Resistance of ground glass hepatocytes to oral antivirals in chronic hepatitis B patients and implication for the development of hepatocellular carcinoma.

Hung-Wen Tsai,Yih-Jyh Lin,Shih-Huang Chan,Wenya Huang,Pin-Nan Cheng,Ting-Tsung Chang,I-Chin Wu,Han-Chieh Wu,Chia-Jui Yen,Ih-Jen Su

doi:10.18632/oncotarget.8388

Abstract

Ground glass hepatocytes (GGHs) have been shown to predict the development of hepatocellular carcinoma (HCC). Type I GGH and type II GGH harbor hepatitis B virus (HBV) pre-S1 and pre-S2 deletion mutants, respectively. Whether anti-HBV therapy can inhibit the expression of GGHs and potentially reduce HCC development is explored in this study. Two sets of liver specimens were included: the first contained 31 paired biopsy specimens obtained from chronic HBV patients receiving oral nucleos(t)ide analogue (NA) treatment; the second contained 186 resected liver tissues obtained from HBV-related HCC patients receiving surgery: 82 received NA before surgery and 104 did not. Compared with the baseline biopsy specimens, type I (P=0.527) and type II GGH (P=0.077) were not significantly decreased after 48 weeks of NA treatment in the first set of patients. In the second set, despite suppression of viral load (P<0.001) and periportal necrosis (P=0.006) in treated patients, GGH (P=0.594), cccDNA (P=0.172) and serum pre-S mutants (p=0.401) were not significantly suppressed. A significant decrease of type I (P=0.049) and type II GGH (P=0.029) could only be observed in patients after long duration of treatment (median duration: 4.3 years). In the treated patients, the persisted type II GGH remained an independent variable associated with decreased local recurrence-free survival of HCC (P=0.019) as in non-treated patients (P=0.001). In conclusion, the persistence of GGHs could explain the residual risk of HCC development under anti-HBV treatment. Therefore, intrahepatic GGHs and pre-S mutant are potential additional targets for HCC prevention in patients already receiving anti-HBV treatment.

Highlights

The majority of hepatocellular carcinoma (HCC) cases are attributable to either hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
We first confirmed the resistance of Ground glass hepatocytes (GGHs) to nucleos(t)ide analogue (NA) treatment in patients with paired liver biopsy samples
Since GGH is one of the factors that are responsible for hepatocarcinogenesis, we wanted to investigate whether antiviral treatments can suppress GGH formation in patients with chronic HBV infection

Summary

Introduction

The majority of hepatocellular carcinoma (HCC) cases are attributable to either hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Oral nucleos(t) ide analogues (NAs), including lamivudine, adefovir, entecavir, telbivudine, tenofovir are currently used to treat chronic HBV infection [1]. Observations revealed that NA treatment significantly reduces the incidence of HCC [2] and lowers HCC recurrence rate [3]. Short-term treatment could result in the suppression of viral replication and improvements of liver necroinflammation. Long-term treatment for at least 3 years could result in no worsening of the Knodell fibrosis score in most patients [4]. NAs are effective to suppress HBV replication and reduce HCC development, a high proportion, up to 45%, of patients still suffered from HCC recurrence after surgery despite anti-HBV therapy [3]. The intrahepatic covalently closed circular DNA (cccDNA) was found to persist after oral antiviral NA [5], explaining the persistence of HBV infection

Methods

Results

Conclusion