Efficacies of one year nucleos(t)ide analogue therapy in intrahepatic HBV DNA and covalently closed circular DNA reduction

Abstract

BACKGROUND AND AIMS: Nucleos(t)ide analogues (NA) are effective in the reduction of HBV viral load. We aimed to investigate their 1 year effects on intrahepatic total HBVDNA and covalently closed circular DNA (cccDNA) levels. METHODS: We recruited from our center 124 patients who had baseline and year 1 liver biopsies and taken part in three phase III international clinical trials (BEHoLD [entecavir vs. lamivudine], GLOBE [telbivudine vs. lamivudine] and QUASH [clevudine vs. adefovir]). These NA were categorized into the more potent group (entecavir, telbivudine, and clevudine; 36 HBeAg-positive and 35 HBeAg-negative patients) and less potent group (lamivudine and adefovir; 31 HBeAg-positive and 22 HBeAg-negative patients). Intrahepatic HBV DNA and cccDNA were measured by real-time PCR. Serum HBV DNA was measured by the COBAS TaqMan HBV Monitor Test. RESULTS: After 1 year of NA therapy, in the HBeAg-positive patients, the more potent NA caused a greater mean reduction of serum HBV DNA than the less potent group (6.7 vs. 5.0 logs, respectively; P = 0.005). In the HBeAg-negative patients, there was no significant difference in serum HBV DNA reduction between the more potent and less potent groups (4.9 vs. 4.7 logs, respectively, P = NS). There were no significant differences between the more potent and less potent groups in the mean reduction of intrahepatic total HBV DNA (2.1 vs. 1.8 logs respectively in HBeAg-positive patients and 1.4 vs. 1.6 logs respectively in HBeAg-negative patients) and cccDNA (1.1 vs. 0.9 logs respectively in both HBeAg-positive and HBeAg-negative patients; all P = NS). Although 88/124 (71%) patients had undetectable serum HBV DNA at year 1, all patients had detectable intrahepatic total HBV DNA. Only five patients (all HBeAg-negative) had undetectable cccDNA after 1 year; nine patients had an increase in cccDNA. CONCLUSIONS: 71% of patients had undetectable serum HBV DNA after 1 year, but intrahepatic total HBV DNA and cccDNA, though reduced, were still detectable in the majority of patients. This suggests that even when highly potent NA are used, a longer term of NA therapy is needed to reduce intrahepatic HBV DNA.