BACKGROUND: Although nucleos(t)ide analog (NA) therapy effectively reduces the hepatitis B virus (HBV) DNA load in the serum of patients with chronic hepatitis B, it does not completely reduce the incidence of hepatocellular carcinoma (HCC). METHODS AND RESULTS: A total of 109 patients who had chronic hepatitis B and were receiving NA therapy were analyzed. Multivariate Cox regression analysis showed that age (>60 years had a hazard ratio [HR] of 2.66), FIB-4 index (an index of >2.1 had a HR of 2.57), and the presence of HBV core-related antigen (HBcrAg; HR, 3.53) during treatment were significantly associated with the development of HCC. The amount of HBV DNA and pregenomic RNA in liver were significantly higher in 16 HBcrAg-positive patients, compared with 12 HBcrAg-negative patients, suggesting active HBV replication in HBcrAg-positive livers. Hepatic gene expression profiling showed that HBV-promoting transcriptional factors, including HNF4α, PPARα, and LRH1, were upregulated in HBcrAg-positive livers. HepAD38 cells overexpressing LRH1 increased HBV replication, characterized by higher HBV DNA and pregenomic RNA levels, during long-term exposure to entecavir. Conversely, overexpression of precore/core in HepG2 cells increased levels of these transcriptional factors. Metformin efficiently repressed HBV replication in primary human hepatocytes. CONCLUSIONS: Modulating HBV transcriptional factors by metformin in combination with NA therapy would potentiate anti-HBV activity and reduce the incidence of HCC in HBcrAg-positive patients.
BACKGROUND: Although nucleos(t)ide analog (NA) therapy effectively reduces the hepatitis B virus (HBV) DNA load in the serum of patients with chronic hepatitis B, it does not completely reduce the incidence of hepatocellular carcinoma (HCC). METHODS AND RESULTS: A total of 109 patients who had chronic hepatitis B and were receiving NA therapy were analyzed. Multivariate Cox regression analysis showed that age (>60 years had a hazard ratio [HR] of 2.66), FIB-4 index (an index of >2.1 had a HR of 2.57), and the presence of HBV core-related antigen (HBcrAg; HR, 3.53) during treatment were significantly associated with the development of HCC. The amount of HBV DNA and pregenomic RNA in liver were significantly higher in 16 HBcrAg-positive patients, compared with 12 HBcrAg-negative patients, suggesting active HBV replication in HBcrAg-positive livers. Hepatic gene expression profiling showed that HBV-promoting transcriptional factors, including HNF4α, PPARα, and LRH1, were upregulated in HBcrAg-positive livers. HepAD38 cells overexpressing LRH1 increased HBV replication, characterized by higher HBV DNA and pregenomic RNA levels, during long-term exposure to entecavir. Conversely, overexpression of precore/core in HepG2 cells increased levels of these transcriptional factors. Metformin efficiently repressed HBV replication in primary human hepatocytes. CONCLUSIONS: Modulating HBV transcriptional factors by metformin in combination with NA therapy would potentiate anti-HBV activity and reduce the incidence of HCC in HBcrAg-positive patients.
Authors: Carla S Coffin; Scott K Fung; Fernando Alvarez; Curtis L Cooper; Karen E Doucette; Claire Fournier; Erin Kelly; Hin Hin Ko; Mang M Ma; Steven R Martin; Carla Osiowy; Alnoor Ramji; Edward Tam; Jean Pierre Villeneuve Journal: Can Liver J Date: 2018-12-25
Authors: Anna Kramvis; Kyong-Mi Chang; Maura Dandri; Patrizia Farci; Dieter Glebe; Jianming Hu; Harry L A Janssen; Daryl T Y Lau; Capucine Penicaud; Teresa Pollicino; Barbara Testoni; Florian Van Bömmel; Ourania Andrisani; Maria Beumont-Mauviel; Timothy M Block; Henry L Y Chan; Gavin A Cloherty; William E Delaney; Anna Maria Geretti; Adam Gehring; Kathy Jackson; Oliver Lenz; Mala K Maini; Veronica Miller; Ulrike Protzer; Jenny C Yang; Man-Fung Yuen; Fabien Zoulim; Peter A Revill Journal: Nat Rev Gastroenterol Hepatol Date: 2022-07-20 Impact factor: 73.082