Liver function and portal-systemic shunting quantified by the oral cholate challenge test and risk for large oesophageal varices.

BACKGROUND: The quantitative HepQuant SHUNT test of liver function and physiology generates a disease severity index (DSI) that correlates with risk for clinical complications, such as large oesophageal varices (LEVs). A derivative test, HepQuant DuO, generates an equivalent DSI and simplifies testing by requiring only oral administration of the test solution and two blood samples at 20 and 60 min. AIMS: Since the DSIs measured from DuO and SHUNT are equivalent, we compared the diagnostic performance for large oesophageal varices (LEVs) between the DSIs measured from DuO and SHUNT tests. METHODS: This study combined the data from two prospectively conducted US studies: HALT-C and SHUNT-V. A total of 455 subjects underwent both the SHUNT test and esophagogastroduodenoscopy (EGD). RESULTS: DSI scores correlated with the probability of LEVs (p < 0.001) and demonstrated a stepwise increase from healthy lean controls without liver disease to subjects with chronic liver disease and no, small or large varices. Furthermore, a cutoff of DSI ≤ 18.3 from DuO had a sensitivity of 0.98 (missing only one case) and, if applied to the endoscopy (EGD) decision, would have prevented 188 EGDs (41.3%). The AUROC for DSI from DuO did not differ from that of the reference SHUNT test method (0.82 versus 0.81, p = 0.3500). CONCLUSIONS: DSI from HepQuant DuO links liver function and physiology to the risk of LEVs across a wide spectrum of patient characteristics, disease aetiologies and liver disease severity. DuO is minimally invasive, easy to administer, quantitative and may aid the decision to avoid or perform EGD for LEVs.

Prognostic factors of unresectable hepatocellular carcinoma treated with yttrium-90 radioembolization: results from a large cohort over 13 years at a single center.

BACKGROUND: A previous study of patients with unresectable hepatocellular carcinoma (HCC) was extended to further examine factors associated with overall survival (OS) after selective internal radiation therapy with yttrium-90 resin microspheres (Y90 SIRT). METHODS: Data from patients of any age diagnosed with unresectable HCC and treated with Y90 SIRT at our institution from 2004 through 2017 were retrospectively analyzed. Among other criteria, patients had to have Eastern Cooperative Oncology Group performance status 0 to 2, not have received Y90 SIRT previously, and not have extrahepatic disease. Primary outcome was OS; secondary outcomes included tumor response and adverse events (AEs). Kaplan-Meier survival analyses and multivariable Cox proportional hazards models were used to evaluate prognostic factors for OS. RESULTS: Of the 226 patients, 59% were White, 77% were male, and the mean age at first SIRT procedure was 65.1±9.4 years. More than half had received previous treatment for HCC. The most common etiology was hepatitis C (n=138/224 available, 62%), followed by alcohol use (n=45, 20%), and nonalcoholic steatohepatitis (n=27, 12%). The mean model for end-stage liver disease score at baseline was 8.8±2.2. Patients were followed-up for a median of 12.2 months (95% CI, 0.0-62.6). Median OS was 16.6 months (95% CI, 13.1 to not reached). Bilobar disease, higher albumin-bilirubin score at baseline, prior treatment with sorafenib, alcohol use etiology, and higher administered dose were associated with shorter survival, whereas subsequent liver transplant [in 26 patients (11.5%)] was associated with longer survival. Of the 186 patients with AEs data, 75 (40.3%) patients reported an event and, of these, 13 (17.3%) patients had grade 4 bilirubin values. CONCLUSIONS: In a large, diverse population treated at a single center over 13 years, Y90 SIRT produced a median OS of 16.6 months in patients with unresectable HCC and enabled subsequent transplantation in a subset of patients. Factors affecting the length of survival should be considered when making treatment decisions for unresectable HCC.

Mindfulness at Methodist-A Prospective Pilot Study of Mindfulness and Stress Resiliency Interventions in Patients at a Tertiary Care Medical Center.

