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Abstract: Objectives: Pegylated-interferon-α (IFN-α)-based therapies for viral hepatitis C (HCV) are effective, but they are associated with several adverse events (AEs). The primary objectives of this study were to quantify the burden of IFN-α–based treatment and to measure the prevalence and burden of IFN-α–related AEs in Japan. Methods: A cross-sectional survey was administered online to patients with HCV in 2013. Patients who were currently taking IFN-α–based therapy (n = 188) were compared with patients who were taking a liver protectant but not IFN-α–based therapy (n = 180) and with patients who were untreated (n = 365) on measures of health-related quality of life (using the Hepatitis Quality of Life Questionnaire, version 2), work productivity, and health care resource use, controlling for sociodemographic characteristics and health history. Among patients taking IFN-α–based therapy, the prevalence and burden of AEs was examined on the same set of health outcomes as noted above along with treatment satisfaction and adherence. Results: Compared with untreated patients, patients using IFN-α reported poorer health-related quality of life (physical component summary score, 50.13 vs. 52.04; mental component summary score, 44.12 vs. 47.97), more overall work impairment (32.73 vs. 25.64), more physician visits in the past 6 months (14.51 vs. 8.36), and an increased likelihood of an emergency room visit (odds ratio = 7.25) and hospitalization (odds ratio = 4.05) (all P < 0.05). The mean number of AEs was 6.05 for patients using IFN-α. All AEs were associated with poorer health outcomes (particularly the mental component summary score), and most were also associated with lower treatment satisfaction and medication adherence. Conclusions: A significant patient burden for IFN-α treatment itself and various AEs was observed. The results suggest that effective, non-IFN-α–based treatments may reduce the societal burden. [Copyright &y& Elsevier]

In the 2008 guidelines for the treatment of patients with cirrhosis, who are infected with hepatitis B virus (HBV), the main goal is to normalize levels of alanine and aspartate aminotransferases by eliminating HBV or reducing viral loads. In patients with compensated cirrhosis, the clearance of HBV from serum is aimed for by entecavir, as the main resort, for histological improvement toward the prevention of hepatocellular carcinoma (HCC). In patients with decompensated cirrhosis, by contrast, meticulous therapeutic strategies are adopted for the reversal to compensation, toward the eventual goal of decreasing the risk of HCC. For maintaining liver function and preventing HCC, branched chain amino acids and nutrient supplements are applied, in addition to conventional liver supportive therapies. For patients with chronic hepatitis B, separate guidelines are applied to those younger than 35 years and those aged 35 years or older. Even for patients with chronic hepatitis who are negative for hepatitis e antigen (HBeAg), but who harbor HBV DNA in titers of 7 log copies/mL or more, a “drug-free state” is aimed for by sequential treatment with interferon (IFN) plus entecavir as the first line. For patients with chronic hepatitis B aged 35 years or older, who are HBeAg-negative and carry HBV DNA in titers of less than 7 log copies/mL, long-term IFN for 24–48 weeks is adopted anew. To HBeAg-negative patients who have either or both platelet counts of less than 150 × 103/mm3 and less than 7 log copies of HBV DNA, also, long-term IFN for 24–48 weeks is indicated. [ABSTRACT FROM AUTHOR]

In the 2008 guidelines for the treatment of patients with chronic hepatitis C, pegylated interferon (Peg-IFN) combined with ribavirin for 48 weeks are indicated for treatment-naive patients infected with hepatitis C virus (HCV) of genotype 1. Treatment is continued for an additional 24 weeks (72 weeks total) in the patients who have remained positive for HCV RNA detectable by the real-time polymerase chain reaction at 12 weeks after the start of treatment, but who turn negative for HCV RNA during 13–36 weeks on treatment. Re-treatment is aimed to either eradicate HCV or normalize transaminase levels for preventing the development of hepatocellular carcinoma (HCC). For patients with compensated cirrhosis, the clearance of HCV RNA is aimed toward improving histological damages and decreasing the development of HCC. The recommended therapeutic regimen is the initial daily dose of 6 million international units (MIU) IFN continued for 2–8 weeks that is extended to longer than 48 weeks, if possible. IFN dose is reduced to 3 MIU daily in patients who fail to clear HCV RNA by 12 weeks for preventing the development of HCC. Splenectomy or embolization of the splenic artery is recommended to patients with platelet counts of less than 50 × 103/mm3 prior to the commencement of IFN treatment. When the prevention of HCC is at issue, not only IFN, but also liver supportive therapy such as stronger neo-minophagen C, ursodeoxycholic acid, phlebotomy, branched chain amino acids (BCAA), either alone or in combination, are given. In patients with decompensated cirrhosis, by contrast, reversal to compensation is attempted. [ABSTRACT FROM AUTHOR]

Abstract: Amino-acid substitution at positions 70 and 91 of the hepatitis C virus (HCV)-1b core region is a factor that contributes to a non-virological response in treatment using interferon/ribavirin combination. In this study, a system was developed for detection of nucleotide sequence variation in the core region that is simpler and less expensive than the current direct sequencing method. A PCR detection method using mutation-specific primers was developed, and amino acids at positions 70 and 91 were identified. The protein type was determined based on band intensity in electrophoresis, and classified into wild (70:R, 91:L), mutant (70:Q/H, 91:M) and competitive types. The detection rate, sensitivity and reproducibility were investigated in 108 patients with HCV-1b who were treated with interferon/ribavirin combination therapy, and correlation with the results of direct sequencing was examined. The detection rate was 94.4%, the sensitivity was 10KIU/mL, the reproducibility was high, and in detectable cases the consistency with direct sequencing was 97.1%; inconsistency was noted in two competitive-type cases and in one case with an unusual amino-acid substitution. The results suggest that the system described in this paper provides an effective, simple and low-cost approach to detection of nucleotide sequence variation in the core region of HCV-1b. [Copyright &y& Elsevier]

