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Background: Hepatocellular carcinoma (HCC) caused by hepatitis B virus (HBV) often recurs after surgical or medical treatment.Methods: Eighty consecutive patients with HBV-positive cirrhosis and HCC who underwent potentially curative ablation for HCC were analyzed. Eleven patients received long-term interferon (IFN) therapy. HBV DNA was quantified at the time of HCC treatment. A DNA value of <6.0 log copies/ml was considered low.Results: Initial DNA was low in 39 and high in 41 patients. HCC recurrence rates in the low DNA group and high DNA group were 46.9% and 82.6% at the fifth year, and 73.5% and 91.3% at the tenth year, respectively (P = 0.0103). Similarly, recurrence rates after treatment of HCC in the normal aspartate aminotransferase (AST) group (<38 IU/l, n = 42) and abnormal AST group (n = 38) were 50.6% and 84.0% at the fifth year, and 71.3% and 100% at the tenth year, respectively (P = 0.0003). Six of the 38 patients with abnormal AST, and 5 of 42 patients with normal AST, received IFN after confirmation of tumor ablation. In the subgroup of abnormal AST, tumor recurrence rates in the IFN and untreated groups were 16.7% and 37.9% at the end of the first year, 16.7% and 60.1% at the second year, and 16.7% and 83.4% at the third year, respectively (P = 0.0139). Multivariate analysis revealed that IFN significantly reduced the recurrence rate (hazard ratio = 0.21, P = 0.037) even after adjusting for background characteristics.Conclusions: IFN was inferred to decrease tumor recurrence after treatment of HCC in patients with HBV-related cirrhosis, especially in the subgroup with high AST. [ABSTRACT FROM AUTHOR]

Background: Although pegylated interferon (IFN) is now used in many countries as a standard therapy for chronic hepatitis C, the efficacy and safety of combination therapy of high-dose interferon alpha-2b induction with ribavirin are not fully evaluated, especially in Japanese patients infected with hepatitis C virus (HCV) genotype 1b with a high viral load.Methods: Patients ( n = 83) received daily, high-dose induction therapy of interferon alpha-2b (6 million units [MU] once daily for 2 weeks), followed by 6 MU three times weekly for 22 weeks. Oral ribavirin (800 or 600 mg/day) was given daily for 24 weeks, and then the patients were followed up for 24 weeks.Results: Of the 83 patients, 67 (81%) had a biochemical response (BR), and 37 (45%) achieved a sustained BR (SBR). Virologic response (VR; undetectable serum HCV RNA level by polymerase chain reaction [PCR]) was noted in 55 (66%) patients, and sustained VR (SVR) in 16 (19%) patients. Baseline viral load did not influence treatment outcome. There was no significant difference in treatment outcome among treatment-naIve patients, relapsers, and nonresponders to previous IFN monotherapy. Multivariate analyses identified serum ribavirin concentrations at week 8 of therapy (odds ratio [OR], 23.7; 95% confidence interval [CI], 1.84-61.1; P = 0.015) and negativity for serum HCV RNA at week 8 (OR, 22.5; CI, 1.76-57.5; P = 0.017, respectively) as two significant and independent predictors of SVR.Conclusions: The efficacy of 24-week combination therapy of high-dose IFN alpha-2b induction and ribavirin deserves attention in HCV genotype 1b patients with a high viral load, especially in nonresponders to previous IFN monotherapy and patients with a very high viral load. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: A phase II randomized controlled trial was conducted in patients with compensated liver cirrhosis to investigate the inhibitory effect of branched-chain amino acid (BCAA) granules for oral use (TK-98) on disease progression., Methods: Patients who had compensated liver cirrhosis due to hepatitis C virus with baseline serum albumin levels between 3.6 and 4.5 g/dl were assigned to the TK-98 group, which was treated with BCAA granules (TK-98) for 168 weeks, or to a control group (no treatment)., Results: No symptoms indicating decompensated cirrhosis, including ascites, edema, and hepatic encephalopathy were reported in either the TK-98 or control group during the study observation period. Hepatocellular carcinoma (HCC) was noted in eight of the 39 patients studied, and of these three received TK-98 (15.8%) and five were untreated (25.0%). A time-to-event analysis for the effect of BCAA therapy on development of HCC revealed no statistically significant differences between the two groups. However, an additional analysis of data from a subgroup with a baseline serum albumin level of <4.0 g/dl showed that the incidence of HCC was likely to be lower in BCAA-treated patients., Conclusions: BCAA may inhibit hepatic carcinogenesis in patients with compensated cirrhosis with a serum albumin level of <4.0 g/dl.

