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Zinc deficiency is likely to occur in chronic liver disease. The aim of this study was to determine the prevalence of zinc deficiency in different types of chronic liver disease and to identify the factors that predicted low serum zinc levels.The study was an observational single-center design. We obtained the medical records of 666 patients with chronic liver disease whose serum zinc levels had been measured. The cutoff value for zinc deficiency was a serum level 70 µg/dL.Serum zinc levels in the alcoholic liver disease (ALD) group were significantly lower than in the other groups (hepatitis C virus [HCV], hepatitis B virus [HBV], and other cause) (P 0.01). The CONUT and ALBI score (r = 0.527, P 0.01), serum zinc level and ALBI score (r = - 0.607, P 0.01), and serum zinc level and CONUT score (r = - 0.465, P 0.01) correlated with each other. The prevalence of zinc deficiency were 44.8%, 63.2%, 86.7%, 97.1%, and 100% in the mALBI grade 1-CONUT normal, CONUT undernutrition, and mALBI grade 2a, 2b, and 3 groups, respectively. Multivariate analysis identified ALD, CONUT score, aspartate aminotransferase, and hemoglobin as significant, independent predictors of zinc deficiency (P 0.05).This study identified ALD, CONUT score, aspartate aminotransferase, and hemoglobin as predictors of zinc deficiency in chronic liver disease. The rate of zinc deficiency is high even in patients classified as mALBI grade 1, especially in ALD, while caution may be required in those classified as mALBI grade 1-CONUT undernutrition.

Few studies have demonstrated the potency of tenofovir alafenamide (TAF) in patients with poor response to other nucleos(t)ide analogs (NAs). We conducted a retrospective study comprising consecutive 40 patients exhibiting a poor response to other NAs, who subsequently received TAF-containing regimens. The primary outcome was the prevalence of virological response (VR) at each time and maintained virological response (MVR) under TAF-containing regimens until week 96. In the entire cohort, the prevalence of MVR was 71.1% (27/38). Further, poor tenofovir disoproxil fumarate (TDF) response was significantly associated with a lower prevalence of MVR (p = 0.014). In TDF-naive patients, the prevalence of MVR was 92.3% (12/13) and 62.5% (5/8) in patients with lamivudine resistance (LAM-r) and entecavir resistance (ETV-r), respectively. Further, viral load and HBeAg status at baseline were associated with a lower prevalence of MVR (p = 0.013). Among the seven patients with prior TDF exposure, 2 patients achieved MVR. Among them, one patient with development of viral breakthrough during TDF/LAM achieved MVR after switching to TAF/ETV. In contrast, one of the five patients with non-MVR had three substitutions (rtS106C, rtD134N/S, and rtL269I) of quadruple mutations in addition to ETV-r. Other patients with rtA181T + rtN236T also could not achieve MVR. TAF exhibited high antiviral potency in patients with LAM-r and ETV-r. However, TAF potency was associated with previous TDF response, viral load, and HBeAg status at baseline. Additionally, a quadruple mutation may impact tenofovir resistance; however, further studies are needed to verify this.

Glecaprevir and pibrentasvir (GLE/PIB) are potent antiviral agents for hepatitis C virus (HCV) pan-genotypic infections; however, their clinical effectiveness and safety remain limited in the real-world. This study aimed to evaluate viral responses and the safety of GLE/PIB for patients with chronic HCV-1/2/3 infections during both initial- (Arm A) and re-treatment (Arm B) with all-oral direct-acting antiviral agents (DAAs). This prospective-observational cohort study included Japanese patients with chronic HCV-1/2/3 infections (n = 271: 183 in Arm A and 83 in Arm B), who had started receiving GLE/PIB. Primary end point was a sustained virological response (SVR) rate at week 12 (SVR12) after the end of GLE/PIB treatment (EOT). SVR12 was achieved by 99.4% of patients (180/181: modified intention-to-treat (mITT) analysis excluding 2 patients lost to follow-up) in Arm A. One patient with an HCV-3b infection who discontinued at week 8 failed to achieve SVR12. SVR12 was achieved by 97.7% of patients (85/87: mITT excluding 1 patient lost to follow-up) in Arm B. Virological relapse occurred in 2 patients with HCV-1b, presenting common 5 loci of resistance-associated substitutions (RASs) including A92 RASs in the NS5A lesion at baseline. Any adverse events (AEs) (grade ≥ 3) occurred in 8 patients (3.0%). 8 patients (3.0%) discontinued due to AEs, however, all of them achieved SVR12. Initial and re-treatment with GLE/PIB are effective and safe for Japanese patients with HCV-1/2/3 in real-life settings. Further studies are required to elucidate the mechanism underlying treatment failures of GLE/PIB to completely eradicate HCV worldwide.

