HBV Genotypes Geographic Distribution And Their Clinical Relevance And HBV Mutations In Patients With Acute On Chronic Liver Failure In China

Objective The study examined the geographic distribution of Hepatitis B virus (HBV) genotypes in China and evaluated the correlation between HBV genotypes and chronicity and poor outcomes of HBV infection and explored the relationship of HBV mutation and acute on chronic liver failure(ACLF).Methods We examined HBV genotypes of 2922 HBV infection in China, and summarized the geographic distribution of HBV genotypes, and compared HBV genotypes in different outcomes and liver function and virology. BCP/Pre-C and C region was sequenced and analyzed from serum samples of 190 patients including chronic hepatitis (CHB n=52), liver cirrhosis (LC n=51), ACLF(n=87).Results In this study, genotypes B, C, B/C, and D accounted for 15.9%,83.5%, 0.41%, and 0.21%, respectively in 2922 HBV-infected patients,. In Northern China, genotype C was most prevalent, while it was less common in Southern China. Genotype B was more prevalent in AH than CH patients (P=0.003), while genotype C was more often found in LC and HCC than CH patients (P<0.001). No statistically significant differences were observed in the rate of positivity for hepatitis B antigen (HBeAg), the HBV DNA viral load, and liver function in AH and CH patients with genotypes B or C. The HBeAg positive rate for genotype C was significantly higher than for genotype B in ACLF, LC, and HCC patients (P<0.001, P=0.024, and P= 0.003, respectively). The HBV DNA viral load for genotype C was also significantly higher than for genotype B in HCC patients (P=0.025). Cholinesterase, however, was significantly lower for genotype C than for genotype B in ACLF and HCC patients (P<0.001 and P=0.02). The second study showed that the rate of nt1753, nt1762, nt1764, nt1846, nt1899 and nt1913 mutations were significant different between 3 groups (P<0.01). Between group ACLF and CHB, nt1753,1846,1899and nt1913 had significant difference (P<0.05), and between group ACLF and LC, mutation rates of nt 1762,1764,1846 and nt1913 had significant difference (P<0.05), and between group CHB and LC, mutation rates of nt 1753, 1762,1764 and nt1899 had significant difference (P<0.05). We found that the number of mutations had a relation to the progress of the disease, and HBV from ACLF patients presented more mutations. HBV DNA levels were lower in HBV with nt1753, nt1846 mutations compared to wild type. And the more nucleotide mutations, the lower HBV DNA level. Furthermore, we found that HBeAg negative patients had more nt1846, nt1896 mutations than HBeAg positive patients. And mutations at nt1753, nt1762 and nt1764 were seen more frequently in HBV genotype C. Multivariate analysis showed that nt1913(C→A or G) are independent factor for the ACLF [Exp(B)=4.76; P<0.001].Conclusion HBV genotypes B, C, B/C, and D are prevalent in China. Genotype C is more often identified in North China compared with South China. Genotype C tends to be more associated with chronicity and progression to LC and HCC than genotype B. Genotypes B and C have no apparent impact on the disease in mild HBV infections, but genotype C is associated with more severe liver dysfunction compared with genotype B on the disease in severe HBV infections. Nucleotide mutations of BCP/Pre-C are related to HBV genotype,HBeAg positive rate and HBV DNA level. Mutations at nt1846 and nt1913 are possibly related to ACLF, and nt1913 mutations are indenpendant factor for ACLF.