Background: The aim of this study was to investigate the factors associated with the response of lamivudine-resistant hepatitis B virus (HBV) during combination therapy with adefovir dipivoxil plus lamivudine., Methods: Sixty-three patients with breakthrough hepatitis received a 10-mg once-daily dose of oral adefovir dipivoxil., Results: The rates of undetectable serum HBV-DNA were 49.2% after 24 weeks, 61.9% after 48 weeks, and 67.2% after 72 weeks. The cumulative hepatitis B e antigen (HBeAg) loss rates in patients with alanine aminotransferase (ALT) levels of more than twice the upper limit of normal (ULN) were significantly higher than in patients with ALT less than twice the ULN (P = 0.0145). Multivariate analysis revealed that baseline ALT level (P = 0.003) and HBeAg status (P = 0.049) were associated with early virological response., Conclusions: Baseline ALT level was associated with HBeAg loss and seroconversion, and baseline ALT level and HBeAg status were associated with the virological response of lamivudine-resistant HBV during combination therapy with adefovir dipivoxil plus lamivudine.

Background: Suppression of the progression to cirrhosis and hepatocellular carcinoma is important, especially for young hepatitis C virus (HCV)-infected patients. The aim of this study was to analyze the response to interferon (IFN) monotherapy in young HCV patients., Methods: Between 1989 and 2002, 1021 anti-HCV-positive patients hospitalized at Toranomon Hospital received IFN monotherapy. Among these patients, 144 were < or =35 years of age, while the remaining 877 were 36-73 years old. We retrospectively identified 209 patients with known dates of blood transfusion (i.e., start of HCV infection) among the 1021 patients. IFN treatment lasted 6 months., Results: HCV RNA level (P < 0.001), HCV genotype (P < 0.001), age (P < 0.001), and liver histology (P = 0.01) were identified as determinants of the response to IFN monotherapy in 1021 patients. Moreover, in patients with high viral load and genotype 1b, the sustained virological response (SVR) rate was significantly higher in those aged < or =35 years than in older patients (P < 0.001). In patients with genotype 1b with known date of blood transfusion, a longer duration of infection negatively influenced the SVR rate. In the 209 patients, multivariate analysis identified HCV RNA level (P < 0.001), age (P = 0.002), and duration of infection (P = 0.049) as determinants of SVR., Conclusions: The response of IFN monotherapy is better in patients aged < or =35 years than in older patients, probably because of mild stage histology, the effect of host-related factors, and shorter period of infection. Long-term IFN monotherapy may be suitable for young women who desire to become pregnant or those with anemia.

