Switching to tenofovir alafenamide for nucleos(t)ide analogue-experienced patients with chronic hepatitis B: week 144 results from a real-world, multi-centre cohort study.

BACKGROUND: Tenofovir alafenamide (TAF) may be preferable to other nucleos(t)ide analogues (NA) regarding outcomes against chronic hepatitis B virus (HBV) infection. AIMS: To evaluate the longer term virological/biochemical effectiveness of TAF and the renal safety of sequential therapy to TAF in real-world settings METHODS: This multi-centre, retrospective cohort study included consecutive adult patients who were switched from other NAs to TAF. We assessed the virological and biochemical responses up to 144 weeks. We performed sensitivity analyses for a subgroup with chronic kidney disease (CKD) at baseline. RESULTS: We analysed the data of 391 patients with chronic hepatitis B previously treated with entecavir (ETV) (n = 174), tenofovir disoproxil fumarate (TDF) (n = 116) or an NA combination (n = 101) for ≥ 24 months. HBV DNA <10 IU/ml at week 144 was found for 99% of patients, regardless of prior NA regimen or HBV DNA level at baseline. For patients who switched from TDF to TAF, total, low-density lipoprotein, high-density lipoprotein cholesterol and triglycerides were significantly increased after the switch. Patients who switched from a nucleotide analogue to TAF had an improved estimated glomerular filtration rate, although the rate of hypophosphataemia (<2.5 mg/dl) remained 9.7% at week 144. The virological and biochemical responses of patients with CKD were similar to the overall results. CONCLUSIONS: Switching to TAF remained effective and safe for up to 3 years. Given the increasing comorbidities related to ageing, it will be important to carefully follow the change in the lipid levels of patients with a prior TDF-based regimen.

Sequential HBV treatment with tenofovir alafenamide for patients with chronic hepatitis B: week 96 results from a real-world, multicenter cohort study.

BACKGROUND AND AIMS: Outcome data of sequential hepatitis B virus treatment with tenofovir alafenamide (TAF) are limited. We aimed to assess the effectiveness and renal safety of TAF in chronic hepatitis B (CHB) patients who were previously treated with entecavir (ETV), tenofovir disoproxil fumarate (TDF), or a nucleos(t)ide analogue (NA) combination. METHODS: This multicenter, retrospective, cohort study included 458 consecutive CHB patients who switched to TAF monotherapy after at least 2 years of treatment with another NA. The longitudinal virological/laboratory responses were evaluated up to 96 weeks after switchover. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. RESULTS: The proportions of complete viral suppression (CVS) (HBV DNA < 20 IU/mL) at week 96 were 99.0%, 98.5%, and 98.4% in the prior ETV (n = 198), TDF (n = 137), and NA combination (n = 123) groups, respectively. Almost all patients with HBV DNA of 20-2000 IU/mL at baseline achieved CVS at week 96. On multivariable generalized estimated equation analysis, a low quantitative hepatitis surface antigen (qHBsAg) level at baseline was associated with a lower follow-up qHBsAg level (coefficient 0.81, p < 0.001). The eGFR showed greater improvement in patients with CKD compared to those without (coefficient 21.7, p < 0.001). However, the increase of eGFR reached a peak between weeks 24 and 48. CONCLUSIONS: Based on this longitudinal data analysis up to 96 weeks, sequential NA therapy with a switch to TAF is a good option to achieve high viral suppression and renal safety.

Development of Hepatocellular Carcinoma in Patients Aged 75-84 Years With Chronic Hepatitis C Treated With Direct-Acting Antivirals.

BACKGROUND: Direct-acting antiviral (DAA) treatment has revolutionized hepatitis C virus (HCV) care. We aimed to evaluate the risk for the development of hepatocellular carcinoma (HCC) in patients aged 75-84 years with chronic hepatitis C after HCV elimination. METHODS: This multicenter cohort study included 2405 consecutive patients with chronic hepatitis C without a history of HCC who achieved HCV elimination by DAAs. Patients in whom HCC developed within 1 year of DAA initiation were excluded. Propensity score matching analysis was used to evaluate differences in HCC risk between patients aged 75-84 versus 60-74 years. RESULTS: The median observational period was 3.5 years. Among patients aged 75-84 years with a high Fibrosis-4 (FIB-4) index (≥3.25 at baseline), there was no significant difference in the annual incidence of HCCs between groups with an FIB-4 index ≥3.25 (2.75 per 100 person-years [PY]) versus <3.25 (2.16 per 100 PY) at 12 weeks after the end of treatment, unlike the results in those aged 60-74 years (3.61 and 1.51 per 100 PY, respectively) (adjusted hazard ratio, 2.20; P = .04). In 495 pairs matched by propensity score matching, in patients without cirrhosis, the cumulative HCC incidence was significantly higher in the 75-84-year than in the 60-74-year age group (P = .04). CONCLUSIONS: Older patients aged 75-84 years remained at high risk for the development of HCC, even after HCV elimination and the improvement of the FIB-4 index to <3.25.

