Faculty Bibliography

BACKGROUND/AIMS/OBJECTIVE:Treatment options are limited for patients with hepatitis C (HCV) infection with treatment failure after sofosbuvir plus an NS5A inhibitor. There are some data for the efficacy of glecaprevir/pibrentasvir (G/P) in these patients. We performed a randomized trial of the safety and efficacy of 12 and 16 weeks of G/P, with or without ribavirin, in patients with HCV genotype 1 infection with treatment failure after sofosbuvir and an NS5A inhibitor. METHODS:We performed a phase 3b, open label study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor. Patients without cirrhosis were randomly assigned to groups that received G/P for 12 weeks (n=78, group A) or 16 weeks (n=49, group B). Patients with compensated cirrhosis were randomly assigned to groups that received G/P and ribavirin for 12 weeks (n=21, group C) or G/P for 16 weeks (n=29, group D). The primary endpoint was a sustained virologic response 12 weeks after treatment (SVR12). Samples collected at baseline and at time of treatment failure were sequenced for resistance-associated substitutions (RASs) in NS3 and NS5A. RESULTS:Of the 177 patients in the 4 groups, 81% were men, 79% had HCV genotype 1a infection, and 44% were black. Proportions of patients with an SVR12 in groups A, B, C, and D were 90%, 94%, 86%, and 97%, respectively. The treatment failed in 13 patients with HCV genotype 1a infection (7.3%), 6 in group A (7.9%), 3 in group B (6.1%), 3 in group C (14.3%), and 1 in group D (3.4%). Most patients had baseline RASs in NS5A. Treatment-emergent RASs in NS3 and NS5A were observed in 9 and 10 patients with treatment failure, respectively. G/P was well tolerated. Ribavirin increased adverse events but did not increase efficacy. CONCLUSIONS:In a randomized study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor, 16 weeks treatment with G/P produced an SVR12 in more than 90% of patients, including those with compensated cirrhosis. ClinicalTrials.gov no: NCT03092375.

Abstract LBO-06 is under embargo until Saturday 13 April 2019, 07:00. This abstract has been selected to be highlighted during official EASL Press Office activities or in official EASL Press Office materials that will be made publicly available on the congress website at 07:00 (CET) on the day of their presentation at the congress. Industry must not issue press releases - even under embargo - covering the data contained in abstracts selected to be highlighted during official EASL Press Office activities or in official EASL Press Office materials until the individual embargo for each data set lifts. Media must not issue coverage of the data contained in abstracts selected to be highlighted during official EASL Press Office activities or in official EASL Press Office materials until the individual embargo for each data set lifts. Journalists, industry, investigators and/or study sponsors must abide by the embargo times set by EASL. Violation of the embargo will be taken seriously. Individuals and/or sponsors who violate EASL's embargo policy may face sanctions relating to current and future abstract submissions, presentations and visibility at EASL Congresses. The EASL Governing Board is at liberty to ban attendance and/or retract data. Copyright for abstracts (both oral and poster) on the website and as made available during The International CongressTM 2019
Copyright

Background and aims: Although improvement of PROs in CHC patients who achieve SVR with direct-acting antivirals (DAAs) has been demonstrated, PROs of CHC patients who failed to achieve SVR with new DAAs have not been documented. AIM: Compare post-treatment PRO scores between CHC patients who did and did not achieve SVR after DAA treatment.
Method(s): Patients who had completed treatment in a clinical trial were prospectively enrolled in two registries based on treatment outcomes: the SVR Registry and Non-SVR Registry. PRO scores were prospectively collected using the Short Form-36 (SF-36) every 12-24 weeks.
Result(s): There were 4, 234 patients with SVR and 242 without SVR who were enrolled in these two registries and had pre-treatment PRO data: 54 +/- 10 years old, 63% male, 83% white, 65% enrolled in the U.S., 17% with cirrhosis prior to treatment, 12% with coinfection with HIV, and 25% with history of depression. Upon registry enrollment, patients with SVR experienced significant improvement in all their PRO scores in comparison to their own pre-treatment baseline scores (all p < 0.0001) while there was no improvement in any PRO score (all one-sided p > 0.05) and, in fact, a significant decrement in General Health of SF-36 (mean -2.8 points, p = 0.008) in CHC patients without SVR. Furthermore, CHC patients without SVR experienced significant PRO decrements while followed on the registry (up to -7.0 points decrements in 4/8 SF-36 domains at registry week 12; up to -9.2 points in all 8 domains at week 24; up to -8.3 points in 5/8 domains at week 48, and up to -9.0 points in 4/8 domains at week 96 (all p < 0.05). In contrast, patients with SVR experienced sustained improvement of their PRO scores while on the registry (up to +7.0 points at registry week 24, up to +6.9 points at week 48, up to +6.1 points at week 96 (all p < 0.001) (Figure). In multivariate analysis, having achieved SVR was independently associated with superior scores in all SF-36 domains at all registry time points: beta from +4.8 to +14.9 points (all p <= 0.01). PRO scores were lower and their decrements were greater in cirrhotics without SVR than non-cirrhotic without SVR (p < 0.05).
Conclusion(s): These data clearly show the benefit of achieving SVR for patients' well-being which is contrasted to the deleterious impact of viremia (not achieving SVR). These data should inform payers and policy makers to remove any barriers to HCV treatment which could lead to the cure and reduce patients' suffering and PRO impairment. NAFLD: Diagnostics and non-invasive assessment
Copyright