Few studies have investigated the efficacy of long-term tenofovir disoproxil fumarate (TDF)-based rescue therapy in patients with chronic hepatitis B refractory to nucleoside/nucleotide analogs. We retrospectively analyzed 40 Japanese patients with chronic hepatitis B refractory to nucleoside/nucleotide analogs who received TDF-based rescue therapy [TDF monotherapy, TDF plus lamivudine (LAM) combination therapy, or TDF plus entecavir (ETV) combination therapy] followed up for a median of 45 months (range 14–99 months). Viral response, changes in hepatitis B surface antigen levels from the baseline, and viral breakthrough during therapy were analyzed. The proportion of patients with undetectable serum hepatitis B virus (HBV) DNA levels (less than 2.1 log copies per milliliter) (viral response) during TDF-based rescue therapy was 68, 78, 85, 88, 83, 81, 88, and 100 % at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, and 4 years respectively. There were no differences in the viral response rate between the TDF plus LAM group and the TDF plus ETV group. The mean reduction from the baseline in hepatitis B surface antigen levels in patients with LAM-resistant HBV was greater than the reductions in patients with adefovir dipivoxil (ADV)-resistant or ETV-resistant HBV at 2 and 3 years (P = 0.024, and P = 0.025 respectively). However, two patients with ADV- or ETV-resistant HBV at the baseline developed viral breakthrough during TDF-based rescue therapy. Long-term therapy with a TDF-based rescue regimen demonstrated high viral suppression in patients in whom LAM plus ADV combination therapy, ETV plus ADV combination therapy, or ETV monotherapy had failed. However, patients with ADV- or ETV-resistant HBV at the baseline may develop viral breakthrough and resistance, and careful follow-up is advised.

We determined the antiviral potency and viral breakthrough rate after 10 years of continuous entecavir treatment in patients with chronic hepatitis B (CHB) infection. The cumulative rates of undetectable hepatitis B virus DNA (HBV-DNA

Two nucleotide polymorphisms of the interleukin-28B (IL28B) gene, at rs8099917 and rs12979860, influence the response to interferon (IFN)-based therapies in patients infected with hepatitis C virus (HCV) of genotype 1. We aimed to investigate whether these polymorphisms showed complete linkage in Japanese patients.A total of 1,518 Japanese patients infected with HCV were genotyped for the two IL28B loci, and the two sets of genotypes were compared.TT at rs8099917 and CC at rs12979860 were detected in 77.7 and 76.8%, respectively, of the 1,518 patients and TG/GG and CT/TT were detected in 22.3 and 23.2%. These two sets of IL28B genotype stood in strong linkage disequilibrium (r (2) = 0.98). Discordance between the two IL28B polymorphisms occurred in 16 (1.1%) patients, and 13 (0.9%) of them possessed IFN-sensitive TT at rs8099917 and IFN-resistant CT at rs12979860. Three of these 13 patients had HCV of genotype 1b and had received pegylated-interferon and ribavirin, and none of them gained a sustained virological response. At rs8099917, IFN-resistant TG/GG were more frequent in patients infected with HCV of genotype 1 than in those infected with HCV of genotype 2 [258/1,046 (24.7%) vs. 75/441 (17.0%), p = 0.001]. The response to pegylated-interferon/ribavirin in 279 patients who were infected with HCV-1 and the response to IFN monotherapy in 361 patients who were infected with HCV-1 , was higher in those with TT than in those with TG/GG at rs8099917, as well as being higher in those with CC than in those with CT/TT at rs12979860 (p 0.001).Linkage disequilibrium between two IL28B polymorphisms at rs8099917 and rs12979860 is strong in Japanese HCV patients, but there are some discrepancies between the two sets of genotypes.

