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Background & Aims The effect of ethanol consumption on hepatocarcinogenesis in patients with fatty liver disease (FLD) is not clear. We aimed to investigate the influence of alcohol consumption on hepatocarcinogenesis and determine the risk factors for hepatocellular carcinoma (HCC) in a large number of Japanese patients with FLD without viral hepatitis. Methods This multicenter, retrospective cohort study was conducted at a specialized center for hepatology in Japan and included 9959 patients with FLD without viral hepatitis, diagnosed by ultrasonography from January 1997 through December 2011. The patients’ level of ethanol consumption was divided into 4 categories: <20 g/day (n = 6671), 20–39 g/day (n = 753), 40–69 g/day (n = 1589), and ≥70 g/day (n = 946). The primary endpoint was the onset of HCC. Statistical analyses performed included the Kaplan-Meier method and Cox proportional hazard analysis. The median follow-up period was 5.4 years. Results Of the study cohort, 49 cases (0.49%) developed HCC during the follow-up period. The annual incidence rate of HCC was 0.05% in patients with FLD and a daily ethanol consumption <20 g/day. Increasing levels of ethanol consumption were associated with increased annual incidence rates of HCC: 0.06% for patients with 20–39 g/day ethanol consumption (hazard ratio [HR], 1.54; 95% confidence interval [CI], 0.34–7.04), 0.16% for patients with 40–69 g/day ethanol consumption (HR, 3.49; 95% CI, 1.50–8.12), and 0.22% for patients with ≥70 g/day ethanol consumption (HR, 10.58; 95% CI, 5.06–22.13), compared with patients with ethanol consumption <20 g/day. Multivariate analysis showed that ethanol consumption ≥40 g/day was an independent risk factor for HCC: for 40–69 g/day the HR was 2.48 (95% CI, 1.01–6.05; P < .047) and for ≥70 g/day the HR was 12.61 (95% CI, 5.68–28.00; P < .001). Conclusions Based on a multicenter, retrospective analysis of almost 10,000 patients with FLD, ethanol consumption ≥40 g/day is an independent risk factor for HCC. [ABSTRACT FROM AUTHOR]

