Patients in the low replicative phase are believed to have good prognosis. There is increasing evidence that a fourth phase, the immune escape phase, is also common in Asian patients in association with evolution of HBeAg negative mutant forms of HBV.21 These patients have elevated HBV DNA with intermittent elevated ALT levels. Similar to the reports in Europe, HBeAg-negative patients with persistent viremia and biochemical activity have a higher risk of cirrhotic complications and HCC.22 The presence of viral mutations and immune escape has cast doubt on the importance

of HBeAg seroconversion. Previous reports suggested that approximately one-third of patients would develop HBeAg reversion or disease reactivation within 6 months after HBeAg seroconversion.23,24 PD98059 nmr HBV DNA usually falls to below 20 000 IU/mL after HBeAg seroconversion, but no clear HBV DNA level can predict viral reactivation.25,26 With long-term follow-up studies, we now learn that the long-term prognosis is better if the age ABT-263 of HBeAg seroconversion is younger. In a long-term follow-up of

64 untreated Caucasian pediatric chronic hepatitis B patients who cleared HBeAg without liver cirrhosis, 59 (92%) of them had stable disease.27 Among 408 Taiwanese patients who had no evidence of cirrhosis at the time of HBeAg seroconversion, the 15-year cumulative incidences of HBeAg-negative hepatitis, cirrhosis and HCC among patients who seroconverted at age younger than 30 versus those seroconverted after age 40 were 31.2% vs 66.7% (P < 0.001), 3.7% vs 42.9% (P < 0.001) and 2.1% vs 7.7% (P = 0.29), respectively.28 The age of HBeAg seroconversion is influenced by the HBV genotype. Patients infected with HBV genotype A, B, D and F tend to undergo HBeAg seronconversion at a much earlier age than those infected with genotype C HBV.29 上海皓元 Furthermore, patients infected with genotype C HBV also tend to have more frequent hepatitis B reactivation after HBeAg seroconversion than those infected

with genotype B HBV.30 All these findings have provided supportive evidence on the higher rate of HBeAg-negative active hepatitis,31 worse liver histology32,33 and higher risk of HCC34,35 among patients infected with genotype C HBV. In the last decade, HBV DNA could only be measured by the relatively insensitive non-polymerase chain reaction (PCR) based assays with a lower limit of detection at approximately 20 000 IU/mL.36 The lack of sensitivity of the HBV DNA assays precluded accurate assessment of the viral load among HBeAg-negative patients who tend to have lower viremia than their HBeAg-positive counterparts.37 The development of real-time PCR based assays has brought the sensitivity of HBV DNA measurement down to lower than 20 IU/mL (or 100 copies/mL). In several recent histologic series, HBV DNA lower than 2000 IU/mL were associated with mild histologic necroinflammation and fibrosis among HBeAg-negative patients.