The aim of this study was to evaluate the efficacy of lamivudine therapy in elderly patients with chronic HBV infection.Patients agedor=60 years (n = 40) received lamivudine monotherapy between February 1995 and September 2005 at Toranomon Hospital. We compared the efficacy of lamivudine therapy in these patients and in 639 patients aged60 years, including 80 patients aged60 years matched for sex, hepatitis B e antigen (HBeAg) status, and hepatitis B virus (HBV) DNA level.The rates of normalization of alanine aminotransferase (ALT) level in 40 patients agedor=60 years and 639 patients aged60 years were 85% versus 76%, and 86% versus 73% at 1 and 3 years, respectively. The respective rates of loss of HBV-DNA were 74% versus 74%, and 76% versus 68% at 1 and 3 years. The respective cumulative emergence rates of the YMDD mutant were 16% and 17% at 1 year, and 46% and 49% at 3 years. In 80 patients60 years old matched for sex, HBeAg status, and HBV-DNA level, the rates of normalization of the ALT level and loss of HBV-DNA were similar to those in the 639 patients aged60 years. The emergence rate of YMDD mutants in patients agedor=60 years were similar to those in matched patients aged60 years. Multivariate analyses identified low serum bilirubin (1 mg/dl) as an independent factor associated with the emergence of the YMDD motif mutation in patients agedor=60 years.Our results suggest that treatment with lamivudine is both well tolerated and efficacious in elderly patients with chronic HBV infection.

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.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.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 indexor =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.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.

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.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.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.The response rate to 6-month IFN therapy among HBeAg-positive patients was low. However, young patients may require long-term IFN therapy.

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.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.Lymphocytes with CD8+/CD25+ markers in pretreatment blood were significantly more prevalent in acute-onset than chronic AIH patients (24% vs 14%; P0.05). 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.Activated CD8+ T lymphocytes with CD25 markers may be implicated in the development of acute-onset AIH.

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.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.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.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.

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. 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. 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. Our results suggest that lamivudine-resistant YMDD mutant viruses were present in a few patients with HBV infection who before they have been treated with lamivudine.

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.

Few studies have investigated the emergence of multidrug resistance to adefovir dipivoxil (ADV) plus lamivudine (LAM) combination therapy for patients with LAM-refractory chronic hepatitis B (CHB). In this retrospective study, we investigated the long-term clinical course of these patients with or without multidrug resistance mutations. We analyzed 406 Japanese patients with LAM-refractory CHB treated with combination therapy with follow-up for a median of 5.4 (0.5–9.5) years. Multidrug resistance of hepatitis B virus (HBV) DNA was analyzed using direct sequencing or cloning methods at baseline and viral breakthrough or insufficient decline during combination therapy. Ratio of patients with undetectable serum HBV DNA levels (

Rate of hepatitis B surface antigen (HBsAg) seroclearance was determined in 2,112 Japanese patients with chronic hepatitis B who were followed up for at least 15 years.Patients had a median age of 37 years and included 1,431 (67.8 %) men. Median values were AST/ALT, 43/62 IU/L; platelet counts, 182 × 10(3)/mm(3); HBsAg, 3,400 IU/mL; and hepatitis B virus (HBV) DNA, 6.2 log copies/mL. Factors influencing HBsAg seroclearance were evaluated by the Cox proportional model and annual rate of HBsAg seroclearance by the Kaplan-Meier life table method.The overall annual rate of HBsAg seroclearance was 1.75 % in 2,112 patients; it was 1.65 % in 1,130 untreated and 2.05 % in 982 treated patients (p = 0.289). In untreated patients, seroclearance was influenced by age, no HBV infections in third-degree or closer relatives, and HBsAg levels in univariate analysis. Seroclearance was influenced by a median age ≥50 years [relative risk (RR) 1.61 (p = 0.018)] and HBsAg ≤2,000 IU/mL [RR 1.77 (p = 0.014)] in multivariate analysis. In treated patients, age, male gender, no HBV infections in third-degree or closer relatives, interferon therapy, chronic hepatitis, high AST and γ-GTP levels, low platelet counts, hepatitis B e antigen (HBeAg)-negative status, low HBsAg levels and the wild-type precore sequence significantly influenced HBsAg seroclearance. In multivariate analysis, no family history [RR 2.22 (p = 0.006)], interferon treatment [RR 3.15 (p0.001)], and HBeAg-negative status [RR 3.75 (p0.001)] significantly influenced HBsAg seroclearance.In this retrospective cohort study, the annual rate of HBsAg seroclearance was 1.65 % in untreated patients and 2.05 % in treated patients.