Background and Aims: Predictive factors for hepatocarcinogenesis following eradication of hepatitis C virus (HCV) RNA by antiviral therapy with direct-acting antivirals are unknown. Especially the impact of treatment with or without interferon on hepatocarcinogenesis is not clear. Methods: A total of 958 patients with HCV genotype 1-related chronic liver disease and a sustained virological response defined as negative HCV RNA 24 weeks after cessation of antiviral therapy with direct-acting antivirals (triple therapy of NS3/4A protease inhibitor/peginterferon/ribavirin or all-oral combination therapy with NS3/4A protease inhibitor plus NS5A inhibitor) were included in a retrospective study. None of the patients had hepatocellular carcinoma before and during antiviral therapy. Results: In all, 14 patients developed hepatocellular carcinoma during follow-up, and the development rate per 1,000 person-years was 7.35. The cumulative hepatocarcinogenesis rates were 4.2 and 4.2% at the end of 5 and 7 years, respectively. Multivariate analysis identified fibrosis 4 (FIB4) index (= 2.7) and body mass index (= 23.0) as determinants of hepatocarcinogenesis, but they did not identify the treatment regimen. In patients with a FIB4 index = 2.7, the hepatocarcinogenesis rates with the interferon regimen were not different from those for the regimen without interferon, regardless of gender. Conclusion: Liver fibrosis and body mass index, but not treatment regimen, are important predictors of hepatocarcinogenesis following eradication of HCV RNA by direct-acting antivirals. [ABSTRACT FROM AUTHOR]

Aim This study evaluated the efficacy of interferon plus ribavirin and examined whether interleukin 28B ( IL28B) polymorphism influenced treatment outcome in Japanese patients with hepatitis C virus ( HCV)-related liver cirrhosis ( LC). Methods Fourteen collaborating centers provided details of 261 patients with HCV-related LC undergoing treatment with interferon plus ribavirin. Univariate and multivariate analyses were used to establish which factors predicted treatment outcome. Results Eighty-four patients (32.2%) achieved a sustained virological response ( SVR). SVR rates were 21.6% (41/190) in patients with HCV genotype 1 with high viral load ( G1H) and 60.6% (43/71) in patients with non- G1H. In patients with non- G1H, treatment outcome was effective irrespective of IL28B polymorphism. In those with G1H, SVR was achieved in 27.1% of patients with the IL28B rs8099917 TT allele compared with 8.8% of those with the TG/ GG alleles ( P = 0.004). In patients with G1H having TT allele, treatments longer than 48 weeks achieved significantly higher SVR rates than treatments less than 48 weeks (34.6% vs 16.4%, P = 0.042). In patients with G1H having TG/ GG alleles, treatments longer than 72 weeks achieved significantly higher SVR rates than treatments less than 72 weeks (37.5% vs 4.1%, P = 0.010). Conclusion Interferon plus ribavirin treatment in Japanese patients with non- G1H HCV-related LC was more effective than those with G1H and not influenced by IL28B polymorphism. In those with G1H, IL28B polymorphism may predict SVR and guide treatment duration: SVR rates were higher in those with the TT allele treated for more than 48 weeks and those with the TG/ GG alleles treated for more than 72 weeks. [ABSTRACT FROM AUTHOR]

Background: The significance of anti-inflammatory therapy has not been fully evaluated in hepatitis C virus (HCV)-related cirrhosis. Patients and Methods: We analyzed stepwise progression rates from cirrhosis to hepatocellular carcinoma (HCC) and to death using a Markov model in 1,280 patients with HCV-related cirrhosis. During the observation period, 303 patients received interferon and 736 received glycyrrhizin injections as anti-inflammatory therapy. Results: In the entire group, annual progression rates from cirrhosis to HCC and from cirrhosis to death were 6.8 and 1.9%, and the rate from HCC to death was 19.0%. When sustained virological response (SVR) or biochemical response (BR) was attained with interferon, the annual rate to HCC decreased to 2.6%. On the contrary, the progression rates to HCC and to death in the patients without SVR and BR were 7.2 and 2.0%, respectively (p < 0.0001). Continuous interferon administration significantly decreased the carcinogenesis rate to 5.5% (p = 0.0087). In the analysis of the remaining patients with high alanine transaminase of 75 IU/l or more but without interferon response or without interferon administration, glycyrrhizin injection significantly decreased annual non-progression probability (no glycyrrhizin 88.0% vs. glycyrrhizin therapy 92.3%, p = 0.00055). Conclusion: Glycyrrhizin injection therapy is useful in the prevention of disease progression in interferon-resistant or intolerant patients with HCV-related cirrhosis. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Clearance of hepatitis B surface antigen (HBsAg) is considered the ultimate goal in chronic hepatitis B treatment. One treatment option is long-term nucleot(s)ide analog (NA) therapy. We followed a group of long-term NA therapy patients to evaluate the efficacy of this treatment in promoting clearance and longitudinal declines of HBsAg. Method: The study included 791 NA therapy patients who received lamivudine as their first drug. At the baseline, 442 patients were hepatitis B e antigen (HBeAg)+ and 349 were HBeAg−. All analyses were performed after separating the HBeAg+ and HBeAg− cohorts. Cox proportional hazards models were used to determine which factors were associated with HBsAg clearance. Results: HBsAg clearance was observed in 18 (4.1 %) of the HBeAg+ patients and 20 (5.7 %) of the HBeAg− patients at baseline, giving seroclearance rates of 6.4 and 6.9 %, respectively, over the nine-year study period. HBsAg clearance was influenced by several independent factors that varied according to HBeAg cohort. For HBeAg+ patients, these included previous interferon therapy, infection with hepatitis B virus (HBV) genotype A, a ≥0.5 log IU/mL decline in HBsAg level within six months, and clearance of HBeAg at six months. For HBeAg− patients, these included infection with HBV genotype A, decline in HBsAg at six months, and a baseline HBsAg level of <730 IU/mL. Conclusion: This study suggests that both direct antiviral potential and host immune response are needed to achieve HBsAg clearance by NA therapy. Viral genotype strongly influenced HBsAg clearance during NA therapy. [ABSTRACT FROM AUTHOR]

