[Show abstract][Hide abstract] ABSTRACT: Background:
There is no information on the long-term effects of peginterferon (PEG-IFN) alfa-2a therapy for chronic hepatitis B (CHB) in Japan. This double-blind, randomized trial investigated the efficacy of PEG-IFN therapy.
We analyzed 22 Japanese patients with CHB (hepatitis B e antigen [HBeAg]-positive: 17, HBeAg-negative: 5) treated with PEG-IFN alfa-2a and followed-up posttreatment for 5 years. Responders represented patients who showed persistent normalization of alanine transferase (ALT) levels, HBeAg clearance, and low hepatitis B virus (HBV) DNA levels (HBeAg-positive patient; <5 log copies/mL, HBeAg-negative patient; <4.3 log copies/mL) at end of treatment, and at 1, 2, 3, 4 and 5 years posttreatment. In addition, baseline HBeAg-positive patients who showed sustained normalization of ALT level, HBeAg clearance, and low HBV DNA level for more than 6 months until at 1, 2, 3, 4, and 5 years after completion of PEG-IFN were also classified as "triple responders" and the proportion of triple responders relative to all patients was termed the "triple response rate".
The response rates among HBeAg-positive patients were 13 %, 25 %, 14 %, 21 % and 21 % at end of treatment, and at 1, 2, 3, 4, and 5 years, respectively. The response rate tended to be higher in patients treated for 48 than 24 weeks. The respective response rates among HBeAg-negative patients were 0 %, 20 %, 20 %, 20 % and 25 %. During the treatment period, hepatitis B surface antigen (HBsAg) clearance at 3.5 years was noted in one patient, who was 37-year-old, male, had genotype C and received PEG-IFN alfa-2a at 90 μg for 48 weeks.
At 5 years after completion of PEG-IFN, the triple response rate in HBeAg-positive patients and combined response rate in HBeAg-negative patients were 21 % (3/14) and 25 % (1/4), respectively. The triple response was seen in three patients who had all been treated with PEG-IFN for 48 weeks.
[Show abstract][Hide abstract] ABSTRACT: Background/aims:
It is important to determine the noninvasive parameters of histological features in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the value of genetic variations as surrogate markers of histological features.
The parameters that affected the histological features of NAFLD were investigated in 211 Japanese patients with biopsy-proven NAFLD. The relationships between genetic variations in PNPLA3 rs738409 or TM6SF2 rs58542926 and histological features were analyzed. Furthermore, the impact of genetic variations that affected the pathological criteria for the diagnosis of nonalcoholic steatohepatitis (NASH) (Matteoni classification and NAFLD activity score) was evaluated.
The fibrosis stage of PNPLA3 GG was significantly more progressive than that of CG by multiple comparisons. Multivariate analysis identified PNPLA3 genotypes as predictors of fibrosis of stage 2 or more, but the impact tended to decrease at stage 3 or greater. There were no significant differences among the histological features of the three genotypes of TM6SF2. PNPLA3 genotypes partly affected the definition of NASH by the NAFLD activity score, but TM6SF2 genotypes did not affect the definition of NASH.
In Japanese patients with biopsy-proven NAFLD, PNPLA3 genotypes may partly affect histological features, including stage of fibrosis, but the TM6SF2 genotype does not affect histological features.
[Show abstract][Hide abstract] ABSTRACT: Alanine aminotransferase (ALT) elevations were the most frequent adverse events during all-oral combinations with daclatasvir and asunaprevir for patients with hepatitis C virus (HCV) infection, but the underline mechanisms are unclear. 70 patients with chronic HCV genotype 1b infection, who were introduced daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily for 24 weeks, were measured serum asunaprevir concentrations at the one point or more of 2, 4, and 8 weeks after the start of treatment. In 4 and 8 weeks after the start of treatment, asunaprevir concentrations in patients with albumin levels <3.6 g/dl at baseline were significantly higher than those in patients with albumin levels ≥3.6 g/dl. The baseline factors did not affect to ALT severe elevations (≥300 IU/l). At 2 weeks after the start of treatment, ALT severe elevations with asunaprevir concentrations of ≥800 ng/ml (54.5%) tended to indicate the higher rates than those of <800 ng/ml (17.6%). Furthermore, the discontinuation or reduction of asunaprevir improved ALT levels, regardless the significant decrease of serum asunaprevir concentrations. In conclusion, serum albumin levels affected to serum asunaprevir concentrations, and serum asunaprevir concentrations might partly affect to ALT severe elevations. Further large-scale prospective studies are needed to investigate the impact of the discontinuation or reduction of asunaprevir to help in the design of more effective therapeutic regimens. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
No preview · Article · Aug 2015 · Journal of Medical Virology
[Show abstract][Hide abstract] ABSTRACT: Currently, non-alcoholic steatohepatitis (NASH) can only be diagnosed histopathologically. Our objective was to establish a new scoring system for the fibrotic stage of NASH.
