Genetic diversity of hepatitis B virus as an important factor associated with differences in clinical outcomes.

Approximately 350 million people worldwide are persistently infected with hepatitis B virus (HBV) [1], which has been classified into 8 genotypes (A–H) by means of molecular evolutionary analyses [2–4]. HBV genotypes have different geographic distributions [5]. Genotype D is ubiquitous and scattered worldwide, whereas genotype A is prevalent in sub-Saharan Africa, North America, and Eu-rope and genotypes B and C are common in Asia. Genotype E is mainly restricted to western Africa, and genotype F is considered to be indigenous to aboriginal populations in Central and South America [6]. In addition, a number of genotype F–spe-cific phylogenetic clusters have been attributed to local populations in different Genotype G has been detected infrequently , and its epidemiologic profile is unclear. Genotypes are further subdivided into subgenotypes, on the basis of phylogenetic relationships [16]. Subgenotype Aa/A1 has been identified in South Africa and Asia, whereas subgenotype Ae/A2 has been detected in Europe and the United States [17, 18]. Subgenotype Ac/A3 has been detected in central and western Africa [19]. Sugau-chi et al. [20] identified 2 subgenotypes within genotype B in Asian countries. One subgenotype (Bj/B1) is the authentic genotype B and is indigenous in Japan, whereas another subgenotype (Ba/B2) is predominant in Asian countries other than Japan and exhibits a recombination with genotype C over the precore region and core gene [20, 21]. Recently, subgenotypes have also been recognized in genotypes C and D [16, 22–24]. There is increasing evidence regarding the influence of HBV genotypes/subgeno-types on liver disease, in both acute and chronic HBV infections [5, 25]. Owing to the geographic distribution of genotype prevalence, comparative analyses have been restricted mainly to the predominant ge-notypes—namely, genotype B versus genotype C in some Asian countries and genotype A versus genotype D in Europe and India [26–28]—although a few multinational studies also have compared 12 genotypes [29, 30]. In Asian cohorts, genotype C has been associated with a higher frequency of cirrhosis or hepatocellular carcinoma (HCC) and a weaker patient response to interferon-a–based treatment, compared with genotype B [31]. Similarly, genotype-related differences have been reported for long-term outcomes of chronic infection with HBV genotype A, D, or F [32]: rates of sustained biochemical remission and clearance of HBV DNA and hepatitis B surface antigen were significantly higher among patients infected with genotype A than among patients infected with genotype D or F. In addition, the frequency of death related to liver disease has …