Background The implication of extremely high preoperative alpha-fetoprotein (AFP) values for the long-term outcomes of hepatectomy for resectable hepatocellular carcinoma (HCC) remains uncertain. Methods A total of 762 hepatectomized HCC patients were divided into 3 groups according to preoperative AFP serum concentrations: 578 patients with AFP <100 ng/mL (low [LAP]), 147 patients with AFP 100–4,000 ng/mL (high [HAP]), and 37 patients with AFP ≥4,000 ng/mL (extremely high [EAP]). The clinicopathologic features and prognosis of the EAP group were compared with those of the other 2 groups to investigate their characteristics and whether the choice of hepatectomy was valid. Results The EAP group had a greater proportion of younger patients and those with hepatitis B compared with the other 2 groups. Large tumor size, poor histologic differentiation, and microscopic vascular invasion were also more common in the EAP group. The recurrence-free and overall survival rates of the EAP group were worse than those of the LAP group (both P < .01) but were not greatly different from those of the HAP group ( P = .65 and P = .80, respectively). When the analysis was limited to solitary HCC cases, both recurrence-free and overall survival rates of EAP were not significantly different from those of LAP ( P = .79 and P = .99, respectively). Conclusion An extremely high AFP level does not provide additional postoperative prognostic implications beyond those provided by a high AFP level. Hepatectomy should be performed without reservation for cases of HCC associated with an extremely high AFP value. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Japan has one of the highest endemic rates of hepatitis C virus (HCV) infection. Treatments in Japan are currently limited to interferon-alfa–based regimens, which are associated with tolerability and efficacy issues. A novel regimen combining two oral HCV therapies, daclatasvir and asunaprevir (DCV + ASV), has shown favorable results in Japanese patients with chronic genotype 1b HCV infection. Comparisons of clinical and economic outcomes associated with DCV + ASV treatment and current standards of care were investigated. Methods: The MOdelling the NAtural histoRy and Cost-effectiveness of Hepatitis cost-effectiveness model projected outcomes in 1000 patients aged 70 years with either chronic hepatitis C or compensated cirrhosis over a lifetime simulation. Japanese-specific disease transition rates were used, and discounting was applied annually at a rate of 2%. Efficacy data for DCV + ASV and telaprevir triple therapy (telaprevir + pegylated interferon-alfa + ribavirin [TVR + pegIFN-α/RBV]) were obtained from a Japanese subgroup analysis found within a global meta-analysis: sustained virological response rates of 74%, 85%, and 87% were reported for null responders (NRs), partial responders (PRs), and interferon-alfa–ineligible/intolerant patients, respectively, treated with DCV + ASV, and rates of 42% and 59% were reported for NRs and PRs, respectively, treated with TVR + pegIFN-α/RBV. Results: Initiating DCV + ASV treatment in patients in the chronic hepatitis C disease stage resulted in quality-adjusted life-year gains of 0.96 and 0.77 over TVR + pegIFN-α/RBV for NRs and PRs, respectively, and a gain of 2.61 in interferon-alfa–ineligible/intolerant patients over no treatment. Similarly, quality-adjusted life-year gains of 1.11, 0.90, and 3.05 were observed when initiating treatment in patients in the compensated cirrhosis stage. Cumulative lifetime events of decompensated cirrhosis, hepatocellular carcinoma, and liver-related mortality were reduced by up to 66, 115, and 128, respectively, with DCV + ASV treatment. Conclusions: There is a lack of successful therapies for patients with HCV who have previously failed to achieve sustained virological response or are ineligible for interferon-alfa–based therapies. Results demonstrate that the provision of an alternative, interferon-alfa–free regimen, such as DCV + ASV, offers significant value in terms of avoiding life-threatening liver complications and increasing patients’ quality of life. [Copyright &y& Elsevier]

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]

Background & Aims: To evaluate the efficacy and safety of telaprevir in combination with peginterferon-α2b (PEG-IFN) and ribavirin (RBV) in patients with chronic hepatitis C. Methods: In a multi-center randomized clinical trial in Japan, on patients infected with HCV of genotype 1, 126 patients were assigned to telaprevir for 12weeks along with PEG-IFN and RBV for 24weeks (Group A), while 63 to PEG-IFN and RBV for 48weeks (Group B). Results: HCV RNA disappeared more swiftly in patients in Group A than B, and the frequency of patients without detectable HCV RNA at week 4 (rapid virological response (RVR)) was higher in Group A than B (84.0% vs. 4.8%, p <0.0001). Grade 3 and 4 skin disorders, including Stevens–Johnson syndrome and drug rashes with eosinophilia and systemic symptoms, as well as Grade 3 anemia (<8.0g/dl), occurred more frequently in Group A than B (skin disorders, 11.9% vs. 4.8%; anemia, 11.1% vs. 0.0%). The total RBV dose was smaller in Group A than B (47.0% vs. 77.7% of the target, p <0.0001). Despite these drawbacks, sustained virological response (SVR) was achieved more frequently in Group A than B (73.0% vs. 49.2%, p =0.0020). Conclusions: Although the triple therapy with telaprevir-based regimen for 24weeks resulted in more adverse events and less total RBV dose than PEG-IFN and RBV for 48weeks, it was able to achieve higher SVR within shorter duration by carefully monitoring adverse events and modifying the RBV dose as required. [ABSTRACT FROM AUTHOR]

