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Background. In Japan, there are few studies of long-term (more than 1 month)interferon (IFN) therapy for chronic hepatitis B (CHB). In this retrospective study, we investigated the efficacy and predictors of response to 6-month IFN therapy. Methods. We analyzed 66 Japanese patients with CHB who were treated with IFN for 6 months. They comprised patients who were hepatitis B e antigen (HBeAg)-positive (n = 45) and -negative (n = 21). One (2%), 8 (12%), and 51 (77%) patients were infected with hepatitis B virus (HBV) genotypes A, B, and C, respectively. Responders in patients positive for HBeAg were defined as those who showed normalization of serum alanine aminotransferase (ALT) level, HBeAg loss, and HBV DNA negativity at 6 months after completion of IFN therapy. In patients negative for HBeAg, responders were defined as those patients who showed normalization of ALT level and HBV DNA negativity at the same 6-month time point. Results. Of the 45 patients with HBeAg at the commencement of IFN therapy, 9 (20%) were responders. Young patients, especially those with a high serum ALT level, were significantly more likely to respond to IFN therapy. Of the 21 patients negative for HBeAg, 13 (62%) were responders. There were no significant differences in clinical characteristics between responders and nonresponders among patients negative for HBeAg. Multivariate analyses identified HbeAg negativity and young age as independent factors associated with a positive response to 6-month IFN therapy. However, long-term follow-up of the treated patients showed a fall in the response rate. Conclusions. The response rate to 6-month IFN therapy among HbeAgpositive patients was low. However, young patients may require long-term IFN therapy. [ABSTRACT FROM AUTHOR]

The article presents a study on infection with hepatitis B virus genotype A (HBV) in Tokyo, Japan, during the period between 1976 to 2001. In the present study, 68 Japanese patients infected with HBV/A who visited Toranomon Hospital in the Tokyo metropolitan area during 1976 through 2001 were examined along with their clinicopathological characteristics and virological features. It has been found that HBV/A infection has become more frequent during recent years, predominantly presenting as acute hepatitis, while subtype A' is uncommon in the Tokyo metropolitan area.

Objective: Several reports have examined the efficacy of long-term lamivudine therapy and the risk factors involved in emergence of viral resistance in Japanese patients with hepatitis B virus (HBV) infection. However, the patient cohorts in such studies are relatively small. Methods: We analyzed 234 chronically HBV-infected Japanese patients who were treated with lamivudine for more than 12 months. They comprised patients with HBV genotype A (n = 8), genotype B (n = 21), genotype C (n = 203) and other HBV genotypes (n = 2). Results: In most patients, lamivudine resulted in normalization of alanine transaminase (ALT) levels at 6 and 12 months, and suppression of serum HBV DNA to undetectable levels by the branched chain DNA probe assay (bDNA). Rates of ALT normalization and non-detection of HBV DNA were higher among patients with genotype B than genotype C disease. The proportions of patients who achieved HBeAg loss were 27, 42 and 45% after 6 months, 1 year and 2 years, respectively. The emergence of mutations was not different among genotypes A, B and C by the Kaplan-Meier method. Multivariate analyses identified high HBV DNA level (bDNA ≥ 100 MEq/ml) as an independent factor associated with emergence of the YMDD motif mutation in all patients. Among patients with genotype C disease, which is the predominant HBV genotype in Japan, multivariate analysis also identified high HBV DNA level and HBeAg positivity as factors associated with emergence of resistance. Conclusion: Patients exhibiting these factors at the commencement of lamivudine treatment must be monitored carefully at regular intervals for emergence of viral resistance. [ABSTRACT FROM AUTHOR]

Patients who develop YMDD mutant during lamivudine therapy for hepatitis B virus (HBV) infection exhibit various clinical courses. Some patients show normal ALT levels, whereas others develop severe hepatitis exacerbations (SHEs) due to YMDD mutants. We studied 136 patients with YMDD mutant among 362 Japanese adult patients on lamivudine therapy. Clinical and virological features of patients without elevated HBV DNA after emergence of YMDD mutant (non-elevated group) were investigated. Moreover, virological analysis was also performed in patients with SHE due to YMDD mutants. Patients in the non-elevated group were characterized by HBeAg-negative pretreatment, HBeAg loss during therapy, a longer duration from commencement of therapy until emergence of YMDD mutant, and no mixed-type YMDD mutants. Patients with SHE had more substitutions in the reverse transcriptase (rt) region within the polymerase gene at the time of exacerbation than those without SHE, although no specific substitutions were noted. Sequence analysis of full-length HBV genome showed more substitutions in X, rt, and surface proteins in patients with SHE than in those without elevated HBV DNA level. In conclusion, negativity for HBeAg at commencement of therapy or before emergence of YMDD mutant was an important factor among non-elevated group. More substitutions in the rt region and the other proteins may be related to the emergence of severe hepatitis caused by lamivudine-resistant virus.

Among the 97 adult patients with acute hepatitis B who were admitted to the Toranomon Hospital in Metropolitan Tokyo during 28 years from 1976 to 2003, 31 (32%) were infected with hepatitis B virus (HBV) genotype A, nine (9%) with genotype B, 44 (45%) with genotype C, one (1%) each with genotypes E and F. HBV in the remaining 11 (11%) patients were untypeable. All the 31 patients with acute hepatitis B caused by HBV genotype A infection were male with a median age of 31 years, and 16 (52%) contracted infection through extramarital sexual contacts. The baseline HBV DNA level was higher in the seven (23%) patients in whom infection with HBV genotype A persisted than the remaining 24 (77%) with spontaneous resolution (median: >8.7 vs. 6.0 log genome equivalents/ml, P = 0.004). Persistent infection was more frequent in patients with maximum alanine aminotransferase <500 IU/L than > or =500 IU/L (83% [5/6] vs. 4% [1/25], P = 0.0001). Of the six patients with persistent HBV genotype A infection who received interferon and/or lamivuidine for treatment of chronic active hepatitis, three (50%) responded with the loss of hepatitis B e antigen (HBeAg); hepatitis B surface antigen (HBsAg) was cleared from serum in one patient who received interferon and lamivudine in sequence. HBV genotype A persisted along with HBeAg in the remaining three patients given antiviral therapy as well as another who was not treated. In conclusion, infection with HBV genotype A prevails in patients with acute hepatitis B in Japan where genotypes B and C are common, is often contracted sexually (16/31 [52%]) and tends to persist (7/31 [23%]). Infection was cleared in only one of the six (17%) patients who received antiviral therapy., (Copyright 2005 Wiley-Liss, Inc.)

Objective: Patients with high titer (>/=100 kIU/ml) of hepatitis C virus (HCV) genotype 1b do not achieve highly sustained virological response rates to combination therapy with interferon plus ribavirin. Non-virological responders (NVRs, namely ultimate resistant cases) who do not achieve HCV-RNA negativity during treatment are also encountered. We investigated the pretreatment virological features of NVRs., Methods: We evaluated 50 consecutive Japanese adults with high titer of HCV genotype 1b who received combination therapy for 48 weeks. We investigated the pretreatment substitution patterns in amino acids 1-191 of the core region and amino acids 2209-2248 of NS5A, and early viral kinetics., Results: Overall, a non-virological response was noted in 12 (24%) patients. Multivariate analysis identified serum albumin <3.9 g/dl, substitutions of amino acid 70 in the core region, and substitutions of amino acid 91 as independent and significant factors associated with a non-virological response. Especially, substitutions of arginine (R) by glutamine (Q) at amino acid 70, and/or leucine (L) by methionine (M) at amino acid 91 were significantly more common in NVRs. The falls in HCV-RNA levels during treatment in patients with specific substitutions in the core region were significantly less than in those without such substitutions., Conclusions: Our results suggest that serum albumin and amino acid substitution patterns in the core region in patients with high titers of HCV genotype 1b may have an effect on combination therapy in NVRs. Further large-scale studies are required to examine the role of amino acid substitutions specific to a non-virological response to combination therapy., (Copyright (c) 2005 S. Karger AG, Basel.)