Long-term hepatic function of patients with compensated cirrhosis following successful direct-acting antiviral treatment for hepatitis C virus infection.

BACKGROUND AND AIM: Direct-acting antivirals (DAAs) have contributed to the improvement of outcomes for all patients with chronic hepatitis C. The aim of this study was to evaluate the long-term hepatic benefits of hepatitis C virus (HCV) cure by DAAs in patients with compensated cirrhosis. METHODS: This multicenter cohort study consisted of consecutive patients with compensated cirrhosis who initiated interferon-free DAA treatment before September 2016. The impact of treatment on long-term hepatic function was followed for at least 4 years after the end of treatment, and the progression to decompensation was evaluated. RESULTS: The data of 394 patients were available for study. The median age was 70, and 41% had modified albumin-bilirubin (ALBI) grade 2b. During a short-term follow-up 1 year after the end of treatment, FIB-4 index and ALBI score significantly improved. The achievement rates of FIB-4 < 3.25 (40%) and ALBI grade 1 (70%) reached their plateau in the first year; however, there were significant further improvements in platelet count and α-fetoprotein level after the first year. The annual incidence of decompensation was 1.30 (95% confidence interval 0.83-2.02) per 100 person-years. In multivariable analysis, male sex and modified ALBI grade 2b at baseline were associated with decompensation. CONCLUSIONS: In a large real-world cohort of patients with compensated cirrhosis treated with a DAA, remarkable improvement in hepatic function was seen after HCV cure, especially during the first year after the end of treatment. Treatment in the early stage of cirrhosis would be of great benefit for preventing liver deterioration to decompensation.

Long-term assessment of recurrence of hepatocellular carcinoma in patients with chronic hepatitis C after viral cure by direct-acting antivirals.

BACKGROUND AND AIM: Early hepatocellular carcinoma (HCC) recurrence is common, even after achieving hepatitis C virus (HCV) cure. This study was carried out to assess the long-term trends and predictors of recurrence after HCV cure by direct-acting antivirals (DAAs). METHODS: This retrospective, multicenter cohort study enrolled 365 consecutive patients with chronic hepatitis C who required HCC treatment following sustained viral response (SVR) by DAA administration. Patients with HCC recurrence before SVR were excluded. Late HCC recurrence and its predictors beyond the post-treatment early phase (24 weeks after SVR) were evaluated. RESULTS: The data of 326 patients were available for the final analysis. The median follow-up duration from SVR determination was 2.7 years. Median age was 74, and 220 (67.5%) were 70 or over. The corresponding 5-year cumulative HCC recurrence rates of previous curative and palliative treatment groups were 45.4% and 65.7%, respectively (log-rank test: P < 0.001). Cox regression multivariable analysis revealed that cirrhosis (hazard ratio [HR] 1.85, P = 0.021), the number of HCC nodules (≥ 2) (HR 1.52, P = 0.031), and previous palliative HCC treatment (HR 1.71, P = 0.012) were independent predictors of late recurrence, in addition to the predictors of early recurrence; AFP > 7 ng/mL at 12 weeks after DAA administration, time from HCC complete response (CR) to DAA initiation (< 1 year), and the number of HCC treatments necessary to achieve CR (≥ 2). CONCLUSIONS: The evaluation of fibrosis and characteristics of the previous HCC would allow for better HCC recurrence stratification, which would be helpful for developing long-term surveillance strategies.

Dissolution Profiles of Generic Products in Dissolution Media Defined by Japanese Guidelines for Bioequivalence Studies.