Background & Aims: Nutritional intervention with branched-chain amino acid (BCAA) is reported to increase serum albumin concentration in patients with decompensated cirrhosis. However, a definite conclusion on whether it can improve patients’ survival has not yet been reached. The present study aimed to test possibilities of improving survival of patients with decompensated cirrhosis by using a BCAA preparation that is suitable for long-term oral administration. Methods: A multicenter, randomized, and nutrient intake-controlled trial on the comparative effects of BCAA orally administered at 12 g/day for 2 years versus diet therapy with defined daily food intake (1.0–1.4 g protein kg−1 day−1 including BCAA preparation and 25–35 kcal kg−1 day−1) was conducted in 646 patients with decompensated cirrhosis. The primary end point was a composite of death by any cause, development of liver cancer, rupture of esophageal varices, or progress of hepatic failure (event-free survival). The secondary end points were serum albumin concentration and health-related quality of life (QOL) measured by Short Form-36 questionnaire. Results: The incidence of events comprising the primary end point significantly decreased in the BCAA group as compared with the diet group (hazard ratio, 0.67; 95% confidence interval, 0.49–0.93; P = .015; median observation period, 445 days). Serum albumin concentration increased significantly in the BCAA group as compared with the diet group (P = .018). The “general health perception” domain in Short Form-36 measures was also improved (P = .003). Patients’ adherence to the prescription was favorable. Conclusions: Oral supplementation with a BCAA preparation that can be administered for a long period improves event-free survival, serum albumin concentration, and QOL in patients with decompensated cirrhosis with an adequate daily food intake. [Copyright &y& Elsevier]

Systemic therapies have improved the management of hepatocellular carcinoma, but there is still a need to further enhance overall survival in first-line advanced stages. This study aimed to evaluate the addition of pembrolizumab to lenvatinib versus lenvatinib plus placebo in the first-line setting for unresectable hepatocellular carcinoma. In this global, randomised, double-blind, phase 3 study (LEAP-002), patients aged 18 years or older with unresectable hepatocellular carcinoma, Child Pugh class A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment were enrolled at 172 global sites. Patients were randomly assigned (1:1) with a central interactive voice-response system (block size of 4) to receive lenvatinib (bodyweight <60 kg, 8 mg/day; bodyweight ≥60 kg, 12 mg/day) plus pembrolizumab (200 mg every 3 weeks) or lenvatinib plus placebo. Randomisation was stratified by geographical region, macrovascular portal vein invasion or extrahepatic spread or both, α-fetoprotein concentration, and Eastern Cooperative Oncology Group performance status. Dual primary endpoints were overall survival (superiority threshold at final overall survival analysis, one-sided p=0·019; final analysis to occur after 532 events) and progression-free survival (superiority threshold one-sided p=0·002; final analysis to occur after 571 events) in the intention-to-treat population. Results from the final analysis are reported. This study is registered with ClinicalTrials.gov , NCT03713593 , and is active but not recruiting. Between Jan 17, 2019, and April 28, 2020, of 1309 patients assessed, 794 were randomly assigned to lenvatinib plus pembrolizumab (n=395) or lenvatinib plus placebo (n=399). Median age was 66·0 years (IQR 57·0–72·0), 644 (81%) of 794 were male, 150 (19%) were female, 345 (43%) were Asian, 345 (43%) were White, 22 (3%) were multiple races, 21 (3%) were American Indian or Alaska Native, 21 (3%) were Native Hawaiian or other Pacific Islander, 13 (2%) were Black or African American, and 46 (6%) did not have available race data. Median follow up as of data cutoff for the final analysis (June 21, 2022) was 32·1 months (IQR 29·4–35·3). Median overall survival was 21·2 months (95% CI 19·0–23·6; 252 [64%] of 395 died) with lenvatinib plus pembrolizumab versus 19·0 months (17·2–21·7; 282 [71%] of 399 died) with lenvatinib plus placebo (hazard ratio [HR] 0·84; 95% CI 0·71–1·00; stratified log-rank p=0·023). As of data cutoff for the progression-free survival final analysis (April 5, 2021), median progression-free survival was 8·2 months (95% CI 6·4–8·4; 270 events occurred [42 deaths; 228 progressions]) with lenvatinib plus pembrolizumab versus 8·0 months (6·3–8·2; 301 events occurred [36 deaths; 265 progressions]) with lenvatinib plus placebo (HR 0·87; 95% CI 0·73–1·02; stratified log-rank p=0·047). The most common treatment-related grade 3–4 adverse events were hypertension (69 [17%] of 395 patients in the lenvatinib plus pembrolizumab group vs 68 [17%] of 395 patients) in the lenvatinib plus placebo group), increased aspartate aminotransferase (27 [7%] vs 17 [4%]), and diarrhoea (25 [6%] vs 15 [4%]). Treatment-related deaths occurred in four (1%) patients in the lenvatinib plus pembrolizumab group (due to gastrointestinal haemorrhage and hepatorenal syndrome [n=1 each] and hepatic encephalopathy [n=2]) and in three (1%) patients in the lenvatinib plus placebo group (due to gastrointestinal haemorrhage, hepatorenal syndrome, and cerebrovascular accident [n=1 each]). In earlier studies, the addition of pembrolizumab to lenvatinib as first-line therapy for advanced hepatocellular carcinoma has shown promising clinical activity; however, lenvatinib plus pembrolizumab did not meet prespecified significance for improved overall survival and progression-free survival versus lenvatinib plus placebo. Our findings do not support a change in clinical practice. Eisai US, and Merck Sharp & Dohme, a subsidiary of Merck. [ABSTRACT FROM AUTHOR]

