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Aim: The aim of this study was to evaluate the use of a new classification for safer transradial access hepatic interventional radiology, based on preoperative evaluation of the location of the left subclavian artery bifurcation in the aortic arch. Methods: A total of 38 consecutive patients with hepatocellular carcinoma and 74 sessions of radial access for visceral intervention (R.A.V.I.) were reviewed. We classified the location of the left subclavian artery bifurcation in the aortic arch in three areas using an oblique view computed tomography image matched with the curve of the aortic arches according to a new criteria Three Areas Criteria For R.A.V.I. (named "TAC‐F‐R"), and measured the required time from initial left radial artery arteriography to celiac artery or superior mesenteric artery arteriography. Results: The median time required for left radial artery arteriography to the celiac artery or superior mesenteric artery arteriography in each of the three areas were: area A, 0:11:10 (h, min, s); area B, 0:14:44; and area C, 0:31:51. There were significant differences between each area after Bonferroni correction (p < 0.01; A vs. B, p = 0.086; A vs. C, p = 0.001; and B vs. C, p = 0.045), with areas A and B requiring a significantly shorter time. Finally, no patients showed neurogenic disfunction within 1 week after the R.A.V.I. procedure. Conclusions: The new classification, "TAC‐F‐R," for safer transradial access hepatic interventional radiology is effective for avoiding difficult cases, and selects more suitable patients with hepatocellular carcinoma for the R.A.V.I. procedure. [ABSTRACT FROM AUTHOR]

Aims: The effects of genetic polymorphism on a personalized diet and exercise program for steatotic liver disease (SLD) are still unclear. Methods: Participants of this retrospective cohort study were 203 Japanese patients with SLD diagnosed by abdominal ultrasonography. All of them were introduced the personalized diet and exercise treatment. A diet of 25–30 kcal/kg multiplied by ideal body weight (BW) daily and aerobic and resistance exercise (exercise intensity of 4–5 metabolic equivalents daily, respectively) were performed for 6 days. Treatment efficacy was evaluated in terms of the rate of decrease of liver function tests, glycolipid metabolism markers, physical findings, image findings, and cardiovascular disease (CVD) risk score at 6 months compared with baseline. Furthermore, the impact of genetic polymorphism was also investigated. Results: At 6 months compared with baseline, liver function tests (AST, ALT, γGTP), glycolipid metabolism markers (hemoglobin A1c, triglycerides [TG], low‐density lipoprotein cholesterol), physical findings (BW, body mass index), image finding (liver stiffness measurement), and CVD risk score (Suita score) improved significantly. There was no significant difference in treatment efficacy, except for the rates of decrease of TG, according to genotype PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs6834314. The rates of decrease of TG with TM6SF2 CT were significantly higher than those with CC or TT, and the rates of TG with HSD17B13 AA were significantly higher than those with AG by multiple comparisons. Conclusion: Personalized diet and exercise program for SLD improved liver function tests, physical findings, glycolipid metabolism markers, and CVD risk score. Genetic polymorphism might partially affect treatment efficacy. Further studies should be performed to develop an individualized program for SLD, considering genetic polymorphism. [ABSTRACT FROM AUTHOR]

Aim: There are few reports on the prognosis of liver‐related events in Japanese patients with nonalcoholic fatty liver disease (NAFLD). We undertook an observational study to compare the prognosis between fibrotic and nonfibrotic groups in Japanese NAFLD patients. Methods: Prognosis in 393 NAFLD patients who underwent liver biopsy between April 2013 and April 2015 at multiple centers were investigated. The time to onset of liver‐related events, cardiovascular events, development of extrahepatic cancers, and death were compared between the pathologically fibrotic nonalcoholic steatohepatitis (NASH) group and nonalcoholic fatty liver (NAFL) + nonfibrotic NASH group. A similar analysis was carried out based on the fibrotic classification diagnosed using four noninvasive fibrosis prediction models. Results: The mean age and body mass index at the time of liver biopsy was 55.7 years old and 28.04 kg/m2, respectively The cumulative incidence of liver‐related events at 1080 days after liver biopsy was 5.79% in the pathologically fibrotic NASH group and 0% in the NAFL + nonfibrotic NASH group, with a significant difference (p = 0.0334). The cumulative incidence of liver‐related events was significantly higher in the positive group for the prediction model than in the negative group in all four models (all p values were <0.0001). There was no significant difference between the pathologically fibrotic NASH group and NAFL + nonfibrotic NASH group in terms of cumulative incidence of cardiovascular events, development of extrahepatic cancers, and death. Conclusions: The incidence of liver‐related events was significantly higher in the fibrotic NASH group than that of the NAFL + nonfibrotic NASH group in Japanese NAFLD patients. [ABSTRACT FROM AUTHOR]

Aims: Both diet and exercise counseling are recommended for patients with fatty liver, including nonalcoholic fatty liver disease (NAFLD), to achieve weight loss goals. However, data evaluating treatment efficacy are limited. Methods: The subjects of this retrospective cohort study were 186 consecutive Japanese cases with fatty liver diagnosed by abdominal ultrasonography. Treatment efficacy and predictive factors of "Hospitalization Program for Improvement Purpose for Fatty Liver" as a combined diet and aerobic and resistance exercise program were evaluated according to the hospitalization group (153 cases) or the no hospitalization group (33 cases). To balance the confounding biases, treatment efficacy was evaluated using propensity score‐matched analysis. In the hospitalization group, a diet of 25–30 kcal/kg multiplied by ideal body weight (BW) daily and aerobic and resistance exercise (exercise intensity of 4–5 metabolic equivalents daily, respectively) were performed for 6 days. Results: In liver function tests and BW at 6 months compared with baseline, the rates of decrease of the hospitalization group (24 cases) were significantly higher than those of the no hospitalization group (24 cases), using propensity score‐matched analysis. In markers of glycolipid metabolism and ferritin levels, the rates of the hospitalization group were not different from those of the no hospitalization group. In the hospitalization group (153 cases), multivariate regression analysis identified the etiology of non‐NAFLD, the presence of diabetes mellitus, and large waist circumference as independent predictors of decreased rates of hemoglobin A1c levels. Conclusion: The diet and exercise program for fatty liver improved liver function tests and BW. Further study should be performed to develop a feasible and suitable program. [ABSTRACT FROM AUTHOR]

Chronic hepatitis C virus (HCV) infection has the greatest health impact in patients with advanced liver disease. The direct‐acting antiviral (DAA) regimen glecaprevir/pibrentasvir (G/P) is approved for treatment of HCV‐infected patients without cirrhosis and with compensated cirrhosis. However, events of liver decompensation/failure have been reported in patients treated with protease‐inhibitor–containing DAA regimens, often in patients with advanced liver disease. This study examines the safety of on‐label G/P treatment in patients with compensated cirrhosis (F4 at baseline) with markers of advanced liver disease. Patients with cirrhosis were categorized into 4 subgroups, based on different noninvasive markers of advanced liver disease identified using laboratory measures: platelet count < or ≥ 100 × 109/L, and Child‐Pugh score 5 or 6. Separate analyses were performed using pooled data from clinical trials and from real‐world post‐marketing observational studies. G/P was well tolerated in patients with platelet count ≥100 × 109/L (n = 800), platelet count <100 × 109/L (n = 215), a Child‐Pugh score of 5 (n = 915) and a Child‐Pugh score of 6 (n = 95). In the clinical trial and real‐world cohorts two patients and no patients experienced a serious adverse event (AE) possibly related to study drug, respectively; three patients and no patients experienced an AE of special interest for hepatic decompensation and hepatic failure. This analysis reaffirms G/P's safety profile in indicated patients with compensated cirrhosis, including those with markers of more advanced liver disease. Increasing the number of patients treated with short‐duration G/P therapy may contribute to meeting HCV elimination targets. [ABSTRACT FROM AUTHOR]

Background & Purpose: Protease‐free regimens for chronic hepatitis C virus (HCV) infection are safe and effective for persons with either compensated or decompensated cirrhosis. We examined the efficacy and safety of sofosbuvir–velpatasvir in participants with HCV and compensated cirrhosis in Japan. Methods: This was a Phase 3, multi‐center, open‐label study. At 20 sites, 37 individuals with chronic HCV infection of any genotype and compensated cirrhosis received sofosbuvir–velpatasvir (400 mg/100 mg) daily for 12 weeks. Participants were treatment‐naïve or treatment‐experienced with interferon‐based treatments with or without HCV NS3/4A protease inhibitors. Prior exposure with HCV NS5A or NS5B inhibitors was prohibited. The primary study endpoint was sustained virologic response 12 weeks after treatment (SVR12). Results: Among participants, 62% had HCV genotype 1 infection, and 38% had HCV genotype 2. More than three quarters (29/37, 78%) were HCV treatment naïve. All participants (37/37, 100%) achieved SVR12. Seventeen participants (46%) and three participants (8%) had pretreatment resistance‐associated substitutions to HCV NS5A and NS5B nucleoside inhibitors respectively, yet no on‐treatment breakthrough or relapse occurred. Sofosbuvir–velpatasvir for 12 weeks treatment was safe and well tolerated. The most commonly reported adverse events were headache (8%, 3/37) and diarrhea (5%, 2/37). One serious adverse event, patella fracture, occurred and was considered not treatment related. No participants discontinued study treatment due to an adverse event. Three participants (8%) had a Grade 3 laboratory abnormality; all were hyperglycemia. Conclusion: Sofosbuvir–velpatasvir resulted in high SVR rates and was well tolerated among Japanese patients with HCV and compensated cirrhosis. This single‐tablet regimen offers a highly effective, protease‐inhibitor free regimen for treating HCV. ClinicalTrials.gov Identifier: NCT04112303. [ABSTRACT FROM AUTHOR]