The International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use M9 Guidelines for Biopharmaceutics Classification System Biowaivers reached harmonization in November 2019. However, guidelines for bioequivalence studies are not internationally harmonized, and water as a dissolution medium is only required in Japanese guidelines, regardless of drug solubility. This study investigated the dissolution profiles of generic products in Japan that differ from those of original drugs in dissolution media defined in guidelines. Dissolution profiles disclosed on websites of generic manufacturers were investigated for 262 active ingredients listed in the bluebook (4638 oral solid products listed in the National Health Insurance drug price list) issued by the Ministry of Health, Labour and Welfare. 5% of all generic products were different from the original products in dissolution media, of which 20% was observed in water only. Among the active pharmaceutical ingredients that showed different dissolution profiles only in water, the ratio of original products that showed slower dissolution profiles to the generics was 73%. The ratio of products showing different dissolution in water only was higher than in other media investigated in this study; however, these do not reflect disintegration and dissolution of drug products in the gastrointestinal tract, since bioequivalence has been confirmed in human studies and the generic products were approved by Japanese authorities. Therefore, a discussion about the required use of water as a dissolution medium in the Japanese guidelines is needed among industry, academia, and regulatory authorities.

Impact of Quality by Design Development on the Review Period of New Drug Approval and Product Quality in Japan.

BACKGROUND: For pharmaceutical products, an in-depth understanding of manufacturing processes and quality risks associated with quality by design (QbD) development enables the production of high-quality products. Product recall due to quality issues could be minimized for QbD-developed products. Furthermore, the review period instituted by regulatory authorities could be shortened by allowing reviewers to access technical documents with QbD elements. The aim of this study was to examine the impact of QbD development from the viewpoints of regulatory flexibility, product quality related to recall, and review period in Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. METHODS: QbD developments for new active ingredients, approved from 2009 to 2018, were surveyed in the PMDA review reports, and review periods were investigated on the PMDA website. Voluntary product recalls and their rationale were investigated using the website of the Japan Ministry of Health, Labour and Welfare. RESULTS: Although the developmental ratio with QbD elements was increased from 9% in 2009 to 71% in 2018, the development of design space for drug substances and products between 2009 and 2018 was only 2%, and real time release testing (RTRT) for drug products was limited to 3%. Voluntary recall and extension of the review period for QbD-developed products were not observed. CONCLUSION: The advantages of systematic QbD development were suggested for no voluntary recall of QbD-developed products. Conversely, applicants did not actively seek regulatory flexibility with design space or RTRT, and QbD development failed to impact the PMDA review period.

Incidence of Hepatocellular Carcinoma after Treatment with Sofosbuvir-Based or Sofosbuvir-Free Regimens in Patients with Chronic Hepatitis C.

Advanced fibrosis/cirrhosis and related biomarkers have been recognized as useful predictors of the development of hepatocellular carcinoma (HCC) by patients with chronic hepatitis C (CHC) following hepatitis C virus (HCV) cure by direct-acting antivirals (DAAs). However, it remains unclear if DAAs themselves have an influence on or facilitate the development of HCC. This multicenter cohort study included CHC patients without a history of HCC who achieved HCV elimination by DAAs. Cohorts of 835 patients treated with a sofosbuvir (SOF)-based regimen and 835 treated with a SOF-free regimen were matched 1:1 by propensity scoring with nine variables to evaluate differences in HCC incidence. The median observation period was 3.5 years. Sixty-nine cases of HCC were found during 5483.9 person-years (PY) over the entire follow-up period. The annual incidence was similar for both groups (SOF-based 1.25 and SOF-free 1.27 per 100 PY, respectively: adjusted hazard ratio (HR) 1.26, 95% confidence interval (CI) 0.75-2.12, p = 0.39). However, the annual incidence within the first two years was higher for patients treated with SOF than for those without, but did not reach significance (1.50 and 0.97 per 100 PY incidence rates, respectively: adjusted HR 2.05, 95% CI 0.98-4.25, p = 0.06). In summary, DAA treatment with SOF was not associated with an increase in the development of de novo HCC.

Considerations and Regulatory Challenges for Innovative Medicines in Expedited Approval Programs: Breakthrough Therapy and Sakigake Designation.