We enrolled 139 patients with histologically proven NASH and divided them into two groups to construct (n = 90) and validate (n = 49) a fibrotic score for NASH (FSN). We used 17 variables and their natural logarithmic transformations in the multivariate analysis. To assess the accuracy of the FSN in determining NASH advanced fibrosis (stages 3-4), we compared various fibrotic scores for NASH.
In the construct group, multivariate regression analysis ultimately obtained the following function: z = 1.022 × ln (type IV collagen 7S) (ng/mL) - 0.00680 × (platelet count) (×10(9)/L) + 1.925 × ln (AST) (IU/L) - 1.239 × ln (ALT) (IU/L) + 0.249. Median values of the FSN for stages 1, 2, 3 and 4 were 1.87, 2.14, 3.26 and 3.89, respectively. The multiple regression coefficient and coefficient of determination were 0.70 and 0.46, respectively. In the validation group, the median value was 2.00, 2.83, 3.08 and 4.37 in each stage. With regard to the utility of the FSN for predicting advanced fibrosis of NASH (stage ≥3), the area under the receiver operating characteristic curves (AUROC), 0.909 (95 % CI 0.847-0.970, p < 0.001), was higher than that for the other fibrotic scores (APRI, NAFLD fibrosis score, FIB-4 index, BARD score, NIKEI) in the construct group.
This simple scoring system accurately predicts fibrotic stage and discriminates patients with advanced fibrosis of NASH.
Preview · Article · Jan 2015 · Hepatology International
[Show abstract][Hide abstract] ABSTRACT: The correlation and sensitivity of TaqMan HCV v1.0 (v.1.0) and TaqMan HCV v2.0 (v.2.0) were evaluated by using 239 clinical specimens from 40 patients undergoing Telaprevir-based triple therapy. A correlation study was performed with the specimens from patients at baseline, day 1 and day 3 of the therapy and a clinical sensitivity study was performed on day 3, week 1, week 2, and week 4. Analytical sensitivity was measured by using WHO dilution panels (50, 25, 15, 10, 5 IU/mL and negative). Passing-Bablok regression analysis of the correlation study was y=0.907x+0.093 (rs=0.985). When clinical sensitivity was evaluated, there were no significant differences between v1.0 and v2.0 by McNemar analysis. Analytical sensitivities of v1.0 and v2.0 were calculated by Probit analysis (95% hit rate, v1.0: 11.59 IU/mL, v2.0: 10.49 IU/mL). Comparison of the treatment outcome (SVR 12) based on RVR (undetectable HCV RNA at week 4) by v2.0 showed almost the same results as those by v1.0. These results showed that correlation and sensitivity of v.2.0 were the same as for v1.0. Therefore, v2.0 can be used for the medical decision points and guideline rules of HCV treatments which have been established based on v1.0.
[Show abstract][Hide abstract] ABSTRACT: Chronic hepatitis B virus (HBV) infection leads to cirrhosis and hepatocellular carcinoma (HCC). However, the risk of HCC in each patient is non-uniform. We newly created an easy-to-calculate risk estimation scale of HCC in Japanese untreated chronic hepatitis B (CHB) patients. Our hospital-based cohort (n=1143) in which no patients received antiviral therapy was used to generate a risk scale of HCC development. We generated a new risk scale of HCC development based on the results of Cox regression analysis. Multivariate Cox model showed that predictive factors of HCC development were age, gender, preexisting cirrhosis, ALT, AFP, platelet count, HBeAg, and HBVDNA. Projected HCC risk score is sum total of each risk score in these nine parameters (range 0-24).
