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Background and Aims Chronic hepatitis B (CHB) can lead to hepatocellular carcinoma (HCC). While both tenofovir disoproxil (TDF) and entecavir (ETV) have been shown to reduce the risk of HCC, their comparative effectiveness is unclear. We estimated the comparative effectiveness of these two agents in reducing the risk of HCC in patients with CHB, through a systematic review and meta‐analysis. Approach and Results We searched multiple electronic databases from January 1, 1998, to October 31, 2019, for randomized controlled trials and observational comparative effectiveness studies in adults with CHB treated with ETV compared to TDF, reporting the incidence of HCC (minimum follow‐up 12 months). Primary outcome was incidence of HCC, calculated as incidence rate ratio (IRR) with 95% confidence interval (CI, unadjusted analysis) and hazard ratio (HR) with 95% CI (adjusted analysis, where reported). Of 1,971 records identified, 14 studies (263,947 person‐years) were included for quantitative analysis. On unadjusted meta‐analysis of 14 studies, the risk of HCC was not statistically different between ETV and TDF (IRR, 1.28; 95% CI, 0.99‐1.66). When using available adjusted data (multivariate or propensity‐matched data), the risk of HCC among patients treated with ETV was 27% higher when compared to TDF (seven studies; 95% CI, 1.01‐1.60, P = 0.04). Additional analysis of adjusted data when separately reported among patients with cirrhosis demonstrated an adjusted HR of 0.90 (95% CI, 0.66‐1.23), suggesting no difference between ETV‐treated and TDF‐treated groups. The overall confidence in estimates was very low (observational studies, high heterogeneity). Conclusions TDF may be associated with lower risk of HCC when compared to ETV.

Summary Background Nonalcoholic steatohepatitis (NASH) is a common cause of chronic liver disease. There is a major need to understand the efficacy of different pharmacological agents for the treatment of NASH. Aim To assess the relative rank‐order of different pharmacological interventions in fibrosis improvement and NASH resolution. Methods A comprehensive search of several databases was conducted by an experienced librarian. We included randomised controlled‐trials (RCTs) comparing pharmacological interventions in patients with biopsy‐proven NASH. The primary outcome was ≥1 stage improvement in fibrosis. The secondary outcome was NASH resolution. Results A total of 26 RCTs with 23 interventions met the eligibility criteria. Lanifibranor and obeticholic acid had the highest probability of being ranked the most effective intervention for achieving ≥1 stage of fibrosis improvement (SUCRA 0.78) and (SUCRA 0.77), respectively. For NASH resolution, semaglutide, liraglutide and vitamin E plus pioglitazone had the highest probability of being ranked the most effective intervention for achieving NASH resolution (SUCRA 0.89), (SUCRA 0.84) and (SUCRA 0.83), respectively. Lanifibranor, obeticholic acid, pioglitazone and vitamin E were significantly better than placebo in achieving ≥1 stage of fibrosis improvement. Conversely, semaglutide, liraglutide, vitamine E plus pioglitazone, pioglitazone, lanifibranor and obeticholic acid were significantly better than placebo in achieving NASH resolution. Conclusion These data provide relative rank‐order efficacy of various NASH therapies in terms of their improvements in liver fibrosis and NASH resolution. Therapies that have been shown to improve NASH resolution may be combined with therapies that have an antifibrotic effect to further boost treatment response rate in future.

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Previous studies have established a correlation between increasing chronological age and risk of cirrhosis. This pattern raised interest in the role of telomeres and the telomerase complex in the pathogenesis of liver fibrosis and cirrhosis. This review aims to summarize and analyze the current understanding of telomere regulation in hepatocytes and lymphocytes and how this ultimately relates to the development of liver fibrosis. Notably, in chronic viral hepatitis, telomere shortening in hepatocytes and lymphocytes occurs in such a way that may promote further viral replication while also leading to liver damage. However, while telomere shortening occurs in both hepatocytes and lymphocytes and ultimately results in cellular death, the mechanisms of telomere loss appear to be initiated by independent processes. The understanding of telomere maintenance on a hepatic and immune system level in both viral and non-viral etiologies of cirrhosis may open doors to novel therapeutic strategies.