The study was undertaken to investigate the features and clinical implications of hepatitis B virus (HBV) genotypes, basal core promoter (BCP) and precore (PC) mutations in hepatitis B-related acute-on-chronic liver failure (HB-ACLF). Samples from 75 patients with HB-ACLF and without pre-existing liver cirrhosis and 328 age-matched patients with chronic hepatitis B (CHB) were analyzed. HBV genotype and BCP/PC mutations were determined by direct sequencing. Mutations at 8 sites of the BCP/PC region were compared between the two groups of patients. A significantly higher ratio of genotype B to C was found in patients with HB-ACLF than in patients with CHB (30.7–69.3%vs16.5–82.6%, P < 0.01). Single mutations including T1753V (C/A/G), A1762T, G1764A, G1896A and G1899A and triple mutations T1753V/A1762T/G1764A and A1762T/G1764A/C1766T (or T1768A) were more frequently detected in patients with HB-ACLF than in patients with CHB. Correspondingly, BCP/PC wild-type sequences were absent in patients with HB-ACLF in contrast to 27.1% in patients with CHB. The BCP/PC mutations were found to be associated with increased HBeAg negativity, higher alanine aminotransferase level and lower viral load. Patients with HB-ACLF infected with the PC mutant virus had a higher mortality. The findings suggest that patients with CHB infected with genotype B with BCP/PC mutations were more likely to develop HB-ACLF than those with genotype C with wild-type BCP/PC regions, and patients with HB-ACLF with the PC mutation had increased risk of a fatal outcome.

The study investigated the hepatitis B virus (HBV) genotypic resistance profile in 1803 nucleos(t)ide analogue (NA)-experienced Chinese patients with chronic HBV infection. Serum HBV DNA was extracted, and the reverse transcriptase region was analysed by a high-sensitive direct PCR sequencing and verified by clonal sequencing if necessary. Drug-resistant mutations were detected in 560 of the 1803 patients, including 214 of 490 patients who received lamivudine (LAM), 35 of 428 patients who received adefovir (ADV), five of 18 patients who received telbivudine and 306 of 794 patients who received various sequential/combined NA therapies. ADV-resistant mutations were detected in 36 of 381 patients who received LAM and then switched-to ADV in contrast to one of 82 patients who received ADV add-on LAM. Entecavir (ETV)-resistant mutations were detected not only in LAM- and ETV-treated patients but also in LAM-treated ETV-naïve patients. Double mutations rtM204I and rtL180M were detected more frequently in genotype C than in genotype B virus, and patients infected with this mutant had higher alanine transaminase levels than those infected with mutant containing the rtM204I substitution alone. Multidrug-resistant HBV strains were identified in eight patients, including two novel strains with mutational patterns rtL180M + A181V + S202G + M204V + N236T and rtL180M + S202G + M204V + N236T. The results provide new information on HBV genotypic resistance profiles in a large cohort of Chinese patients with chronic HBV infection and may have important clinical implication for HBV drug resistance management in China.

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We aimed to study the prevalence and clinical implications of hepatitis B virus (HBV) subgenotypes in Chinese patients. A total of 4,300 patients, mainly from northern China, were enrolled, including 182 patients with acute hepatitis B and 4,118 patients with chronic HBV infection who had been exposed to nucleoside or nucleotide analogs. HBV genotypes/subgenotypes were determined by direct sequencing of the HBV S/Pol region. The prevalence rates were 0.40% for HBV/B1, 14.30% for HBV/B2, 0.25% for HBV/B3, 0.35% for HBV/B4, 1.05% for HBV/C1, 81.72% for HBV/C2, 0.93% for HBV/C3, 0.16% for HBV/C4, and 0.84% for HBV/D. In chronic HBV infection, patients with HBV/B2 were younger and had lower ⌯BeAg positive rates than patients with HBV/C2. The incidence of lamivudine-resistant mutations was significantly higher in HBV/C2 compared to HBV/B2 (27.9% versus 19.8%; P < 0.01), and the significant difference was observed only for rtM204I and not rtM204V. In addition, compensatory mutations were more frequently detected in HBV/C2. The incidence of adefovir-resistant mutations was similar between the two subsets, but HBV/C2 inclined to show rtA181V (3.6% for C2 versus 0.9% for B2; P < 0.01), while HBV/B2 inclined to show rtN236T (4.5% for versus 2.5% for C2; P < 0.01). The ratios of HBV/B2 to HBV/C2 infection were 1.7 (110/65), 5.7 (2,653/463), 7.5 (520/69), 8.0 (48/6), and 15.3 (183/12) for acute hepatitis B, chronic hepatitis B, liver cirrhosis, acute-onchronic liver failure, and hepatocellular carcinoma, respectively. In conclusion, HBV/C2 and HBV/B2, two prevalent subgenotypes, differ in lamivudine-and adefovir-resistance-associated mutational patterns. HBV/ C2-infected patients are more likely to have disease progression than HBV/B2-infected ones.Hepatitis B virus (HBV) infection remains a serious health problem that currently affects about 350 million people worldwide and 93 million in China (12,20). HBV infection is associated with a wide spectrum of clinical presentations, including asymptomatic subclinical infection, acute hepatitis B (AHB), chronic hepatitis (CHB), liver cirrhosis (LC), acute-on-chronic liver failure (ACLF), and hepatocellular carcinoma (HCC). Factors associated with disease progression remain largely unknown. Viral factors have been implicated in the pathogenesis and clinic outcome of HBV infection (23).HBV exhibits a mutation rate of around 2 ϫ 10 4 base substitutions/site/year, which is an approximately 100 times higher than that of other DNA viruses (5). HBV is at least classified into eight genotypes, based on nucleotide sequence divergence among strains of Ͼ8%. In Asia, HBV genotypes B and C are the predominant genotypes, and HBV genotype C is associated with more severe liver disease, delayed HBeAg seroconversion, and a high risk of HCC (7,8,10,17,18,24). Within each HBV genotype, subgenotypes have been identified based on a 4 to 8% difference in the complete nucleotide sequence. HBV/B, HBV/C, and HBV/D have been individually classified into five subgenotypes each, namely, HBV/B1 through HBV/ ...

Our findings suggest that CHB patients infected with BCP/PC mutant viruses are more susceptible to severe hepatitis and ACLF than those with the BCP/PC wild-type virus and that ACLF patients with PC mutant viruses have an increased risk of death. As such, the HBV PC mutation is a potential predictive indicator of ACLF outcome.

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Here, we report a case of multidrug resistance in a patient with chronic hepatitis B. The patient sequentially received lamivudine, adefovir dipivoxil and entecavir, and subsequently developed single-, double- and triple-drug-resistant HBV strains. We consider this case report important because it documents, for the first time, that triple-drug-resistant HBV strains identified in a clinical setting were suppressible by lamivudine add-on adefovir dipivoxil when tenofovir disoproxil fumarate was not available.

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