Among patients with HBeAg-positive chronic hepatitis B, the rates of histologic, virologic, and biochemical improvement are significantly higher with entecavir than with lamivudine. The safety profile of the two agents is similar, and there is no evidence of viral resistance to entecavir. (ClinicalTrials.gov number, NCT00035633.).

Among patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue, the rates of histologic improvement, virologic response, and normalization of alanine aminotransferase levels were significantly higher at 48 weeks with entecavir than with lamivudine. The safety profile of the two agents was similar, and there was no evidence of viral resistance to entecavir. (ClinicalTrials.gov number, NCT00035789.).

In patients with HBeAg-positive chronic hepatitis B, 48 weeks of 10 mg or 30 mg of adefovir dipivoxil per day resulted in histologic liver improvement, reduced serum HBV DNA and alanine aminotransferase levels, and increased the rates of HBeAg seroconversion. The 10-mg dose has a favorable risk-benefit profile for long-term treatment. No adefovir-associated resistance mutations were identified in the HBV DNA polymerase gene.

One year of treatment with entecavir (0.5 mg daily) in nucleoside-naive patients with hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B (CHB) resulted in significantly improved liver histology and virological and biochemical endpoints in comparison with lamivudine. Patients who received at least 3 years of cumulative entecavir therapy in phase 3 studies and a long-term rollover study and underwent long-term liver biopsy were evaluated for improvements in histological appearance. Sixty-nine patients [50 HBeAg-positive and 19 HBeAg-negative] receiving entecavir therapy underwent longterm liver biopsy (median time of biopsy 5 6 years, range 5 3-7 years). Histological improvement was analyzed for 57 patients who had adequate baseline biopsy samples, baseline Knodell necroinflammatory scores !2, and adequate long-term biopsy samples. At the time of long-term biopsy, all patients in the cohort had a hepatitis B virus DNA level <300 copies/mL, and 86% had a normalized alanine aminotransferase level. Histological improvement (!2-point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score) was observed in 96% of patients, and a !1-point improvement in the Ishak fibrosis score was found in 88% of patients, including all 10 patients with advanced fibrosis or cirrhosis at the phase 3 baseline. Conclusion: The majority of nucleoside-naive patients with CHB who were treated with entecavir in this longterm cohort achieved substantial histological improvement and regression of fibrosis or cirrhosis. (HEPATOLOGY 2010;52:886-893)

Sustained virologic suppression is a primary goal of therapy for chronic hepatitis B (CHB). In study entecavir (ETV)-C hronic hepatitis B (CHB) affects over 350 million people worldwide. Long-term complications of infection include cirrhosis and hepatocellular carcinoma (HCC), which together cause over 500,000 deaths annually. 1,2 CHB patients with an elevated viral load (ongoing viral replication) have the highest risk of progressing to these life-threatening complications. 3,4 To avoid or minimize liver disease progression, CHB treat-

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Several types of naturally occurring pre-S mutants in sera or liver tissues in patients with chronic hepatitis B virus (HBV) infection have been identified. To clarify the prevalence and significance of emergence of pre-S mutants, 140 sera and 18 resected livers from patients with HBV were studied. Replicative status was designated as high, intermediate, and low based on the HBV-DNA levels in serum or the expression of HBV antigens in liver. In vitro transfection and Western blot analysis were performed to characterize expression and secretion of HBsAg by the mutant constructs. Five major types (I to V) of pre-S deletion mutants in serum and liver and 2 types (VI and VII) in liver were identified. Pre-S mutant was 6.4% at high replicative phase, 13% at intermediate, and 37.5% at low or nonreplicative phases in serum. In livers, the same tendency existed: pre-S2 deletion mutants emerged and prevailed at a low replicative phase in hepato- Hepatitis B virus (HBV) is a small, enveloped DNA virus that causes acute and chronic liver diseases. The majority of acute HBV infection are usually self-limited, whereas patients with chronic HBV infection usually pursue a life-long course that can be categorized into 3 phases based on the replicative status of HBV in serum and liver. [1][2][3][4][5][6][7][8][9] In the early or high replicative phase, there are high levels of hepatitis B e antigen (HBeAg), hepatitis B surface antigen (HBsAg), and HBV DNA in serum and an active replication of HBV genome with nuclear expression of core antigen (HBcAg) in liver. 3,[8][9][10] The HBsAg-expressing hepatocytes or ground glass hepatocytes (GGH) are usually singly scattered in distribution. In the intermediate or immune clearance phase, there is an HLA-restricted cytotoxic T lymphocyte (CTL) response to viral antigen-expressing hepatocytes, which may result in a decrease of HBeAg and HBV DNA in serum. In the late or nonreplicative phase, there is a low titer or absence of viremia and an integration of HBV genomes in host cells. The serum HBsAg, albeit decreased in level, usually persists for life. Contrary to that at the active replicative stage, the HBsAg-containing hepatocytes are inversely increased and clustered in groups at the late or nonreplicative stage, usually associated with an absence of intrahepatic HBcAg expression. [9][10][11] The underlying mechanism of the life-long persistence of serum HBsAg and the novel discrepancy between the levels of HBsAg in serum and liver have not yet been clarified. In the past years, many studies have documented the accumulation of pre-S1 or large surface antigen in the hepatocytes during chronic HBV infection. [12][13][14][15] The large (pre-S1), middle (pre-S2), and small (major) surface proteins have been found to be differentially expressed in hepatocytes at different stages of HBV replication. 13,14 Most liver samples from viremic carriers show a prevalence of 2 smaller surface proteins whereas the large surface antigen is the predominant intrahepatic protein in nonviremic carriers. 14 ...

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