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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.)

Background: Hepatitis B virus (HBV) genotype B is classified into subtype Ba with the recombination with genotype C in the precore region plus core gene and subtype Bj without recombination. Virological and clinical differences between infections with subtypes Ba and Bj, however, are yet to be determined., Methods: During 1976 through 2001, 224 patients visited Toranomon Hospital in Tokyo, Japan who were infected with HBV genotype B. Subtypes of genotype B were determined by sequencing HBV-DNA recovered from sera for detecting recombination with genotype C., Results: Subtype Ba was detected in 53 patients (24%) and Bj in 167 (75%); subtypes were not able to be determined in the remaining four (1%). The only virological difference was that detection of hepatitis B e antigen at the presentation was more frequent in the patients infected with subtype Ba than those with Bj (63% vs 33%, P = 0.016). There were no differences in the distribution of liver disease of various forms between the patients infected with subtypes Ba and Bj at presentation. No differences were noted, either, in the development of liver cirrhosis or hepatocellular carcinoma, or the loss of hepatitis B surface antigen from serum, between the patients infected with subtypes Ba and Bj during follow up of up to 26 years., Conclusions: Although there were some virological differences between the patients infected with subtypes Ba and Bj of HBV genotype B, they do not seem to influence the long-term clinical outcome.

Hepatitis B virus (HBV) mutants with mutations in the YMDD motif of viral DNA polymerase/reverse transcriptase are described in patients infected with HBV who have not received lamivudine therapy, but their pathogenetic potential is not clear. These mutants were detected by the polymerase chain reaction with peptide nucleic acid clamping in pretreatment sera from two patients who later received lamivudine. One patient developed acute exacerbation with hepatic encephalopathy and received lamivudine along with plasma exchange, which were effective on his illness. YIDD mutants were detected in all three pretreatment sera and both posttreatment sera from him. HBV DNA clones from pretreatment and posttreatment sera, however, did not have the same amino acid sequence. In the other patient who developed severe breakthrough hepatitis after receiving lamivudine, YIDD mutants were detected in two pretreatment and two posttreatment sera. When amino acid sequences of HBV DNA clones with the YIDD mutation were compared before and after he received lamivudine, however, they were not in accord. Hence, YIDD mutants in both patients with chronic hepatitis B before treatment were not selected by lamivudine after they had been placed on it. Numerous amino acid conversions were detected in HBV DNA clones with YIDD mutations, and some of them created stop codons in the overlapping S gene sequence. In Conclusion, HBV mutants with mutations in the YMDD motif in patients before treatment would not be selected by lamivudine or induce breakthrough hepatitis, and some of these would not be replication-competent due to stop codons in the S gene.

Background: Because genotype A of hepatitis B virus (HBV) is not indigenous, there have been only few data on infection with it in Japan., Methods: We examined clinical and virological features of the 66 Japanese patients who admitted Toranomon Hospital in Tokyo, Japan, between 1976 and 2001, who were found to have HBV/A infection. HBV genotype A was classified into subtype A (European type) and A' (South African type) by phylogenetic analysis of the preS1 and preS2 regions, and the S gene sequences., Results: Of the 66 patients infected with HBV/A, 14 (21%) were asymptomatic carriers, 26 (39%) presented with acute hepatitis, 22 (33%) with chronic hepatitis, and 4 (6%) with liver cirrhosis. HBV/A infection persisted for more than 6 months in 5 of the 26 (19%) patients with acute hepatitis. The frequency of acute hepatitis in patients infected with HBV/A was higher after than before 1991 (2/22 [9%] vs 24/44 [55%]; P < 0.0001). The frequency of nucleotide 1858 of T was higher in asymptomatic carriers than in patients with acute hepatitis in whom infection was resolved (5/14 [36%] vs 0/21 [0%]; P = 0.008). Of the 57 patients for whom subtypes of genotype A were determined, subtype A was identified in 53 (93%) and subtype A' in only 4 (7%). All patients infected with subtype A' were persistently infected with HBV., Conclusions: HBV/A infection has become more frequent during recent years, predominantly presenting as acute hepatitis, and subtype A' is uncommon in the Tokyo metropolitan area.