Background & Aims: In approximately 70% of patients with hepatocellular carcinoma (HCC) treated by resection or ablation, disease recurs within 5 years. Although gene expression signatures have been associated with outcome, there is no method to predict recurrence based on combined clinical, pathology, and genomic data (from tumor and cirrhotic tissue). We evaluated gene expression signatures associated with outcome in a large cohort of patients with early stage (Barcelona–Clinic Liver Cancer 0/A), single-nodule HCC and heterogeneity of signatures within tumor tissues. Methods: We assessed 287 HCC patients undergoing resection and tested genome-wide expression platforms using tumor (n = 287) and adjacent nontumor, cirrhotic tissue (n = 226). We evaluated gene expression signatures with reported prognostic ability generated from tumor or cirrhotic tissue in 18 and 4 reports, respectively. In 15 additional patients, we profiled samples from the center and periphery of the tumor, to determine stability of signatures. Data analysis included Cox modeling and random survival forests to identify independent predictors of tumor recurrence. Results: Gene expression signatures that were associated with aggressive HCC were clustered, as well as those associated with tumors of progenitor cell origin and those from nontumor, adjacent, cirrhotic tissues. On multivariate analysis, the tumor-associated signature G3-proliferation (hazard ratio [HR], 1.75; P = .003) and an adjacent poor-survival signature (HR, 1.74; P = .004) were independent predictors of HCC recurrence, along with satellites (HR, 1.66; P = .04). Samples from different sites in the same tumor nodule were reproducibly classified. Conclusions: We developed a composite prognostic model for HCC recurrence, based on gene expression patterns in tumor and adjacent tissues. These signatures predict early and overall recurrence in patients with HCC, and complement findings from clinical and pathology analyses. [Copyright &y& Elsevier]

Background & Aims: Ribavirin-induced anemia is one of the major causes of discontinuation and dose reduction during anti-hepatitis C virus therapy. Factors influencing this anemia, especially host genetic factors, are poorly understood. In this study we investigated predictive factors in hepatitis C virus patients treated with combination therapy. Methods: We performed a 2-step genome-wide screening followed by replication analysis and fine-mapping using a total of 923 Japanese hepatitis C virus 1b−infected patients treated with pegylated-interferon plus ribavirin. We also applied logistic regression analysis to search for possible independent associations of clinical parameters and genetic variants with treatment-induced hemoglobin (Hb) decline as well as treatment outcomes. Results: We identified a variant, located upstream of the inosine triphosphate pyrophosphatase gene on chromosome 20p13 that is significantly associated with treatment-induced anemia (combined P = 6.0 × 10−14). Resequencing and fine-mapping revealed several single nucleotide polymorphisms (SNPs) strongly associated with Hb decline, including the nonsynonymous SNP rs1127354 (P = 3.5 × 10−44), which was recently reported for other ethnic groups. Another reported SNP, the splicing variant-related SNP rs7270101, was not polymorphic in the Japanese population. Stratified analysis based on rs1127354 genotype revealed that inosine triphosphate pyrophosphatase expression is not correlated with Hb decline, suggesting that rs1127354 is a direct causal variant in the Japanese population. Multivariate analysis demonstrated that age, baseline Hb, baseline platelet count, and rs1127354 were independently associated with severe anemia (Hb <10 g/dL). Conclusions: A missense substitution in inosine triphosphate pyrophosphatase gene affects ribavirin-induced anemia in hepatitis C virus−infected Japanese patients. [ABSTRACT FROM AUTHOR]