Individuals with chronic medical conditions like cancer often experience heightened stress levels that can impact medical decision-making. The aim of this study was assess the impact of mindful stress-reduction interventions in cancer patients and support group participants (which included current and former cancer patients and their caregivers). A pilot study was conducted in which participants were provided a mindful stress-reduction intervention to determine whether they reduced stress, anxiety, and communication issues. Participants were provided a one-hour mindful stress-reduction intervention by a licensed physical therapist. Surveys were given to participants immediately before and after, and again 7-days after the intervention. Perceived stress was ascertained by asking participants: "Which emotional/mental state do you most frequently find yourself in?" Anxiety and communication abilities were measured using Neuro-QoL™ Anxiety and Communication v.1 instruments. Fifty-nine participants with a mean age of 60.6 years completed the study. Of these, 30.5%, 6.8%, 23.7%, and 39% were diagnosed (or were a caregiver to someone diagnosed) with pancreas, liver, breast, or unknown cancers, respectively. The surveys showed that participants' perceived stress scores (p < 0.001), anxiety levels (p = 0.0067), and pain scores (p < 0.0001) were reduced after the mindful stress-reduction intervention. Larger studies with control groups are needed to confirm the interventions' benefits.

Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis. METHODS: This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points. RESULTS: There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (95% CI 0.59-1.77; p = 0.94) and 1.28 (95% CI 0.75-2.21; p = 0.37) for 5 mg and 25 mg of emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated. CONCLUSIONS: Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis. LAY SUMMARY: Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis are at high risk of additional decompensation events and death. Post hoc analyses in previous pilot studies suggested that emricasan might improve portal hypertension and liver function. In this larger randomized study, emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated cirrhosis related to non-alcoholic steatohepatitis. CLINICALTRIALS. GOV IDENTIFIER: NCT03205345.

Morphological Characteristics of Biliary Strictures after Liver Transplantation Visualized Using SpyGlass™ Cholangioscopy.

Biliary complications following liver transplant are common. Endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP) are the main techniques used to diagnose and treat biliary complications; however, these techniques have limits to the depth of visualization. In this report, we present five cases of orthotopic liver transplant patients with biliary complications that underwent ERCP- or MRCP-guided cholangioscopy with the SpyGlass™ DS Direct Visualization System (SDDVS). The SDDVS allowed for the visualization of the morphological characteristics of biliary strictures, and images collected using the SDDVS allowed for four of the cases to be treated endoscopically. Our findings suggest that cholangioscopy with the SDDVS is a promising method to guide the endoscopic treatment of biliary complications after liver transplantation.

Volixibat in adults with non-alcoholic steatohepatitis: 24-week interim analysis from a randomized, phase II study.

BACKGROUND & AIMS: Volixibat is an inhibitor of the apical sodium-dependent bile acid transporter (ASBT) that has been hypothesized to improve non-alcoholic steatohepatitis (NASH) by blocking bile acid reuptake and stimulating hepatic bile acid production. We studied the safety, tolerability and efficacy of volixibat in patients with NASH. METHODS: In this double-blind, phase II dose-finding study, adults with ≥5% steatosis and NASH without cirrhosis (N = 197) were randomized to receive volixibat (5, 10 or 20 mg) or placebo once daily for 48 weeks. The endpoints of a predefined interim analysis (n = 80), at week 24, were: ≥5% reduction in MRI-proton density fat fraction and ≥20% reduction in serum alanine aminotransferase levels. The primary endpoint was a ≥2-point reduction in non-alcoholic fatty liver disease activity score without worsening fibrosis at week 48. RESULTS: Volixibat did not meet either interim endpoint; the study was terminated owing to lack of efficacy. In participants receiving any volixibat dose, mean serum 7-alpha-hydroxy-4-cholesten-3-one (C4; a biomarker of bile acid synthesis) increased from baseline to week 24 (+38.5 ng/ml [SD 53.18]), with concomitant decreases in serum total cholesterol (-14.5 mg/dl [SD 28.32]) and low-density lipoprotein cholesterol (-16.1 mg/dl [SD 25.31]). These changes were generally dose-dependent. On histological analysis, a greater proportion of participants receiving placebo (38.5%, n = 5/13) than volixibat (30.0%, n = 9/30) met the primary endpoint. Treatment-emergent adverse events (TEAEs) were mainly mild or moderate. No serious TEAEs were related to volixibat. Diarrhoea was the most common TEAE overall and the most common TEAE leading to discontinuation. CONCLUSIONS: Increased serum C4 and decreased serum cholesterol levels provide evidence of target engagement. However, inhibition of ASBT by volixibat did not elicit a liver-related therapeutic benefit in adults with NASH. LAY SUMMARY: A medicine called volixibat has previously been shown to reduce cholesterol levels in the blood. This study investigated whether volixibat could reduce the amount of fat in the liver and reduce liver injury in adults with an advanced form of non-alcoholic fatty liver disease. Volixibat did not reduce the amount of fat in the liver, nor did it have any other beneficial effect on liver injury. Participants in the study generally tolerated the side effects of volixibat and, as in previous studies, the main side effect was diarrhoea. These results show that volixibat is not an effective treatment for people with fatty liver disease. CLINICAL TRIAL IDENTIFIER: NCT02787304.

