It is generally presumed that a form of hepatitis B virus DNA, called covalently closed circular DNA (cccDNA), which hides inside the nuclei of liver cells of patients with chronic hepatitis B, cannot be reduced by antiviral treatment. The present study showed that with prolonged treatment (median period 126months), cccDNA can be markedly reduced, with 49% of liver biopsies having undetectable cccDNA. This suggests that viral replication capacity would be very low after prolonged antiviral treatment.

BackgroundMeasuring liver stiffness is becoming more popular as a non-invasive tool for assessing liver fibrosis.AimTo assess the effect of severe hepatitis B flare on liver stiffness and determine factors that correlate with liver stiffness measurements.MethodsTwenty-nine patients with severe hepatitis B flare (ALT > 10 × upper limit of normal) were followed up for 1 year. Serial transient elastography was performed at the time of flare, 3–6, and 12 months after flare.ResultsAt the time of flare, the median liver stiffness was 16.8 kPa, with no patients having normal liver stiffness (<6 kPa). There was a significant decrease in liver stiffness from baseline to 3–6 months (16.8 vs. 7.9 kPa, respectively, P < 0.001), and a further smaller decline from 3–6 to 12 months (7.9 vs. 6.9 kPa, respectively, P = 0.039). By 12 months, 10 (34%) had normalized their liver stiffness. Baseline parameters which correlated with liver stiffness include bilirubin, ALT, albumin, prothrombin time and platelet levels (all P < 0.05).ConclusionLiver stiffness was increased in patients with severe hepatitis B flares, with return to near normal levels by 6 months. Transient elastography for proper assessment of liver fibrosis should be performed at least 6 months after flare.

We aimed to determine the 2-year outcomes of entecavir followed by lamivudine in patients with undetectable viral load (<12 IU/mL) and normal alanine aminotransferase (ALT) after initial entecavir treatment for at least 6 months. Patients were randomly assigned 1:1 to continue with entecavir or switch to lamivudine. Liver biochemistry and hepatitis B virus (HBV) DNA were determined at weeks 0, 4, 12, 24, 48, 72, and 96. Mutational analysis using line-probe assay were performed at weeks 0, 24, 48, and 96 and at the time of HBV DNA relapse. There was no elevation of ALT observed in any patients up to 96 weeks. At 96 weeks of follow-up, 19/25 (76%) patients in the lamivudine arm had persistently undetectable HBV DNA, compared with 25/25 (100%) patients in the entecavir arm. Six patients in the lamivudine arm had HBV DNA >20 IU/mL, occurring at a range of 12 to 96 weeks. Of these, four patients had HBV DNA of less than 100 IU/mL during rebound (three had undetectable HBV DNA after switching back to entecavir), and the remaining two patients had HBV DNA levels of 7,973 and 699 IU/mL. Three patients (12%) had evidence of drug-resistant mutations, of which two patients had rtM204I mutation and one patient had rtM204V mutation. One of these three patients had previous lamivudine exposure before entecavir treatment and one patient had questionable drug compliance. Conclusion: Sequential therapy using entecavir followed by lamivudine resulted in virological rebound in 24% of patients after 96 weeks. Prior optimal viral suppression with entecavir did not confer any significant advantage in patients who switched to lamivudine. (HEPATOLOGY 2011;53:1148-1153 C hronic hepatitis B (CHB) affects 400 million people worldwide, constituting an important health burden in areas where hepatitis B virus (HBV) infection is endemic. Up to 40% of CHB patients may develop cirrhosis and its complications, including hepatocellular carcinoma (HCC).1 Lamivudine (LAM) was the first oral nucleoside analog available for the treatment of CHB, and is effective in retarding disease progression, including liver decompensation and HCC in both patients with cirrhosis and without cirrhosis. 2,3 Unfortunately, long-term LAM therapy is associated with high rates of drug-resistance, with 76% after 8 years of treatment. 3Previous studies have identified early viral suppression to be a predictor of long-term outcomes including the development of drug resistance. In a study of 159 hepatitis B e-antigen (HBeAg)-positive CHB patients treated with LAM, viral suppression at 24 weeks was predictive of long-term resistance risks with a median follow-up of 29 months. 4 In those patients who achieved undetectable HBV DNA by real-time polymerase chain reaction (PCR) assay at week 24, the long-term resistance risk was only 8% compared to 64% for those with HBV DNA of >4 log copies/mL. Similar findings have also been shown in other antiviral agents including adefovir (ADV) and telbivudine. 5,6