Background: Phlebotomy is performed to reduce excessive iron accumulation in hepatic tissue. We studied serum alanine aminotransferase (ALT) normalization rates and 50% reduction in initial serum ALT (ALT(50%) reduction rate) in patients with hepatitis C viral (HCV) infection and investigated the factors that influenced the response to phlebotomy therapy., Methods: We evaluated 23 consecutive patients with HCV infection who underwent phlebotomy. Phlebotomy was performed a few times per week, then a few times per month, and 200-400 ml of blood was removed at each session, depending on the clinical response. During the course of therapy, hemoglobin (Hb), serum ALT, and ferritin levels were assessed monthly., Results: In patients with Hb of less than 11 g/dl, the ALT(50%) reduction rate was 87.5%. In patients with a serum ferritin level of less than 10 g/dl the ALT(50%) reduction rate was 83.3%. In patients with Hb of less than 11 g/dl, the ALT normalization rate was 50%, and in those with a serum ferritin level of less than 10 g/dl, the ALT normalization rate was 41.7%. Multivariate analysis identified ALT less than 100 IU/l at the start of phlebotomy as an independent factor associated with ALT normalization. Of the 7 patients who showed no response to phlebotomy, 85.7% were obese (body mass index > or =25 kg/m(2)), and 40% showed more than 30% steatosis on liver histology. The cumulative ALT normalization rate in relation to the total volume of blood loss was 43.9% with a blood less or more than 3 l, and thus was optimal above 3 l., Conclusions: Although the sample number was relatively small, the results of our study suggest that phlebotomy is effective therapy for HCV patients who are nonobese, show little or no steatosis on liver histology, and have a baseline serum ALT level of less than 100 IU/l.

Background: Hemolytic anemia is one of the major adverse events of the combination therapy of interferon and ribavirin. Because of ribavirin-related hemolytic anemia, dose reduction is a common event in this therapy. In this clinical retrospective cohort study we have examined the suitable timing of ribavirin reduction in patients with hemolysis during combination therapy., Methods: Thirty-seven of 160 patients who had HCV-genotype 1b, had high virus load, and received 24-week combination therapy developed anemia with hemoglobin level <10 g/dl or anemia-related signs during therapy. After that, these 37 patients were reduced one tablet of ribavirin (200 mg) per day. After reduction of ribavirin, 27 of 37 patients could continue combination therapy for a total of 24 weeks (group A). However, 10 of 37 patients with reduction of ribavirin could not continue combination therapy because their <8.5 g/dl hemoglobin values decreased to or anemia-related severe side effects occurred (group B). We assessed the final efficacy and safety after reduction of ribavirin in groups A and B., Results: A sustained virological response (SVR) was 29.6% (8/27) in group A and 10% (1/10) in group B, respectively. A 34.4% (12/27) of SVR + biological response in group A was higher than 10% (1/10) in group B ( P = 0.051), with slight significance. With respect to hemoglobin level at the time of ribavirin reduction, a rate of continuation of therapy in patients with > or =10 g/dl hemoglobin was higher than that in patients with <10 g/dl ( P = 0.036)., Conclusions: Reduction of ribavirin at hemoglobin level > or =10 g/dl is suitable in terms of efficacy and side effects.

Background: Several clinical trials have suggested that lamivudine therapy is effective in patients with hepatitis B virus (HBV)-related cirrhosis. However, there are few studies of lamivudine therapy in Japanese patients with HBV cirrhosis. The aim of this study was to evaluate the efficacy of lamivudine therapy in Japanese patients with cirrhosis, and to evaluate the clinical course after the emergence of YMDD mutants., Methods: Fifty-four consecutive adult Japanese patients with HBV-related cirrhosis were enrolled and continuously treated with lamivudine, daily for 6-35 months (median, 25 months). Twelve of the 54 patients were hepatitis B envelope antigen (HBeAg)-positive. The clinical courses of 21 of the patients were evaluated using the Child-Pugh-Turcott (CPT) score., Results: Lamivudine suppressed serum HBV-DNA to undetectable levels (<3.7 LGE/ml) in 77.8% of patients at 12 months and in 61.3% at 24 months. Before the emergence of YMDD mutants, clinical improvement, defined as a decrease in the CPT score of 2 points or more, was apparent in 6 of 21 (29%) patients. No change in CPT score was evident in 14 of 21 patients (67%). YMDD mutants emerged in 19 of 54 (35%) patients. The cumulative emergence rates increased each year. The emergence rate of YMDD mutants in patients with HBV cirrhosis was higher than that in patients with chronic hepatitis. After the emergence of YMDD mutants, 3 of 12 (25%) patients with YMDD mutants showed CPT score increases of 2 points or more., Conclusions: Lamivudine therapy improved the clinical course in some cirrhotic patients. However, in patients with Child's B and C cirrhosis, the emergence of YMDD mutants sometimes led to deterioration of liver function.

