Hepatitis B Virus (HBV) Core-Related Antigen During Nucleos(t)ide Analog Therapy Is Related to Intra-hepatic HBV Replication and Development of Hepatocellular Carcinoma

Abstract

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.

Impact of hepatitis B core‐related antigen on the incidence of hepatocellular carcinoma in patients treated with nucleos(t)ide analogues

“…Therefore, patients who maintain high HBcrAg levels, irrespective of the NA treatment status, would be expected to harbor increased intrahepatic cccDNA levels and to remain in a state of higher upstream HBV translational activity due to NA activity. However, other studies have observed decreases in HBV RNA and intrahepatic cccDNA attributed to NA administration, and with reduced HBcrAg levels have exhibited reductions in cccDNA levels and translational activity, as well as HBV RNA production . Although the mechanisms underlying the relationship between these phenomena and the development of HCC are unclear, references to some published reports can be made.…”

“…Although the mechanisms underlying the relationship between these phenomena and the development of HCC are unclear, references to some published reports can be made. For example, Honda et al reported elevated HBx RNA levels in patients with elevated HBcrAg levels . HBx protein, a regulator of HBV replication, is essential for cccDNA translation and viral replication and also contributes to hepatocyte function via different mechanisms .…”

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection

“…It has been demonstrated that the serum HBcrAg levels may partly reflect the amount of intrahepatic DNA and cccDNA in hepatocytes especially in HBeAg-positive patients. 228,229 It might also be helpful in defining the phase of chronic HBV infection, especially in HBenegative patients, as well as predicting the long-term HCC risk. 228,[230][231][232] Some studies suggest that this biomarker can be also used to monitor NA or PegIFNa based treatments and predicting therapeutic efficacy including the risk of relapse after stopping NAs.…”

“…228,229 It might also be helpful in defining the phase of chronic HBV infection, especially in HBenegative patients, as well as predicting the long-term HCC risk. 228,[230][231][232] Some studies suggest that this biomarker can be also used to monitor NA or PegIFNa based treatments and predicting therapeutic efficacy including the risk of relapse after stopping NAs. [233][234][235] Most of these studies were performed in Japan, and large correlation studies derived from Caucasian patients are lacking.…”

Metformin and the incidence of viral associated cancers in patients with type 2 diabetes

“…It is hypothesized metformin may induce antineoplastic properties by influencing the same ATM pathway as oncoviruses, stimulating AMPK activation thus limiting the activity of the PI3K/AKT/mTOR signaling pathway and down regulating cellular proliferation . Indeed, preclinical studies have shown these effects in both cervical cancer and HPV associated oral squamous carcinoma models, as well as HBV infected cell lines in which metformin modulated HBV transcriptional factors . Despite this, it is unclear whether these chemoprotective properties of metformin can be translated at the population level.…”