Abstract: Hepatitis C virus (HCV) is a major worldwide public health problem, and mutations at amino acids 70 and 91 in the genotype 1b core region predict the effectiveness of combination therapy with peginterferon and ribavirin. An assay based on the Q-Invader technology was developed to determine the relative ratios of the mutant to wild-type virus with high sensitivity. The assay detected a minor type plasmid that constituted only 1% of a mixture of plasmids containing wild-type and mutant sequences. The calculated ratios agreed with those of the template DNA. A total of 123 serum samples of HCV in Japan were examined with the Q-Invader assay. The Q-Invader assay detected all of the mutations that were detected by direct sequencing and even some mutants that direct sequencing could not. PCR with mutant specific primers confirmed those mutations found by the Q-Invader assay and not by direct sequencing. The Q-Invader assay, thus, is a useful tool for detecting mutations at positions 70 and 91 in the HCV-1b core region. [Copyright &y& Elsevier]

Objective: Anticarcinogenic activity of ribavirin combination therapy for hepatitis C virus (HCV)-related compensated cirrhosis is still unclear. Methods: In study 1, in 157 consecutive patients with HCV-related compensated cirrhosis, treatment efficacy with interferon plus ribavirin therapy was evaluated for 48 weeks of HCV genotype 1b (HCV-1b) or 24 weeks of HCV-2a/2b. In study 2, in 185 consecutive patients with HCV-related compensated cirrhosis, who showed no sustained virological response following the first course of interferon monotherapy, hepatocarcinogenesis rates were evaluated according to the additional treatment, and they were classified into three groups: no treatment, interferon monotherapy, and ribavirin combination therapy. Results: In study 1, in HCV-1b, rates of sustained virological response and sustained biochemical response were 21 and 56%, respectively. In HCV-2a/2b, rates of sustained virological response and sustained biochemical response were 70 and 78%, respectively. In HCV-1b, sustained biochemical response rates were significantly higher than those of sustained virological response. In study 2, the hepatocarcinogenesis rates in ribavirin combination therapy were significantly lower than those in interferon monotherapy and no treatment, respectively. Conclusion: Ribavirin combination therapy for HCV-related compensated cirrhosis reduces the risk of hepatocarcinogenesis in comparison with interferon monotherapy, and higher rates of sustained biochemical response might be associated with lower hepatocarcinogenesis rates. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Substitution of amino acid 70 and/or 91 in the core region of hepatitis C virus (HCV) genotype 1b (HCV-1b) is an important predictor of hepatocellular carcinoma (HCC), but its impact on HCC in nonresponders to interferon (IFN) and ribavirin (RIB) combination therapy is not clear. Methods: A total of 292 patients with HCV-1b-related chronic liver disease who did not achieve a sustained virological response to 24-48 weeks of IFN+RIB combination therapy were included in a follow-up study to investigate the risk factors for HCC. Results: Sixteen patients developed HCC during the follow-up. The cumulative HCC rates were 5.0, 13.1 and 16.9% at the end of 3, 5 and 7 years, respectively. Multivariate analysis identified substitution of core amino acid 70 (Gln70/His70; hazard ratio 4.64, p = 0.018) and low serum levels of high-density lipoprotein cholesterol (<50 mg/dl; hazard ratio 9.35, p = 0.041) as determinants of HCC. Gender, stage of fibrosis and interleukin-28B showed no such relationship. Conclusions: Amino acid substitution in the core region of HCV-1b and low serum levels of high-density lipoprotein cholesterol are significant and independent predictors of HCC in nonresponders to IFN+RIB combination therapy. These results emphasize the importance of viral and lipid metabolic factors in the development of HCC after combination therapy. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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 = 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). Conclusions: 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. [ABSTRACT FROM AUTHOR]

