BackgroundHepatitis B e Antigen (HBeAg)-negative chronic hepatitis B (CHB) patients have an active liver disease with a high risk of progression to decompensated cirrhosis and hepatocellular carcinoma. The management strategy for HBeAg-negative CHB patients treated with nucleos(t)ide analogues (NUCs) is a topic of concern. To observe the outcomes for this population after NUCs withdrawal, HBeAg-negative CHB patients with loss of hepatitis B surface antigen (HBsAg) or sustained undetectable HBV DNA levels who had discontinued NUCs therapy were included in the study.MethodsA total of 66 patients (2 patients with HBsAg loss and 64 patients with sustained undetectable HBV DNA levels) were examined. HBV DNA levels and alanine aminotransferase (ALT) levels were monitored regularly after discontinuation of NUCs therapy. Relapse was defined as HBV DNA levels >2,000 IU/mL while off therapy in at least two determinations more than 4 weeks apart.ResultsThe time to achieve undetectable HBV DNA levels was 14 weeks (interquartile range (IQR): 12–24 weeks). The time until consolidation therapy was 144 weeks (IQR: 96–168 weeks). No relapses occurred in either of the HBsAg loss patients. Among the 64 patients with undetectable HBV DNA levels, 19 (29.7%) patients demonstrated evidence of relapse. All the relapses occurred within 96 weeks after discontinuation. The median duration of relapse was 36 weeks (IQR: 12–48 weeks). Elevation of HBV DNA and ALT levels over baseline was only observed in 10% of the relapse patients. There were no significant differences among the baseline characteristics (sex, HBV genotype, age, or ALT level) or the time until consolidation therapy between relapse and sustained-response patients.ConclusionsNUC discontinuation is feasible after achieving undetectable HBV DNA levels in HBeAg-negative CHB patients. Prolonging the time until consolidation therapy may be a good strategy to decrease the rate of relapse. More than 96 weeks of sustained response is a predictive marker of long-term sustained response.

Nucleos(t)ide analogue (NUC) resistance is an important clinical risk resulting from long-term therapy in chronic hepatitis B (CHB) management. Discontinuation of NUCs is a feasible strategy to reduce resistance. We aimed to observe the outcomes after NUC withdrawal in HBeAg-positive CHB patients. A total of 97 patients (11 patients with HBsAg loss and 86 patients with sustained HBeAg seroconversion) were enrolled. HBV DNA levels and alanine aminotransferase (ALT) levels were monitored regularly after discontinuation. Relapse was defined as HBV DNA levels >2000 IU/mL in at least two determinations more than 4 weeks apart. HBeAg seroconversion was achieved within 48 weeks (interquartile range (IQR), 24-72 weeks). The time on consolidation therapy was 96 weeks (IQR, 84-144 weeks). No relapses occurred for HBsAg loss patients. Evidence of relapse was observed in 9.3% of HBeAg seroconversion patients. All relapse cases occurred within 48 weeks after discontinuation. The time to relapse was 33 ± 15 weeks. Elevation of HBV DNA and ALT levels over baseline were only observed in 12.5% of relapse patients. There were no significant differences in baseline characteristics (sex, HBV genotype, age or ALT levels) or time on consolidation therapy between patients with relapse or sustained response. NUC discontinuation in HBeAg-positive CHB patients is feasible after achieving HBeAg seroconversion at a minimum of 24 weeks. There is further benefit to prolonging the time on consolidation therapy to reduce relapse. More than 48 weeks of sustained response is a predictive marker for long-term sustained response.

Background & Aims: The toll-like receptor-interferon (TLR-IFN) signalling pathway plays a crucial role in HBV infection. Human leucocyte antigen (HLA) polymorphisms are associated with chronic HBV infection by genome wide association study (GWAS). We aimed to explore interaction between TLR-IFN and HLA gene polymorphisms in susceptibility of chronic HBV infection. Methods: In the Chinese Southwest Han population, 1191 chronic HBV infection patients and 273 HBV clearance were selected. A total of 39 single nucleotide polymorphism loci in 23 genes of the TLR-IFN pathway and four HLA polymorphism loci associated with chronic HBV infection identified by GWAS were selected for genotyping. SNPStats, QVALUE, and multifactor dimensionality reduction were used for statistical analysis. Results: A significant association was seen in several of the TLR-IFN pathway genes, TLR9 rs352140 (OR = 0.70, P = 0.0088), IL1B rs16944 (OR = 0.67, P = 0.016), IL12B rs3212227 (OR = 1.38, P = 0.021), IFNGR1 rs3799488 (OR = 1.48, P = 0.0048), IFNGR2 rs1059293 (OR = 0.27, P = 0.011), MX1 rs467960 (OR = 0.68, P = 0.022), as well as four loci in HLA, rs3077 (OR = 0.55, P < 0.0001), rs2856718 (OR = 0.60, P = 4e-04), rs9277535 (OR = 0.54, P < 0.0001) and rs7453920 (OR = 0.43, P < 0.0001). A synergistic relationship was seen between rs9277535 and rs16944 (0.13%), rs1143623 and rs6613 (0.10%). The combination of rs9277535 in HLA and rs16944 in IL1B was the best model to predict chronic HBV infection (testing accuracy = 0.6040, P = 0.0010, cross-validation consistency = 10/10). Conclusions: TLR-IFN pathway gene polymorphisms are associated with chronic HBV infection. Interactions with polymorphisms in these genes may be one mechanism by which HLA polymorphisms influence susceptibility to chronic HBV infection, as specific single nucleotide polymorphism combinations are highly predictive of chronic HBV infection.