BACKGROUND: In the breakthrough therapy designation (BTD) and Sakigake designation programs, rolling submission and close communication between applicants and regulatory authorities enable the timely access of patients to innovative medicines. However, challenges in the quality development, including chemistry, manufacturing, and control (CMC), are expected during the accelerated timeline. This study focused on development with quality by design (QbD) concept, shelf life of drug product, and post marketing commitment (PMC) to clarify developmental strategies and regulatory challenges associated with expedited approval programs. METHODS: QbD developments, shelf life of drug products, and PMC were surveyed in the review reports of the US Food and Drug Administration (FDA) and Pharmaceuticals and Medical Devices Agency (PMDA) websites. RESULTS: Overall, 86% of BTD products and two out of three Sakigake products were developed using a QbD approach. Furthermore, 92% of BTD products and two out of three Sakigake products were granted a shelf life of at least 18 months. In the BTD pathway, 50% of PMCs concerned the reevaluation of specification and test method. CONCLUSION: For most BTD and Sakigake products, the control strategy was developed utilizing the QbD concept, and long shelf life was granted despite the accelerated timeline. No discount for specification setting was observed for assuring quality, based on the available data at the time of approval in the BTD and Sakigake programs, although PMCs were mainly required for reevaluation of the specification and test method in BTD programs. Further efforts should focus on creating/revising guidelines for CMC development.

Tenofovir alafenamide after switching from entecavir or nucleos(t)ide combination therapy for patients with chronic hepatitis B.

BACKGROUND AND AIMS: Tenofovir alafenamide (TAF) has been newly approved for the treatment of chronic hepatitis B (CHB). We aimed to assess the effectiveness and renal safety of switching from entecavir (ETV) or nucleos(t)ide analogue (NA) combination therapy to TAF. METHODS: This multicentre, retrospective, cohort study included 313 consecutive CHB patients who switched to TAF monotherapy after treatment with ETV or a nucleos(t)ide analogue (NA) combination for over 2 years. Virological/laboratory responses were evaluated for 48 weeks after switchover. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 . Differences in longitudinal parameters were compared by the generalized estimating equation method. RESULTS: In the prior ETV group (n = 191), the HBV DNA suppression rate at week 48 was significantly increased, from 75.9% to 96.9% (P < .001). Additionally, mean changes in the HBsAg level at week 48 in HBsAg ≥ 3.0 logIU/mL and < 3.0 logIU/mL groups were -0.09 and -0.13 logIU/mL respectively. In the prior NA combination group (n = 122), the mean changes in HBsAg level at week 48 in the HBsAg ≥ 3.0 logIU/mL and <3.0 logIU/mL groups were -0.08 and -0.11 logIU/mL respectively. For patients with CKD, the eGFR at week 48 was significantly improved compared to those with non-CKD (adjusted slope coefficient difference: 2.75 mL/min/1.73 m2 /48 weeks; P = .001). CONCLUSIONS: Switching from ETV or an NA combination to TAF was effective for HBV suppression and continued HBsAg reduction. Moreover, the renal glomerular function of patients in the prior NA combination group with CKD was significantly improved compared to those with non-CKD. LAY SUMMARY: Nucleos(t)ide analogues, such as entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide, inhibit hepatitis B virus (HBV) replication and are recommended as first-line oral agents for chronic HBV infection. We evaluated the virological/biochemical effects and renal safety when patients are switched from entecavir or nucleoside-nucleotide analogue combination therapy to tenofovir alafenamide. Our findings suggest that switching to tenofovir alafenamide was effective for HBV suppression and the improvement in renal function for patients with chronic kidney disease.

Ledipasvir and sofosbuvir for 12 weeks for hepatitis C virus genotype 2 infection: A propensity score matched analysis.

AIM: Hepatitis C virus genotype 2 is common in East Asia, sub-Saharan Africa, and Latin America. However, many countries in these areas lag behind other areas of the world in government approval for new direct-acting antivirals. The aim of this study was to evaluate the treatment outcome of ledipasvir/sofosbuvir (LDV/SOF) for patients with chronic hepatitis C virus genotype 2 infection. METHODS: This is a two-part multicenter, real-world cohort study. Study 1 consisted of 58 consecutive patients who were treated with LDV/SOF for 12 weeks. Study 2 used propensity score matching for LDV/SOF (n = 58) and glecaprevir/pibrentasvir (n = 207) treatment groups (1:1) with a set of clinically important variables. Sustained viral response 12 weeks after the end of treatment (SVR12) and adverse events were evaluated in both studies. RESULTS: In study 1, the overall SVR12 rates of the intention-to-treat and modified intention-to-treat populations were 94.8% (55/58) and 96.5% (55/57), respectively. High SVR12 rates were observed in almost all subgroups, including older age, compensated cirrhosis, and treatment experience. In study 2, propensity score matching of the entire study population yielded 52 matched pairs with similar baseline characteristics. There were no statistically significant differences between the LDV/SOF (96.1%) and glecaprevir/pibrentasvir (98.0%) groups in the overall SVR12 rates of the modified intention-to-treat populations, and their rates of treatment discontinuation and adverse events were similar. CONCLUSIONS: Treatment with LDV/SOF for hepatitis C virus genotype 2 resulted in a high rate of SVR12 and excellent tolerability. The outcomes of LDV/SOF were very similar to those of glecaprevir/pibrentasvir.

Cost-effectiveness analysis of sofosbuvir plus ribavirin in patients with genotype 2 chronic hepatitis C: an analysis with real world outcomes from a multicentre cohort in Japan.

OBJECTIVES: A number of publications have demonstrated the cost-effectiveness of sofosbuvir plus ribavirin (SOF+RBV) compared with the former standard therapy with interferon (IFN)-containing regimens. Unlike these cost-effective analyses, where efficacy parameters were obtained from registration trials for drug approval, this analysis is a cost-effectiveness analysis of SOF+RBV for genotype (GT) 2 non-cirrhosis (NC) and compensated cirrhosis (CC) patients using efficacy parameters obtained from a multicentre cohort study (Kyushu University Liver Disease Study; KULDS) in Kyushu area in Japan in order to reflect real-world clinical practice in Japan. METHOD: A Markov model followed 10 000 patients (62 years old) over their lifetime. Four populations were followed: treatment-naïve (TN)-NC, treatment-experienced (TE)-NC, TN-CC and TE-CC. Comparators were Peg-IFNα2b+RBV for TN-NC and CC patients and telaprevir (TVR)+Peg-IFNα2b+RBV for TE-NC patients. The sustained virological response (SVR) rates of SOF+RBV were taken from KULDS and those of comparators were obtained from systematic literature reviews. There were nine states (NC, CC, decompensated cirrhosis [DC], hepatocellular carcinoma [HCC], SVR [NC], SVR [CC], liver transplantation [LT], post-LT and death) in this model, and an increase in the progression rate to HCC due to ageing was also considered. The analysis was conducted from the perspective of a public healthcare payer, and a discount rate of 2% was set for both cost and effectiveness. RESULTS: Incremental cost-effectiveness ratios (ICERs) of SOF+RBV versus Peg-IFNα2b+RBV were ¥323 928 /quality-adjusted life year (QALY) for TN-NC patients, ¥92 256/QALY for TN-CC patients and ¥1 519 202/QALY for TE-CC patients. The ICER of SOF+RBV versus TVR+Peg-IFNα2b+RBV was ¥849 138/QALY for TE-NC patients. The robustness of the results was determined by sensitivity analysis. CONCLUSIONS: The results of this analysis strongly demonstrate the robustness of our previous findings that SOF+RBV regimens are cost-effective in the real world and clinical trial settings for Japanese GT2 NC and CC patients.

Glecaprevir and pibrentasvir for Japanese patients with chronic hepatitis C genotype 1 or 2 infection: Results from a multicenter, real-world cohort study.

AIM: Glecaprevir (GLE) and pibrentasvir (PIB) are new direct-acting antiviral agents (DAAs) with pangenotypic inhibitors that respectively target the hepatitis C virus (HCV) NS3/4 protease and NS5A. The aim of this study was to evaluate the effectiveness and safety of combining GLE and PIB for patients with HCV genotype (GT) 1 or 2 infection in the clinical setting, including patients DAA-experienced or on hemodialysis. METHODS: This multicenter, real-world, retrospective, cohort study consisted of 314 Japanese patients who were treated with GLE (300 mg) and PIB (120 mg) for a fixed 8- or 12-week duration. We evaluated the sustained virologic response rate 12 weeks after the end of treatment (SVR12) and adverse events. RESULTS: Among the treated patients, 122 had GT1 and 192 GT2 infection. The overall SVR12 rates in the per-protocol populations were 99.2% (119/120) for GT1 and 98.9% (183/185) for GT2. High SVR12 rates were observed in almost all subgroups, including cirrhosis, receiving hemodialysis, or previous all-oral DAA groups treated with asunaprevir and daclatasvir (GT1b), ledipasvir/sofosbuvir (GT1), or sofosbuvir and ribavirin (GT2). Virological relapse occurred in only 1.0% (3/305) of the patients who completed treatment. The most common adverse events were pruritus and fatigue (>5% of patients). Serious adverse events were rare and discontinuation due to an adverse event was required for 1.6% of the patients. CONCLUSIONS: In this real-world cohort study, treatment with GLE/PIB achieved high SVR12 rates with a low rate of serious adverse events among patients with HCV GT1 or 2 infection.

Elbasvir plus grazoprevir for patients with chronic hepatitis C genotype 1: A multicenter, real-world cohort study focusing on chronic kidney disease.

The real-world effectiveness and safety of all-oral direct-acting antivirals (DAAs) for chronic hepatitis C (HCV) infection and chronic kidney disease (CKD) have not been fully elucidated. This study assesses elbasvir (EBR) plus grazoprevir (GZR) for patients with HCV genotype 1 infection in the clinical setting, focusing on CKD stage 3-5D. This multicenter, real-world cohort study consisted of 282 Japanese patients who were treated with EBR (50 mg) plus GZR (100 mg) for a fixed 12-week duration. We evaluated the sustained viral response rate 12 weeks after the end of treatment (SVR12), longitudinal liver and renal parameters, and adverse effects according to the cirrhosis and CKD status. Of those enrolled, 89 (31.6%) were CKD stage 3-5 and 21 (7.4%) were CKD stage 5D (hemodialysis-dependent). The overall and CKD stage 3-5D SVR12 rates in the per protocol populations were 98.6% (272/276) and 98.1% (101/103). High SVR12 rates were observed in almost all groups, except for prior all-oral DAA failure with NS5A resistance-associated substitutions. There was no significant change during treatment or follow-up period in estimated glomerular filtration rate, irrespective of CKD status. In contrast, the serum complement level (C3 and C4) increased, with significance for C3. Serious adverse effects were very rare, both in the groups with normal eGFR and CKD, and discontinuation was required for only six (2.1%) patients. EBR plus GZR for HCV genotype 1 was highly effective with a low rate of adverse effects, regardless of CKD status. In addition, liver parameters and complement levels improved longitudinally.

Genome-Wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection.

BACKGROUND & AIMS: There is still a risk for hepatocellular carcinoma (HCC) development after eradication of hepatitis C virus (HCV) infection with antiviral agents. We investigated genetic factors associated with the development of HCC in patients with a sustained virologic response (SVR) to treatment for chronic HCV infection. METHODS: We obtained genomic DNA from 457 patients in Japan with a SVR to interferon-based treatment for chronic HCV infection from 2007 through 2015. We conducted a genome-wide association study (GWAS), followed by a replication analysis of 79 candidate single nucleotide polymorphisms (SNPs) in an independent set of 486 patients in Japan. The study end point was HCC diagnosis or confirmation of lack of HCC (at follow-up examinations until December 2014 in the GWAS cohort, and until January 2016 in the replication cohort). We collected clinical and laboratory data from all patients. We analyzed expression levels of candidate gene variants in human hepatic stellate cells, rats with steatohepatitis caused by a choline-deficient L-amino acid-defined diet, and a mouse model of liver injury caused by administration of carbon tetrachloride. We also analyzed expression levels in liver tissues of patients with chronic HCV infection with different stages of fibrosis or tumors vs patients without HCV infection (controls). RESULTS: We found a strong association between the SNP rs17047200, located within the intron of the tolloid like 1 gene (TLL1) on chromosome 4, and development of HCC; there was a genome-wide level of significance when the results of the GWAS and replication study were combined (odds ratio, 2.37; P = 2.66 × 10-8). Multivariate analysis showed rs17047200 AT/TT to be an independent risk factor for HCC (hazard ratio, 1.78; P = .008), along with male sex, older age, lower level of albumin, advanced stage of hepatic fibrosis, presence of diabetes, and higher post-treatment level of α-fetoprotein. Combining the rs17047200 genotype with other factors, we developed prediction models for HCC development in patients with mild or advanced hepatic fibrosis. Levels of TLL1 messenger RNA (mRNA) in human hepatic stellate cells increased with activation. Levels of Tll1 mRNA increased in liver tissues of rodents with hepatic fibrogenesis compared with controls. Levels of TLL1 mRNA increased in liver tissues of patients with progression of fibrosis. Gene expression levels of TLL1 short variants, including isoform 2, were higher in patients with rs17047200 AT/TT. CONCLUSIONS: In a GWAS, we identified the association between the SNP rs17047200, within the intron of TLL1, and development of HCC in patients who achieved an SVR to treatment for chronic HCV infection. We found levels of Tll1/TLL1 mRNA to be increased in rodent models of liver injury and liver tissues of patients with fibrosis, compared with controls. We propose that this SNP might affect splicing of TLL1 mRNA, yielding short variants with high catalytic activity that accelerates hepatic fibrogenesis and carcinogenesis. Further studies are needed to determine how rs17047200 affects TLL1 mRNA levels, splicing, and translation, as well as the prevalence of this variant among other patients with HCC. Tests for the TLL1 SNP might be used to identify patients at risk for HCC after an SVR to treatment of HCV infection.

Effectiveness and safety of daclatasvir plus asunaprevir for patients with hepatitis C virus genotype 1b aged 75 years and over with or without cirrhosis.

AIM: The aim of this study was to evaluate the efficacy and safety of 24-week daclatasvir (NS5A inhibitor) plus asunaprevir (NS3/4 A protease inhibitor) treatment for elderly patients with hepatitis C virus (HCV) genotype 1b infection. METHODS: This prospective, multicenter study consisted of 321 Japanese HCV genotype 1b patients who were interferon-ineligible/intolerant or non-responders to interferon-based regimens, including 103 (32.1%) aged ≥75 years and 127 (39.6%) with cirrhosis. Sustained virological response (SVR) at 24 weeks after the end of treatment and adverse effects were analyzed according to age. RESULTS: The overall SVR rate was 90.3%. In terms of by age, 94.5% (69/73), 88.3% (128/145), and 90.3% (93/103) of the patients aged <65, 65-74, and ≥75 years, respectively, achieved SVR. For the entire cohort, pre-existent NS5A resistance-associated variants and prior simeprevir failure were independently associated with treatment failure. According to the analysis of patients without these unfavorable pretreatment factors, 90.8% (89/98) aged ≥75 years achieved SVR, although this was significantly lower than for those aged <65 years (98.5%, 66/67) (P < 0.05). The frequency of adverse effects was comparable for the <75 and ≥75 age groups, the most common being an elevated alanine aminotransferase level (>150 U/L, 8.7%), however, no decompensating events were seen. CONCLUSIONS: Daclatasvir plus asunaprevir for HCV genotype 1b was well tolerated and effective for patients without pre-existent NS5A resistance-associated variants or simeprevir failure, irrespective of fibrosis status. However, it was less effective for very old patients aged ≥75 years compared to those aged <65.

NS5A resistance-associated variants undermine the effectiveness of ledipasvir and sofosbuvir for cirrhotic patients infected with HCV genotype 1b.

BACKGROUND: Little real-world cohort data has been reported for Asians who have received interferon-free regimens with sofosbuvir (SOF) for chronic hepatitis C virus (HCV) infection. We evaluated the effectiveness and safety in clinical practice of ledipasvir (LDV) plus SOF for Japanese patients infected with HCV genotype 1. METHODS: This large, multicenter, real-world cohort study consisted of 772 patients treatment-naive or -experienced, with or without compensated cirrhosis, who were treated with LDV (90 mg)/SOF (400 mg) for a fixed 12-week duration. Direct sequence analysis of the NS5A genes (L31 and Y93) was performed at baseline. RESULTS: Almost all (99.6%) were infected with HCV genotype 1b. The overall sustained virological response 12 weeks after the end of treatment (SVR12) rate was 98.8% (763/772). Multivariable logistic regression analysis extracted male (odds ratio [OR] 6.62, p = 0.024), cirrhosis (OR 20.1, p = 0.0054), and baseline NS5A resistance-associated variants (RAVs) (OR 29.3, p = 0.0018) as independently associated with treatment failure. Notably, the SVR12 rate for cirrhosis patients with baseline NS5A RAVs (87.5%, 49/56) was statistically lower than for the other groups. This tendency was found except for patients with prior daclatasvir/asunaprevir failure. All patients with treatment failure had NS5A Y93H at relapse, whether or not they had NS5A RAVs at baseline. Serious adverse effects were very rare, and discontinuation was required for only five (0.6%) patients. CONCLUSIONS: LDV/SOF for HCV genotype 1b was exceptionally effective, however, NS5A RAVs undermined the virological effect for cirrhosis patients. Moreover, LDV/SOF was shown to be safe, irrespective of age or fibrosis status.

Effectiveness and safety of sofosbuvir plus ribavirin for HCV genotype 2 patients 65 and over with or without cirrhosis.