Background & Aims: This study aimed to identify host single nucleotide polymorphisms (SNPs) that are associated with the efficacy of interferon (IFN) therapy in patients with chronic hepatitis C. Methods: We examined whether 116 tagging-SNPs from 13 genes that are involved in type I IFN signaling associate with the outcome of IFN therapy in Japanese case-control groups; the study included 468 sustained responders and 587 nonresponders. Results: We identified 2 SNPs (rs3792323 [A/T] and rs616589 [G/A]), located in intron 2 of mitogen-activated protein kinase–activated protein kinase 3 (MAPKAPK3) that were associated with the outcome of IFN therapy in patients infected with hepatitis C virus (HCV) genotype 1b (P = 4.6 × 10−5 and 4.8 × 10−5, respectively). The 2 SNPs were in strong linkage disequilibrium and multivariate logistic regression analysis showed that rs3792323 is an independent factor associated with the IFN efficacy (genotype 1b; P = .0011). MAPKAPK3 is a kinase involved in the mitogen and stress responses, but the biological significance of MAPKAPK3 in IFN responses is poorly understood. By using an allele-specific transcript quantification assay in liver biopsy, we showed that allele-specific expression of MAPKAPK3 messenger RNA, corresponding to the risk allele for nonresponse, was significantly higher than that of the other allele. Luciferase reporter assay data indicated that overexpression of MAPKAPK3 inhibits IFN-alfa–induced gene transcription via IFN-stimulated response element and IFN-γ–activated site. Conclusions: The SNP rs3792323 in MAPKAPK3 associates with the outcome of IFN therapy in patients with HCV genotype 1b. Our functional analyses indicate that MAPKAPK3 inhibits IFN-alfa–induced antiviral activity. [Copyright &y& Elsevier]

In the phase III registration studies conducted in Japan, Japanese HCV gt1 patients administered vaniprevir 300 mg twice daily plus pegylated interferon/ribavirin for 12 or 24 weeks achieved SVR 24 rates of 83.7–84.5% among treatment-naïve patients, and 92.0–96.2% and 61.9% among breakthrough/relapsers or null-responders to prior interferon based therapy. As evidenced by direct sequencing, patients who did not achieve SVR 24 principally failed due to treatment-emerging mutations at D168 or in a few cases R155. In this work, additional sequence analysis was conducted to address whether there were baseline polymorphisms associated with failure, evaluate the persistence of resistant virus among treatment failures, and assess for evidence of second site co-evolution with R155 or D168 mutations. To accomplish this, clonal sequencing (up to 40 clones per sample) was conducted on baseline, failure, and follow-up samples from all 38 patients among the vaniprevir treatment arms who met virologic failure criteria (37 gt1b, 1 gt1a, herein referred to as virologic failures) and baseline samples from 41 vaniprevir-treated SVR 24 patients (all gt1b) selected among the three studies. SVR 24 and virologic failure patients showed similar distributions of baseline polymorphisms previously associated with failure to one or more protease inhibitors. Furthermore, there was no evidence for baseline polymorphisms or a genetic signature across the NS3 protease domain specific to virologic failure patients, and which distinguishes them from baseline SVR 24 sequences beyond a chance distribution. 24 of 32 virologic failures for whom baseline, failure, and follow-up samples were available showed reduced prevalence of the resistant virus first observed at the time of failure during the protocol-defined follow-up period of 24 weeks. Finally, pairwise analysis using either alignment or phylogenetic based methodologies provided no evidence for second site evolution with either the R155 or D168 mutations attributed to failure. This work supports and extends earlier findings based upon direct sequencing that attributed virologic failure to vaniprevir in the Phase III studies solely to the emergence of R155 or D168 mutations, with no apparent influence by other residues within the NS3 protease domain on treatment outcome. ClinicalTrials.govIdentifiers NCT01370642 , NCT01405937 , NCT01405560 [ABSTRACT FROM AUTHOR]