Background: Lamivudine is used for the treatment of chronic hepatitis B (CH-B), and exhibits excellent antiviral activity. However, longterm administration increases the likelihood of the emergence of resistant viruses, with an accompanying relapse of hepatitis. However, recent studies have reported lamivudine-resistant viruses in patients with CH-B before such treatment. The aim of this study was to investigate whether YMDD mutants occur in nature., Methods: The existence of lamivudine-resistant viruses was examined in 20 asymptomatic carriers of hepatitis B virus (ASC), 10 patients who lost hepatitis B surface antigen (HBsAg) during follow-up and in 20 lamivudine-treated patients with and without breakthrough hepatitis. Both polymerase chain reaction (PCR) restriction fragment length polymorphism and SMITEST hepatitis B virus (HBV)-YMDD mutation detection methods were used to detect resistant viruses., Results: No YMDD mutants were detected in the sera of the 20 ASC at the initial and final medical examinations, nor were YMDD mutants detected in sera collected at the initial medical examination, about 6 months before, or immediately after the loss of HBsAg in the 10 patients. In the 20 patients treated with lamivudine, YMDD mutants were not detected in any of them before treatment, whereas mutants were detected in the sera of 10 patients during treatment., Conclusions: Our results suggest that lamivudine-resistant YMDD mutant viruses were present in a few patients with HBV infection before they have been treated with lamivudine.

Whether the type of lamivudine-resistant virus in hepatitis B virus (HBV) influences the clinical outcome, it is not completely understood. We evaluated the serial changes in YMDD motif mutant in 60 Japanese genotype C-HBV patients who received long-term lamivudine monotherapy. YIDD or YVDD alone tended to stop shifting to the mixed type (YVDD and YIDD) within 12 months after the detection of mutant virus. Hence, the characteristics, virological relapse (DNA breakthrough) and biochemical relapse (breakthrough hepatitis) of 49 patients, who could be classified into three types (continuous YVDD, continuous YIDD, and the mixed type), were investigated. YVDD and YIDD type tended to have the opposite background with regard to age, histology, and viral load. The mixed and YIDD types tended to have similar backgrounds, except for viral load. In the mixed type, both the HBeAg-positive rate and viral load as risk factors for emergence of the mutant tended to be high. Mutant virus, DNA breakthrough and breakthrough hepatitis emerged significantly earlier in the mixed type than the two other types. The incidence of severe breakthrough hepatitis accompanied by icteric flare-up tended to be higher in the mixed type than the other types. Our results suggest that the YMDD motif mutant type might emerge from different backgrounds and modulate the virological and biochemical relapse after the emergence. Large-scale studies of each mutant type should be conducted in the future to confirm these findings., (Copyright 2003 Wiley-Liss, Inc.)

HBe antigen (HBeAg) loss or seroconversion can occur during lamivudine therapy. The purpose of this study was to analyze nucleotide sequences in precore and core promoter regions, and examine the influence of mutations in these regions on the disappearance of HBeAg during lamivudine therapy. Serial serum samples were obtained from 51 patients (HBeAg loss in 26 patients) at commencement of therapy (baseline) and after 1 year of lamivudine therapy. Serum samples were amplified with PCR and nucleotide sequences of HBV were analyzed. At baseline, a precore stop codon mutation (A1896) was identified in 8 of 26 HBeAg loss patients and in 8 of 25 HBeAg non-loss patients. At 1 year, precore mutation was observed in 4 of 14 patients analyzed who showed HBeAg loss. At 1 year, however, a precore mutation was observed also in 3 of 9 analyzed patients who showed no HBeAg loss. Core promoter mutations were noted in 21 of 26 HBeAg loss patients and in 20 of 25 HBeAg non-loss patients. At 1 year, core promoter mutations were noted in 11 of 14 HBeAg loss patients and in 8 of 9 HBeAg non-loss patients. Our data suggested that during lamivudine therapy, core promoter and precore mutations do not influence HBeAg loss or seroconversion but may reduce the viral level upon HBeAg loss or seroconversion., (Copyright 2003 Wiley-Liss, Inc.)