Objective: To evaluate predictive factors of treatment efficacy to interferon (IFN)/ribavirin in patients infected with HCV genotype 1b (HCV-1b). Methods: This study investigated pretreatment predictors, including viral- (aa substitutions in core aa 70/91 and NS5A-ISDR/IRRDR) and host-related factors (genetic variation near IL28B gene), to 48-week IFN/ribavirin in 490 Japanese adults infected with HCV-1b. Results: The proportion of patients who showed end-of-treatment response (ETR), sustained virological response (SVR), and SVR after ETR was 76, 54, and 76%, respectively. There was a significant positive correlation between the number of aa substitutions in ISDR and those in IRRDR. Concerning the substitution of core aa 91, the number of aa substitutions in ISDR/IRRDR of patients with Leu91 was significantly higher than that of patients with Met91. Furthermore, levels of viremia were influenced by aa substitutions in core aa 91 and ISDR/IRRDR. By multivariate analysis, rs8099917 genotype was an important predictor of ETR and SVR. With regard to viral factors, core aa 70/91 was an important predictor of ETR, and SVR after ETR. ISDR was an important predictor of SVR, and SVR after ETR. Conclusion: aa substitution in core/NS5A region and genetic variation near IL28B were important predictors of treatment efficacy to IFN/ribavirin. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background & Aims: Cdc42 is a Rho family GTPase protein and was recently implicated in mediating hepatitis C virus (HCV) infectivity. This study examines the association between Cdc42-related gene and interferon (IFN) therapy in HCV patients. Methods: We analyzed the associations between the outcome of IFN therapy and 17 tagging single nucleotide polymorphisms (SNPs) within two genes involved in Cdc42 signaling (CDC42 and ACK1). A total of 295 out of the 409 study subjects were sustained responders (SR) and 114 were non-responders (NR). Replication was performed using an independent set of 794 IFN-treated patients. Results: SNP rs2278034 [A/G] in intron 11 of activated Cdc42 associated tyrosine kinase (ACK) 1 was associated with the outcome of IFN therapy (p =6.4×10−4). Replication analysis confirmed the association (p =2.2×10−3) for patients treated with IFN monotherapy, but the association was not significant for pegylated-IFN-plus ribavirin therapy. Analysis using published HapMap expression data revealed that ACK1 expression correlates with IFN-stimulated gene (ISG) expression independently of ethnicity, but the relationship between rs2278034 and ACK1 expression was observed only within Asian populations. Over-expression of ACK1, but not the kinase-inactive mutant, increased ISG transcription in Huh7 cells. ACK1 expression enhanced the IFN-stimulated response element (ISRE) and interferon-γ-activated site (GAS) promoter activity through tyrosine phosphorylation of signal transducers and activators of transcription (STAT) 1. Furthermore, ACK1 over-expression in HCV-N replicon cells inhibited HCV replication. Conclusions: SNP rs2278034 in ACK1 is associated with IFN therapy outcome in patients with HCV. ACK1 may play a role in innate and IFN-induced antiviral action against HCV. [ABSTRACT FROM AUTHOR]

Objective: In treatment-resistant patients with genotype 2 chronic hepatitis C the suitable treatment duration is still unclear. The aims were to investigate extending combination therapy with peginterferon plus ribavirin for genotype 2. Methods: 7 patients infected with genotype 2 at a high viral load and who did not achieve a sustained virological response (SVR) with the first course of 24-week IFN plus ribavirin were recruited into the study protocol with a total of 48 weeks of peginterferon plus ribavirin therapy. Results: SVR was achieved in 5 of 7 patients (71%). All 4 patients (100%) who were in relapse with the first course achieved SVR. Only 1 of 3 patients (33%) who had a non-virological response (NVR) with the first course achieved SVR. All 4 patients who had an early virological response (EVR) with the first course achieved EVR and SVR. Two of 3 patients who had no EVR with the first course also did not achieve EVR and SVR. One patient who had no EVR or a NVR during the first course achieved EVR and SVR with the second course. Conclusions: Our results suggest that extending combination therapy for genotype 2 chronic hepatitis C might be useful for patients who relapse following 24-week combination therapy. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Substitution of amino acids (aa) 70 and 91 in the core region of HCV genotype 1b is a useful pretreatment predictor of poor response to interferon + ribavirin combination therapy, but the impacts of aa substitutions in the core region of HCV genotype 2a are still not clear. Methods: 154 consecutive Japanese adults with a high viral load (≥100 kIU/ml) of genotype 2a who could complete combination therapy for 24 weeks were evaluated. To examine the differences in virological characteristics between non-sustained virological response (non-SVR) and rapid responder (SVR patients who could achieve a HCV-RNA-negative status within 8 weeks), 86 patients could be analyzed by pretreatment substitution patterns of the core region. Results: SVR was achieved in 127 of 154 patients (83%), and rapid response in 113 of 127 (90%). In all 154 patients, multivariate analysis identified younger age, lower level of viremia, and higher level of albumin as significant determinants of SVR. As significant determinants of rapid response in 86 patients, multivariate analysis identified substitution of aa 4 (non-asparagine) in addition to the significant determinants of SVR. Conclusions: Our results suggest that the aa substitution pattern of the core region in patients with a high titer of genotype 2a may partly affect the virological response to combination therapy. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy and safety of the triple treatment with telaprevir (MP-424), pegylated interferon (PEG-IFN) and ribavirin during 12 weeks on-treatment. Methods: The triple treatment was given to 20 patients with chronic hepatitis C who had been infected with hepatitis C virus (HCV)-1b in high viral load (median: 6.8 log IU/mL [range: 5.5–7.2]), with a median age of 54 years (range: 36–65 years). They were followed for early dynamics of HCV RNA in serum during 12 weeks and side-effects. Results: HCV RNA levels decreased by 4.8 logs by 7 days and 5.5 logs by 14 days. HCV RNA disappeared in 50% (10/20) at 2 weeks, 79% (15/19) at 4 weeks, 88% (14/16) at 6 weeks, 94% (15/16) at 8 weeks and 100% (13/13) at 12 weeks. HCV RNA disappeared equally frequently in 10 treatment-naive patients, six non-responders to IFN monotherapy and four non-responders to PEG-IFN and ribavirin. It was no different in the patients with and without amino acid substitutions reducing the response to IFN. The treatment was withdrawn in seven (35%) patients, mostly due to reduced hemoglobin of less than 8.5 g/dL, of whom six (86%) remained clear of HCV RNA at 12 weeks. Conclusion: HCV RNA was lost from serum rapidly and universally in patients infected with HCV-1b in high viral loads by the triple treatment. Because an early loss of HCV RNA correlates with high rates of sustained virological response (SVR), it would increase SVR substantially, and merit the patients who have not responded to previous therapies. [ABSTRACT FROM AUTHOR]