Aim: The phase III REFLECT study utilized bodyweight‐based lenvatinib dosing in patients with unresectable hepatocellular carcinoma, based on results of the phase II Study 202. This post hoc analysis compared efficacy and safety in patients with lower and higher bodyweights. Methods: This comparison included patients from Study 202 (Japanese, n = 43; Korean, n = 3) and Japanese patients from REFLECT (n = 81) who received lenvatinib. In Study 202, all patients received a starting dose of lenvatinib 12 mg/day; in REFLECT, patients received starting doses based on bodyweight (patients <60 kg, 8 mg/day; ≥60 kg, 12 mg/day). Safety and efficacy were assessed in both studies according to bodyweight. Results: In Study 202, treatment‐related, treatment‐emergent adverse events (TEAEs) led to dose reductions in 80.8% and 55.0% of patients in the lower and higher bodyweight groups, respectively. In REFLECT, treatment‐related TEAEs led to dose reductions in 52.5% and 70.7% of patients in the 8 and 12 mg groups, respectively. In Study 202, median overall survival (OS) was 16.2 months (95% confidence interval [CI], 9.8–25.1) and 21.3 months (95% CI, 10.1–not estimable) in the lower and higher bodyweight groups, respectively. In REFLECT, median OS was 15.8 months (95% CI, 10.4–27.6) and 18.2 months (95% CI, 11.3–26.9) in the 8 and 12 mg groups, respectively. Conclusions: Comparison between patients in Study 202 and REFLECT demonstrates efficacy was maintained with improved safety in patients with lower bodyweights who received lenvatinib 8 mg/day in REFLECT versus patients who received lenvatinib 12 mg/day in Study 202. [ABSTRACT FROM AUTHOR]

Background: Long‐term use of nucleotide analogs such as adefovir (ADV) or tenofovir disoproxil fumarate (TDF) may cause renal impairment. Tenofovir alafenamide (TAF) has less systemic exposure than TDF did. The aims were to examine longitudinal changes in renal function and biochemical parameters for 2 years after switching from long‐term ADV and TDF to TAF, and to explore factors associated with improved renal function after TAF in patients with chronic hepatitis B. Methods: The prospective observational cohort study included 306 patients with chronic hepatitis B who underwent switching from long‐term TDF or ADV to TAF. The primary outcome was the changes in estimated glomerular filtration rate (eGFR) after TAF. Results: Among 306 patients, 190 (65.3%) and 106 (34.7%) had chronic kidney disease (CKD) stages 1–2 and 3a–4 at baseline. In patients with CKD stages 3a–4, the mean eGFR significantly increased until week 12 and plateaued from week 12 to year 2 (adjusted slope using linear mixed effect models: +9.01 ml/min/1.73 m2/year until week 12; p < 0.001). In contrast, the mean eGFR plateaued from baseline to year 2 in the CKD stages 1–2 subgroup. Multivariate logistic regression showed that baseline CKD stage ≥3a, steeper decline in eGFR 1 year before TAF, and shorter duration of any nucleotide analog use was significantly associated with ≥10% improvement in eGFR in year 1. Conclusions: Switching from TDF or ADV to TAF resulted in favorable renal safety for 2 years. In CKD stage 3a–4 subgroup, eGFR after TAF was recovered in the first 12 weeks and subsequently stabilized. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy, safety, and tolerability of apararenone 10 mg/day in patients with nonalcoholic steatohepatitis (NASH). Methods: In this multicenter, randomized, double‐blind, placebo‐controlled phase II study, patients received apararenone 10 mg or placebo once daily for 72 weeks. The primary efficacy end‐point was percent change in serum alanine aminotransferase (ALT) from baseline to 24 weeks after randomization. Secondary efficacy end‐points included changes in liver fibrosis markers. Adverse drug reactions (ADRs) and serum potassium levels were evaluated. Results: Forty‐eight patients were randomly assigned to treatment (placebo, 23; apararenone, 25). The percent change in ALT at 24 weeks was −3.0% and −13.7% with placebo and apararenone, respectively (p = 0.308). The apararenone group showed greater reductions from baseline in fibrosis markers (type IV collagen 7S and procollagen‐3 N‐terminal peptide) and noninvasive tests of fibrosis (enhanced liver fibrosis score and Fibrosis‐4 index) at all time points versus placebo. The percentage of patients with improvement of 1 point or more in fibrosis stage/without nonalcoholic fatty liver disease activity score worsening was 41.7% with apararenone and 26.1% with placebo (p = 0.203). Adverse drug reactions were reported in three (13.0%) and three (12.5%) patients in the placebo and apararenone groups, respectively. Serum potassium levels increased in the apararenone group during the study and decreased to near baseline after the end of treatment. Conclusions: In patients with NASH, apararenone 10 mg/day for 72 weeks was effective in decreasing ALT levels, improved multiple potential fibrosis markers, and was safe and well tolerated. Pathological findings showed anti‐inflammatory and antifibrotic effects of apararenone. [ABSTRACT FROM AUTHOR]

Tenofovir disoproxil fumarate (TDF) is widely used to treat hepatitis B virus (HBV) patients worldwide. We previously reported a patient with CHB and cirrhosis in whom viral breakthrough occurred during combination therapy with TDF and entecavir (ETV) against ETV‐resistant virus. A recent Korean report showed that two patients with viral breakthrough during treatment with TDF‐containing regimens were found to carry five reverse transcriptase (rt) mutations ([rt]S106C[C], rtH126Y[Y], rtD134E[E], rtM204I/V, and rtL269I [I]), with the C, Y, E, and I mutations being associated with tenofovir resistance. We report the clinical course up to September 2019 in our patient, and compare the HBV mutations to those of the two Korean patients. Four mutations (rtS106C, rtD134N/S[N/S], rtM204V, and rtL269I) plus ETV resistance (rtL180M and rtS202G) existed when she developed viral breakthrough during ETV and TDF combination therapy in April 2013. Moreover, three mutations (rtS106C, rtD134N, and rtL269I) existed at baseline. Our patient's father is Korean. Considering these factors, patients with these three or four mutations (CYEI or CN/SI) at baseline could experience tenofovir resistance in addition to lamivudine (LAM) or ETV resistance. In addition, HBV DNA levels fluctuated during tenofovir alafenamide (TAF) and LAM therapy in our patient, although treatment was switched from LAM, TDF, and ETV to LAM and TAF combination therapy in April 2018. In conclusion, three mutations (CN/SI) plus ETV resistance (rtL180M, rtM204V, and rtS202G) can cause tenofovir resistance. Long‐term therapy with tenofovir against ETV‐resistant virus has the potential to induce viral breakthrough and resistance, necessitating careful follow‐up. [ABSTRACT FROM AUTHOR]

Aims: Hepatitis B surface antigen (HBsAg) seroclearance indicates a "functional cure" in chronic hepatitis B (CHB) virus infection. However, several cases of hepatocellular carcinoma (HCC) development have been reported after HBsAg seroclearance. We evaluated the potential of HBsAg and hepatitis B core‐related antigen (HBcrAg), measured by the ultra‐highly sensitive assays, in cases with HCC development after HBsAg seroclearance. Methods: We enrolled 17 patients with CHB who achieved HBsAg seroclearance, defined by the conventional assay using Architect HBsAg QT kit (five HCC patients and 12 non‐HCC patients). HBsAg and HBcrAg were measured in their stored serum samples using ultra‐highly sensitive assays featuring "immunoassay for total antigen including complex via pretreatment (iTACT)" technology. Results: All five patients who developed HCC were positive for HBsAg or HBcrAg by iTACT‐HBsAg or iTACT‐HBcrAg at all follow‐up points. HBcrAg levels in the HCC group, using iTACT‐HBcrAg, were significantly higher than those in the non‐HCC group at HBsAg seroclearance (3.6 LogU/ml (2.8–4.2) versus 2.6 (<2.1–3.8), p = 0.020). The best cutoff value of iTACT‐HBcrAg for predicting HCC development was 2.7 LogU/ml by receiver operating characteristic curve analysis. The prevalence of HBcrAg ≥2.7 in the HCC group was significantly higher than that in non‐HCC group (100% [5/5] versus 33% [4/12], p = 0.029). Conclusions: Residual low viral antigen might predict HCC development even if HBsAg seroclearance was achieved according to a conventional assay. The results suggest that iTACT assays of HBsAg and HBcrAg would be useful for monitoring CHB patients. [ABSTRACT FROM AUTHOR]

Aim: The number of patients with fatty liver disease (FLD) is increasing globally. Ethanol consumption in FLD is known to be associated with an increased risk of hepatocellular carcinoma (HCC), but the effects of alcohol consumption on the occurrence of multiple HCCs remain unclear. We explored the relationship between the daily ethanol intake and the HCC number. Methods: This single‐center retrospective study enrolled 114 patients without viral or immune hepatitis undergoing first‐line HCC treatment who had been diagnosed with FLD by abdominal ultrasonography or a liver biopsy at the same time as or before HCC detection. We categorized patients into four groups according to the daily alcohol consumption (<20 g: non‐alcoholic fatty liver disease, n = 45; 20–39 g: low‐intermediate ethanol intake with FLD, n = 13; 40–69 g: high‐intermediate ethanol intake with FLD, n = 31; ≥70 g: alcoholic fatty liver disease, n = 25). The relationship between the daily ethanol consumption and the number of HCCs (single or multiple) was examined. Results: The risk of multiple HCCs was significantly higher in the high‐intermediate ethanol intake with FLD (HR 2.89, 95% CI 1.04–8.02, P = 0.042) and alcoholic fatty liver disease (HR 3.14, 95% CI 1.07–9.22, P = 0.037) groups than in the others. A multivariate analysis showed that a daily ethanol intake ≥40 g was associated with a significantly increased risk of multiple HCCs (HR 2.82, 95% CI 1.16–6.88, P = 0.023). Conclusions: Our findings suggest that a high daily ethanol intake might lead to multiple hepatocarcinogenesis in patients with FLD. [ABSTRACT FROM AUTHOR]

Telomerase reverse transcriptase (TERT) promoter mutation is the most frequent genetic alteration in hepatocellular carcinoma (HCC). However, there is currently no suitable highly sensitive method that can detect such mutation using serum cell‐free DNA (cfDNA). We analyzed somatic point mutations that substitute cytosine for thymidine at position 228 (C228T), as one of the hotspots of TERT promoter mutations, in serum cfDNA using a highly sensitive detection method of wild‐type blocking polymerase chain reaction (WTB‐PCR) combined with Sanger sequencing. In TERT promoter mutation sensitivity study, synthetic oligonucleotides were prepared to determine the lowest detection limit of the WTB‐PCR, using serial dilutions of mutant‐type (MT) DNA in the background of wild‐type (WT) DNA. Using this technique, we conducted a longitudinal study in one patient who developed HCC during the follow‐up and determined the relationship between HCC and TERT C228T in serum cfDNA. In the sensitivity study, the mutant peak at position 228 was detected at 0.7% or higher but was not detected at 0.6%. Thus, sequencing analysis of WTB‐PCR product demonstrated the limit of detection in excess of 0.7% MT DNA in the background of WT DNA. One male patient with HCV‐related cirrhosis developed HCC during the follow‐up. TERT C228T was negative before the diagnosis of HCC, positive at the diagnosis of HCC and did not increase with advancement of malignancy. We developed a highly sensitive method for detection of TERT promoter mutation using WTB‐PCR combined with Sanger sequencing and demonstrated its clinical usefulness in the measurement of TERT C228T in serum cfDNA. Larger studies are needed to confirm these results and establish the clinical utility of this new method. Research Highlights: We developed a highly sensitive method for detection of TERT promoter mutation using WTB‐PCR combined with Sanger sequencing and demonstrated its clinical usefulness in the measurement of TERT C228T in serum cfDNA. [ABSTRACT FROM AUTHOR]

Aim: The risk of development of hepatocellular carcinoma (HCC) persisted in patients with advanced fibrosis, even after achieving sustained virologic response (SVR). This study aimed to show the advantage of liver stiffness measurement (LSM) at baseline and after SVR to predict HCC occurrence and esophageal varices (EV) exacerbation. Methods: These risks were evaluated in 398 chronic hepatitis C patients without a history of HCC who achieved SVR after direct‐acting antiviral agent and evaluated LSM at least twice during follow up. We defined liver cirrhosis and chronic hepatitis as LSM of ≥12 kPa and <12 kPa, respectively. Results: LSM was significantly correlated with serum fibrosis markers, such as Fib‐4 index and Wisteria floribunda agglutinin‐positive Mac‐2 binding protein, at baseline and SVR at 24 weeks after treatment (SVR24). Five patients received preventive treatment of EV, but no EV bleeding occurred after SVR, and their LSM at baseline and SVR24 was significantly higher than that of other cirrhosis patients. The annual rate of HCC during the first 4 years was 1.5%. LSM in HCC patients tended to decrease after direct‐acting antiviral agent therapies, but significantly higher than that of cirrhosis patients without HCC before and after treatment. Multivariate analysis identified LSM and alpha‐fetoprotein at baseline and LSM at SVR24 as significant independent predictors of HCC. Conclusions: Evaluating LSM not only at baseline, but also SVR24, was found to be useful for the detection of advanced fibrosis patients at high risk of HCC occurrence and EV exacerbation. We recommend focused surveillance of HCC and EV for these patients. [ABSTRACT FROM AUTHOR]

Glecaprevir (GLE)/pibrentasvir (PIB) 300 mg/120 mg once daily (Mavyret/Maviret) is an all‐oral, pangenotypic, interferon‐ and ribavirin‐free combination regimen approved for the treatment of chronic hepatitis C virus (HCV) infection. The objective of the current analyses was to characterize the pharmacokinetics (PK) of GLE/PIB in HCV‐infected Japanese patients. Data from 332 subjects enrolled in 2 Japan phase 3 trials, CERTAIN‐1 and CERTAIN‐2, were used in the analyses. Pharmacokinetics of GLE/PIB were characterized using a nonlinear mixed‐effects modeling. The analyses evaluated the impact of covariates (concomitant medications and demographic and clinical covariates such as renal impairment, effect of cirrhotic status) on GLE/PIB PK. GLE and PIB PK were described by 1‐ and 2‐compartment models, respectively. Presence of cirrhosis, age, and body weight were identified as significant covariates on GLE/PIB PK. A trend toward higher GLE and PIB exposures in older patients and higher PIB exposures in heavier patients was observed; however, these increases were not considered clinically meaningful. GLE and PIB exposures were higher in HCV‐infected subjects with cirrhosis (Child‐Pugh A; GLE area under the plasma concentration–time curve was 160% higher, and PIB area under the plasma concentration–time curve was 21% higher) compared to subjects without cirrhosis. Renal function (including subjects with end‐stage renal disease with dialysis) had no impact on GLE or PIB exposures. The GLE/PIB dose was well tolerated in the Japanese population, and no dose adjustment is needed for the evaluated intrinsic and extrinsic factors. [ABSTRACT FROM AUTHOR]

Aim: The long‐term effects of sustained virologic response (SVR) to antiviral therapy on the risk of liver complications, such as exacerbation of esophageal varices (EV), hepatocellular carcinoma (HCC), malignant lymphoma, and liver‐related and overall death in hepatitis C virus (HCV)‐infected patients with liver cirrhosis are not fully known. Methods: These risks were evaluated during long‐term follow up of 457 patients with HCV‐related Child–Pugh Class A liver cirrhosis without history of HCC. Results: The respective cumulative 5‐ and 10‐year rates of EV exacerbation were 2.0% and 3.1%. Multivariate analysis identified the presence of EVs, thrombocytopenia at baseline. and alcohol intake as significant independent predictors of EV exacerbation before and after SVR. The cumulative 5‐ and 10‐year rates of HCC were 6.8% and 10.2%, respectively. Male sex and the presence of EV were significant independent determinants of HCC before and after SVR. Although the cumulative 5‐year HCC recurrence rate was 49.4%, the overall survival rate since HCC was 73.6% at 5 years. The overall survival rates since SVR were 98.7% and 93.6% at 5 and 10 years, respectively. Progression of HCC was the most frequent all‐cause mortality, but none of the patients died of liver decompensation. Male sex and Fibrosis‐4 index of ≥3.0 after SVR were significant and independent predictors of mortality. Conclusion: Patients with HCV remain at risk of HCC for >10 years after achieving SVR, and HCC is the most common cause of mortality. We recommend long‐term surveillance of cirrhotic patients with HCV, even after achieving SVR. [ABSTRACT FROM AUTHOR]

Aim: Rifaximin (RFX) improves hepatic encephalopathy (HE). However, information on long‐term treatment with RFX is limited. In this study, we aimed to investigate the effect of long‐term treatment with RFX on HE and liver function. Moreover, we investigated factors associated with the recurrence of HE under RFX treatment. Methods: In this retrospective cohort study, we consecutively enrolled 65 patients with HE who initiated RFX treatment (1200 mg/day) in our hospital from January 2017 to June 2018. We evaluated liver function test results, including blood ammonia levels, and the recurrence rate of HE after RFX treatment. Results: The median follow‐up duration was 41.6 weeks (range, 1.4–96.7 weeks). The blood ammonia level significantly declined from 157 to 86 μg/dL at 4 weeks after RFX treatment (P < 0.01), and the effect was prolonged. Furthermore, Child–Pugh score decreased in 51% (26/51) of the patients at 12 weeks during RFX treatment. The recurrence rate of HE after RFX treatment was 26.2% (17/65), and presence of ascites at baseline was identified as the only independent risk factor for HE recurrence (hazard ratio 4.71; 95% confidence interval, 1.27–17.5; P = 0.02). The cumulative recurrence rate of HE was significantly lower in patients without ascites than in patients with ascites at baseline (13.8% vs. 50.8%, P = 0.001). Conclusions: Long‐term treatment with RFX was beneficial for HE and liver function in patients with HE. Furthermore, the recurrence rate of HE was low in RFX‐treated patients without ascites. Thus, long‐term treatment with RFX could be effective for the management of Japanese patients with HE. [ABSTRACT FROM AUTHOR]

Background and Aim: Estimates suggest that in Asia, more than 31 million individuals have hepatitis C virus infection. The present analysis was conducted to assess the efficacy and safety of elbasvir/grazoprevir in Asian participants enrolled in the elbasvir/grazoprevir phase 2/3 clinical trials. Methods: This is an integrated analysis of data from 12 international phase 2/3 clinical trials. Asian participants with chronic hepatitis C virus genotype 1 or 4 infection who received elbasvir 50 mg/grazoprevir 100 mg once daily for 12 weeks or elbasvir/grazoprevir plus ribavirin for 16 weeks were included in this analysis. The primary end point was sustained virologic response at 12 weeks after completion of therapy (SVR12). Results: Seven hundred eighty Asian participants from 15 countries were included in this analysis. SVR12 was achieved by 756/780 (96.9%) of all participants, including 748/772 (96.9%) of those who received elbasvir/grazoprevir for 12 weeks and 8/8 (100%) of those who received elbasvir/grazoprevir plus ribavirin for 16 weeks. In the genotype 1b‐infected population, the SVR12 rate was 691/709 (97.5%), and there was no impact of age, high baseline viral load, or presence of cirrhosis. The most frequently reported adverse events were nasopharyngitis (8.0%), upper respiratory tract infection (5.4%), and diarrhea (5.2%). Twenty participants receiving elbasvir/grazoprevir for 12 weeks reported a total of 25 serious adverse events, and 7 (0.9%) discontinued treatment because of an adverse event. Conclusion: Elbasvir/grazoprevir administered for 12 weeks is an effective and generally well‐tolerated treatment option for Asian individuals with hepatitis C virus genotype 1b infection. [ABSTRACT FROM AUTHOR]

Primary liver carcinoma with sarcomatous change is a rare malignancy associated with high aggressiveness and poor prognosis. However, the characteristics of these types of tumors are still unknown. The aim of this study was to assess the imaging features, prognostic significance, and clinicopathological characteristics of patients with these tumors. Of 1070 patients who underwent surgical resection of primary liver carcinoma at Toranomon Hospital (Tokyo, Japan) from 2003 to 2017, 10 patients were diagnosed with primary liver carcinoma containing sarcomatous component. This study included all 10 patients. We evaluated the percentage of the sarcomatous component in each tumor. Patients were classified into two groups: the low percentage group (area of sarcomatous changes ≤30%) and high percentage group (area sarcomatous component ≥70%). We also divided patients into two groups based on the combination of the percentage of sarcomatous tissue and tumor size (≥40 mm or <40 mm). The overall survival rate of patients with ≥70% sarcomatous component and ≥40 mm tumor was significantly worse than that of patients with ≤30% sarcomatous tissue or <40 mm tumor size (P = 0.0059). The results confirmed the poor prognosis of patients with sarcomatous changes in primary liver carcinoma, especially those with large sarcomatous component and large tumor size. Radical resection in the early stage is recommended to improve prognosis. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate the therapeutic potential of sodium glucose cotransporter 2 inhibitor (SGLT2I) as an effective therapeutic option for non‐alcoholic fatty liver disease (NAFLD). Methods: In this prospective study, nine patients with NAFLD complicated by type 2 diabetes mellitus (DM), were introduced to the regimen of canagliflozin 100 mg once daily for 24 weeks and were evaluated by liver histology at pretreatment and at 24 weeks after the start of treatment. The primary outcome was histological improvement, defined as a decrease in NAFLD activity score of one point or more without worsening in fibrosis stage. Glucose metabolism was evaluated based on the meal tolerance test. The usefulness of extracellular and exosome microRNA‐122 (miR‐122) as early predictors of histological improvement was investigated. Results: All of the nine patients achieved histological improvement. Scores of steatosis, lobular inflammation, ballooning, and fibrosis stage decreased by 78%, 33%, 22%, and 33% at 24 weeks compared to the pretreatment, respectively. Six patients showed improvement in insulin resistance, and the other three patients showed partial improvement of insulin secretion function. Six patients, who showed a decrease in both extracellular and exosome miR‐122 ratios (the ratio of miR‐122 levels at 1 day after treatment to that at baseline), showed histological improvement. Furthermore, one patient, who showed a decrease in exosome miR‐122 ratios regardless of the increase in extracellular miR‐122 ratios, also showed decreases in NAFLD activity score and fibrosis stage. Conclusion: A prospective study showed that SGLT2I for NAFLD complicated by DM improved histological features in connection with glucose metabolism. This trial was registered as clinical trial UMIN000018166. [ABSTRACT FROM AUTHOR]

Aim: Treatment with all‐oral direct‐acting antiviral agents (DAAs) elbasvir/grazoprevir (EBR/GZR) is associated with high sustained virologic response (SVR). The aim of this study was to evaluate the safety and treatment efficacy of EBR/GZR in hepatitis C virus (HCV)‐infected patients. Methods: This retrospective cohort study included 147 consecutive patients with chronic HCV genotype 1b infection who were treated with EBR (50 mg) plus GZR (100 mg) once daily for 12 weeks. The rates of SVR at 12 weeks after the end of treatment (SVR12) were evaluated based on patient baseline characteristics. Treatment efficacy was analyzed according to background chronic kidney disease (CKD), and retreatment efficacy in patients who failed to respond to previous DAAs. Results: The SVR12 was 94% (138 of 147 patients), based on intention‐to‐treat analysis. Rates of SVR12 were 97% (131 of 135) and 58% (7 of 12) in cases naïve to DAA treatment and failure to respond to prior DAAs, respectively. The SVR12 rates in patients with CKD stage 4–5 was 100% (8 of 8). All patients (4 of 4 patients) with stage 4–5 and advanced fibrosis (Fibrosis‐4 index ≥3.25) also achieved SVR12. Multivariate analysis that included the above variables identified pretreatment with other DAAs as an independent factor that was significantly and independently associated with non‐SVR12 (odds ratio, 97.5; P < 0.001). Relapsers of first DAAs, excluding the combination of ledipasvir and sofosbuvir, achieved SVR12. Characteristic novel non‐structural protein 5A substitutions were not detected after failure of retreatment with EBR/GZR. Conclusion: Treatment with EBR/GZR was highly efficacious with acceptable safety, even in patients with CKD stage 4–5. Retreatment of relapsers to prior DAAs, excluding ledipasvir and sofosbuvir, achieved SVR12. [ABSTRACT FROM AUTHOR]

Summary: Background: Chronic hepatitis B virus (HBV) infection is an aetiologic factor for hepatocellular carcinoma (HCC). Baseline HBV DNA is a known independent predictor of HCC, and the serum hepatitis B core‐related antigen (HBcrAg) level corresponds to intrahepatic covalently closed circular DNA. Aim: To investigate whether the baseline and on‐treatment serum HBcrAg levels can predict HCC incidence in patients with chronic hepatitis B following nucleos(t)ide analogue (NA) therapy. Methods: This retrospective cohort study included 1268 patients treated with NAs for >1 year. In all patients, serum HBcrAg and hepatitis B surface antigen levels were measured at baseline and 1 year. Results: During a median follow‐up of 8.9 years, 113 patients (8.9%) developed HCC (10.3/1000 person‐years). These patients were stratified by baseline hepatitis B e‐antigen (HBeAg) status into HBeAg+ and HBeAg‐ cohorts. High on‐treatment HBcrAg levels at 1 year were found to associate significantly with HCC (HBeAg+ cohort: P = 0.017; HBeAg‐ cohort: P = 4.30 × 10−5; cut‐off values: 4.9 log U/mL and 4.4 log U/mL, respectively). In a multivariate Cox regression analysis, patients with persistently high on‐treatment HBcrAg levels had a higher risk of HCC than those with low HBcrAg levels (HBeAg+: hazard ratio [HR], 6.15, 95% confidence interval [CI]: 1.89‐20.0, P = 0.003; HBeAg‐ cohort: HR, 2.54, 95% CI: 1.40‐4.60; P = 0.002). A sub‐analysis of patients without alcoholism yielded similar findings. Conclusions: Patients with persistently high on‐treatment HBcrAg levels were more likely to develop HCC despite sustained viral suppression via long‐term NA treatment. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to clarify the utility of a no‐touch pincer ablation procedure that uses bipolar electrodes to prevent intrasubsegmental tumor recurrence after radiofrequency ablation (RFA) for patients with hepatocellular carcinoma (HCC) compared to surgical resection. Methods: We evaluated 175 consecutive patients with HCC (single nodule, tumor diameter ≤ 30 mm) who underwent surgical resection (146 received partial resection) and 313 patients who received RFA; 277 patients received touch ablation using a monopolar or bipolar RFA device, and 36 received no‐touch ablation using a bipolar RFA device. Pretreatment arterial and portal phase dynamic computed tomography (CT) or magnetic resonance imaging (MRI) images were classified into four enhancement patterns: Type 1 and Type 2 are homogeneous enhancement patterns without or with increased arterial blood flow, respectively; Type 3 is a heterogeneous enhancement pattern with a septum‐like structure; and Type 4 is an irregularly shaped ring structure enhancement pattern. Results: Cumulative recurrence rates significantly differed between procedures (surgical resection, 7.5%; no‐touch ablation, 2.9%; and touch ablation, 17.7% at the third year; P = 0.005). Multivariate Cox proportional hazards analysis revealed that enhancement pattern type (Type 3: hazard ratio [HR], 2.95; P = 0.002; and Type 4: HR, 3.88, P = 0.002), treatment procedure (touch ablation: HR, 3.36; P < 0.001), and serum α‐fetoprotein level (≥30 μg/L: HR, 1.87; P = 0.009) were significant predictors of intrasubsegmental recurrence. No significant differences between no‐touch ablation and surgical resection were observed. Conclusion: The no‐touch pincer ablation procedure has the potential to prevent intrasubsegmental recurrence after RFA for patients with HCC to the same degree as partial resection. [ABSTRACT FROM AUTHOR]

In real‐world settings, not much information is probably available on the treatment efficacy of the combination of glecaprevir and pibrentasvir (G/P) as a salvage therapy in failures of prior direct‐acting antiviral (DAA) regimens. Especially, the evolution of NS5A resistance‐associated variants (RAVs) and treatment efficacy in patients who received G/P for failures of prior treatment more than once is unknown. Twenty patients, who were exposed to glecaprevir 300 mg/d and pibrentasvir 120 mg/d for 12 weeks in failures of prior DAAs regimens were evaluated for sustained virological response at 12 weeks after the end of treatment (SVR12). The overall rate of SVR12 was 100%, based on intention‐to‐treat analysis. Five patients infected with genotype 1b, who received G/P for failures of prior treatment more than once, were analyzed for the evolution of RAVs in NS5A region. All of the five patients exhibited SVR12, regardless of the numbers of times of prior treatment (more than once), prior treatment response (nonresponse), and fibrosis stage (FIB‐4 index ≥ 3.25). At the commencement of G/P, all five patients were detected with NS5A RAVs at the position of aa 93. Four patients, except for one, were detected with RAVs at both positions of aa 31 and aa 93 (double mutation). All patients could achieve SVR12 with G/P, regardless of the emergence of NS5A RAVs, accompanied by failure to prior NS5A regimens more than once. In conclusion, our study indicated that G/P was a potentially useful salvage treatment for patients who failed prior DAAs regimens more than once. Highlights: The overall rate of SVR12, with glecaprevir and pibrentasvir (G/P) as salvage therapy in failures to prior direct‐acting antivirals (DAAs) regimens, was 100%.All patients could achieve SVR12 with G/P, regardless of emergence of NS5A RAVs, accompanied by failure to prior NS5A regimens more than once.G/P was a potentially useful salvage treatment for patients who fail prior DAAs regimens more than once. [ABSTRACT FROM AUTHOR]

Aim: A novel jelly lactulose preparation (SK‐1202) has been developed to improve compliance and reduce the elevation of blood glucose levels in diabetic patients. To compare the equivalence in the efficacy and safety of SK‐1202 and an approved commercially available syrup preparation, we undertook a randomized multicenter cross‐over study in hyperammonemia patients with liver cirrhosis who were taking lactulose. Methods: Forty‐four patients were enrolled and took each preparation for 2 weeks. Efficacy was evaluated using the Number Connection Test, blood ammonia concentration, coma grade, and the flapping tremor grade. Safety was evaluated by the number of adverse events observed, vital signs, and laboratory tests. We also examined the acceptability of each preparation using questionnaires evaluating sweetness, aftertaste, ease of use, and preference of the preparations. Results: There were no differences in efficacy or safety between SK‐1202 and the approved syrup preparation. With regard to the acceptability evaluation, given over 80% of the participants chose the SK‐1202 preparation, it appears to be preferred by patients. Conclusions: It is expected that SK‐1202 could represent a useful agent for patients with hepatic encephalopathy. [ABSTRACT FROM AUTHOR]

Aim: Hepatic fibrosis is the most important factor for estimating the prognosis of patients with non‐alcoholic fatty liver disease (NAFLD). A novel non‐invasive scoring system, the FM‐fibro index, showed high accuracy in a pilot study. The purpose of this study was to validate the efficacy of the FM‐fibro index in a multicenter cohort. Methods: Among 18 institutions, we analyzed 400 Japanese patients with biopsy‐proven NAFLD. We evaluated the accuracies of the FM‐fibro index, CA‐fibro index, and European Liver Fibrosis (ELF) panel by area under the receiver operator characteristics curves (AUROC). The FM‐fibro index includes three formulas for type IV collagen 7S, hyaluronic acid, and vascular cell adhesion molecule‐1. Results: Among 400 patients, 205 were women, and the median age was 56 years. The histological distribution of Matteoni types 1, 2, 3, and 4 was 11, 40, 15, and 334, and the distribution of hepatic fibrosis stages 0 to 4 was 67, 183, 55, 63, and 32, respectively. The AUROCs of the FM‐fibro index, CA‐fibro index, and ELF panel for non‐alcoholic steatohepatitis (NASH)‐related fibrosis were 0.7178/0.7095/0.7065, 0.7093, and 0.7245, respectively. The sensitivity and specificity of the FM‐fibro index for predicting NASH‐related fibrosis was 0.5359/0.5210/0.4641 and 0.8333/0.8182/0.8788, respectively. The accuracy of the FM‐fibro index was not significantly different from that of the CA‐fibro index or the ELF panel. Conclusions: The FM‐fibro index can predict NASH‐related fibrosis with sufficient accuracy compared with previous scoring systems. Further analyses that verify the accuracy of the FM‐fibro index to distinguish significant or advanced fibrosis in patients with NAFLD are awaited. (UMIN‐CTR: UMIN000018158). [ABSTRACT FROM AUTHOR]

It is currently unclear what impact serum microRNA‐122 (miR‐122) levels have on clearance of hepatitis B virus (HBV) surface antigen (HBsAg) in HBV‐infected patients who had not received antiviral therapy. The current study evaluated the impact of serum miR‐122 levels on HBsAg seroclearance in 367 consecutive HBV‐infected patients who had not received antiviral therapy between their initial and last visit, and investigated the predictive factors of HBsAg seroclearance. Cumulative HBsAg seroclearance rates were 13.5%, 32.0%, and 37.4% after 10, 20, and 30 years, respectively. The yearly incidence of HBsAg seroclearance over the investigated 30‐year period was 1.25%. A significant and strong correlation was observed between serum miR‐122 and HBsAg levels. Moreover, there was a significant correlation between serum miR‐122 levels and the levels of HBV DNA, hepatitis B e‐antigen, and HBV core‐related antigen. The HBsAg seroclearance rate in patients with a <1.0‐fold change of serum miR‐122 levels was significantly higher than in those with a ≥1.0‐fold change. Multivariate analysis identified age (≥30 years), HBV DNA levels (<2.2 log U/mL), HBV genotype (non‐C), and serum miR‐122 levels (<1.0‐fold change) as significant predictors of HBsAg seroclearance. Our results indicated that serum miR‐122 level is an important predictor of HBsAg seroclearance in Japanese patients who do not receive antiviral therapy. Understanding the complexity of the interactions among various virus‐related and host‐related factors could potentially help in the design of new therapies that enhance HBsAg seroclearance. [ABSTRACT FROM AUTHOR]

Aim: The recurrence rates of pruritus after stopping nalfurafine hydrochloride are unknown in chronic liver disease. Methods: A prospective confirmatory trial was carried out to determine the recurrence rates of pruritus after cessation of nalfurafine hydrochloride in chronic liver disease. After pretreatment with nalfurafine hydrochloride for 4 weeks or more, 15 consecutive Japanese patients, who confirmed the improvement of pruritus (decrease in the visual analogue scale (VAS) of ≥50 mm), were enrolled in the present study. Patients were classified to the continuous group (continuation of nalfurafine hydrochloride for 4 weeks) or the discontinuous group (cessation of nalfurafine hydrochloride) at the time of consent to study protocol, by self‐determination. Results: The recurrence rates (increase in VAS of ≥25 mm after stopping nalfurafine hydrochloride) were 100% (5 of 5 patients) and 0% (0 of 10) in the discontinuous and continuous groups, respectively. In the discontinuous group, 3 patients selected retreatment with nalfurafine hydrochloride as salvage therapy, and they generally recovered to the levels of VAS at the discontinuation of treatment. Conclusion: The present prospective trial showed the high recurrence rates of pruritus after the stop of nalfurafine hydrochloride in chronic liver disease. [ABSTRACT FROM AUTHOR]

Impact of substitution of aa70 in the core region (Core aa70) in HCV genotype 1b (HCV‐1b) on hepatocarcinogenesis following eradication of HCV RNA by direct‐acting antiviral therapy is not clear. In a retrospective study, 533 patients with HCV‐related chronic liver disease, with sustained virological response defined as negative HCV RNA at 12 weeks after cessation of direct‐acting antiviral therapy, were examined to evaluate the relationship between Core aa70 substitution and hepatocarcinogenesis. Twelve patients developed hepatocellular carcinoma during the follow‐up period. The cumulative hepatocarcinogenesis rates were 1.7% and 2.4% at the end of 1 and 2 years, respectively. Overall, multivariate analysis identified HCV subgroup (HCV‐1b with Gln70(His70); P = 0.003) and age (>65 years; P = 0.049), as pretreatment predictors of hepatocarcinogenesis. In HCV‐1b patients, multivariate analysis identified post‐treatment Wisteria floribunda agglutinin positive Mac‐2 binding protein (>1.8 COI; P = 0.042) and HCV subgroup (HCV‐1b with Gln70(His70); P = 0.071), as predictors of hepatocarcinogenesis, including post‐treatment parameter. In conclusion, Core aa70 substitution in HCV‐1b at the start of direct‐acting antiviral therapy is an important predictor of hepatocarcinogenesis following eradication of HCV RNA. This study emphasizes the importance of detection of Core aa70 substitution before initiating antiviral therapy. [ABSTRACT FROM AUTHOR]

While the combination therapy of ribavirin (RBV) and sofosbuvir (SOF) is effective in genotype 2 HCV infection, the predictors of treatment efficacy and posttreatment changes in α‐fetoprotein (AFP) and liver stiffness (markers of hepatocellular carcinoma), remain unclear. In this study, 302 patients with chronic HCV genotype 2 infection were treated with SOF (400 mg) plus RBV (400‐1000 mg; based on body weight) for 12 weeks. We evaluated the efficacy and safety of treatment, as well as measured serum AFP, liver stiffness, and controlled attenuation parameter (CAP, a surrogate marker of steatosis) at baseline and within 48 weeks of treatment completion. The intention‐to‐treat analysis showed a sustained virological response (SVR) rate of 95.7%. None of the patients discontinued treatment due to side effects. Multivariate analysis identified pretreatment (no treatment with interferon), level of AFP (AFP; <10 μg/L), and RBV/body weight (BW) ratio (≥9.0 mg/kg) as independent predictors of SVR. The SVR rate in patients with two predictors of poor response (AFP ≥10 μg/L and RBV/BW ratio <9.0 mg/kg) was significantly lower than in other patients. In the SVR group, posttreatment AFP level and liver stiffness were significantly lower than at baseline. CAP tended to be higher after treatment than at baseline in all patients. SOF plus RBV combination therapy achieved a high SVR rate and was safe in HCV genotype 2 infected patients. Treatment reduced AFP levels and improved liver stiffness, but increased CAP. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Daclatasvir has achieved high sustained virologic response (SVR) rates in diverse hepatitis C virus (HCV) populations. This study evaluated the long‐term efficacy and safety of daclatasvir‐based regimens administered during clinical studies. Methods: Patients enrolled within 6 months of parent study completion or protocol availability at the study sites. The primary objective was durability of SVR at follow‐up Week 12 (SVR12). Secondary objectives included analysing HCV sequences in non‐responders or responders who relapsed, and characterization of liver disease progression. Results: Between 24 February 2012 and 17 July 2015, this study enrolled and began following 1503 recipients of daclatasvir‐based regimens (follow‐up cut‐off, 13 October 2015); 60% were male, 18% aged ≥65 years, 87% had genotype‐1a (42%) or ‐1b (45%) infection, and 18% had cirrhosis. Median follow‐up from parent study follow‐up Week 12 was 111 (range, 11‐246) weeks. 1329/1489 evaluable patients were SVR12 responders; 1316/1329 maintained SVR until their latest visit. Twelve responders relapsed by (n = 9) or after (n = 3) parent study follow‐up Week 24; one was reinfected. Relapse occurred in 3/842 (0.4%) and 9/487 (2%) responders treated with interferon‐free or interferon‐containing regimens, respectively. Hepatic disease progression and new hepatocellular carcinoma were diagnosed in 15 and 23 patients, respectively. Among non‐responders, emergent non‐structural protein‐5A (NS5A) and ‐3 (NS3) substitutions were replaced by wild‐type sequences in 27/157 (17%) and 35/47 (74%) patients, respectively. Conclusions: SVR12 was durable in 99% of recipients of daclatasvir‐based regimens. Hepatic disease progression and new hepatocellular carcinoma were infrequent. Emergent NS5A substitutions persisted longer than NS3 substitutions among non‐responders. [ABSTRACT FROM AUTHOR]

Aim: To assess the efficacy and safety of telaprevir (TVR) when used in combination with natural human interferon‐β (IFN‐β) and ribavirin (RBV) for genotype 1 patients with depression compared to IFN‐β/RBV therapy in Japan. We also examined the efficacy of the TVR/IFN‐β/RBV therapy in treatment failure genotype 2 patients with depression. Methods: For the genotype 1 patients, 30 patients received TVR (750 mg every 8 h) for 12 weeks combined with IFN‐β and RBV for 24 weeks (Group A), and 30 received IFN‐β and RBV for 48 weeks (Group B). For the genotype 2 patients, 14 patients were dosed only with the TVR‐based regimen. Results: The sustained virologic response (SVR) rates for Group A and Group B were 63.3% and 20.0%, respectively (P = 0.001, likelihood ratio test). The SVR rate for genotype 2 patients previously treated with pegylated IFN and/or RBV was 71.4%. No patient dropped out due to exacerbation of depression. The trend of platelet counts after the drugs were given was similar in the TVR/IFN‐β/RBV therapy group and the IFN‐β/RBV therapy group. Common resistance‐associated variants of TVR were identified in 4 of the 13 patients who did not achieve SVR. Conclusion: This study showed that an addition of TVR to IFN‐β/RBV therapy raised SVR in previously treated and untreated genotype 1 patients and previously treated genotype 2 patients with chronic hepatitis C and depression. [ABSTRACT FROM AUTHOR]

Little information is available on the impact of direct-acting antiviral (DAA) therapy on changes in liver fibrosis and steatosis. Liver stiffness (LS) and controlled attenuation parameter (CAP) values were evaluated using transient elastography. The study subjects were 214 elderly patients infected with HCV genotype 1b who received 24-week daclatasvir and asunaprevir dual therapy. All patients of this retrospective study had no hepatocellular carcinoma before and during DAA therapy. LS and CAP were assessed before treatment (baseline), at end of treatment (EOT), and at 24, 48, 72 weeks (W) after EOT. The rate of sustained viral response (SVR) by daclatasvir and asunaprevir therapy was 91%. LS values for the entire group correlated with Fib-4 index at baseline ( r = 0.565, P < 0.001). LS in both chronic hepatitis group (Fib-4 index <3.25) and cirrhosis group (Fib-4 index ≥3.25) decreased significantly at each time point compared with baseline ( P < 0.001). Especially, a larger decrease in LS from baseline to EOT was seen in the cirrhosis group than chronic hepatitis group ( P < 0.001). LS was also significantly lower in the SVR group at EOT, 24W, 48W, 72W compared with baseline ( P < 0.001). Even in the non-SVR group, LS tended to be lower at EOT ( P = 0.039), 24W ( P = 0.009), 48W ( P = 0.475), 72W ( P = 0.033) compared with baseline. CAP increased significantly following the treatment from baseline to 48W post-EOT ( P = 0.018). Our results showed significant improvement in LS in response to daclatasvir and asunaprevir dual therapy. In the other hand, there was a tendency that CAP increased from baseline. [ABSTRACT FROM AUTHOR]

Aim Pruritus is one of the complications of chronic liver disease, and it is important to investigate the predictors. Methods Six hundred and seventy-three consecutive Japanese patients with chronic liver disease were retrospectively investigated for itch severity. Furthermore, 138 of all 673 patients were introduced to nalfurafine hydrochloride, and the improvement of itch severity was evaluated. The itch severity was self-assessed using the pruritus scores by Kawashima's criteria and visual analog scale. Results Two hundred and twenty-nine of the 673 patients (34.0%) were evaluated as 1 point or more of pruritus severity of Kawashima's criteria, and 46 patients (6.8 %) as 3 points or more. Multivariate analysis established that being negative for hepatitis B surface antigen (HBsAg) and presence of hepatocellular carcinoma (HCC) were significant determinants of pruritus (≥1 point of Kawashima's criteria), and being negative for HBsAg and having lower levels of platelet count were significant determinants of severe pruritus (≥3 points). Ninety-three of the 138 patients (67.4%) with nalfurafine hydrochloride indicated improvement of itch, defined as a decrease in VAS of 50 mm or more. There were no significant differences in treatment efficacy of nalfurafine hydrochloride, regardless of the three predictors of pruritus (HBsAg, HCC and platelet count). Conclusion The present retrospective study indicated the predictors for pruritus, based on the large number of patients with chronic liver disease. Furthermore, this study demonstrated that nalfurafine hydrochloride may be useful for pruritus, regardless of the predictors. [ABSTRACT FROM AUTHOR]

Treatment of HCV genotype (GT) 2-infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) without ribavirin for 12 weeks in the phase 2 study M12-536, and with ribavirin for 16 weeks in phase 3 study GIFT II resulted in SVR rates of 72.2% to 91.5%. Overall, 11 out of 125 patients with GT2a and 37 out of 79 patients with GT2b infection experienced virologic failure. The prevalence of baseline polymorphisms in NS3 and NS5A and their the impact on treatment outcome, as well as the development of viral resistance in GT2-infected patients experiencing virologic failure were evaluated by HCV NS3 and NS5A population and clonal sequence analyses. Baseline polymorphisms in NS3 that confer resistance to paritaprevir were rare in both GT2a- and GT2b-infected patients, while baseline polymorphisms in NS5A that confer resistance to ombitasvir were detected in 11.2% and 14.1% of the GT2a- and GT2b-infected patients, respectively. There was no significant impact of baseline polymorphisms on treatment outcome in Japanese patients. The most common treatment-emergent substitutions at the time of virologic failure occurred at amino acid positions 168 in NS3 and 28 in NS5A in both GT2a- and GT2b-infected patients. Although there was a higher rate of virologic failure in patients with GT2b infection, the resistance analyses presented in this report support the conclusion that testing for baseline resistance-associated polymorphisms is not warranted for HCV GT2-infected patients treated with a regimen of ombitasvir/paritaprevir/ritonavir + ribavirin for 16 weeks. [ABSTRACT FROM AUTHOR]

With rapidly aging population in the world, many elderly patients present with hepatitis B virus (HBV) infection. We conducted a retrospective cohort study involving 359 untreated HBV patients aged 60 and older who were free of hepatocellular carcinoma (HCC) and acute hepatitis at the initial visit, and examined the incidence of HCC and liver-related mortality rate. During the follow-up period of 7.9 years (range, 0-25 years), 26 patients (7.2% of patients) developed HCC, 20 patients died from liver-related diseases (61% of total deaths), including HCC, liver failure, and gastrointestinal bleeding. The cumulative rates of HCC at years 5, 10, and 15 were 6.5%, 15.6%, and 15.6%, respectively. The cumulative rates of mortality from liver-related diseases at years 5, 10, 15 were 3.3%, 12.3%, and 15.7%, respectively. Multivariate analysis identified HBV DNA (≥5.0 Log IU/mL), male gender, and FIB4-Index (≥3.6) as significant independent risk factors for HCC, and alpha-fetoprotein (≥10 ng/mL) as significant independent predictors of liver-related mortality. We conclude that high levels of HBV DNA, progression of liver fibrosis, and male gender are independent risk factors of HCC in untreated patients infected with HBV aged 60 and older. [ABSTRACT FROM AUTHOR]

Aims Patients with chronic liver disease sometimes develop cholestasis, which induces severe whole-body pruritus that may disrupt daily activities and sleep. To determine the efficacy of nalfurafine hydrochloride (5 μg), which is a selective κ-opioid receptor agonist, in improving pruritus, we undertook a double-blind placebo-controlled study in patients with chronic liver disease with refractory pruritus. Nalfurafine hydrochloride at 2.5 μg was also used to evaluate the dose-response relationship. Methods In total, 318 subjects were randomly assigned to receive the placebo or nalfurafine hydrochloride (2.5 or 5 μg) given orally once daily for 84 consecutive days. Pruritus was assessed based on the visual analog scale and pruritus scores. Results Changes in the visual analog scale at week 4 (last observation carried forward) were significantly greater in the nalfurafine hydrochloride groups at 28.56 and 27.46 mm in the 2.5 μg and 5 μg groups, respectively, compared to 19.25 mm in the placebo group ( P = 0.0022 and 0.0056, respectively). The major adverse drug reactions (ADRs) included pollakiuria (including nocturia), somnolence, insomnia (including middle insomnia), and constipation. Most ADRs were mild. Conclusions Nalfurafine hydrochloride (2.5 or 5 μg daily) was effective in the treatment of refractory pruritus in patients with chronic liver disease. Furthermore, no clinically significant ADRs were observed at either dose. [ABSTRACT FROM AUTHOR]