Background & Aims: We performed a genome-wide association study (GWAS) of hepatitis C virus (HCV)-induced liver cirrhosis (LC) to identify predictive biomarkers for the risk of LC in patients with chronic hepatitis C (CHC). Methods: A total of 682 HCV-induced LC cases and 1045 CHC patients of Japanese origin were genotyped by Illumina Human Hap 610-Quad bead Chip. Results: Eight SNPs which showed possible associations (p <1.0×10−5) at the GWAS stage were further genotyped using 936 LC cases and 3809 CHC patients. We found that two SNPs within the major histocompatibility complex (MHC) region on chromosome 6p21, rs910049 and rs3135363, were significantly associated with the progression from CHC to LC (p combined =9.15×10−11 and 1.45×10−10, odds ratio (OR)=1.46 and 1.37, respectively). We also found that HLA-DQA1 * 0601 and HLA-DRB1 * 0405 were associated with the progression from CHC to LC (p =4.53×10−4 and 1.54×10−4 with OR=2.80 and 1.45, respectively). Multiple logistic regression analysis revealed that rs3135363, rs910049, and HLA-DQA1 * 0601 were independently associated with the risk of HCV-induced LC. In addition, individuals with four or more risk alleles for these three loci have a 2.83-fold higher risk for LC than those with no risk allele, indicating the cumulative effects of these variations. Conclusions: Our findings elucidated the crucial roles of multiple genetic variations within the MHC region as prognostic/predictive biomarkers for CHC patients. [Copyright &y& Elsevier]

Background & Aims: Improved therapeutic options for chronic hepatitis C virus (HCV) infection are needed for patients who are poor candidates for treatment with current regimens due to anticipated intolerability or low likelihood of response. Methods: In this open-label, phase 2a study of Japanese patients with chronic HCV genotype 1b infection, 21 null responders (<2log10 HCV RNA reduction after 12weeks of peginterferon/ribavirin) and 22 patients intolerant to or medically ineligible for peginterferon/ribavirin therapy received dual oral treatment for 24weeks with the NS5A replication complex inhibitor daclatasvir (DCV) and the NS3 protease inhibitor asunaprevir (ASV). The primary efficacy end point was sustained virologic response at 12weeks post-treatment (SVR12). Results: Thirty-six of 43 enrolled patients completed 24weeks of therapy. Serum HCV RNA levels declined rapidly, becoming undetectable in all patients on therapy by week 8. Overall, 76.7% of patients achieved SVR12 and SVR24, including 90.5% of null responders and 63.6% of ineligible/intolerant patients. There were no virologic failures among null responders. Three ineligible/intolerant patients experienced viral breakthrough and four relapsed post-treatment. Diarrhea, nasopharyngitis, headache, and ALT/AST increases, generally mild, were the most common adverse events; three discontinuations before week 24 were due to adverse events that included hyperbilirubinemia and transaminase elevations (two patients). Conclusions: Dual therapy with daclatasvir and asunaprevir, without peginterferon/ribavirin, was well tolerated and achieved high SVR rates in two groups of difficult-to-treat patients with hepatitis C virus genotype 1b infection. [Copyright &y& Elsevier]