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 HBeAg-positive patients was low. However, young patients may require long-term IFN therapy.

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: Approximately 30% of patients with chronic hepatitis C have normal serum alanine amino transferase (ALT) levels. While interferon (IFN) monotherapy is approved for patients with chronic hepatitis C infection, the effectiveness of such therapy for chronic hepatitis C patients with normal ALT levels at commencement of treatment remains poorly understood., Methods: Ninety-four individuals (M/F, 54 : 40; median age, 46 years) with normal ALT levels (< 50 IU/l) at the commencement of treatment who were positive for both anti-hepatitis C virus (HCV) and serum HCV-RNA were studied. Among this group, 18 individuals (M/F, 9 : 9; median age, 50 years) had had persistently normal ALT levels for at least 3 months prior to treatment. All patients received their first course of IFN therapy in this study., Results: Forty-three (45.7%) of 94 individuals had lost serum HCV-RNA at 6 months after cessation of therapy (complete response; CR). The proportion of patients with genotype 2a and HCV-RNA level over 1 Meq/ml who showed CR was significantly lower in those with normal ALT levels than in those with elevated ALT levels (23.8% vs 55.6%; P = 0.0189). Two patients who had persistently normal ALT levels and HCV-RNA level over 1 Meq/ml were nonresponders (NR) and had ALT flare-ups after IFN therapy. Patients with HCV-RNA levels of less than 1 Meq/ml did not show differential responses based on ALT levels., Conclusions: Our data suggest that IFN therapy is effective for patients with normal ALT levels and less than 1 Meq/ml HCV-RNA. Thus, such patients should be considered for curative IFN therapy.

Background: The mechanism of liver injuries in autoimmune hepatitis (AIH) is not fully understood, especially because the onset is insidious and the clinical courses fluctuate with spontaneous exacerbation and improvement even without immunosuppressive therapies., Methods: Eleven patients with acute-onset AIH, some of whom were without hypergammaglobulinemia or anti-nuclear antibodies, and 41 patients with chronic AIH were compared serologically, biochemically, and histologically to determine differences in liver injuries between patients with acute-onset and chronic AIH. All patients fulfilled the diagnostic criteria according to a scoring system proposed in 1999., Results: Lymphocytes with CD8+/CD25+ markers in pretreatment blood were significantly more prevalent in acute-onset than chronic AIH patients (24% vs 14%; P < 0.05). After treatment, however, CD8+/CD25+ lymphocytes were fewer in patients with acute-onset than in those with chronic AIH at 1 and 2 weeks ( P = 0.0001). No other differences were noted in clinical characteristics or immunological parameters between patients with acute-onset and those with chronic AIH. In a patient with typical acute-onset AIH, CD8+/CD25+ lymphocytes increased and decreased in parallel with the activity of liver disease., Conclusions: Activated CD8+ T lymphocytes with CD25 markers may be implicated in the development of acute-onset AIH.

Background: Recent studies indicate that combination therapy with ribavirin and interferon alfa2b (IFNAlpha2b) is effective for chronic hepatitis C virus (HCV) infection. However, reversible hemolytic anemia is a common side effect of this therapy., Methods: We determined those factors that contribute to ribavirin dose reduction due to anemia during this treatment by using multiple logistic regression analysis in Japanese patients. The study included 123 patients with chronic hepatitis C (85 male, 38 female; mean age, 50 years; range, 20-70 years), who received 24-week combination therapy. All patients were treated with IFNAlpha2b daily for 2 weeks, followed by three times weekly dosing for 22 weeks, with oral ribavirin twice daily, at a total daily dose of 600 or 800 mg., Results: Of the 123 patients, 34 patients required dose reduction of ribavirin, and 78 patients required no dose reduction. Overall, 20 patients discontinued. On univariate analysis, reduction of the ribavirin dose correlated significantly with pretreatment hemoglobin (Hb) levels of less than 14 g/dl, female sex, and patient age 55 years or older. On multivariate analysis, pretreatment Hb of less than 14 g/dl level and age 55 years or older were significantly associated with ribavirin dose reduction. The hazard ratios were 3.56 (95% confidence interval [CI], 1.48-8.53) for pretreatment Hb levels of less than 14 g/dl, and 2.50 (95% CI, 1.05-5.94) for age 55 years or more., Conclusions: Because patient age of 55 years or more, and Hb levels of less than 14 g/dl are significant factors that influence ribavirin-induced hemolytic anemia, more careful monitoring is necessary during combination therapy for patients with these risk factors.

