9%) receiving peginterferon alfa-2a (alone or in combination with lamivudine) experienced HBsAg seroconversion and were considered cured. This dogma was challenged when we discovered two patients who experienced HBsAg seroconversion after they had been treated with peginterferon but continued to be viremic. Strikingly, one of the patients subsequently experienced an episode of hepatitis relapse, which was found to be HBsAg-negative CHIR99021 hepatitis. Here we analyze the genetic and phenotypic changes in the S gene sequences

of these two patients. ALT, alanine aminotransferase; anti-HBs, antibody to hepatitis B surface antigen; CMV, cytomegalovirus; DAPI, 4′,6-diamidino-2-phenylindole; GP27, glycoprotein 27; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; MAHBs, monoclonal antibody against Obeticholic Acid HBsAg; mRNA, messenger RNA; P24, protein 24; PCR, polymerase chain reaction; PEG-IFN, peginterferon; Tris-HCl, trishydroxymethylaminomethane hydrochloride. From May 2002 to November 2009, 245 patients received anti-HBV therapy with peginterferon at the Liver Research Center of Chang Gung Memorial Hospital (Taipei, Taiwan). HBsAg

seroclearance was documented in eight patients (3.27%). Two remained viremic according to standard HBV DNA assays. These two patients were included in this study. Patient 1 was a 57-year-old male who was negative for HBeAg. A liver biopsy sample showed an Ishak histology activity index of 8 and a fibrosis score of 4. Immunohistochemistry revealed tissue positive for HBV core antigen and HBsAg. He had genotype B HBV. Peginterferon alpha-2a (180 μg/week) was given to the patient. The treatment course is plotted in Fig. 1. After 48 weeks of treatment, the alanine aminotransferase (ALT) level was 44 U/L; check details the patient was negative for HBsAg and positive for antibody to hepatitis B surface antigen (anti-HBs) according to a radioimmunoassay

at the end of the treatment. However, the HBV DNA level remained 2.73 × 104 IU/mL. After informed consent was obtained, serum samples were used for quantitative HBsAg assays and HBV S gene sequence analysis. Patient 2 was a 20-year-old male who was positive for HBeAg. A liver biopsy sample showed an Ishak histology activity index of 7 and a fibrosis score of 2. Immunohistochemistry revealed tissue positive for HBV core antigen and HBsAg. He also had genotype B HBV. The serum HBV DNA level was 1.21 × 107 IU/mL, and the ALT level was 706 U/L before the treatment. Peginterferon alfa-2b (120 μg/week) was given to the patient. The clinical course is plotted in Fig. 2. HBeAg seroclearance was not achieved during the clinical course. However, he became negative for HBsAg and subsequently became positive for anti-HBs according to a radioimmunoassay at the end of treatment. Notably, the HBV DNA level remained 4.12 × 104 IU/mL. After informed consent was obtained, serum samples were used for quantitative HBsAg assays and HBV S gene sequence analysis.