Background & Aims: Daclatasvir and asunaprevir are NS5A and NS3 protease-targeted antivirals currently under development for treatment of chronic hepatitis C virus infection. Clinical data on baseline and on-treatment correlates of drug resistance and response to these agents are currently limited. Methods: Hepatitis C virus genotype 1b Japanese patients (prior null responders to PegIFN-α/RBV [n=21] or PegIFN-α/RBV ineligible or intolerant [n=22]) were administered daclatasvir/asunaprevir for 24weeks during a phase 2a open-label study. Genotypic and phenotypic analyses of NS3 and NS5A substitutions were performed at baseline, after virologic failure, and post-treatment through follow-up week 36. Results: There were three viral breakthroughs and four relapsers. Baseline NS3 polymorphisms (T54S, Q80L, V170M) at amino acid positions previously associated with low-level resistance (<9-fold) to select NS3 protease inhibitors were detected in four null responders and three ineligibles, but were not associated with virologic failure. Baseline NS5A polymorphisms (L28M, L31M, Y93H) associated with daclatasvir resistance (<25-fold) were detected in five null responders and six ineligibles. All three viral breakthroughs and 2/4 relapsers carried a baseline NS5A-Y93H polymorphism. NS3 and NS5A resistance-associated variants were detected together (NS3-D168A/V, NS5A-L31M/V-Y93H) after virologic failure. Generally, daclatasvir-resistant substitutions persisted through 48weeks post-treatment, whereas asunaprevir-resistant substitutions were no longer detectable. Overall, 5/10 patients with baseline NS5A-Y93H experienced virologic failure, while 5/10 achieved a sustained virologic response. Conclusions: The potential association of a pre-existing NS5A-Y93H polymorphism with virologic failure on daclatasvir/asunaprevir combination treatment will be examined in larger studies. The persistence of treatment-emergent daclatasvir- and asunaprevir-resistant substitutions will require assessment in longer-term follow-up studies. [Copyright &y& Elsevier]

Background & Aims: We determined the antiviral potency and viral resistance rate after 4years of continuous entecavir treatment in patients with chronic hepatitis B (CHB) infection. Methods: The cumulative rates of undetectable hepatitis B virus DNA (HBV DNA;<2.6 log10 copies/ml), hepatitis B e antigen (HBeAg) seronegativity, seroconversion, alanine aminotransferase (ALT) normalization, and entecavir signature mutations were calculated in 474 nucleos(t)ide-naïve CHB patients (HBeAg-positive: 47%) on continuous entecavir treatment for 4years. Results: Median age was 47years and follow-up period was 2.4years, with 403, 281, 165, and 73 patients followed-up for at least 1, 2, 3, and 4years, respectively. Incremental increases were observed in the rates of undetectable HBV DNA, HBeAg seroclearance and seroconversion, and ALT normalization, reaching 96%, 42%, 38% and 93%, respectively, by the fourth year. In all, 100% and 93% of patients negative and positive for HBeAg, respectively, had undetectable HBV DNA at year 4. Of 165 patients, HBV DNA was detectable in nine patients after 3years. Multivariate analysis identified HBV DNA level (⩽7.6log10 copies/ml, OR=15.8; 95% CI=43.1–79.9, P=0.001) as an independent predictor of undetectable HBV DNA at year 3. Five patients experienced virological breakthrough including two (0.4%) who developed entecavir-resistance mutations. Conclusions: Continuous treatment of nucleos(t)ide-naïve CHB patients with entecavir over 4years was associated with 96% chance of undetectable HBV DNA and only 0.4% chance of emerging entecavir-resistant mutations. [ABSTRACT FROM AUTHOR]