Background: The aims of this study were to define the clinical characteristics of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in young adult patients without cirrhosis and to evaluate the efficacy of interferon (IFN) therapy on HCC recurrence., Methods: Of 187 patients with HBV-related HCC treated at our hospital, 4 had no liver cirrhosis and were less than 30 years of age (10, 22, 23, and 26 years)., Results: At the time of diagnosis of HCC, all cases had antibody to hepatitis B e antigen (anti-HBe) and histological staging of nontumorous liver was F0 or F1, i.e., low-grade hepatitis. The mothers of all 4 young adult patients with HCC had HBV-related liver disease. Three cases developed recurrence of HCC. In these patients, long-term intermittent IFN therapy after reresection of HCC resulted in long-term survival without recurrence for more than 3 years of follow-up., Conclusions: (1) Young adult patients with HCC are positive for anti-HBe, lack cirrhosis, and the route of infection seems to be mother-to-infant transmission. Transplacental transmission of HBV and HBV DNA integration into the cellular genomic DNA during fetal life is a possible explanation of HBV-related hepatocarcinogenesis in young adults; and (2) long-term IFN therapy seems to be useful for prevention of tumor recurrence after radical operation for HBV-related HCC.

Background: With respect to interferon (IFN) treatment for chronic hepatitis C, normalization of alanine aminotransferase (ALT) as well as clearance of hepatitis C virus (HCV)-RNA after IFN therapy is important. It has been shown that the incidence of hepatocellular carcinoma (HCC) in patients with normal ALT is significantly lower than that in those with elevated ALT after IFN therapy. We assessed the efficacy of IFN retreatment for chronic hepatitis C patients who had a biochemical response (BR) after the first IFN therapy and reelevated ALT during follow up, by a case control study., Methods: Fifteen patients (case group; group 1) enrolled in this study showed a BR after the first IFN therapy and reelevated ALT during follow up. Next, we retrospectively selected 30 patients (control group; group 2) with no response (NR) after the first IFN therapy. Group 2 patients were matched 1 : 2 with group 1 patients for sex and age. All patients were given intramuscular injections of human lymphoblastoid IFN alpha daily (6 MU) for 8 weeks and then three times a week for 16 weeks. We compared the clinical and biological differences between group 1 patients and group 2 patients. Virological response (VR) was defined when serum HCV-RNA showed negativity more than 6 months after the completion of IFN therapy. BR was defined when ALT values remained normal during more than 6 months in spite of positive serum HCV-RNA, by reverse-transcription nested polymerase chain reaction, 3 and 6 months after the completion of IFN therapy. NR was defined as any response except for VR or BR., Results: The rate of patients showing VR in this study was 6.7% (1/15) in group 1 and 13.3% (4/30) in group 2. There was no significant difference between the groups with respect to VR. BR occurred in 73.3% (11/15) of patients in group 1, but in only 3.3% (1/30) of patients in group 2 (P = 0.0002)., Conclusions: We conclude that IFN retreatment is one of the effective strategies with which to achieve BR again in HCV-positive patients who had a BR after their first IFN therapy and reelevation of ALT during follow up., (Copyright 2004 Springer-Verlag)

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.

Background: Tumor recurrence is common after potentially curative ablation of hepatocellular carcinoma; therefore, the incidence of intrahepatic metastasis and multicentric carcinogenesis was evaluated., Methods: A cohort of 892 patients with cirrhosis caused by either hepatitis B virus (n=246) or hepatitis C virus (n=646) was followed up without interferon administration., Results: Hepatocellular carcinogenesis rates were 28.0% at the end of the fifth year, 49.2% at the tenth year, and 61.3% at the fifteenth year. Sex, hepatitis virus, alpha-fetoprotein, platelet count, age, and indocyanine green retention test value significantly affected the carcinogenesis rate. Of 372 patients with tumor development, 162 (43.5%) received surgical or radical locoregional therapy. On the assumption that a second carcinogenesis after sufficient ablation of well-differentiated cancer was attributable to multicentric carcinogenesis, recurrence rates after curative therapy in all the 162 patients, and the recurrence rates in 39 patients with solitary, small, and well-differentiated histology were analyzed: the rates were 58.2% and 30.9% at the third year, 75.9% and 53.4% at the fifth year, and 89.6% and 79.9% at the tenth year, respectively. The estimated incidence of multicentric recurrence was, therefore, 31% or higher at the third year and 53% or higher at the fifth year. The actual second carcinogenesis rates (multicentric recurrence) were approximately 1.6 times as high as those of the virtual second carcinogenesis rates calculated from statistical simulation., Conclusions: A longterm cohort study disclosed that multicentric carcinogenesis was the principal mechanism of recurrence after curative ablation of hepatocellular carcinoma and that the concept of "carcinogenic stage" should be introduced to improve the understanding of carcinogenic events in viral cirrhosis.

Background: In patients with hepatitis C virus (HCV)-genotype 1b and a high virus load, of more than 1 Meq/ml by the DNA probe assay, the clearance of HCV-RNA was achieved in only 10% with a 6-month interferon (IFN) course. We therefore assessed the efficacy of prolonged IFN therapy in patients with HCV-genotype 1b and a high virus load., Methods: A total of 51 patients with HCV genotype 1b who were given 6 million units (MU) of natural IFN-alpha daily for 8 weeks followed by three-times-weekly treatment with natural IFN-alpha for 16 weeks, were enrolled in this trial. These 51 patients were randomly assigned to one of two schedule groups at the time of termination of the first IFN therapy. The 48-week-group patients (n = 25) were given 6 MU of natural IFN-alpha by intramuscular injection three times weekly for 24 weeks, beginning within a week after the termination of the first IFN therapy. The 72-week-group patients (n = 26) were given 6 MU of IFN-alpha by intramuscular injection three times a week for 48 weeks, beginning within a week after the termination of the first IFN therapy. The therapeutic efficacy was evaluated 24 and 30 months after the initiation of the first IFN treatment. A virological response (VR) to IFN therapy was defined as the normalization of serum alanime amino transferase (ALT) level (ALT less, similar 50 IU) and HCV-RNA negativity at the two time points. Biochemical response (BR) was defined as the normalization of serum ALT, but positivity for HCV-RNA, assessed by commercial Amplicor HCV qualitative assays, at the two time points., Results: The efficacy of IFN treatment was assessed in relation to the IFN administration schedule by intention-to-treat (ITT) analysis and per-protocol analysis. With respect to the IFN regimen, VR occurred in 16.6% (4/24) of the patients in the 48-week-group with additional IFN and in 20% (5/25) in the 72-week-group with additional IFN by ITT analysis. The BR rate was 33.3% (8/24) in the 48-week group and 48% (12/25) in the 72-week group., Conclusions: We found that prolonged IFN therapy could be a worthwhile treatment strategy for patients with HCV genotype 1b and a high serum virus load.

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.