Provider Attitudes and Practice Patterns for Direct-Acting Antiviral Therapy for Patients With Hepatocellular Carcinoma.

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) are effective against hepatitis C virus and sustained virologic response is associated with reduced incidence of hepatocellular carcinoma (HCC). However, there is controversy over the use of DAAs in patients with active or treated HCC and uncertainty about optimal management of these patients. We aimed to characterize attitudes and practice patterns of hepatology practitioners in the United States regarding the use of DAAs in patients with HCC. METHODS: We conducted a survey of hepatology providers at 47 tertiary care centers in 25 states. Surveys were sent to 476 providers and we received 279 responses (58.6%). RESULTS: Provider beliefs about risk of HCC recurrence after DAA therapy varied: 48% responded that DAAs reduce risk, 36% responded that DAAs do not change risk, and 16% responded that DAAs increase risk of HCC recurrence. However, most providers believed DAAs to be beneficial to and reduce mortality of patients with complete response to HCC treatment. Accordingly, nearly all providers (94.9%) reported recommending DAA therapy to patients with early-stage HCC who received curative treatment. However, fewer providers recommended DAA therapy for patients with intermediate (72.9%) or advanced (57.5%) HCC undergoing palliative therapies. Timing of DAA initiation varied among providers based on HCC treatment modality: 49.1% of providers reported they would initiate DAA therapy within 3 months of surgical resection whereas 45.9% and 5.0% would delay DAA initiation for 3-12 months and >1 year post-surgery, respectively. For patients undergoing transarterial chemoembolization (TACE), 42.0% of providers would provide DAAs within 3 months of the procedure, 46.7% would delay DAAs until 3-12 months afterward, and 11.3% would delay DAAs more than 1 year after TACE. CONCLUSIONS: Based on a survey sent to hepatology providers, there is variation in provider attitudes and practice patterns regarding use and timing of DAAs for patients with HCC. Further studies are needed to characterize the risks and benefits of DAA therapy in this patient population.

Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection Is Associated With Increased Survival in Patients With a History of Hepatocellular Carcinoma.

BACKGROUND & AIMS: There is controversy regarding the benefits of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection for patients with a history of hepatocellular carcinoma (HCC). We performed a multicenter cohort study to compare overall survival between patients with HCV infection treated with DAAs and patients who did not receive DAA treatment for their HCV infection after complete response to prior HCC therapy. METHODS: We conducted a retrospective cohort study of patients with HCV-related HCC who achieved a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy, from January 2013 through December 2017 at 31 health care systems throughout the United States and Canada. We used Cox proportional hazards regression to determine the association between receipt of DAA therapy, modeled as a time-varying covariate, and all-cause mortality, accounting for informative censoring and confounding using inverse probability weighting. RESULTS: Of 797 patients with HCV-related HCC, 383 (48.1%) received DAA therapy and 414 (51.9%) did not receive treatment for their HCV infection after complete response to prior HCC therapy. Among DAA-treated patients, 43 deaths occurred during 941 person-years of follow-up, compared with 103 deaths during 526.6 person-years of follow-up among patients who did not receive DAA therapy (crude rate ratio, 0.23; 95% confidence interval [CI], 0.16-0.33). In inverse probability-weighted analyses, DAA therapy was associated with a significant reduction in risk of death (hazard ratio, 0.54; 95% CI, 0.33-0.90). This association differed by sustained virologic response to DAA therapy; risk of death was reduced in patients with sustained virologic response to DAA therapy (hazard ratio, 0.29; 95% CI, 0.18-0.47), but not in patients without a sustained virologic response (hazard ratio, 1.13; 95% CI, 0.55-2.33). CONCLUSIONS: In an analysis of nearly 800 patients with complete response to HCC treatment, DAA therapy was associated with a significant reduction in risk of death.