Older patients with chronic hepatitis C virus (HCV) infection have historically been designated difficult-to-treat. We evaluated the efficacy and safety of sofosbuvir (nucleotide NS5B polymerase inhibitor) plus ribavirin for patients with HCV genotype 2 infection in a real-world clinical setting, with the focus on elderly patients aged ≥ 65. This large, multicenter study consisted of 446 Japanese HCV genotype 2 patients (303 treatment-naïve and 143 treatment-experienced), including 190 (42.6%) aged ≥ 65 and 90 (20.2%) with compensated cirrhosis. Efficacy was assessed by the sustained virological response 12 weeks post-treatment (SVR12). The overall SVR12 rate was 95.7% (427/446), and the SVR12 rate of patients aged ≥ 65 was 95.3% (181/190). For treatment-naïve patients, almost all with compensated cirrhosis (95.6%, 43/45) achieved SVR12, irrespective of age. For treatment-experienced patients, cirrhosis undermined the treatment outcome, both for the aged ≥65 (SVR12: 80.0%, 20/25) and <65 (85.0%, 17/20) patient groups when compared to non-cirrhosis patients (≥65: 95.7%, 45/47 and < 65: 96.2%, 50/52). The most common adverse effect was anemia (hemoglobin <10 g/dL), especially for patients aged ≥ 65 with the inosine triphosphate pyrophosphatase CC genotype at rs1127354 (26.2%, 33/126). Notably, ribavirin reduction was not related to treatment failure. Only three (0.7%) patients, all aged ≥ 65, discontinued treatment, but all achieved SVR12. Sofosbuvir plus ribavirin for HCV genotype 2 was effective for patients aged ≥65, especially those who were treatment-naïve or treatment-experienced/non-cirrhosis.

Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity.

Hepatic insulin signalling involves insulin receptor substrates (Irs) 1/2, and is normally associated with the inhibition of gluconeogenesis and activation of lipogenesis. In diabetes and obesity, insulin no longer suppresses hepatic gluconeogenesis, while continuing to activate lipogenesis, a state referred to as 'selective insulin resistance'. Here, we show that 'selective insulin resistance' is caused by the differential expression of Irs1 and Irs2 in different zones of the liver. We demonstrate that hepatic Irs2-knockout mice develop 'selective insulin resistance', whereas mice lacking in Irs1, or both Irs1 and Irs2, develop 'total insulin resistance'. In obese diabetic mice, Irs1/2-mediated insulin signalling is impaired in the periportal zone, which is the primary site of gluconeogenesis, but enhanced in the perivenous zone, which is the primary site of lipogenesis. While hyperinsulinaemia reduces Irs2 expression in both the periportal and perivenous zones, Irs1 expression, which is predominantly in the perivenous zone, remains mostly unaffected. These data suggest that 'selective insulin resistance' is induced by the differential distribution, and alterations of hepatic Irs1 and Irs2 expression.

Inhibition of emotional needs and emotional wellbeing predict disease progression of chronic hepatitis C patients: an 8-year prospective study.

BACKGROUND: The role of psycosocial factors in the disease progression of chronic hepatitis C (CHC) patients remains unclear. The aim of the present study was to prospectively evaluate the prognostic value of behavioral patterns and the quality of life (QOL) of patients with CHC. METHODS: Two hundred and forty Japanese CHC patients (mean age 62.4 years) were assessed for behavioral patterns (Stress Inventory), QOL (Functional Assessment of Chronic Illness Therapy-Spiritual), and known prognostic factors at baseline then followed for a maximum of 8 years for disease progression, defined as either the first diagnosis of hepatocellular carcinoma (HCC) or hepatitis-related death. RESULTS: Forty-nine events occurred during the study period (46 newly diagnosed HCC cases, three hepatitis-related deaths). In a Cox proportional hazard model including known prognostic factors and treatment-related factors as time-dependent variables, behavioral patterns associated with inhibition of emotional needs (hazard ratio (HR): 1.35; 95 % confidence interval (CI): 1.02-1.77; p = 0.036) and QOL, representing emotional wellbeing (HR 0.60; 95 % CI 0.37-0.98; p = 0.041), were each associated with the risk of disease progression. CONCLUSION: Psychosocial factors such as behavioral patterns relevant to the inhibition of emotional needs and emotional wellbeing independently affect the clinical course of patients with CHC.