Of a total of 2342 patients with type-C chronic hepatitis treated with interferon (IFN) at this hospital, 3 patients developed jaundice during the course of IFN therapy, but all 3 of them exhibited negative conversion of hepatitis C virus (HCV)-RNA following readministration of IFN. All 3 patients were assessed as having "probable autoimmune hepatitis (AIH)" in accordance with the AIH scoring system, indicating association with an "autoimmune phenomenon". Readministration of IFN at a low-dose induced activation of the autoimmune phenomenon, leading to fulminant hepatocellular impairment. As a result, HCV-RNA content dropped dramatically, possibly contributing to the negative conversion of HCV-RNA noted following the readministration of IFN. At present, no adequate therapy has been established for type-C chronic hepatitis with autoimmune manifestations. However, in conclusion, our findings suggested that: IFN should be a frontline regiment: (1). if autoantibody titers are low or patients are rated as having "probable AIH" or lower in accordance with the AIH scoring system, indicating a strong link to chronic hepatitis or (2). if IFN is expected to be efficacious on the basis of genotype of HCV-RNA level; even if there is acute exacerbation of type-C chronic hepatitis, IFN should be re-administered in the HCV-RNA level has dropped subsequently.

Background: We aimed to treat patients with chronic hepatitis B on long-term treatment with lamivudine who developed lamivudine-resistant hepatitis B virus (HBV) mutants along with clinical relapses., Methods: Of 217 patients with chronic hepatitis B who had been treated with lamivudine for 1-6 years, 23 (11%) developed lamivudine-resistant hepatitis B virus (HBV) mutants. Seven of them, including 1 whose case was previously reported, received interferon (IFN) daily for 4 weeks and then two or three times a week thereafter to cope with exacerbation of hepatitis. We investigated the efficacy of this IFN therapy in 6 patients, excluding the 1 previously reported., Results: In 4 patients, HBV DNA decreased to below the detectable limit of the branched DNA assay (<0.7 MEq/ml) accompanied by normalization of transaminase levels. During IFN therapy, 2 patients seroconverted to antibody to hepatitis B e antigen (HBeAg) and showed normalized transaminase levels. Interferon was required in 7 of the 111 (6%) patients with chronic hepatitis B who were positive for HBeAg, but in none of the 106 who were positive for antibody to HBeAg ( P = 0.014)., Conclusions: The efficacy of IFN in controlling virological breakthroughs and exacerbation of hepatitis by infection with lamivudine-resistant HBV mutants in patients with HBeAg-positive chronic hepatitis B could enhance the versatility of lamivudine, which may have to be given to them indefinitely.

Purpose: Although interferon (IFN) is commonly used for the treatment of chronic hepatitis C virus (HCV) infection, eradication of the virus occurs in only a small proportion of patients with genotype 1b and a high virus titer. Modified IFN therapies have been tried, with only limited benefit. Recently, the administration of IFN-beta twice per day has been reported to be more effective than the usual once-daily administration regimen. The aim of this study was to evaluate whether twice-daily IFN results in a sustained response in patients with chronic HCV infection with genotype 1b, and a high virus titer., Methods: Twenty patients with genotype 1b and high HCV RNA level (more than 1 MEq/ml by branched DNA probe assay) were randomly assigned to receive either twice-daily 3 MU of IFN beta (group A) or once-daily 6 MU of IFN-beta (group B) for 4 weeks. All patients received a further daily dose of 6 MU IFN-beta for 12 weeks, followed by IFN-alfa three times a week for 16 weeks., Results: Although a rapid fall in HCV RNA levels was noted in group A, a sustained response was observed in only one of nine patients in this group, and none of group B. Adverse effects of IFN were more frequent and pronounced in group A than in group B., Conclusions: We conclude that further modification, which combines the early strong anti-viral effects of the twice-daily regimen with long-term sustained response, is necessary for effective therapy of HCV patients with genotype 1b and high HCV RNA levels.

A 61-year-old man with chronic hepatitis B was treated with interferon (IFN)-alpha for flare-up after the emergence of a lamivudine-induced YMDD motif mutant. The YMDD mutant emerged 13 months after the initiation of lamivudine therapy. Despite this, lamivudine therapy was continued. Acute exacerbation occurred 25 months after the emergence of the YMDD mutant. Treatment with IFN-alpha resulted in rapid loss of hepatitis, B virus DNA, resolution of hepatitis, and clinical recovery.