Abstract: Background: The significance of antiviral therapy for elderly patients with chronic hepatitis C virus (HCV) infection has not been elucidated. Patients and Methods: Among 5645 patients with HCV-related chronic liver disease, the prognosis of 1917 elderly patients aged 60 years or more was analyzed. A total of 454 patients underwent interferon (IFN) therapy. By using multivariate analysis, carcinogenesis and survival were analyzed according to initial findings. Results: At 10 and 15 years, cumulative survivals in untreated elderly patients were 90.7% and 72.7% in the high platelet (≥150,000/mm3) group, 78.6% and 47.8% in the intermediate (100,000-149,000/mm3) group, and 52.5% and 25.0% in the low platelet group (<100,000/mm3), respectively. At 5 and 10 years, hepatocarcinogenesis rates in the intermediate and low platelet groups were 10.9% and 21.6% in the IFN group (N=217) and 19.5% and 43.0% in the untreated group (N=459), respectively (P =.0005). IFN independently decreased carcinogenesis risk with a hazard ratio of 0.56 (P =.035). In the high platelet group, 5- and 10-year carcinogenesis rates were 3.7% and 8.3% in the IFN-treated group (N=228) and 5.1% and 14.0% in the untreated group (N=585), respectively (P =.69). IFN treatment significantly increased cumulative survivals in the lower platelet subgroup (P =.0001) but did not affect the higher platelet subgroup (P =.08). IFN was independently associated with a longer survival in the lower platelet subgroup (hazard ratio 2.33, P =.005). Conclusion: In elderly patients with chronic HCV, IFN for a subgroup with intermediate and low platelet counts had significant advantages in regard to hepatocarcinogenesis and survival. [Copyright &y& Elsevier]

Objectives: The aim of this study was to elucidate the efficacy of interferon (IFN) therapy in liver cirrhosis Japanese patients with genotype 1b and low virus load. Methods: The present study was a retrospective cohort study. Inclusion criteria were liver cirrhosis, HCV genotype 1b, HCV RNA of <100 KIU/ml, and natural IFN-α monotherapy for 24 weeks. In 23 consecutive patients who satisfied the above criteria the efficacy and side effects of IFN were examined. Independent factors that might have influenced a sustained virologic response (SVR) were studied using logistic regression analysis. Results: The clinical patient profiles were as follows: median (range) age 52 (37–69) years; male/female 18/5, and median (range) HCV RNA 52 (<5–92) KIU/ml. Eight of the 23 patients (34.8%) had SVR by intention-to-treat analysis. Logistic analysis indicated that an HCV RNA level of <50 KIU/ml was associated with SVR (p = 0.049). The median (range) HCV RNA levels were 28 (<5–68) KIU/ml in patients with SVR and 60 (6–92) KIU/ml in patients without SVR. Conclusions: 24-week IFN monotherapy is a suitable therapy for type C cirrhotic patients with genotype 1b and an HCV RNA level of <50 KIU/ml. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Purpose: A high prevalence of malignant lymphoma among patients with hepatitis C virus (HCV) infection has been reported. The aim of this retrospective study was to determine the incidence of malignant lymphoma and the relationship between malignant lymphoma and viral elimination in patients with HCV. Method: We studied 501 consecutive HCV-infected patients who had never received interferon therapy and 2708 consecutive HCV-infected patients who received interferon therapy. Results: In the non-interferon group, the cumulative rates of malignant lymphoma development were 0.6% at the 5th year, 2.3% at the 10th year, and 2.6% at the 15th year. The cumulative rates of malignant lymphoma development in interferon-treated patients with sustained virologic response were 0% at the 5th year, 0% at the 10th year, and 0% at the 15th year. The cumulative rates of malignant lymphoma development with persistent infection were 0.4% at the 5th year, 1.5% at the 10th year, and 2.6% at the 15th year. The malignant lymphoma development rate was higher in patients with persistent infection than in patients with sustained virologic response (P =.0159). The hazard ratio of lymphomagenesis in 1048 patients with sustained virologic response was significantly lower than in patients with persistent infection (hazard ratio: 0.13; P =.049). Conclusion: Our retrospective study is the first to determine the annual incidence of malignant lymphoma among patients with HCV at 0.23%. Our results indicate that sustained virologic response induced by interferon therapy protects against the development of malignant lymphoma in patients with chronic HCV. [Copyright &y& Elsevier]

