Early studies found that orthotopic liver transplantation (OLT) for hepatitis B virus (HBV)-related liver failure was associated with a very high rate of reinfection and severe and rapidly progressive liver disease, resulting in a significant decrease in graft and patient survival compared with patients transplanted for other causes of liver disease. 1,2 Various measures have been tried in an attempt to reduce the rate of reinfection. The most promising results have come from the use of long-term (Ն 6 months) high-dose hepatitis B immune globulin (HBIG). 3,4 However, this regimen is expensive, and a significant reduction in the rate of reinfection is mainly seen in patients who have nonreplicative infection pre-OLT. Reinfection despite HBIG immunoprophylaxis may be caused by inadequate neutralization of overwhelming amounts of wildtype HBV, or to breakthrough infection by immune escape mutants.The major B-cell epitopes of hepatitis B surface antigen (HBsAg) have been shown to reside in the 'a' determinant region located at amino acid positions 124-149. 5,6 This region is conformational and is thought to consist of two loops held by disulfide bridges between cysteines 124 and 137, and cysteines 138 and 147. 7 The second loop is more conserved and confers most of the antigenicity of the 'a' determinant; this loop is sometimes referred to as the major hydrophilic region (MHR). HBV can be classified into four major subtypes: adr, adw, ayr, and ayw. Antibodies to the 'a' determinant confer protection against all subtypes of HBV. 8 Mutations in the HBV S gene have been reported in OLT recipients who developed HBV reinfection despite prophylaxis with monoclonal or polyclonal hepatitis B surface antibody (anti-HBs). McMahon et al. found amino acid substitutions in the 'a' determinant in all three patients who were reinfected despite monoclonal anti-HBs prophylaxis, 9 while the incidence of mutations in the 'a' determinant in OLT recipients who were reinfected despite HBIG prophylaxis varied from 0% to 33%. 10-12 Some of these mutations, including the glycine-to-arginine substitution at codon 145, have been shown to decrease binding to monoclonal antiHBs, suggesting that the breakthrough infections were caused by immune escape mutants. 9,11,13 The number of patients cited in the above studies ranged from three to seven patients; therefore, the significance of S escape mutants in HBV reinfection post-OLT remains unclear. It is also possible that additional mutations may be present in the HBV S gene outside the 'a' determinant in patients who received polyclonal anti-HBs (HBIG). Unfortunately, there are very few data on the sequence in the rest of the S gene. In addition, to date, there are no data on the reversibility of these mutations after withdrawal of HBIG therapy.

rates of changes were found during the immune clearCross-sectional studies reported that hepatitis B core ance of chronic hepatitis B infection. Interferon therapy gene mutations are associated with active liver disease did not induce a higher rate or specific pattern of mutaand responsiveness to interferon therapy. In view of the tions in the hepatitis B core gene. Response to interferon heterogeneity in published sequences, it is not possible therapy in HBeAg positive patients was unrelated to the to tell whether the differences in sequences observed number or location of hepatitis B core gene mutations. were true mutations that developed during the course (HEPATOLOGY 1996;24:32-37.) of infection. We conducted a longitudinal study to determine the rate of hepatitis B core gene mutations and the timing of these mutations in relation to hepatitis B virus Naturally occurring mutations in the hepatitis B virus replication, activity of liver disease, hepatitis B e antigen (HBV) genome have been attributed to play a role in the (HBeAg) seroconversion, and interferon therapy. Serial activity of HBV-related liver disease and in the persistence sera from 55 patients with chronic hepatitis B infection of HBV infection. were analyzed by direct sequencing of the hepatitis BWe and others have reported that mutations in the HBV precore/core gene to identify the nucleotide and amino core gene can be frequently detected in patients with chronic acid changes that emerged during follow-up. Patients HBV infection and that these mutations were significantly who remained HBeAg positive and had normal aminoassociated with the appearance of precore stop codon mutatransferase levels (Group I) maintained higher serum tion (G-A, nucleotide 1896), hepatitis B e antigen (HBeAg) hepatitis B virus (HBV) DNA levels but significantly negativity, and active liver disease. 1-8 These findings suggest lower rates of both nucleotide and amino acid changes that mutations in the HBV core gene sequence may affect during follow-up compared with patients who remained immune clearance of HBV and activity of liver disease. HowHBeAg positive but had elevated aminotransferase levever, most reports were based on cross-sectional studies in els (Group II) and patients who cleared HBeAg (Group which sequences of individual patients were compared III). The rates of nucleotide and amino acid changes in against published sequences. In view of the heterogeneity in Groups I, II, and III patients were: 0.4 { 0.1, 1.9 { 0.3, published sequences, it is not possible to tell whether the and 2.4 { 0.4/nucleotide position/year; and 0.04 { 0.02, nucleotide or amino acid differences observed were true mu-0.21 { 0.05, and 0.38 { 0.07/codon/year, respectively. Most tations that developed in the individual patients. In a recent of the amino acid changes in Groups II and III patients study comparing the HBV core gene sequences among hepatioccurred during or shortly after flares in aminotransfertis B surface antigen positive family members, we found that ase levels, before HB...

In a previously reported randomized controlled trial of interferon-alpha (IFN-alpha) for chronic hepatitis B, we found a significant difference in response between Chinese adults with elevated vs normal pretreatment aminotransferase (ALT) levels. The aim of this study was to determine the correlation between serum hepatitis B virus (HBV) DNA levels and response to IFN therapy. HBV DNA levels in residual stored sera from patients who participated in the above trial were quantified by a branched DNA (bDNA) assay. Nominal logistic regression was used to estimate the probability of response to IFN treatment as a function of pretreatment ALT and/or HBV DNA levels. We found a significant (P < 0.01) correlation between the HBV DNA levels at midtreatment and response to IFN therapy. Response was achieved in 53% of patients who had undetectable HBV DNA levels at midtreatment but in only 17% of those who remained HBV DNA positive (P < 0.01). In contrast, the probabilities of response for patients with baseline HBV DNA levels over the range 10 to 10000 million equivalents (MEq) ml-1 were almost identical. We also found a significant correlation between the pretreatment ALT levels and response to IFN therapy. The probabilities of response for patients with pretreatment ALT levels of 500 and 100 IU l-1 were higher than for patients with normal ALT levels by two and onefold, respectively. Our findings may help to improve the cost-effectiveness of IFN therapy for chronic hepatitis B by guiding the selection of patients for therapy and in optimizing the duration of treatment for the individual patient.

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