Mixed hepatitis B virus genotype infections: The more, the worse?
Authors: Chun-Jen Liu, Jia-Horng Kao, Ding-Shinn Chen
Journal: Hepatology (2006)

We read with great interest the article by Toan et al.1 Eight hepatitis B virus (HBV) genotypes have been identified by sequence divergence of >8% in the entire viral genome of about 3,200 nucleotides (nt), and designated by capital letters from A to H in the order of documentation.2 Each genotype has distinct geographical and ethnic distribution. Recently, HBV genotypes have attracted increasing attention since they may affect the disease progression and outcomes of HBV-related chronic liver disease, as well as the response to antiviral treatments.3, 4 In Asian countries, including Taiwan where genotypes B and C prevail, most studies indicate that the severity and outcomes of chronic hepatitis B are more serious in genotype C patients compared to genotype B patients.3, 4 In this article, the authors consistently found that genotype C was more frequent in patients with hepatocellular carcinoma (HCC) in Vietnam.1 Of particular note, Toan et al. also found HBV genotype mixtures were more frequently encountered in patients with chronic hepatitis compared to those with acute hepatitis, liver cirrhosis, and HCC. Further in vivo observation and in vitro transfection assay demonstrated that genotype mixtures were associated with increased HBV replication. They thus suggested co-infection with different HBV genotypes is correlated with altered pathogenesis and clinical outcome. In Taiwan, we earlier studied the prevalence and clinical implications of HBV genotype mixtures and yielded similar findings.5-8 In brief, although superinfection of HBV genotype in a given patient is not common, our earlier study showed that co-infection with distinct HBV genotype is correlated with hepatitis flare in HBV carriers.5 The subsequent studies indicated that mixed HBV genotype B and genotype C infection existed in 7 (17.5%) of 40 HBsAg-positive intravenous drug users (IDUs).6 In the 7 IDUs with mixed HBV genotype B and genotype C infection, by subcloning and direct sequencing of the pre-S region, we found that most of the clones were HBV genotype B and novel recombinations between HBV genotype B and genotype C occurred in two IDUs.7 These results suggested that HBV genotype B is the dominant strain in genotypes B and C co-infected IDUs in Taiwan. The prevalence of mixed HBV genotype infections was further confirmed in a subsequent large cohort study. By using a more sensitive line probe assay, the distribution of HBV genotype was as follows: genotype A alone in 2 (0.6%); genotype B alone in 256 (78.8%); genotype C alone in 10 (3.1%); mixed genotype A and B in 18 (5.5%); genotype B and C in 30 (9.2%); genotype B and D in 1 (0.3%); genotype A and C in 1 (0.3%); and mixed infections of genotype A, B, and C in 3 (0.9%). To further illustrate the interactions between different genotypes of HBV in co-infected patients, the evolution of HBV strains was studied in an acute, self-limited hepatitis B patient co-infected with genotypes B and C.8 We found that all clones propagated from before HBeAg seroconversion were of genotype C. In contrast, genotype B may overtake genotype C as the predominant strain after HBeAg seroconversion. We are now examining the replication potential of mixed genotypes versus single genotype, and its correlates with the clinical manifestations. In summary, these interesting data provided by Toan et al.,1 along with ours, strongly suggest that HBV genotype mixtures may correlate with clinical outcomes of HBV infection. Thus, more large prospective studies are needed to confirm these findings and to examine underlying molecular virologic mechanisms involved in the interplay between HBV genotypes. Chun-Jen Liu*, Jia-Horng Kao* §, Ding-Shinn Chen* , * Division of Gastroenterology, Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan, Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan, § Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.