Background: We assessed the efficacy and anticarcinogenic effects of interferon (IFN) therapy in patients with hepatitis C virus (HCV)-related cirrhosis. Methods: The study subjects were 123 Japanese patients with HCV-related cirrhosis with genotype 1b low viral load or genotype 2 who received IFN from 1989 to 2005 (18 patients continue to receive IFN therapy). They included 81 men and 42 women aged 29–74 years (median, 56 years). Results: Univariate analysis identified four parameters that significantly influenced SVR; viral load (low HCV concentration, P < 0.001), duration of IFN therapy (≥ 52 weeks, P = 0.029), daily dose of IFN (≥ 6 million units, P = 0.018), induction therapy (presence, P = 0.010) and choline esterase (> 1.0 ΔpH, P = 0.037). Multivariate analysis identified viral load (risk ratio = 6.329, P < 0.001) and daily dose of IFN (risk ratio = 2.62, P = 0.042) as two independent parameters thatinfluenced SVR. During the observation period, newly developed hepatocellular carcinoma (HCC) was detected in 22 patients. The rates of development of HCC in patients with SVR were 5.8% at the fifth year and 10.3% at the 10th year, compared with 25.8% at the fifth year and 42.5% at the 10th year in non-SVR patients. Multivariate analysis showed that IFN efficacy (SVR) was the only independent factor of hepatocarcinogenesis (hazard ratio: 0.185, 95% confidence interval: 0.042–0.810, P = 0.025) Conclusion: Among patients with HCV-related cirrhosis, the rate of development of HCC is significantly less in patients with SVR. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to elucidate the long-term outcome after interferon (IFN) therapy in chronic hepatitis C elderly patients. Methods: We studied the incidence of hepatocellular carcinoma (HCC) and survival probability after the initiation of IFN therapy in 500 Japanese chronic hepatitis C patients >60 years. The mean age of initiation of IFN was 63 years and the mean follow-up period was 7.4 years. Cox proportional hazard regression analysis was used to evaluate the long-term outcome after initiation of IFN therapy.Sustained virological response (SVR) was defined as negative HCV-RNA by RT-nested PCR 6 months after the completion of long-term IFN therapy. Non-response (NR) was applied to patients who did not show SVR. Hepatic fibrosis was defined as the fibrosis score (score 0–4) according to Knodell et al. Results: 140 patients (28%) had an SVR and 360 patients (72%) had an NR. 71 of 500 patients developed HCC during follow-up. The cumulative incidence of HCC was 9.6% at the 5th year, 17.4% at the 10th year, and 31.3% at the 15th year. HCC developed with significance when: (1) HCV was not cleared after IFN therapy (p < 0.0001), (2) sex was male (p < 0.0001), and (3) staging of liver fibrosis was >2 (p = 0.008). 53 of the patients died. The cumulative survival probability was 95.7% at the 5th year, 86.4% at the 10th year, and 78% at the 15th year. Patients achieved a long survival with significance when: (1) staging of liver fibrosis was 1 (p < 0.0001), (2) HCV was cleared after IFN therapy (p = 0.034), and (3) sex was female (p = 0.015). Conclusion: Chronic hepatitis C patients with clearance of HCV after IFN therapy had a significantly reduced risk of HCC appearance and achieved prolonged survival even if they are ≥60 years. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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 <6.0 log copies/ml was considered low. 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. 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]

Objective: We assessed the efficacy and safety of interferon (IFN) monotherapy in 84 elderly patients aged ≥65 years with chronic hepatitis C in a retrospective cohort study. Methods:Twenty-two of the 84 elderly patients were treated with IFN at a dose of 6 million units daily for 6–8 weeks, 18 patients were treated 2–3 times a week for 24 weeks and 44 patients were treated daily for 2–8 weeks and 2–3 times a week for 16–24 weeks. Results: A sustained virological response (SVR) occurred in 35.7% (30/84) of the patients by intention-to-treat analysis. Multivariate analysis showed that patients achieved a significant SVR when: (1) serum HCV-RNA level before IFN therapy was <100 KIU/ml (p < 0.0001) and (2) staging of liver fibrosis was mild (p = 0.040). Eleven (13.1%) patients discontinued the IFN regimen due to adverse events. Regarding factors predicting discontinuation of IFN, univariate analysis showed that patients aged >70 years were prone to drop out of therapy due to adverse events in IFN therapy (p = 0.009). Conclusion: Our results suggest that IFN administration is suitable for 65- to 70-year-old patients with chronic hepatitis C without genotype 1b and high virus load. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The anticarcinogenic capacity of interferon (IFN) was assessed in a cohort of Japanese patients with chronic hepatitis C en masse. Patients and Methods: The rate of hepatocarcinogenesis was analyzed in 2,166 patients with chronic hepatitis C, of whom 1,654 had received IFN therapy while 512 had not. Results: Crude rates of hepatocarcinogenesis in treated and untreated patients were 2.6 and 4.6% at the end of the 5th year, 5.8 and 12.7% at the 10th year and 13.9 and 23.9% at the 15th year (after completion of IFN therapy for those treated) (p < 0.001). IFN decreased the hazard ratio of carcinogenesis to 0.42 (p < 0.001) in multivariate analysis with adjustments for significant covariates including fibrotic stage, γ-glutamyl transpeptidase level, gender, platelet count and age. Among the 1,654 patients treated with IFN, 606 (36.6%) achieved persistent loss of hepatitis C virus (HCV) RNA and an additional 266 (16.1%) gained normal levels of alanine aminotransferase without loss of HCV RNA for 6 months or longer after the completion of IFN therpay. Cumulative rates of hepatocarcinogenesis in sustained virological responders and biochemical responders were 1.4 and 2.0% at the end of the 5th year, 1.9 and 3.6% at the 10th year and 1.9 and 7.5% at the 15th year, respectively. The hazard ratio of sustained virological response was 0.10 (p < 0.001), and that of biochemical response was 0.12 (p < 0.001). Normalization of aminotransferase levels after IFN therapy without loss of serum HCV RNA decreased hepatocarcinogenesis. Conclusion: IFN significantly decreased the rate of hepatocarcinogenesis in patients with chronic hepatitis C as a whole in Japan, even in those who fail to clear HCV RNA from serum. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Background/Aims: Controversy over the selection of patients and optimum therapeutic method for acute hepatitis C has continued. The aims of this study were to investigate the source of infection, and to evaluate the timing of interferon (IFN) therapy in patients with acute hepatitis C in Japan. Methods: The records of 102 patients from 12 facilities in Japan who developed acute hepatitis C after 1990 were investigated. In the patients treated with IFN, we performed multivariate analysis to investigate factors related to sustained virological response (SVR). Results: Medical procedure was the most common source of infection, accounting for 32.4% in the 102 patients (33/102). Of 81 patients treated with IFN, 71 patients were followed after IFN therapy, and 57/71 (80.3%) had SVR. The SVR rate was significantly higher in patients treated with IFN within 24 weeks from onset of symptoms than the SVR rate in those treated after 25 weeks (P =0.0016). Multivariate analysis revealed that only the duration between onset of symptoms and initiation of IFN therapy (within 24 weeks) was related to SVR. Conclusions: Our multicenter cooperative survey revealed that medical procedure was the most frequent source of infection in acute hepatitis C. As concerns the therapy, interferon treatment should be initiated within 24 weeks after onset of symptoms. [Copyright &y& Elsevier]