Renal dysfunction and Fanconi's syndrome associated with hypophosphatemia caused by long-term administration of low-dose adefovir dipivoxil (ADV) has been reported in recent years. The aim of this retrospective study was to determine the incidence and factors associated with renal dysfunction and hypophosphatemia in patients with hepatitis B infection on long-term treatment with ADV and lamivudine (LAM).The study subjects were 292 patients treated with 10 mg/day ADV and 100 mg/day LAM for more than 6 months. We evaluated estimated glomerular filtration rate (eGFR), serum creatinine and serum phosphate level at the start of ADV and every 6 months.During a median treatment duration of 64 months, 28 (9.6 %) patients developed renal impairment (defined as eGFR50 ml/min/1.73 m(2)), and 73 (27.1 %) developed hypophosphatemia, including 14 with persistent hypophosphatemia. The cumulative incidences of renal impairment at 1, 3, and 5 years were 1.4, 7.5, 10.5 %, respectively, and those of hypophosphatemia were 6.8, 20.6, 26.7 %, respectively. Multivariate analysis identified old age, liver cirrhosis and hypertension as determinants of renal impairment, and male sex, HCC, low baseline serum phosphate as determinants of hypophosphatemia. Three of the 14 patients with persistent hypophosphatemia developed Fanconi's syndrome; their serum creatinine level remained normal, but eGFR was lower than at baseline.Long-term treatment of hepatitis B with low-dose (10 mg/day) ADV and LAM can potentially cause renal impairment and hypophosphatemia. We advocate regular monitoring of serum phosphate and evaluation of eGFR, in addition to serum creatinine, in such patients.

Few studies have investigated the long-term effects of interferon (IFN) therapy for chronic hepatitis B (CHB). In this retrospective study, we investigated the efficacy of and predictors of response to IFN therapy in CHB patients. We analyzed data for 615 Japanese CHB patients (hepatitis B e antigen [HBeAg]-positive 414, HBeAg-negative 201) treated with IFN, and conducted follow up for a median duration of 8.1 years (range 0.5–23.2). Responders were defined as patients who showed continuously normalized alanine transaminase (ALT) levels, HBeAg clearance, and low hepatitis B virus (HBV) DNA levels at 6 months post-treatment or for a span of more than 6 months until each test point at 1, 3, 5, and 10 years. The IFN response rates of all patients were 21, 18, 21, 23, and 25% at 6 months and 1, 3, 5, and 10 years, respectively. On multivariate analysis, significant determinants of the outcome of IFN therapy were as follows: at 6 months and 1 year, young age, low HBV DNA levels, and long duration of treatment; at 3 years, long duration of treatment, young age, and high level of albumin; at 5 years, high level of albumin, female, and pretreated with IFN; and at 10 years, HBeAg-negative. Sixty-nine of the 615 patients (11%) achieved seroclearance of hepatitis B surface antigen (HBsAg). On multivariate analysis, age ≥30 years, HBV genotype A, and male were all independent factors predicting the achievement of HBsAg seroclearance. HBeAg, HBV DNA level, age, sex, albumin, duration of treatment, pretreatment with IFN, and HBV genotype were important factors in determining long-term response to IFN therapy.