A Cross-Sectional Study of Stress and the Perceived Style of Decision-Making in Clinicians and Patients With Cancer.

BACKGROUND AND AIMS: Perceived stress and mindfulness can impact medical decision-making in both patients and clinicians. The aim of this study was to conduct a cross-sectional evaluation of the relationships between stress, mindfulness, self-regulation, perceptions of treatment conversations, and decision-making preferences among clinicians. Also, perceptions of treatment conversations and decision-making preferences among patients with cancer were evaluated. METHODOLOGY: Survey instruments were developed for clinicians and patients incorporating previously published questions and validated instruments. Institutional review board approval was obtained. Patients, physicians, and advanced practice providers from a tertiary referral center were asked to complete surveys. Continuous variables were evaluated for normality and then bivariate relationships between variables were evaluated using χ2, Fisher's exact test, Cochran-Mantel-Haenszel (CMH) row mean scores differ statistic, or Kruskal-Wallis tests, where appropriate. Significance was defined at P < .05. All tests were conducted using SAS v.9.4. RESULTS: 77 patients and 86 clinicians (60.1% and 43% response rates, respectively) participated in the surveys. More clinicians who reported feeling "great/good" said they always/sometimes had enough time to spend with patients (66.1%) compared to those that hardly ever/never had enough time (26.3%), χ2(1, N = 75) = 6.62, P = .0101; CMH row mean scores differ statistic). Interestingly, 40.3% of patients preferred a paternalistic style of decision-making compared to 6.3% of clinicians, χ2(2, N = 146) = 27.46, P < .0001; χ2 test. Higher levels of dispositional mindfulness (Mindful Attention Awareness Scale) were found among clinicians who reported they felt "great/good" (median = 4.5) as compared to those who reported that they were "definitely stressed/stressed out" (3.3), χ2(2, N = 80) = 10.32, P = .0057; Kruskal-Wallis test. Higher levels of emotional self-regulation (Emotional Regulation Questionnaire-Cognitive Reappraisal facet) were found among clinicians who reported they felt "great/good" (median = 31.0) compared to those who reported that they were "definitely stressed/stressed out" (20.0), χ2(2, N = 79) = 8.88, P = .0118; Kruskal-Wallis test. CONCLUSION: In order to have meaningful conversations about treatment planning, an understanding of mental well-being and its relationship to decision-making preferences is crucial for both oncology patients and clinicians. Our results show that for clinicians, lower perceived stress was associated with higher levels of mindfulness (experiencing the present moment), emotional self-regulation, and spending more time with patients. Larger prospective studies are needed to validate these findings.

Efficacy and Safety of Ombitasvir/Paritaprevir/Ritonavir in Patients With Hepatitis C Virus Genotype 1 or 4 Infection and Advanced Kidney Disease.

INTRODUCTION: Hepatitis C virus (HCV) infection is common in patients with end-stage renal disease. We investigated the safety and efficacy of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) ± dasabuvir (DSV) ± ribavirin (RBV) in 2 phase 3, open-label, multicenter studies in patients with stage 4 or 5 chronic kidney disease (CKD). METHODS: RUBY-I, Cohort 2 enrolled treatment-naïve or -experienced patients with HCV genotype (GT) 1a or 1b infection, with or without cirrhosis. Patients received 12 weeks (24 weeks for GT1a patients with cirrhosis) of OBV/PTV/r + DSV; all GT1a patients received RBV. RUBY-II enrolled treatment-naïve patients with GT1a or GT4 infection without cirrhosis. All patients received 12 weeks of RBV-free treatment: OBV/PTV/r + DSV for GT1a-infected patients; OBV/PTV/r for GT4-infected patients. The primary endpoint was sustained virologic response at posttreatment week 12 (SVR12). RESULTS: RUBY-I, Cohort 2 and RUBY-II enrolled 66 patients, including 50 (76%) on dialysis; 15 (23%) had compensated cirrhosis. Overall, the SVR12 rate was 95% (63/66); 1 patient had virologic failure. There were 3 discontinuations due to adverse events. Seventy-three percent (27/37) of patients receiving RBV had adverse events leading to RBV dose modification. The RBV-free RUBY-II study had no hemoglobin-associated adverse events. CONCLUSION: Treatment with OBV/PTV/r ± DSV ± RBV was well tolerated and patients with HCV GT1 or 4 infection and stage 4 or 5 CKD had high SVR12 rates, including patients with compensated cirrhosis and/or prior treatment experience.

Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study.

BACKGROUND & AIMS: There is controversy over the effects of direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) infection on hepatocellular carcinoma (HCC) recurrence and tumor aggressiveness. We compared HCC recurrence patterns between DAA-treated and untreated HCV-infected patients who had achieved a complete response to HCC treatment in a North American cohort. METHODS: We conducted a retrospective cohort study of patients with HCV-related HCC with a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy from January 2013 through December 2017 at 31 health systems throughout the United States and Canada. Cox regression was used to examine the association between DAA therapy and time to recurrence after a complete response, with DAA therapy analyzed as a time-varying exposure. We also estimated the association between DAA therapy and risk of early HCC recurrence (defined as 365 days after complete response). RESULTS: Of 793 patients with HCV-associated HCC, 304 (38.3%) received DAA therapy and 489 (61.7%) were untreated. HCC recurred in 128 DAA-treated patients (42.1%; early recurrence in 52 patients) and 288 untreated patients (58.9%; early recurrence in 227 patients). DAA therapy was not associated with HCC recurrence (hazard ratio 0.90, 95% confidence interval 0.70-1.16) or early HCC recurrence (hazard ratio 0.96, 95% confidence interval 0.70-1.34) after we adjusted for study site, age, sex, Child-Pugh score, α-fetoprotein level, tumor burden, and HCC treatment modality. In DAA-treated and untreated patients, most recurrences were within the Milan criteria (74.2% vs 78.8%; P = .23). A larger proportion of DAA-treated than untreated patients received potentially curative HCC therapy for recurrent HCC (32.0% vs 24.6%) and achieved a complete or partial response (45.3% vs 41.0%) but this did not achieve statistical significance. CONCLUSION: In a large cohort of North American patients with complete response to HCC treatment, DAA therapy was not associated with increased overall or early HCC recurrence. HCC recurrence patterns, including treatment response, were similar in DAA-treated and untreated patients.

Longitudinal correlations between MRE, MRI-PDFF, and liver histology in patients with non-alcoholic steatohepatitis: Analysis of data from a phase II trial of selonsertib.

BACKGROUND & AIMS: Non-invasive tools for monitoring treatment response and disease progression in non-alcoholic steatohepatitis (NASH) are needed. Our objective was to evaluate the utility of magnetic resonance (MR)-based hepatic imaging measures for the assessment of liver histology in patients with NASH. METHODS: We analyzed data from patients with NASH and stage 2 or 3 fibrosis enrolled in a phase II study of selonsertib. Pre- and post-treatment assessments included centrally read MR elastography (MRE)-estimated liver stiffness, MR imaging-estimated proton density fat fraction (MRI-PDFF), and liver biopsies evaluated according to the NASH Clinical Research Network classification and the non-alcoholic fatty liver disease activity score (NAS). RESULTS: Among 54 patients with MRE and biopsies at baseline and week 24, 18 (33%) had fibrosis improvement (≥1-stage reduction) after undergoing 24 weeks of treatment with the study drug. The area under the receiver operating characteristic curve (AUROC) of MRE-stiffness to predict fibrosis improvement was 0.62 (95% CI 0.46-0.78) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRE had 67% sensitivity, 64% specificity, 48% positive predictive value, 79% negative predictive value. Among 65 patients with MRI-PDFF and biopsies at baseline and week 24, a ≥1-grade reduction in steatosis was observed in 18 (28%). The AUROC of MRI-PDFF to predict steatosis response was 0.70 (95% CI 0.57-0.83) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRI-PDFF had 89% sensitivity and 47% specificity, 39% positive predictive value, and 92% negative predictive value. CONCLUSIONS: These preliminary data support the further evaluation of MRE-stiffness and MRI-PDFF for the longitudinal assessment of histologic response in patients with NASH. LAY SUMMARY: Liver biopsy is a potentially painful and risky method to assess damage to the liver due to non-alcoholic steatohepatitis (NASH). We analyzed data from a clinical trial to determine if 2 methods of magnetic resonance imaging - 1 to measure liver fat and 1 to measure liver fibrosis (scarring) - could potentially replace liver biopsy in evaluating NASH-related liver injury. Both imaging methods were correlated with biopsy in showing the effects of NASH on the liver.