[Show abstract][Hide abstract] ABSTRACT: AimTolvaptan, an oral arginine vasopressin V2 receptor antagonist, became available for hepatic ascites. We evaluated the therapeutic efficacy and safety of tolvaptan administration to treat refractory ascites.Methods
Data were collected from 15 hospitalized patients with cirrhosis (hepatitis C, 10; alcoholism, 5) after adding tolvaptan (3.75-11.25 mg/day) to conventional diuretics. Body weights and serum sodium and creatinine concentrations were measured. Tolvaptan was continued for 4 weeks or longer for a median follow-up period of 42 (28-56) days.ResultsIn the first week (introduction phase), tolvaptan significantly reduced median weight (66.6, 65.9 and 63.1 kg on days 0, 1 and 7, respectively; P<0.004). The numbers of good responders (≧3 kg reduction in 4 days), responders (<3 kg weight reduction), and non-responders (no weight reduction) were 7/15 (46.7%), 6/15 (40.0%), and 2/15 (13.3%), respectively. The 2 non-responders had concomitant chylous pleural effusion or spontaneous bacterial peritonitis. All patients continued tolvaptan for two weeks or longer and 6 (40%, 3 good responders and 3 responders) were treated for a median of 42 days without additional interventions. During this intermediate-term administration of tolvaptan, the median weight reduction was statistically significant (65.4, 61.9 and 56.9 kg on days 0, 7 and 42, respectively; P<0.030) and there was no serum sodium imbalance or renal dysfunction; but 2 of these 6 developed hepatic coma.Conclusion
Tolvaptan safely alleviated fluid retention caused by hepatic cirrhosis. Intermediate-term administration of tolvaptan apparently helped maintain weight reduction achieved during the introduction phase.
No preview · Article · Nov 2014 · Hepatology Research
[Show abstract][Hide abstract] ABSTRACT: Background/AimsGenome-wide association studies (GWAS) recently indicated that polymorphisms in the human leukocyte antigen (HLA)-DP genes were associated with risk of persistent hepatitis B virus (HBV) infection and clearance of HBV, but the effect of HLA-DP gene polymorphisms on the effect of antiviral therapy was unknown. We here investigated whether such polymorphisms were associated with decreases in HBsAg levels and seroclearance in patients who received long-term lamivudine (LAM) treatment.Methods
Japanese patients (202) who were hepatitis B e antigen-positive at baseline, received LAM as first-line treatment, and consented to HLA-DP genotyping (HLA-DPA1 rs3077 and HLA-DPB1 rs9277535) were categorized into 2 cohorts, viz., a cohort who achieved virological response without rescue therapy (cohort 1) and those who did so with rescue therapy (cohort 2).ResultsSerum HBsAg levels declined significantly between year 3 and 9 from baseline among cohort 1 patients possessing ≥ 2 A-alleles at rs3077 and rs9277535. The percentages of such patients in cohort 1 patients with decreases in HBsAg ≥ 0.5 log IU/mL were higher than those with <2 A-alleles (71.8% [28/39] vs. 38.9% [23/59]; P = 0.004). However, there was no significant difference in cumulative HBsAg seroclearance rates between patients with ≥ 2 and those with < 2 A-alleles in cohort 1. In cohort 2, HBsAg seroclearance rates were higher in patients with ≥ 2 A-alleles than in those with < 2 A-alleles (P = 0.003).Conclusion
We found an association between HLA-DP polymorphisms and decreases in HBsAg levels and seroclearance among HBeAg-positive patients treated with LAM.This article is protected by copyright. All rights reserved.
No preview · Article · Aug 2014 · Liver international: official journal of the International Association for the Study of the Liver
[Show abstract][Hide abstract] ABSTRACT: Tenofovir disoproxil fumarate (TDF) is widely used to treat hepatitis B virus (HBV) patients in the USA and Europe. No confirmed report of resistance selection during treatment with TDF in treatment-naïve and nucleoside/nucleotide analog-treated chronic hepatitis B patients has yet been reported. Here, we report for the first time a patient with chronic hepatitis B and cirrhosis who emerged with virologic breakthrough during combination therapy with TDF and entecavir (ETV), against ETV-resistant virus. A 51-year-old Japanese woman with hepatitis B e-antigen (HBeAg), whose genotype was C, received ETV monotherapy continuously followed by TDF and ETV combination therapy, because her HBV DNA levels had been >3.5 log copies/mL. At the start of combination therapy, amino acid substitutions of the reverse transcriptase (rt) gene, rtL180M, rtT184I/M, and rtM204V, were detected. After this, serum HBV DNA decreased to less than 2.1 log copies/mL and remained at this level until 31 months of combination therapy, when it again began to increase. Amino acid substitutions of rtL180M, rtS202G, and rtM204V emerged and were associated with an increase in serum HBV DNA at virologic breakthrough. Long-term therapy with TDF against the ETV-resistant virus has the potential to induce virologic breakthrough and resistance, and careful follow-up should be carried out.