Objective: Comparison of virological and biochemical relapse in patients with chronic hepatitis B, based on continuation or discontinuation of lamivudine monotherapy., Methods: In Japanese genotype C-dominant hepatitis B patients, 25 patients who stopped treatment at normal levels of alanine transferase (ALT) were retrospectively compared with 75 patients who continued treatment. Both groups were matched for age, sex, and observation period after start of treatment. We investigated the relapse rates, and evaluated predictive factors for relapse and efficacy of retreatment of the discontinuous group., Results: Virological and biochemical relapse occurred significantly earlier in the discontinuous than continuous group, and the peak levels and ratios of peak to pretreatment levels of serum bilirubin and ALT after relapse were not significantly different between the two groups. Multivariate analysis identified three independent factors at discontinuation of treatment associated with early biochemical relapse: HBeAg positivity, presence of liver cirrhosis, detection of basic core promoter mutant. Normalization of ALT levels with retreatment occurred in 62.5% of patients, but 2 HBeAg-positive patients retreated after the emergence of YMDD motif mutant developed severe relapse with hyperbilirubinemia., Conclusion: Our results in Japanese patients with genotype C-dominant hepatitis B suggest that discontinuation of lamivudine monotherapy, and retreatment after the emergence of YMDD mutant should be given attention., (Copyright (c) 2005 S. Karger AG, Basel.)

Background: Hepatitis B virus (HBV) genotype A is predominant in northern Europe and central Africa. In the present study, we examined the clinical features associated with HBV genotype A disease in the Tokyo metropolitan area., Methods: We investigated 53 cases of HBV surface antigen (HBsAg)-positive Japanese patients with HBV genotype A. The 53 cases were further classified as to their serum alanine aminotransferase (ALT) status being within the normal range (asymptomatic carriers, n = 17), chronic hepatitis (n = 15), liver cirrhosis (n = 4), and acute hepatitis (n = 17)., Results: Chronic hepatitis patients had significantly higher HBV DNA levels (P = 0.003) and hepatitis B e antigen (HBeAg) positivity rates at the initial visit than did asymptomatic carriers or patients with liver cirrhosis (P = 0.003 and P = 0.054, respectively). The efficacy of treatment (HBeAg seroconversion rate) was 75% in 12 chronic hepatitis patients, which was excellent. A family history of HBsAg positivity was identified in eight (15%) families (five asymptomatic carriers, three with chronic hepatitis). However, none of the mothers in the study was positive for HBV genotype A., Conclusions: Maternal transmission of HBV has often been reported in Japan, but our present findings suggest that horizontal infection of HBV genotype A is more prevalent in the Tokyo metropolitan area. Our data indicate that HBV genotype A exhibits a mode of infection different from that of conventional HBV previously seen in Japan.

Acute hepatitis B virus (HBV) infection was diagnosed in 57 adults admitted to Toranomon Hospital in Tokyo, Japan. Genotypes of HBV were determined by a serological method and compared to those in 1,077 patients with chronic hepatitis B. The distribution of genotypes were: genotype A (acute, 22.8% vs. chronic, 1.9%; P < 0.00001); B (14.0% vs. 9.4%); C (43.9% vs. 87.7%, P = 0.004); D (1.8% vs. 0.2%); F (1.8% vs. 0.2%); and unable to be typed (15.8% vs. 0.6%, P = 0.001). The infection persisted in seven (12%) of them. They included six (86%) of the seven patients who received prednisolone or glycyrrhizin during an acute phase of illness and one of the 41 (2%) who did not (P = 0.01). Interferon was given to the seven patients with acute prolonged HBV infection, and four of them responded by clearing hepatitis B e antigen (HBeAg) and surface antigen (HBsAg) from serum. Of the four responders, one was infected with HBV genotype B and three with genotype C. HBsAg persisted in the remaining three patients all of whom were infected with HBV genotype A, and HBeAg stayed positive in one of them. These results indicate that HBV genotype A prevails in Japanese patients with acute hepatitis B, and suggest a high efficacy of interferon in the adult patients with acute prolonged HBV infection, except in those infected with HBV genotype A., (Copyright 2002 Wiley-Liss, Inc.)