Glecaprevir/Pibrentasvir Treatment in Liver or Kidney Transplant Patients With Hepatitis C Virus Infection.

Well-tolerated, ribavirin-free, pangenotypic hepatitis C virus (HCV) treatments for transplant recipients remain a high priority. Once-daily glecaprevir/pibrentasvir demonstrates high rates of sustained virologic response at 12 weeks posttreatment (SVR12) across all major HCV genotypes (GTs). This trial evaluated the safety and efficacy of glecaprevir/pibrentasvir for patients with chronic HCV GT1-6 infection who had received a liver or kidney transplant. MAGELLAN-2 was a phase 3, open-label trial conducted in patients who were ≥3 months posttransplant. Patients without cirrhosis who were HCV treatment-naive (GT1-6) or treatment-experienced (GT1, 2, 4-6; with interferon-based therapy with or without sofosbuvir, or sofosbuvir plus ribavirin) received glecaprevir/pibrentasvir (300/120 mg) once daily for 12 weeks. The primary endpoint compared the percentage of patients receiving glecaprevir/pibrentasvir with SVR12 to a historic SVR12 rate based on the standard of care. Safety of glecaprevir/pibrentasvir was assessed. In total, 80 liver transplant and 20 kidney transplant patients participated in the trial. Most patients had no or minimal fibrosis (80% had fibrosis scores F0-F1) and were infected with HCV GT1 (57%) or GT3 (24%). The overall SVR12 was 98% (n/N = 98/100; 95% confidence interval, 95.3%-100%), which exceeded the prespecified historic standard-of-care SVR12 threshold of 94%. One patient experienced virologic failure. One patient discontinued because of an adverse event considered to be unrelated to treatment; this patient achieved SVR12. Adverse events were mostly mild in severity, and laboratory abnormalities were infrequent. CONCLUSION: Once-daily glecaprevir/pibrentasvir for 12 weeks is a well-tolerated and efficacious, ribavirin-free treatment for patients with chronic HCV GT1-6 infection who have received a liver or kidney transplant. (ClinicalTrials.gov NCT02692703.) (Hepatology 2018; 00:000-000).

Efficacy of Glecaprevir/Pibrentasvir for 8 or 12 Weeks in Patients With Hepatitis C Virus Genotype 2, 4, 5, or 6 Infection Without Cirrhosis.

BACKGROUND & AIMS: Hepatitis C virus (HCV) has high genotypic diversity and global distribution. Agents that are effective against all major HCV genotypes, with shorter treatment duration, are needed to reduce disease burden. Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) have a high barrier to resistance and synergistic antiviral activity. We evaluated the safety and efficacy of 8 and 12 weeks' treatment with glecaprevir/pibrentasvir in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis in 3 separate phase 3 trials. METHODS: We performed 2 open label, single-arm studies (SURVEYOR-II, Part 4 and ENDURANCE-4) and a randomized, double-blind, placebo-controlled study (ENDURANCE-2). In the ENDURANCE-2 study, adult patients with untreated or previously treated HCV genotype 2 infection without cirrhosis were randomly assigned (2:1) to groups given once-daily oral glecaprevir/pibrentasvir (n = 202; 300 mg/120 mg) or placebo (n = 100) for 12 weeks. In the SURVEYOR-II, Part 4 and ENDURANCE-4 studies, adult patients with untreated or previously treated patients with HCV genotype 2, genotype 4, genotype 5, or genotype 6 infection, without cirrhosis, were given once-daily oral glecaprevir/pibrentasvir (n = 121 in ENDURANCE-4 and n = 145 in SURVEYOR-II) for 12 or 8 weeks, respectively. In all studies the primary endpoint was sustained virologic response at 12 weeks after treatment (SVR12) in the intention-to-treat population. RESULTS: Among patients receiving glecaprevir/pibrentasvir for 8 weeks, rates of SVR12 were 98% (95% CI, 94.1-99.3) in those infected with HCV genotype 2 and 93% (95% CI, 83.6-97.3) in those infected with HCV genotypes 4, 5, or 6. Among patients receiving glecaprevir/pibrentasvir for 12 weeks, rates of SVR12 were 99.5% (95% CI, 98.5-100) in those infected with HCV genotype 2 and 99% (95% CI, 97.6-100) in those infected with HCV genotype 4, 5, or 6. No virologic failures occurred in patients with HCV genotype 4, 5, or 6 infections. The frequency and severity of adverse events in patients receiving glecaprevir/pibrentasvir were similar to those of patients who received placebo. CONCLUSION: In 3 Phase 3 studies, 8 weeks' treatment with glecaprevir/pibrentasivr produced an SVR12 in at least 93% of patients with chronic HCV genotype 2, 4, 5, or 6 infection without cirrhosis, with virologic failure in less than 1%. The drug combination had a safety profile comparable to 12 week's treatment with glecaprevir/pibrentasvir. ClinicalTrials.gov numbers: NCT02640482 (ENDURANCE-2), NCT02636595 (ENDURANCE-4), and NCT02243293 (SURVEYOR-II).

