Siu-Man Sum

Clinical outcome and virologic profiles of severe hepatitis B exacerbation due to YMDD mutations

BACKGROUND/AIMS To study the outcome and the virologic profiles of severe hepatitis exacerbations due to YMDD mutants in lamivudine-treated patients. METHODS Eighteen lamivudine-treated patients with severe hepatitis exacerbations due to YMDD mutants were recruited. Laboratory and clinical parameters were monitored. Viral genotypes and YMDD mutations were determined. RESULTS None of the 18 patients had YMDD wild-type during exacerbations. Three (17%) and 15 (83%) patients had genotypes B and C, respectively. Elevated bilirubin levels and prolonged prothrombin time were found in 11 (61%) and six patients (33%) respectively. Three patients (17%) had adverse outcome with the development of ascites and/or encephalopathy. One of these patients required liver transplantation and one died. Both patients had evidence of cirrhosis before treatment and hepatitis B e antigen (HBeAg) seroreversion from anti-HBe positivity. The remaining 16 patients (89%) have no evidence of pre-existing cirrhosis. Thirty seven percent of patients had normal alanine aminotransferase levels at the last follow-up. The median HBV DNA level at the last follow-up was significantly lower than the pre-treatment level (P=0.009). CONCLUSIONS Though the majority of patients with severe hepatitis exacerbations due to YMDD mutants had uneventful course, early liver transplantation should be considered in patients with pre-existing cirrhosis and HBeAg seroreversion.

Longitudinal Study of Hepatitis Activity and Viral Replication before and after HBeAg Seroconversion in Chronic Hepatitis B Patients Infected with Genotypes B and C

ABSTRACT The aims of this study were to compare chronic hepatitis B (CHB) patients with genotypes B and C for the probability of HBeAg seroconversion, hepatitis activity, and viral replication before and after HBeAg seroconversion and to compare the prevalence of core promoter and precore mutations. A total of 180 asymptomatic Chinese patients with CHB were monitored for a median of 53.8 months, and 38 patients with cirrhosis-related complications were studied. Hepatitis B virus (HBV) DNA levels were measured in 16 patients with HBeAg seroconversion at 3 months before, during, and 3 months after HBeAg seroconversion and in all patients at the last follow-up. Hepatitis B genotypes and core promoter and precore mutations were determined. Compared to patients with genotype C (n = 109), patients with subtype Ba (n = 69) had a higher rate of anti-HBe positivity on presentation (P = 0.05). HBeAg-positive patients with subtype Ba had a higher cumulative rate of HBeAg seroconversion than patients with genotype C (P = 0.02). However, there were no differences between the two groups with regard to the median HBV DNA levels before, during, and after HBeAg seroconversion; the probability of having persistently normal or elevated aminotransferase levels; and the median HBV DNA levels and liver biochemistry at the last follow-up. There was no difference in the prevalence of genotypes and core promoter and precore mutations between patients with and without cirrhosis-related complications. Though patients with subtype Ba had earlier HBeAg seroconversion, the liver biochemistry, HBV DNA levels in different phases of the disease, and the probability of development of cirrhosis-related complications were the same with genotypes Ba and C.

Hepatic necroinflammation and fibrosis in patients with genotypes Ba and C, core‐promoter and precore mutations

Summary.  The role of infection with hepatitis B virus (HBV) genotypes on liver histology is largely unknown. The aim of study was to investigate the relationships between HBV genotypes (B, C), core‐promoter (CP) and precore mutants and liver histology in 66 patients. Liver biopsies were scored by histologic activity index (HAI). HBV genotypes were determined by enzyme‐linked immunosorbent assay (ELISA). Eighteen (27.3%) and 48 patients (72.7%) had genotype B (all were subtype Ba) and C, respectively. Forty‐seven (71.2%) and 27 (40.9%) had CP and precore mutations, respectively. Patients with genotype C compared with subtype Ba had higher median scores of HAI‐necroinflammation (HAI‐NI) (7 vs 3), HAI‐fibrosis (HAI‐F) (1 vs 0) and total HAI (8.5 vs 3) (all P <  0.03). Patients with CP mutations compared with wild‐type had higher median scores of HAI‐NI (7 vs 3), HAI‐F (3 vs 0) and total HAI (9 vs 3) (all P <  0.03). Forty patients (83.5%) with genotype C had CP mutations. Age and alanine aminotransferase levels were positively correlated with HAI scores while albumin levels were negatively correlated (P < 0.01 for all, except albumin levels and HAI‐F, P = 0.08). There was no association between precore mutations and HAI scores. Multivariate analysis indicated that higher alanine aminotransferase (ALT) levels were associated with higher HAI scores (P < 0.04) and CP mutations were associated with higher HAI‐NI (P = 0.034), but not with HAI‐F score (P = 0.3). CP mutations were associated with more severe necroinflammation. The association between genotype C and poor histology was probably because of the association between genotype C and CP mutations.

HBsAg Seroclearance in Chinese Patients Receiving Lamivudine Therapy for Chronic Hepatitis B Virus Infection

ABSTRACT We report two Chinese patients in whom lamivudine treatment resulted in HBsAg seroclearance. One patient received lamivudine, and another patient received 12-week famciclovir treatment followed by lamivudine. Lamivudine was maintained after HBeAg seroconversion. These two patients lost HBsAg at 24 and 27 months (ages, 23 and 19.3 years, respectively) and developed measurable titer of anti-HBs after 65 and 71 months of therapy, respectively. The liver biochemistry was normal after HBeAg seroconversion. The serum hepatitis B virus (HBV) DNA levels were undetectable (<200 copies/ml) both at the time of HBeAg seroconversion and at the last follow-up. Liver biopsy of one patient showed nearly normal histology, with undetectable intrahepatic total HBV DNA and covalently closed circular DNA. In conclusion, lamivudine therapy can result in HBsAg seroclearance at an early age even though the phenomenon is rare.

Impact of precore and core promoter mutations on hepatic histology in patients with chronic hepatitis B

Background:  The details of liver histology of patients with precore and core promoter mutations are still not clear.

Determinants for the Occurrence of Acute Exacerbation of Hepatitis B Virus Infection in Chinese Patients after HBeAg Seroclearance

ABSTRACT This study was performed to determine the factors for predicting the occurrence of acute exacerbation of hepatitis B virus infection in HBeAg-negative patients. Two hundred and sixteen patients with known times of HBeAg seroclearance were recruited. Liver biochemistry and virologic markers were monitored. Precore and core promoter mutations were determined by a line probe assay. The median age at HBeAg seroclearance was 34.5 years. The median follow-up duration was 26.4 months. Fifty-six (27.9%) patients had acute exacerbations. By Cox regression analysis, male gender, older age, and core promoter mutations at the time of HBeAg seroclearance were independently associated with the occurrence of acute exacerbation after HBeAg seroclearance (P = 0.025, 0.018, and 0.001, respectively). Fourteen (7.0%) patients had HBeAg seroreversion within a median follow-up period of 11.6 months after HBeAg seroclearance. By Cox regression analysis, older age at HBeAg seroclearance was independently associated with the chance of HBeAg seroreversion (P = 0.01). We concluded that male patients with core promoter mutations and delayed HBeAg seroclearance had a higher cumulative chance of acute exacerbation in the HBeAg-negative phase. Patients with delayed HBeAg seroclearance had a higher frequency of HBeAg seroreversion.