Severe acute exacerbation of chronic hepatitis B can sometimes occur and lead to hepatic failure and death. The objective of this study was to elucidate the predictors of progression to hepatic decompensation during severe acute exacerbation.We prospectively analyzed 37 consecutive patients with acute exacerbation of chronic hepatitis B (accompanied by jaundice and coagulopathy) for clinical outcome and factors that influenced the development of severe acute exacerbation, including viral kinetics.Fourteen (37.8%) patients progressed to severe acute exacerbation (accompanied by encephalopathy). Multivariate analysis identified serum bilirubin (5 mg/dl, P = 0.002) as a significant determinant of progression to hepatic failure and prothrombin activity (45%, P = 0.028) and as a determinant of liver-related death. The hepatitis B virus (HBV) DNA level before therapy was measured in 25 patients. HBV DNA levels increased or did not change from before commencement of treatment in all 11 patients who progressed to severe acute exacerbation. On the other hand, HBV DNA levels did not change or increased in 8 of 14 patients (57%) with acute exacerbation (P = 0.02).Serum bilirubin and prothrombin activities were significant predictors of clinical outcome in patients with severe acute exacerbation of chronic hepatitis B. Viral kinetics until commencement of therapy can predict the severity of acute exacerbation of chronic hepatitis B.

The aim of this retrospective study was to determine the incidence and characteristics of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV) antibody-positive elderly patients with chronic hepatitis without cirrhosis.The study included 65 patients who developed HCC ator=75 years of age and who received their first HCC therapy at Toranomon Hospital between 1985 and 2005. Their clinicopathological and laboratory data were analyzed and compared with those of 33 patients who developed HCC ator=50 years of age during the same period.The ratio of women patients in the elderly group (M: F = 1.1: 1) was higher than in the younger group (M: F = 5.6: 1). Also, patients in the elderly group had better liver function and prothrombin activity (P = 0.001), and lower total bilirubin (P = 0.002) than the young group. Only 11 of 65 elderly patients were diagnosed with liver cirrhosis by biopsy or peritoneoscopy before or at the time of development of HCC. Based on a discriminate score using gamma-globulin, hyaluronate level, platelet count, and sex, 27 (41.5%) elderly patients were considered to have chronic hepatitis, compared with six of 33 (18.1%) patients in the young group (P = 0.025). There were no differences in tumor number or size or tumor markers between the two groups. Survival rate was higher in the younger patients (P = 0.002), who were more likely to receive radical treatment.Our results showed distinct differences in HCV-related HCC between elderly and young patients and suggested that elderly patients (especially women) could develop HCC even when liver histology shows chronic hepatitis and lack of cirrhosis.

Background. A phase II randomized controlled trial was conducted in patients with compensated liver cirrhosis to investigate the inhibitory effect of branchedchain 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

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.Sixty-three patients with breakthrough hepatitis received a 10-mg once-daily dose of oral adefovir dipivoxil.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.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.

Hepatocellular carcinoma (HCC) caused by hepatitis B virus (HBV) often recurs after surgical or medical treatment. 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

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. Between 1989 and 2002, 1021 anti-HCV-positive patients hospitalized at Toranomon Hospital received IFN monotherapy. Among these patients, 144 were ≤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. 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 ≤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. The response of IFN monotherapy is better in patients aged ≤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.

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.Thirty-seven of 160 patients who had HCV-genotype 1b, had high virus load, and received 24-week combination therapy developed anemia with hemoglobin level10 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 their8.5 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.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 withor =10 g/dl hemoglobin was higher than that in patients with10 g/dl ( P = 0.036).Reduction of ribavirin at hemoglobin levelor =10 g/dl is suitable in terms of efficacy and side effects.

Because genotype A of hepatitis B virus (HBV) is not indigenous, there have been only few data on infection with it in Japan.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.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%]; P0.0001). 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.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.

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. 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. Lamivudine suppressed serum HBV-DNA to undetectable levels (

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.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.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).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.

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. Ninety-four individuals (M/F, 54 : 40; median age, 46 years) with normal ALT levels (

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.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.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.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.

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. 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). 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. (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. 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.