype C