1. Liver disease center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
2. Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment & Research, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
3. Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
4. Department of Clinical Laboratory, Shenzhen Third People's Hospital, Southern University of Science and Technology, National Clinical Research Center for Infectious Diseases, Shenzhen, 518112, PR China.
5. Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
6. Hunan Provincial Key Laboratory of Gene Diagnostic Technology, Changsha 410205, China.
*These authors have contributed equally to this work.
Background & Aims: Correlations between serum viral markers and intrahepatic cccDNA in patients undergoing long-term nucleos(t)ide analogues (NAs) treatment haven't been fully explored. In this study, we evaluate the correlation between intrahepatic cccDNA and other serum viral markers and intrahepatic HBV DNA in HBeAg positive chronic hepatitis B (CHB) patients during 60-month treatment with NAs.
Methods: Fifty-four HBeAg positive CHB patients received long-term NAs treatment were included in this study. Serial serum samples were regularly collected and quantitatively analyzed for HBsAg, HBV DNA, HBV RNA and HBcrAg. Histological samples from liver biopsy at baseline and month 60 were analyzed for intrahepatic HBV DNA and cccDNA.
Results: At baseline, serum HBV DNA plus RNA was positively associated with intrahepatic cccDNA in multivariate regression analysis (β=0.205, P<0.001). In the correlation analysis between cccDNA and serum viral markers, HBV DNA plus RNA had the highest correlation coefficient (r=0.698, P<0.001), followed by serum HBV DNA (r=0.641, P<0.001), HBV RNA (r=0.590, P<0.001), and HBcrAg (r=0.564, P<0.001). At month 60, correlations between these serum viral markers and cccDNA were not observed (P>0.05). Multivariate regression analysis showed that only the decreased HBV DNA plus RNA was positively associated with cccDNA decline (β=0.172, P =0.006). Changes of HBV DNA plus RNA (r=0.525, P=0.001) was better correlated with cccDNA decline as compared to HBV RNA (r=0.384, P=0.008), HBV DNA (r=0.431, P=0.003), and HBsAg (r=0.342, P=0.029).
Conclusions: Serum HBV DNA plus RNA better correlated with intrahepatic cccDNA than other viral makers before and during NAs treatment in HBeAg positive CHB patients.
Keywords: chronic hepatitis B, pregenomic RNA, covalently closed circular DNA, nucleos(t)ide analogues, hepatitis B surface antigen