Aim Acquisition of nucleos(t)ide analog (NA) inhibitor resistance is critical in successful chronic hepatitis B treatment. As the pattern of tenofovir disoproxil fumarate (TDF) resistance mutations differs from that of other antiviral drugs, we sought to clarify the salvaging potential of TDF in patients with hepatitis B virus (HBV) infection who are poor responders or resistant to other NAs. Methods A prospective, multicenter, single-arm, open-label study was carried out from December 2011 to October 2014. Poor responders defined as subjects with serum HBV-DNA levels >4 log10 copies/mL were enrolled. Subjects receiving lamivudine (LAM) + adefovir pivoxil (ADV) before the initiation of the study were switched to LAM + TDF. Subjects on entecavir hydrate (ETV) with or without ADV were switched to ETV + TDF. The primary efficacy end-point was the proportion of subjects achieving HBV-DNA <2.1 log10 copies/mL (LLQ) at week 24. The secondary efficacy end-points were the proportion of subjects with LLQ at weeks 48 and 96, serum alanine aminotransferase normalization, hepatitis B envelope antigen/antibody and hepatitis B surface antigen/antibody seroconversion. Results Thirty-four subjects were enrolled, 21 subjects were switched to ETV + TDF, and 13 subjects were switched to LAM + TDF. Drug resistance mutations were determined in 85% of the subjects at the time of the enrolment. The proportion of subjects who achieved LLQ was 59%, 62%, and 71% at weeks 24, 48, and 96, respectively. No serious adverse event related to TDF was reported. Conclusion Our study clearly showed that TDF containing regimens were effective in salvaging poor responders and/or those who are drug-resistant to other NAs. This study is registered with ClinicalTrials.gov (NCT01475851) and the GSK Clinical Study Register (GSK LOC115912). [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) accounts for up to 90% of primary liver cancer occurrences worldwide. Lenvatinib, a multikinase inhibitor, was approved in radioiodine-refractory differentiated thyroid cancer. In this phase 2 study (study 202), we aimed to identify the lenvatinib optimal dose for subjects with advanced HCC Child-Pugh class A. Pooled data from phase 1 studies in healthy adults and in subjects with mixed tumor types, and from study 202 in subjects with HCC, were analyzed using a population pharmacokinetic approach. The relationship between treatment-emergent adverse events leading to withdrawal or dose reduction during cycle 1 and lenvatinib exposure was explored by logistic regression analysis. A receiver operating characteristics analysis was used to investigate the best cutoff values of lenvatinib exposure and body weight to identify a high-risk group for early dose modification. The final pharmacokinetic model included body-weight effects on apparent clearance and volume. The relationship between the lenvatinib area under the plasma concentration-time curve (AUC) at steady state and body weight demonstrated an increase in AUC as body weight decreased in subjects with HCC. An exposure-response relationship was observed, with higher lenvatinib AUC and lower body weight resulting in earlier drug withdrawal or dose reduction. The best cutoff values for body weight and lenvatinib AUC were 57.8 kg and 2430 ng·h/mL, respectively, to predict the group at high risk for early drug withdrawal or dose reduction. We therefore recommend 12-mg and 8-mg starting doses for subjects ≥60 kg and <60 kg, respectively, in subjects with HCC Child-Pugh class A. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to clarify the usefulness of a no-touch pincer ablation procedure that uses bipolar electrodes to prevent intrasubsegmental tumor recurrence after radiofrequency ablation (RFA) for patients with hepatocellular carcinoma (HCC). Methods We studied 303 consecutive patients with HCC (single nodule and tumor diameter ≤30 mm) who received RFA between January 2005 and April 2015; 268 patients received touch ablation using a monopolar or bipolar RFA device, and 35 received no-touch ablation using a bipolar RFA device. The pretreatment arterial and portal phase dynamic computed tomography or magnetic resonance images were classified into four enhancement patterns. Type 1 and Type 2 are homogeneous enhancement patterns without or with increased arterial blood flow, respectively. Type 3 is a heterogeneous enhancement pattern with a septum-like structure, and Type 4 is an irregularly shaped ring structure enhancement pattern. Results With regard to intrasubsegmental tumor recurrence, among the 268 patients who underwent the touch ablation procedure, tumors recurred in 52 (19.4%) patients, and among the 35 patients who underwent the no-touch ablation procedure, tumors recurred in one (2.9%) patient. Cumulative intrasubsegmental tumor recurrence rates tended to be higher with touch ablation ( P = 0.083). Multivariate Cox proportional hazards analysis revealed that ablation procedure (touch ablation, hazard ratio [HR] 10.32, P = 0.032), type of enhancement pattern (Type 3, HR 3.05, P = 0.006; and Type 4, HR 8.87, P < 0.001) and serum des-γ-carboxyprothrombin level (≥100 AU/L; HR 2.73, P = 0.035) were significant predictors for intrasubsegmental recurrence. Conclusion The no-touch pincer ablation procedure has the potential to prevent intrasubsegmental recurrence after RFA for patients with HCC. [ABSTRACT FROM AUTHOR]

Background & Aims It is important to investigate the treatment outcomes in patients excluded from clinical trials ( CTR). The aims of this study were to evaluate the efficacy and safety of a 24-week daclatasvir ( DCV) and asunaprevir ( ASV) therapy for patients with chronic hepatitis C virus ( HCV)-1b infection. Methods A total of 651 HCV-1b patients started dual oral therapy with DCV and ASV for 24 weeks in Toranomon Hospital, Tokyo. Among them, 276 patients met phase III CTR inclusion criteria. The sustained virological response ( SVR) rate after treatment and the adverse events during therapy were compared between CTR-met (patients who met the inclusion criteria) and CTR-unmet (patients who did not meet the inclusion criteria) groups. Results SVR12 was achieved in 87.0% (240/276) and 86.7% (325/375) in CTR-met and CTR-unmet patients respectively. SVR12 rate in simeprevir-experienced patients was 52.9% (9/17). SVR12 rate in patients without resistance-associated variant ( RAV) of NS3 or NS5A loci was 93.7% (416/444). However, the SVR12 rates in patients with NS3-D168, NS5A-L31 and Y93 single RAV at baseline were 55.0% (11/20), 73.9% (17/23) and 65.6% (63/96) respectively. The safety profiles in both CTR-met and CTR-unmet patients were similar. The discontinuation rate as a result of alanine aminotransferase ( ALT) elevation was only 2.9%. Seven (2.5%) patients in CTR-met group and 20 (5.3%) in CTR-unmet group discontinued therapy because of adverse events other than the ALT elevation. Conclusions Dual oral therapy with DCV and ASV in real-life settings was well tolerated with a similar safety profile and achieved similar SVR12 rates as that of CTR. [ABSTRACT FROM AUTHOR]

There is little information on retreatment efficacy and predictors of the combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) for patients who fail to respond to NS5A inhibitors. NS5A resistance variants are known to persist for long periods after such treatment. Here, we evaluated 54 patients with chronic HCV genotype 1b infection, free of decompensated cirrhosis, and hepatocellular carcinoma, for sustained virological response after 12 weeks (SVR12) of once-daily treatment with 90 mg ledipasvir and 400 mg sofosbuvir. Intention-to-treat analysis showed SVR12 of 70%. Using ultra-deep sequencing, non-responder to ledipasvir/sofosbuvir showed no change in the rates of detection of NS5A and NS5B resistant-variants at re-elevation of viral loads, relative to baseline. According to response to prior treatment, SVR12 rates were 18, 69, 94, and 100% in non response, viral breakthrough, relapse, and discontinuation due to adverse events, respectively. SVR12 rates in non response were significantly lower than those of the others. Multivariate analysis identified response to previous treatment (failure except for non response) and FIB4 index (<3.25) as significant determinants of SVR12. The SVR12 rates were significantly lower in patients with FIB4 index of ≥3.25 and had not responded to prior treatment, relative to others. The specificity, and positive- and negative-predictive values were high for prediction of poor response based on the combination of two predictors. In conclusion, our study indicated that ledipasvir/sofosbuvir is a potentially useful salvage treatment for patients who fail prior NS5A inhibitors-based therapy. Response to prior treatment was an important predictor of retreatment efficacy. [ABSTRACT FROM AUTHOR]

Aim The effect of transcatheter arterial chemoembolization (TACE) is not necessarily sufficient in patients with multiple hepatocellular carcinoma (HCC). We evaluated the antitumor activity and adverse events of TACE using warmed miriplatin suspension for multiple HCC. Methods Seventy patients with multiple HCC received TACE using warmed miriplatin/lipiodol suspension, including patients who were TACE-naïve (group A, n = 5), those undergoing initial TACE after radical therapies (group B, n = 31), and those with a history of repeated TACE (group C, n = 34). Median tumor size was 19.5 mm and a median of four nodules. Results Complete necrosis (TE 4) and partial necrosis (TE 3) of 50% or more were attained in 24 and 19 patients at 3 months after TACE, respectively. Response rates (TE 4 + TE 3) were 60.0% in group A, 83.9% in group B, and 41.2% in group C ( P = 0.038). Survival rates of all patients after TACE were 82.6% after 1 year, 65.6% after 2 years, and 47.7% after 3 years. Three-year survival rates of patients in groups A, B, and C were 53.3%, 78.8%, and 29.7%, respectively ( P = 0.0029). Conclusion Transcatheter arterial chemoembolization using warmed miriplatin induced high response rate in multiple HCC, and the rate was significantly high in those patients with recurrent multiple HCCs after curative therapies. [ABSTRACT FROM AUTHOR]

Aim To assess the efficacy and safety of telaprevir (TVR) in combination with pegylated interferon α-2a (PEG-IFNα-2a) and ribavirin (RBV) for treatment-naïve patients and relapsed patients compared to previous TVR-based triple therapy in Japan. Methods The study group included 35 treatment-naïve (median age, 55 years) and 19 relapsed (median age, 55 years) patients with genotype 1 hepatitis C virus infection. Patients received TVR (750 mg every 8 h) for 12 weeks, in combination with PEG-IFNα-2a and RBV. Results The sustained virological response (SVR24) rates for naïve and relapsed patients were 85.7% (30/35) and 94.7% (18/19), respectively. The discontinuation rate of all study drugs due to adverse events was 5.6% (3/54). Among the 54 patients, grade 3 skin disorders and grade 3 anemia (<8.0 g/dL) were reported in 2 (3.7%) and 6 patients (11.1%), respectively. Although the overall safety profiles were similar for the TVR/PEG-IFNα-2a/RBV and TVR/PEG-IFNα-2b/RBV regimens (previous study), the proportion of patients discontinuing all study drugs due to adverse events was lower in the patients treated with the TVR/PEG-IFNα-2a/RBV regimen (3/54, 5.6%) than TVR/PEG-IFNα-2b/RBV regimen (44/267, 16.5%). Conclusion Telaprevir in combination with PEG-IFNα-2a/RBV provided a high sustained virological response rate for the treatment of genotype 1 hepatitis C virus in both treatment-naïve and relapsed patients in Japan. Telaprevir-based therapy may provide a useful treatment option for patients who are difficult to treat due to NS5A (Y93, L31) and NS3/4A (D168) variants. [ABSTRACT FROM AUTHOR]