The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial.

Inhibition of apoptosis signal-regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. We evaluated the safety and efficacy of selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1, alone or in combination with simtuzumab, in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of open-label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once-weekly injections of 125 mg of simtuzumab or simtuzumab alone. The effect of treatment was assessed by paired pretreatment and posttreatment liver biopsies, magnetic resonance elastography, magnetic resonance imaging-estimated proton density fat fraction, quantitative collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histology or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 weeks of treatment, the proportion of patients with a one or more stage reduction in fibrosis in the 18-mg selonsertib group was 13 of 30 (43%; 95% confidence interval, 26-63); in the 6-mg selonsertib group, 8 of 27 (30%; 95% confidence interval, 14-50); and in the simtuzumab-alone group, 2 of 10 (20%; 95% confidence interval, 3-56). Improvement in fibrosis was associated with reductions in liver stiffness on magnetic resonance elastography, collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups. Conclusion: These findings suggest that selonsertib may reduce liver fibrosis in patients with nonalcoholic steatohepatitis and stage 2-3 fibrosis. (Hepatology 2018;67:549-559).

Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: A multinational, prospective, controlled, randomized trial.

Severe alcoholic hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. Hepatoblastoma-derived C3A cells express anti-inflammatory proteins and growth factors and were tested in an extracorporeal cellular therapy (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin ≥8 mg/dL, Maddrey's discriminant function ≥ 32, and Model for End-Stage Liver Disease (MELD) score ≤ 35 were randomized to receive standard of care (SOC) only or 3-5 days of continuous ELAD treatment plus SOC. After a minimum follow-up of 91 days, overall survival (OS) was assessed by using a Kaplan-Meier survival analysis. A total of 203 subjects were enrolled (96 ELAD and 107 SOC) at 40 sites worldwide. Comparison of baseline characteristics showed no significant differences between groups and within subgroups. There was no significant difference in serious adverse events between the 2 groups. In an analysis of the intent-to-treat population, there was no difference in OS (51.0% versus 49.5%). The study failed its primary and secondary end point in a population with sAH and with a MELD ranging from 18 to 35 and no upper age limit. In the prespecified analysis of subjects with MELD < 28 (n = 120), ELAD was associated with a trend toward higher OS at 91 days (68.6% versus 53.6%; P = .08). Regression analysis identified high creatinine and international normalized ratio, but not bilirubin, as the MELD components predicting negative outcomes with ELAD. A new trial investigating a potential benefit of ELAD in younger subjects with sufficient renal function and less severe coagulopathy has been initiated. Liver Transplantation 24 380-393 2018 AASLD.

Ledipasvir/sofosbuvir for treatment of hepatitis C virus in sofosbuvir-experienced, NS5A treatment-naïve patients: Findings from two randomized trials.