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

Objective: The purpose of this clinical retrospective cohort study was to determine the most suitable ribavirin concentration on combination therapy of interferon (IFN)-ribavirin. Methods: Entry criteria were serum HCV-RNA level ≥100 KIU/ml, HCV-genotype 1b, chronic hepatitis, and initial combination treatment of IFN-α-2b (6 million units daily for 2 weeks and then 3 times weekly for 6 weeks) and ribavirin (600–800 mg/day) for 8 weeks without stopping or decreasing the dosage of IFN and/or ribavirin. Sixty-eight consecutive patients who satisfied the above criteria were given maintenance therapy for another 16 weeks. Results: A sustained virological response (SVR) rate of 25.0% (17/68) was seen in all subjects. The SVR rate was 44.0% (11/25) in the high ribavirin group with a serum ribavirin concentration of ≥3,000 ng/ml at 8 weeks after initiation of combination therapy. SVR was significantly dependent at a serum ribavirin level of ≥3,000 ng/ml (p = 0.005). The incidence of discontinuations and dose modifications for combination therapy in patients having a serum ribavirin concentration of ≥3,500 ng/ml 8 weeks after initiation of therapy was 57.1% (4/7). This value was statistically higher than that in patents with <3,500 ng/ml (p = 0.033). Conclusion: Our results showed that the most suitable serum ribavirin concentrations are from 3,000 to 3,500 ng/ml 8 weeks after initiation of combination therapy. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

To elucidate the influence of serum hepatitis B virus (HBV) load on hepatocellular carcinogenesis in cirrhotic patients, HBV-DNA was sequentially measured. In a nested, case-control study using 96 patients without antiviral therapy, high HBV-DNA (≥103.7 copies/ml) in the last 3 years was significantly associated with carcinogenesis (a patient group without hepatocellular carcinoma (HCC) development; 0/48 vs. a patient group with eventual HCC development; 22/48, p < 0.0001). No patient with a continuously low HBV-DNA for the last 3 years developed HCC. Persistence of high HBV-DNA concentration suggested an increased risk of carcinogenesis. In a retrospective cohort study using 57 patients with interferon therapy, HCC developed in 2 (8.0%) of the 25 patients with HBV-DNA loss, while carcinogenesis was found in 11 (34.4%) of 32 patients without HBV-DNA loss (Fisher’s exact test, p = 0.026). A significant decrease or loss of serum HBV-DNA stops HCC development, and its sequential analysis could be very useful both in the prediction and early detection of small HCC. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Because the anti-carcinogenic effect and mechanism of interferon (IFN) in patients with hepatitis B virus (HBV)-related cirrhosis have not been elucidated, quantitative analysis of HBV-DNA concentration was carried out sequentially.Of 60 consecutive patients with cirrhosis who began IFN therapy between 1986 and 1990, 57 patients were completely observed for the appearance of hepatocellular carcinoma (HCC). All patients underwent intermittent administration of IFN for a median period of 18 months. HBV-DNA was quantified using transcription mediated amplification and hybridization protection assay. A HBV-DNA count<3.7 log-genome equivalent (LGE)/mL (equivalent to 103.7 or 5000 copies/mL) was considered to be a negative value.Of 25 patients who had HBV-DNA loss after IFN therapy, nine lost HBV-DNA during the therapy and 16 lost HBV-DNA after cessation of the therapy. The other nine patients showed a transient loss of HBV-DNA, and the remaining 23 retained persistently positive HBV-DNA during and after therapy. Although HCC developed in two (8.0%) of the 25 patients with HBV-DNA loss, carcinogenesis was found in 11 (34.4%) of 32 patients without HBV-DNA loss (Fisher's exact test,P = 0.026). In the two exceptional patients, HCC was detected at 1.2 and 3.6 years after loss of HBV-DNA, respectively. When the HBV-DNA concentration decreased by 2 LGE/mL (decrease to 1/100) at 6 months after initiation of interferon, HBV-DNA became negative eventually in 15 (60.0%) of 25 patients.A significant decrease or loss of serum HBV-DNA prevents development of HCC, and sequential analysis of HBV-DNA could be very useful in both the prediction and the early detection of small HCC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Although hepatocellular carcinoma does develop after sustained response to interferon (IFN) in patients with chronic hepatitis C, details on the clinical prognosis have not been elucidated yet. Patients and Methods: Among 12 patients with liver cancer arising after hepatitis C virus (HCV) elimination, 10 patients with potentially curative ablation were prospectively analyzed. Matched control patients were chosen from a patient list of surgical resection on the basis of age, sex, cancer stage, and severity of liver disease. Control patients were recruited with a ratio of 1:4, and all the control patients had positive HCV-RNA. Results: One (10.0%) of 10 patients with virus elimination and 31 (77.5%) of 40 control patients eventually developed cancer recurrence during the same follow-up period. Cancer recurrence rates of the 10 cases and 40 controls were 10.0 and 55.3% at the 3rd year, and 10.0 and 72.2% at the 5th year, respectively. The recurrence rate in the 10 cases of virus elimination was significantly lower than that of control patients (p = 0.012). Conclusion: Although hepatocellular carcinogenesis after elimination of HCV-RNA by IFN treatment did rarely occur, the recurrence rate after radical therapy was significantly lower than that of untreated or non-responsive patients.Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We evaluated the efficacy of long-term interferon (IFN) therapy in patients with e-antigen-positive chronic hepatitis B. The study design was a prospective, randomized controlled clinical trial. Fifty-three patients were randomly assigned into one of two groups, treated with 3 million units (MU) of IFN (low dose group; n=27) or 6 MU IFN (high dose group; n=26), administered twice weekly for 52 weeks. Responders were defined as patients whose hepatitis B virus (HBV)-DNA level, determined by branched DNA signal amplification and hepatitis B e-antigen (enzyme immunoassay) were negative and whose serum alanine transaminase (ALT) levels fell to within the normal range (ALT<50 IU/l) at 6 month after termination of IFN therapy. One patient in high dose group was dropped out because of transfer. Remainder 52 patients were examined by intention-to-treat (ITT) analysis. The response rates by ITT analysis were 40.7% (11/27) in low dose group and 20% (5/25) in high dose group. The difference between low and high dose group was not statistically significant. Univariate analysis of clinical factors that contribute to the response demonstrated that IFN therapy had a significant effect when, (1) the serum HBV-DNA level was <200 Meq/ml prior to the commencement of IFN therapy (P=0.0327). (2) Transient acute exacerbation of ALT was present during or after IFN therapy (P=0.0311). Multivariate analysis showed that the risk ratio for the development of response in patients with serum HBV-DNA level of less than 200 Meq/ml was 3.60 compared with patients with that of 200 Meq/ml or more than 200 Meq/ml (95% CI, 1.012–12.81). In conclusion, the results of this trial show that: (1) long-term twice weekly IFN therapy could be a worthwhile strategy for e-antigen-positive chronic hepatitis B patients with serum HBV-DNA level of less than 200 Meq/ml and (2) patients with transient acute exacerbation of ALT during or after IFN therapy could often respond well after exacerbation of ALT. [Copyright &y& Elsevier]

