Editorial Board: Emmet B. Keeffe, MD (Chair);

Anna Lok, MD; Brian McMahon, MD; Albert Min, MD; Myron Tong, MD; Naoky Tsai, MD; Bruce Tung, MD

HBV Watch™

Timely Information for Practicing Physicians

 

JANUARY 2006

Noninvasive model to predict significant fibrosis. Zeng and colleagues constructed a model and scoring system for patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B to discriminate between those with and those without significant fibrosis. Data from 200 consecutive patients were used to construct the model, and the validation group consisted of 172 patients. Multivariate analysis identified alpha-2-macroglobulin concentration, age, and gamma glutamyl transpeptidase and hyaluronic acid concentrations as independent predictors of fibrosis. These factors were used to construct the scoring system. A cutoff score of <3 was found to exclude the presence of significant fibrosis with high accuracy in 43 patients (21.5%) in the training group (86.1% negative predictive value [NPV], 70.1% positive predictive value [PPV], 94.8% sensitivity) and 22 patients (12.8%) in the validation group (90.9% NPV, 64.7% PPV, 98.0% sensitivity). A cutoff score of >8.7 identified the presence of significant fibrosis in 41 patients (20.5%) in the training group (91.1% PPV, 51.6% NPV, 95.2% specificity) and 39 patients (22.7%) in the validation group (84.8% PPV, 52.4% NPV, 90.4% specificity). The application of this model may decrease the need for liver biopsy in about one third of patients with HBeAg-positive chronic hepatitis B. (Zeng M-D, et al. Hepatology 2005;42:1437–1445.)

 

Timing of adefovir dipivoxil (ADV) therapy for lamivudine-resistant hepatitis B virus (HBV). The clinical benefit of long-term lamivudine therapy is limited by the emergence of resistant mutant strains leading to recurrence and clinical worsening of hepatitis B. However, the oral nucleotide analog ADV is now available to manage the emergence of lamivudine-resistant strains. Lampertico and others initiated ADV therapy in 78 patients with HBeAg-negative chronic hepatitis B who were undergoing treatment with lamivudine at the time of the development of genotypic resistance (with the presence of moderate levels of HBV DNA [3 to 6 log10 copies/mL] and persistently normal alanine aminotransferase [ALT] levels; n = 28) or at the time of phenotypic resistance (with the presence of high levels of HBV DNA [> 6 log10 copies/mL] and high ALT levels; n = 46). ADV 10 mg/day was added to ongoing lamivudine therapy and administered for 2 years. ALT levels remained persistently normal in all patients in the genotypic resistance group and normalized at rates of 50% at month 6, 72% at month 12, and 93% at month 24 in the phenotypic resistance group. By month 3, HBV DNA levels had become undetectable in all patients in the genotypic resistance group compared with 46% of patients in the phenotypic resistance group (P < 0.0001). The 2-year virologic response rates were 100% and 78% in the genotypic and phenotypic resistance groups, respectively (P < 0.0001). No ADV-related adverse events were reported and none of the patients developed ADV resistance. These data suggest that ADV should be added to lamivudine therapy as soon as genotypic resistance is detected. (Lampertico P, et al. Hepatology 2005;42:1414–1419.)

 

The influence of genotype on virologic outcomes. Kobayashi and associates reported clinical data from patients with chronic hepatitis B who had HBV genotype A (n = 87), B (n = 413), or C (n = 3,389) infection. These patients had been identified in the Department of Gastroenterology at Toranomon Hospital in Tokyo, Japan between April 1973 and December 2003. At 5 years’ follow-up, hepatitis B surface antigen (HBsAg) was cleared from a greater percentage of patients with genotype A than with genotype B or C (P = 0.0395) and HBeAg was cleared from a greater percentage of patients with genotype B than with genotype A or C (P = 0.0002). Among 45 patients with genotype A who were followed for ≥3 years, HBeAg was seen more frequently (P = 0.0002), and levels of HBV DNA were higher (P = 0.001) in 26 patients with biopsy-proven chronic hepatitis than in 19 asymptomatic carriers. In addition, among patients with genotype A, decreases in HBV DNA serum levels occurred less frequently in the patients who remained HBeAg-positive than in those who seroconverted or remained HBeAg-negative. Thus, the clearance of HBsAg occurred more frequently in patients infected with genotype A than with genotype B or C, and the clearance of HBeAg occurred more frequently in patients infected with genotype B than with genotype A or C, suggesting that patients infected with genotype C may have the least favorable outcomes. (Kobayashi M, et al. J Med Virol 2006;78:60–67.)

 

Different mechanisms of HBeAg seroconversion. While the detailed mechanisms of HBeAg seroconversion have not been fully clarified, the phenomenon has been reported to be associated with mutations in the HBV genome. For example, the G-to-A mutation at nucleotide 1896 in the precore region (G1896A) converts codon 28 for tryptophan to a stop codon and is associated with the loss of HBeAg. In the core promoter, a double mutation (A1762T and G1764A) has been shown to reduce the synthesis of HBeAg by suppressing the transcription of precore mRNA. In addition, the HBV core-related antigen is expressed on the HBeAg and the amount of HBV core-related antigen in the serum reflects the concentration of HBeAg in the serum. Misawa and colleagues retrospectively identified 24 patients with HBV who had been followed from January 1985 to June 2001 at the Shinshu University Hospital in Nagano, Japan, and who had seroconverted from HBeAg-positivity to anti-HBe-positivity. Chronologic changes in levels of HBV DNA and HBV core-related antigen, and HBV genome mutations were evaluated. None of the patients received nucleotide analogs during the follow-up period. Among the 24 patients, six showed continuous loss of HBV DNA in the serum after seroconversion (the inactive replication group) and 18 did not lose HBV DNA after seroconversion (the active replication group). A low serum level of HBV core-related antigen was found in both the inactive and active replication groups after seroconversion. Precore and core promoter mutations were more frequent in the active replication group. The authors concluded that seroconversion in the inactive replication group was due to a decrease in viral replication while seroconversion in the active replication group was due to a decrease in HBeAg production due to mutations in the core region of the virus. (Misawa N, et al. J Med Virol 2006;78:68–73.)

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