Abstract: Background: In Japan and South Korea, transarterial chemoembolisation (TACE) is an important locoregional treatment for patients with unresectable hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, has been shown effective and safe in patients with advanced HCC. This phase III trial assessed the efficacy and safety of sorafenib in Japanese and Korean patients with unresectable HCC who responded to TACE. Methods: Patients (n =458) with unresectable HCC, Child-Pugh class A cirrhosis and ⩾25% tumour necrosis/shrinkage 1–3months after 1 or 2 TACE sessions were randomised 1:1 to sorafenib 400mg bid or placebo and treated until progression/recurrence or unacceptable toxicity. Primary end-point was time to progression/recurrence (TTP). Secondary end-point was overall survival (OS). Findings: Baseline characteristics in the two groups were similar; >50% of patients started sorafenib >9weeks after TACE. Median TTP in the sorafenib and placebo groups was 5.4 and 3.7months, respectively (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.70–1.09; P = 0.252). HR (sorafenib/placebo) for OS was 1.06 (95% CI, 0.69–1.64; P =0.790). Median daily dose of sorafenib was 386mg, with 73% of patients having dose reductions and 91% having dose interruptions. Median administration of sorafenib and placebo was 17.1 and 20.1weeks, respectively. No unexpected adverse events were observed. Interpretation: This trial, conducted prior to the reporting of registrational phase III trials, found that sorafenib did not significantly prolong TTP in patients who responded to TACE. This may have been due to delays in starting sorafenib after TACE and/or low daily sorafenib doses. [Copyright &y& Elsevier]

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]

Background & Aims: Common IL28B locus polymorphisms (SNPs rs8099917 and rs12979860) have been reported to affect peg-interferon plus ribavirin combination therapy (PEG-RBV) for hepatitis C virus (HCV) genotype 1b, but few reports have examined their effect on other two common genotypes, 2a and 2b. Methods: We analyzed predictive factors for sustained virological response (SVR) in a retrospective study of 719 patients with either genotype 2a (530) or 2b (189). Of these patients, 160 were treated with PEG-RBV and 559 were treated with interferon monotherapy. We evaluated predictive factors including HCV RNA, histological findings, IL28B SNP genotypes (rs8099917, rs12979860, and rs12980275), and the effect of treatment regimen and prior treatment history. Results: HCV RNA viral load, treatment regimen, and rs8099917 genotypes independently contributed to the effect of the therapy. For patients treated with PEG-RBV, rs8099917 and viral load were independent predictive factors for SVR in genotype 2b but not in genotype 2a. Conversely, in patients treated with interferon monotherapy, viral load and rs8099917 were independent predictive factors for SVR in genotype 2a but not in genotype 2b. The favorable rs8099917 genotype is also associated with a steep decline in viral load by the second week of treatment. Conclusions: Initial viral load and rs8099917 genotype are significant independent predictors of SVR in genotype 2 patients. [Copyright &y& Elsevier]

Background/Aims: We studied the long-term efficacy (median follow-up of 28 months) of adefovir (ADV) in combination with lamivudine (LAM) in 132 LAM-resistant Japanese patients with chronic genotype C-dominant hepatitis B virus (HBV) infection. Methods: The viral response (undetectable HBV-DNA by PCR assay) and the predictor of viral response were evaluated. The emergence of ADV-resistant mutants was investigated during the combination therapy. Results: The cumulative probability of viral response was 69% at 12 months, and 81% at 24 months. Multivariate analysis identified baseline HBe antigen status (P =0.0001), aspartate aminotransferase level (AST) (P =0.001) and HBV-DNA level (P =0.002) as determinants of viral response to treatment. At the beginning of ADV therapy, substitutions at rtA181 (rtA181T and rtA181S) were identified in 3 patients (2.3%). In the remaining 129 patients, the rtM204 mutants were identified at baseline, and two (1.6%) of the 129 patients developed new ADV-resistant mutants; one was rtA181S and another was rtA181T plus rtN236T mutation. Conclusions: Adefovir and lamivudine combination therapy effectively suppressed viral replication and maintained the efficacy well in LAM-resistant patients with chronic HBV infection. Genotypic analysis indicated that the emergence of ADV-resistant mutants is rare, at least over a period of 2 years, in patients with combination therapy. [Copyright &y& Elsevier]