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 >or=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., (Copyright 2003 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.

Objective: Factors influencing the resolution of persistent hepatitis B virus (HBV) infection were sought for., Methods: The loss of hepatitis B surface antigen (HBsAg) from serum was correlated with mutations in HBV DNA for a hepatitis B e antigen (HBeAg)-minus phenotype in patients infected with HBV genotype C and positive for HBeAg at presentation., Results: HBeAg turned negative in all the 22 patients in whom HBV infection resolved, but only in 11 of the 25 patients with severe liver diseases (100 vs. 44%, p = 0.0001). The precore wild type (G1896) persisted significantly more frequently in the 22 patients in whom HBV infection resolved than in the 11 patients who developed decompensated liver cirrhosis or hepatocellular carcinoma (15/22 or 68% vs. 1/11 or 9%, p = 0.005). The double mutation in the core promoter (T1762/A1764) was comparably frequent in the two groups of patients at presentation (14/22 or 64% vs. 7/11 or 64%) and >15 years thereafter (18/22 or 82% vs. 10/11 or 91%)., Conclusion: The precore wild type (G1896) would seem to facilitate the resolution of HBV infection, while the precore mutant (A1896) may induce severe liver diseases in patients with HBeAg-positive chronic hepatitis who have lost HBeAg from serum., (Copyright 2003 S. Karger AG, Basel)

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.)

Background: The aim of the present study was to evaluate the clinical characteristics at first hospital consultation, according to the genotype of hepatitis B virus (HBV), in patients with chronic liver diseases and positivity for hepatitis B surface antigen (HBsAg) in metropolitan Tokyo., Methods: The subjects consisted of 1077 patients with chronic liver diseases who were HBsAg-positive. HBV genotype was determined by an enzyme-linked immunosorbent assay (ELISA), using PreS2 monoclonal antibody, which is specific for HBV genotypes in the PreS2 region., Results: The proportion of patients with genotype A was 2% (20 patients), genotype, B 9% (101 patients), and genotype C, 88% (945 patients), while 11 patients (1.0%) had other genotypes, including 2 (0.2%) each with genotypes D and F, and 7 (0.6%) that were untypeable. Patients with genotype A were significantly (P = 0.049) more likely to be positive for Hepatitis B envelope antigen (HBeAg) at the first consultation compared with those with genotype B. Patients with genotype B were significantly more likely to be HBeAg-negative at the first consultation compared with those with genotype A (P = 0.049) and genotype C (P = 0.001), significantly more likely to show minimal hepatic fibrosis (P = 0.003), and least likely to develop liver cirrhosis (P = 0.005). Patients with genotype C were likely to be HBeAg-positive (P = 0.001) and to have a positive family history of HBV infection (P = 0.0002)., Conclusions: The clinical features of patients with HBV infection in metropolitan Tokyo varied depending on the HBV genotype.

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]

Abstract: The aim of this study was to elucidate the relationships among serum levels of hepatitis B virus (HBV) DNA, periods after hepatitis B surface (HBs) antigen clearance, and the titer of hepatitis B core (HBc) antibody in 200-fold diluted serum. Twelve patients who had clearance of HBs antigen from serum were studied. Five patients had not received any treatment (group A), and seven had received prednisolone withdrawal therapy. The patients in groups A and B were followed up for 86 months and 108 months (median), respectively. Serum HBV was measured by the nested polymerase chain reaction method. In both groups, serum HBV tended to become gradually undetectable after HBs antigen clearance. The positive rate of HBV in the sera 5 years or more after HBs antigen clearance was significantly lower than that in the sera at less than 5 years, both in group A (P = 0.004) and group B (P = 0.010). In both groups, the titer of HBs tended to decline every year after HBs antigen clearance. HBV was still detectable in the sera of some patients for a long period of time after they showed seroconversion to HBs antibody. The results suggest that detection of HBV was difficult in sera with an HBc titer of 30% or lower and at more than 5 years after HBs antigen clearance in both groups. It is important to note that HBV DNA rarely exists in the serum, even when HBs antigen and HBc are both negative. [ABSTRACT FROM AUTHOR]