Abstract Psychiatric symptoms during interferon (IFN) therapy for viral hepatitis have been a crucial problem in consultation-liaison psychiatry. However, there have been few studies on psychiatric management for these symptoms and their prognosis. Among 943 patients who were treated with IFN for chronic hepatitis C between 1991 and 1995, 43 patients (4.6%) developed psychiatric symptoms during IFN treatment. Three patients (0.3%), with pre-existing psychiatric disorders showed aggravated symptoms and were excluded from the study. All three patients were able to finish the IFN therapy with psychiatric management. Forty patients (4.2%) manifested psychiatric symptoms induced by IFN. Thirteen patients (1.4%) were diagnosed as anxiety disorder and 21 patients (2.2%) revealed mood disorder with depressive features. There were other psychiatric disorders in six patients (0.6%), including psychotic disorder with delusions/hallucinations in four patients (0.4%), mood disorder with manic features in one patient (0.1%) and delirium in one patient (0.1%). Women developed psychiatric symptoms significantly more than men. Ten of 40 patients (25%) stopped IFN treatment because of manifesting psychiatric symptoms induced by IFN. Twelve patients (30%) required psychiatric treatment for more than 24 weeks after ceasing IFN, and seven patients still had anxiety, insomnia and mild hypothymia at the end of the present study. Statistical analysis revealed that IFN-β therapy and psychiatric manifestations including psychotic symptoms, delirium and manic symptoms were significantly related to long-term psychiatric problems. There are considerable numbers of patients who have required long-term psychiatric management even after cessation of IFN treatment. [ABSTRACT FROM AUTHOR]

Abstract: Background: This retrospective cohort study assessed the impact of diabetes mellitus on hepatocarcinogenesis and determined the predictors of hepatocarcinogenesis in noncirrhotic, interferon-treated patients with hepatitis C virus infection. Methods: A total of 2058 hepatitis C virus-positive, noncirrhotic patients treated with interferon were enrolled. The median follow-up period was 6.7 years. The primary end point was the onset of hepatocellular carcinoma. The cumulative rate of new hepatocellular carcinoma cases was computed by the Kaplan–Meier method and Cox proportional hazard analysis according to diabetic state and response to interferon therapy. Results: The cumulative rates of hepatocellular carcinoma in diabetic patients (3.2% at 4 years, 8.5% at 8 years, and 24.4% at 12 years) were significantly higher than those of nondiabetic patients (1.3% at 4 years, 2.2% at 8 years, and 5.6% at 12 years, P <.001). In patients with a sustained virologic response, diabetes had no significant effect on the rate of hepatocarcinogenesis. In contrast, the rate in patients with a nonsustained virologic response was significantly higher in diabetic than in nondiabetic patients. Multivariate analysis identified lack of sustained virologic response (hazard ratio [HR] 7.28; 95% confidence interval [CI], 3.28-16.15; P <.001) and diabetes as independent risk factors for hepatocarcinogenesis (HR 2.00; 95% CI, 1.05-3.84; P =.036). Conclusions: Our results highlight the enhancing effect of diabetes mellitus on hepatocarcinogenesis in noncirrhotic, interferon-treated patients with hepatitis C virus. The sustained virologic response induced by interferon therapy eliminates the influence of diabetes and markedly reduces the rate of hepatocarcinogenesis in such patients. [ABSTRACT FROM AUTHOR]