Substantial loss of intrahepatic HBV cccDNA during antiviral combination therapy translates into long-term clinical benefit

Background/aims: The aim of the study was to determine the virological, serological, and histological outcome, including cccDNA, in chronic Hepatitis B (CH-B) patients after 48 weeks of pegylated interferon (PEG-IFNalpha2b) and adefovir (ADV) combination therapy (year-1-data): Hepatology2006;44:675–684), followed by 96 weeks of ADV mono therapy. Here we report the final analysis of the study after 144 weeks of antiviral treatment.

Methods: 26 patients received a 48 week course of PEG-IFNalpha-2b (1.5µg/kg) and ADV (10mg) followed by 96 weeks of ADV. 21/26 patients reached the end of the three year course and from 16 patients triplet biopsies (baseline, week 48 and week 144) were obtained.

Results: ALT normalised in 95%, median HBV-DNA serum level decreased 4-log and HBV-DNA negativity (LLoD 100 copies/ml) was reached in 43% of the patients at week 144. 2 patients developed ADV resistant viral strains during the third year, and two out of 4 patients which seroconverted HBsAg to anti-HBs-antibodies within the first year of combination therapy, lost HBsAbs during the third year of therapy. Interestingly, 85% (11/13) of HBeAg positive patients showed loss of HBeAg (including 5 HBeAg seroconverters to anti HBe antibodies). Mean total intrahepatic HBV-DNA dropped significantly from 692 and 18,4 copies/cell (baseline) to 0,87 and 0,14 copy/cell (week 144) for HBeAg positive (p=0,008) and HBeAg negative (p=0,016) patients, respectively. cccDNA dropped from 3,3 and 0,2 copies/cell at baseline to 0,08 and 0,01 copies/cell for HBeAg positive (p=0,025) and negative patients (p=0,016). Interestingly, the median ratio of total HBV-DNA and cccDNA changed significantly (p=0,041) during therapy (baseline vs. week 144,) indicating that not only the amount but also the transcriptional activity of cccDNA was reduced during the course of therapy. Furthermore, we observed a significant reduction in both liver inflammation (8/16, p=0,043) and fibrosis (11/16, p=0,027, Ishak).

Conclusions: 48 weeks of combination therapy with PEG-IFNalpha-2b and ADV followed by 96 weeks of ADV mono-therapy led to substantial loss of intrahepatic HBV-DNA, cccDNA and of cccDNA replicative activity and translated into long-term clinical benefit