Aim The two-point Dixon method for magnetic resonance imaging (MRI) is commonly used to non-invasively measure fat deposition in the liver. The aim of the present study was to assess the usefulness of MRI-fat fraction (MRI-FF) using the two-point Dixon method based on the non-alcoholic fatty liver disease activity score. Methods This retrospective study included 106 patients who underwent liver MRI and MR spectroscopy, and 201 patients who underwent liver MRI and histological assessment. The relationship between MRI-FF and MR spectroscopy-fat fraction was used to estimate the corrected MRI-FF for hepatic multi-peaks of fat. Then, a color FF map was generated with the corrected MRI-FF based on the non-alcoholic fatty liver disease activity score. We defined FF variability as the standard deviation of FF in regions of interest. Uniformity of hepatic fat was visually graded on a three-point scale using both gray-scale and color FF maps. Confounding effects of histology (iron, inflammation and fibrosis) on corrected MRI-FF were assessed by multiple linear regression. Results The linear correlations between MRI-FF and MR spectroscopy-fat fraction, and between corrected MRI-FF and histological steatosis were strong ( R2 = 0.90 and R2 = 0.88, respectively). Liver fat variability significantly increased with visual fat uniformity grade using both of the maps (ρ = 0.67-0.69, both P < 0.001). Hepatic iron, inflammation and fibrosis had no significant confounding effects on the corrected MRI-FF (all P > 0.05). Conclusions The two-point Dixon method and the gray-scale or color FF maps based on the non-alcoholic fatty liver disease activity score were useful for fat quantification in the liver of patients without severe iron deposition. [ABSTRACT FROM AUTHOR]

Aim The aim of this study is to clarify the usefulness and limitations of balloon-occluded transcatheter arterial chemoembolization (B-TACE) using miriplatin for patients with four or fewer hepatocellular carcinoma (HCC) nodules. Methods We studied 47 nodules in 30 consecutive patients who received miriplatin by B-TACE to treat HCC with four or fewer nodules per patient. The treatment effect was evaluated using the Response Evaluation Criteria in Cancer of the Liver. Results Nodules were divided according to the presence or absence of portal vein visualization during B-TACE. In the presence group, dynamic computed tomography at 3 months post-therapy showed Response Evaluation Criteria in Cancer of the Liver treatment effect (TE) 4 in 88% (14/16), TE3 in 0% (0/16), TE2 in 0% (0/16), TE1 in 12% (2/16), and objective response in 88% of nodules. In the absence group, the results were TE4 in 35% (11/31), TE3 in 13% (4/31), TE2 in 26% (8/31), TE1 in 26% (8/31), and objective response decreased to 48% of nodules. In addition to typical hypervascular nodules, we treated three nodules with irregular ring enhancement that predicted poorly differentiated HCC and four nodules that included a hypoenhancement area that predicted well to moderately differentiated HCC. All irregular ring enhancement nodules achieved TE4. Other nodules that were predicted to be well to moderately differentiated HCC did not have portal vein visualization during B-TACE and could not achieve TE4. Conclusion Balloon-occluded transcatheter arterial chemoembolization is a useful technique for treatment of classical hypervascular HCC, and portal vein visualization during the B-TACE procedure may provide more favorable local control. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the rate of development of hepatocellular carcinoma (HCC) in patients who achieved sustained virologic response (SVR) by direct antiviral agents (DAA). We retrospectively evaluated patients who achieved SVR by oral DAA interferon-free regimens (n = 77) (daclatasvir/asunaprevir [n = 67], ombitasvir/paritaprevir/ritonavir [n = 9], and telaprevir [n = 1]) and by pegylated-interferon plus ribavirin (Peg-IFN/RBV, n = 528). In all patients, the background was chronic hepatitis or cirrhosis caused by HCV genotype 1b. During a median follow-up period of 4.0 years, two (2.6%) of DAA-treated patients developed HCC. The 3- and 5-year cumulative HCC development rates were 1.30% and 3.03%, respectively, in the DAA group, and 1.02% and 2.19 % in the Peg-IFN/RBV group ( P not significant). In patients with Fib-4 score of >3.25, the 3-year HCC development rates were 4.35% and 3.95%, whereas those of the 5 year were 9.66% and 8.37%, in the DAA and Peg-IFN/RBV group, respectively. In patients with Fib-4 score of ≤3.25, none of the DAA group developed HCC, whereas 0.48% at 3-year and 1.05% at 5-year of patients of the Peg-IFN/RBV group did. Propensity score analysis using the inverse probability of treatment weights (IPTW) also showed no significant difference in HCC development rate between the two groups. Serum AFP gradually and similarly decreased after initiation of antiviral therapy in both groups. Our data indicate that the HCC risk rate after SVR is similar regardless of whether the latter was achieved by DAA or IFN-based regimens. J. Med. Virol. 89:476-483, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Predictors of treatment efficacy with ledipasvir plus sofosbuvir as direct-acting antiviral (DAA) regimen for HCV infection are still unclear. Retreatment efficacy of ledipasvir plus sofosbuvir for failures to prior DAA regimens, including NS5A inhibitors, are also unknown because resistance-associated variants (RAVs) in NS5A have been shown to persist up to the long-term of post-treatment. One hundred seventy-five patients with chronic HCV genotype 1 infection, without decompensated liver cirrhosis and hepatocellular carcinoma, were evaluated SVR12 by ledipasvir 90 mg plus sofosbuvir 400 mg once-daily for 12 weeks. Overall, SVR12 were 92%, based on intention to treat analysis. In failures to daclatasvir plus asunaprevir, SVR12 were 71%. The study using ultra-deep sequencing showed that ledipasvir plus sofosbuvir was effective to one case of failures to daclatasvir plus asunaprevir with multidrug RAVs (triple mutation in NS3-D168/NS5A-L31/NS5A-Y93). Multivariate analysis identified FIB4 index (<3.25), IL28B rs8099917 (TT type), and NS5A-L31 (Wild type) as significant determinants of SVR12. SVR12 rates in patients with three factors of poor response (RAVs Positive, IL28B non-TT, and FIB4 index ≥3.25) simultaneously were significantly lower than those of the other patients. Prediction of response to therapy based on combination of three predictors had high sensitivity and positive predictive values. In conclusions, this study indicated the favorable efficacy of ledipasvir plus sofosbuvir for HCV genotype 1 infection, including multidrug RAVs in Japan. Treatment efficacy could be predicted by the combination of viral and host factors. J. Med. Virol. 89:284-290, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The combination of daclatasvir and asunaprevir is efficacious in the treatment of hepatitis C virus (HCV) infection, but its efficacy and predictors of efficacy in the elderly (≥70 years) remain unclear. In this study, 844 patients with chronic HCV genotype 1b infection, were treated with daclatasvir (60 mg once daily) plus asunaprevir (100 mg twice daily) for 24 weeks. Using the intention-to-treat analysis, the sustained virological response (SVR) rates were 87% and 88% for all 844 patients and 411 elderly (>70 years of age), respectively. In both groups, multivariate analysis identified NS5A-Y93H mutation (<20%), pretreatment (failure of treatment except for triple therapy with simeprevir, or treatment naive), and level of viremia (<6.0 log IU/ml) as independent predictors of SVR. Direct sequencing showed a significantly higher rate of NS3-D168 mutation at baseline in non-responders to triple therapy with simeprevir (44%) than others (2%). Alfa-fetoprotein (AFP) level and liver stiffness were significantly lower after end of treatment than at baseline, in both the SVR and non-SVR groups. In conclusion, daclatasvir-asunaprevir combination achieved high SVR in HCV genotype 1b patients, including elderly patients. Viral factors negatively influenced the response to treatment. Treatment improved AFP level and liver stiffness (surrogate markers of hepatocellular carcinoma), regardless of treatment efficacy. J. Med. Virol. 89:91-98, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background and Aim Vaniprevir is a macrocyclic hepatitis C virus (HCV) non-structural (NS)3/4A protease inhibitor. The objective of these phase 3 multicenter, open-label trials was to evaluate the safety and efficacy of vaniprevir + peginterferon alfa-2b + ribavirin (PR) in Japanese patients with HCV genotype (GT)1 infection who had previously failed treatment with interferon-based regimens. Methods Japanese patients with chronic HCV GT1 were enrolled. In PN044, patients with previous relapse or virologic breakthrough were randomized to vaniprevir (300 mg twice daily) + PR for 12 weeks followed by PR for another 12 weeks (12-week arm) or vaniprevir + PR for 24 weeks (24-week arm). In PN045, patients with previous partial/null response received vaniprevir + PR for 24 weeks. The primary endpoint was sustained virologic response at 24 weeks after completing treatment (SVR24). Results In PN044 ( n = 51), SVR24 was 92.0% and 96.2% in the 12- and 24-week arms, respectively. In PN045 ( n = 42), SVR24 was 61.9% in all patients and 55.2% in previous null responders. In both studies, vaniprevir + PR was generally safe and well tolerated; the majority of adverse events were mild/moderate and included pyrexia, decreased hemoglobin, headache, nausea, pruritus, and decreased platelet count. Polymorphisms in the HCV NS3 gene at baseline (Y56, Q80, and V170) did not impact treatment outcome. Virologic failure was principally associated with the on-treatment emergence of R155 or D168 mutations. Conclusions Vaniprevir + PR is an effective, well-tolerated treatment for Japanese patients with HCV GT1 infection who failed previous interferon-based treatment. ClinicalTrials. gov Identifier NCT01405937 and NCT01405560 (Protocols PN044 and PN045) [ABSTRACT FROM AUTHOR]