BACKGROUND & AIMS: We report data from two similarly designed studies that evaluated the efficacy, safety, and optimal duration of ledipasvir/sofosbuvir (LDV/SOF) ± ribavirin (RBV) for retreatment of chronic hepatitis C virus (HCV) in individuals who failed to achieve sustained virological response (SVR) with prior SOF-based, non-NS5A inhibitor-containing regimens. METHODS: The RESCUE study enrolled HCV mono-infected adults with genotype (GT) 1 or 4. Non-cirrhotic participants were randomized to 12 weeks of LDV/SOF or LDV/SOF + RBV. Compensated cirrhotic participants were randomized to LDV/SOF + RBV (12 weeks) or LDV/SOF (24 weeks). The AIDS Clinical Trials Group A5348 study randomized genotype 1 adults with HCV/HIV co-infection to LDV/SOF + RBV (12 weeks) or LDV/SOF (24 weeks). Both studies used SVR at 12 weeks post-treatment (SVR12) as the primary endpoint. RESULTS: In the RESCUE study, 82 participants were randomized and treated, and all completed treatment. Overall, SVR12 was 88% (72/82); 81-100% in non-cirrhotic participants treated with LDV/SOF or LDV/SOF + RBV for 12 weeks and 80-92% in cirrhotic participants treated with LDV/SOF + RBV for 12 weeks or LDV/SOF for 24 weeks. Adverse events (AEs), mostly mild-to-moderate in severity, were experienced by 78% of participants, with headache and fatigue most frequently reported. One serious AE, not related to treatment, was observed. No premature discontinuations of study drug, or deaths occurred. In the A5348 study, seven participants were randomized (cirrhotic n = 1; GT1a n = 5) and all attained SVR12, with no serious AEs or premature discontinuations. CONCLUSIONS: In this SOF-experienced, NS5A inhibitor-naïve population, which included participants with cirrhosis or HCV/HIV co-infection, high SVR12 rates were achieved.

Selective internal radiation therapy using yttrium-90 resin microspheres in patients with unresectable hepatocellular carcinoma: a retrospective study.

BACKGROUND: Selective internal radiation therapy (SIRT) with yttrium-90 resin (Y-90 resin) microspheres has been used as a locoregional therapy for patients with unresectable hepatocellular carcinoma (HCC). We examined patient and disease characteristics that might affect survival after Y-90 resin, as well as treatment tolerability. METHODS: Data from patients with unresectable HCC treated with Y-90 resin at a single institution were reviewed retrospectively. Survival was assessed with Kaplan-Meier curves and log-rank tests. Response was evaluated with the response evaluation criteria in solid tumors (RECIST) criteria. Adverse events (AEs) were noted, and laboratory values were graded with CTCAE v3.0. RESULTS: Data from 111 patients were analyzed. AEs occurred in 23 patients at 1 week after treatment and in 46 at 3 months. At 6 months, 13 patients had a complete response and 13 had a partial response. Factors associated with longer overall survival (OS) included early-stage disease [27.8 months for patients with Barcelona-Clinic Liver Cancer (BCLC) A vs. 9.2 months for BCLC C]; treatment with other locoregional therapies (69.0 vs. 11.4 months); and lack of bilobar disease (23.5 vs. 9.4 months), portal vein thrombosis (16.2 vs. 8.6 months), ascites (16.6 vs. 10.3 months), and treatment with sorafenib (17.2 vs. 10.3 months). In six patients, Y-90 resin was used as a bridge to liver transplantation, which greatly improved survival (69.0 vs. 12.1 months). CONCLUSIONS: Several characteristics may prove useful for selecting patients likely to respond well to Y-90 resin. These results should be confirmed in prospective studies.

Sorafenib use for recurrent hepatocellular cancer after resection or transplantation: Observations from a US regional analysis of the GIDEON registry.

Treatment of unresectable recurrent hepatocellular carcinoma (HCC) in patients who recur after resection or orthotopic liver transplantation (OLT) remains a clinical challenge. One option is sorafenib, although little is known about its safety and tolerance in this unique patient population; therefore, we analyzed patients who underwent prior surgical resection and/or OLT and were treated with sorafenib in US cohort of GIDEON registry. In US, 645 patients were enrolled; 553 for intent to treat and 563 for safety. Data were analyzed in the safety population of 479 patients no surgery and 56 for resection or OLT. Forty-one patients underwent resection prior to the initiation of sorafenib, 15 patients had previously received an OLT, and 6 patients had both resection and OLT. Initial low starting doses (400 mg/day) were observed for more patients with prior OLT (71%) than prior resection (36%), resection and OLT (50%), concomitant OLT (25%), and no surgery (36%). Most AEs occurred in the first 4 weeks of treatment. Drug-related AEs were higher in patients with prior resection (87%), prior OLT (100%), or both (100%) than in patients with concomitant OLT (63%) or no surgery (70%). However, incidence of AEs resulting in permanent discontinuation were similar in all groups (19-38%).