Preview · Article · Jun 2014 · Drug Design, Development and Therapy
[Show abstract][Hide abstract] ABSTRACT: 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.
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).
Glycyrrhizin injection therapy is useful in the prevention of disease progression in interferon-resistant or intolerant patients with HCV-related cirrhosis.
[Show abstract][Hide abstract] ABSTRACT: Amino acid (aa) substitution at position 93 of the HCV NS5A region predicts the effectiveness of combination therapy with the protease inhibitor and NS5A inhibitor. The qualitative analysis assay and the comparative quantitative analysis assay based on the PCR-Invader technology, were developed to detect drug-resistance substitution at aa93 with high levels of sensitivity. In the mixtures of plasmids containing wild-type and drug-resistance substitution, both assays were able to be distinguished up to a mixed population containing 1%drug-resistance substitution. Clinical samples at the baseline of HCV therapy were examined by the PCR-Invader assays and direct sequencing. The PCR-Invader assays found drug-resistance substitutions that were detected by direct sequencing. Furthermore, they illustrated the presence of drug-resistance substitution that direct sequencing couldn't discover. The PCR-Invader assays were useful in detecting drug-resistance substitution at aa93 of the HCV NS5A region.
[Show abstract][Hide abstract] ABSTRACT: Entecavir (ETV) is reported to result in suppression of hepatitis B virus DNA (HBV DNA) replication with minimal drug resistance. However, information on the long-term effect of such therapy on serum hepatitis B surface antigen (HBsAg) level and elimination of HBsAg is not available. ETV therapy was started in 553 nucleos(t)ide-naïve patients with chronic hepatitis B infection (HBeAg positive: 45%) in our hospital. Serum HBsAg levels were measured serially by the Architect assay. The median baseline HBsAg was 2180 IU/mL (0.12–243 000 IU/mL), and median follow-up period was 3.0 years, with 529, 475, 355, 247 and 163 patients followed-up for 1, 2, 3, 4 and 5 years, respectively. At year 5, the mean log HBsAg decline from baseline was −0.48 log IU/mL, and the cumulative HBsAg clearance rate was 3.5%. Multivariate analysis identified HBV DNA level at baseline (<3.0 log copies IU/mL, odd ratio = 10.2; 95% confidence interval = 1.87–55.5, P = 0.007) and HBsAg level (<500 IU/mL, odd ratio = 29.4; 95% confidence interval = 2.80–333, P = 0.005) as independent predictors of HBsAg seroclearance. These results indicate that although serum HBsAg level declines gradually during ETV therapy, HBsAg seroclearance remains a rare event.
No preview · Article · Dec 2013 · Journal of Viral Hepatitis
[Show abstract][Hide abstract] ABSTRACT: The clinical usefulness of detecting telaprevir-resistant variants is unclear. 252 Japanese patients infected with hepatitis C virus (HCV) genotype 1b, received triple therapy of telaprevir/peginterferon (PEG-IFN)/ribavirin, and were evaluated telaprevir-resistant variants by direct sequencing at the baseline and at the re-elevation of viral load. Analysis of the entire group indicated that 76% achieved sustained virological response. Multivariate analysis identified PEG-IFN dose (<1.3 μg/kg), IL28B rs8099917 (genotype non TT), telaprevir-resistant variants of aa 54 at the baseline (Detection), response to prior treatment (Non response), and leukocyte count (<5,000/mm(3)) as significant pretreatment factors of detection of telaprevir-resistant variants at the re-elevation of viral load. Especially, in 63 patients who showed non response to prior treatment, a higher proportion of patients undetected telaprevir-resistant variants at the baseline (54%) achieved sustained virological response than that of patients detected telaprevir-resistant variants at the baseline (0%). Furthermore, 2 patients, who did not achieve sustained virological response by the first course of triple therapy with telaprevir, received the second course of the triple therapy with telaprevir. They achieved sustained virological response by the second course, despite the persistence of very high frequency variants (98.1% for V36C) or the past history of the emergence of variants (0.2% for R155Q, and 0.2% for A156T) by ultra-deep sequencing. In conclusion, this study indicated that telaprevir-resistant variants at the re-elevation of viral load could be predicted by the combination of host, viral, and treatment factors. Resistant variants at the baseline might partly affect treatment efficacy, especially non response to prior treatment.
No preview · Article · Nov 2013 · Journal of clinical microbiology