BACKGROUND & AIMS/OBJECTIVE:Non-alcoholic and alcohol-related fatty liver disease are overlapping diseases in which metabolic syndrome and alcohol consumption each contribute to progressive liver disease. We aimed to assess the effects of alcohol consumption and metabolic syndrome on mortality in individuals with fatty liver. METHODS:test for independence or survey regression models. We used Cox proportional hazard models to identify independent predictors of all-cause and cause-specific mortality. RESULTS:The study cohort included 4264 individuals with hepatic steatosis (mean age, 45.9 years; 51% male; 76% white; 46% with metabolic syndrome; 6.2% with excessive alcohol use). There was no significant difference in mean age between individuals with vs without excessive alcohol consumption (P=.65). However, overall mortality was significantly higher among participants with excessive alcohol consumption (32.2%) vs participants with non-excessive alcohol use (22.2%) after mean 20 years of follow up (P=.003), as well as after 5 years of follow up. In multivariate analysis, the presence of metabolic syndrome (adjusted hazard ratio [aHR], 1.43; 95% CI, 1.12-1.83) and excessive alcohol consumption (aHR, 1.79; 95% CI, 1.21-2.66) were independently associated with an increased risk of death in individuals with hepatic steatosis; any lower average amount of alcohol consumption was not associated with mortality (all P>.60). In a subgroup analysis, the association of excessive alcohol use with mortality was significant in individuals with metabolic syndrome (aHR, 2.46; 95% CI, 1.40-4.32) but not without it (P=.74). CONCLUSION/CONCLUSIONS:In review of data from the National Health and Nutrition and Examination Survey III, we associated alcohol consumption with increased mortality in participants with fatty liver and metabolic syndrome. These findings indicate an overlap between non-alcoholic and alcohol-related fatty liver disease.

Background and aims: Patients with chronic hepatitis C (CHC)and cirrhosis have severe impairment of health-related quality of life (HRQL)and other patient-reported outcomes (PROs). Although achieving sustained virologic response (SVR)leads to improvement in PROs, the long-term sustainability of this improvement in patients with cirrhosis has not been well established. AIM: To assess long-term changes in PRO scores in patients with cirrhosis who have achieved SVR after treatment with a direct-acting antiviral. Method(s): Patients with HCV and cirrhosis who had been treated in 14 clinical trials and had achieved SVR-12 were prospectively enrolled in a long-term registry (#NCT02292706). PROs were collected every 24 weeks for 120 weeks using Short Form-36 (SF-36), Chronic Liver Disease Questionnaire (CLDQ)-HCV, and Work Productivity and Activity Impairment (WPAI)instruments which collectively return 20 PRO domain scores. Result(s): Data was available for 785 HCV cirrhotics with SVR-12: 659 compensated (CC)and 126 decompensated cirrhosis (DCC). Their pre-treatment characteristics include age 57.6 +/- 7.3 years, 69% male, 22% with type 2 diabetes, 50% employed. Prior to their initial treatment, DCC patients had severely impaired PRO scores in comparison to CC patients (by average 5.8% to 15.6% of a PRO range size; p < 0.05 for 15/20 PRO domain scores); the most pronounced difference between DCC and CC patients was in physical health- and activity-related domains. After achieving SVR and enrollment into the registry, significant PRO improvements from their pre-treatment scores were noted in 19/20 PRO domains in CC patients (ranging from average +2.2% to +17.0% of a PRO range size)and in 10/20 PRO domains in DCC patients (from +4.4% to +20.5% of a PRO score range)(all p < 0.05). These PRO gains persisted or continued to improve over time up to 120 weeks after entering the registry in patients with both CC and DCC (Figure). In DCC patients, the presence of hepatic encephalopathy was the most important contributor to PRO impairment (up to -10.2%, p < 0.01 for 12/20 PRO scores). [Table Presented]Conclusion: Achieving SVR leads to significant and sustainable improvement of PRO scores in patients with pre-treatment cirrhosis.

INTRODUCTION/BACKGROUND:Treatment options are limited for people infected with hepatitis C virus (HCV) with decompensated liver disease. The C-SALT study assessed elbasvir (EBR) plus grazoprevir (GZR) in individuals with HCV genotype 1 infection and Child-Pugh class B (CP-B) cirrhosis. METHODS:In this 12-week, phase 2, nonrandomized, open-label study (NCT02115321; Protocol MK-5172-059), participants with CP-B cirrhosis received EBR 50 mg plus GZR 50 mg once daily, and a control group of noncirrhotic participants received EBR 50 mg plus GZR 100 mg once daily. The primary endpoint was sustained virologic response 12 weeks after the end of therapy. RESULTS:Sustained virologic response at 12 weeks after the end of therapy was achieved by 27/30 (90.0%) CP-B participants and 10/10 (100.0%) noncirrhotic participants. Two participants relapsed, and one died during follow-up after having undetectable HCV RNA at the end of treatment. Most CP-B participants had stable or improved model for end-stage liver disease and Child-Pugh scores at follow-up week 12 compared with baseline. There was no significant difference in drug exposure between groups, despite the differing GZR dose. Adverse events occurring in >10% of participants were fatigue (CP-B: 30.0%; noncirrhotic: 30.0%), arthralgia (16.7%; 20.0%), nausea (10.0%; 20.0%), and headache (10.0%; 50.0%). No serious treatment-related adverse events or hepatic events of clinical interest occurred. CONCLUSIONS:EBR 50 mg plus GZR 50 mg once daily for 12 weeks was highly effective and well tolerated in a traditionally hard-to-treat population. TRANSLATIONAL IMPACT/UNASSIGNED:Although EBR plus reduced-dose GZR is not available for people with CP-B cirrhosis, these results complement phase 2/3 trial data and real-world experience with EBR/GZR.Open Access This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Background: Chronic hepatitis C (CHC) and non-alcoholic steatohepatitis (NASH) are both associated with impairment of healthrelated quality of life (HRQL). The most profound impairment is usually seen in patients with cirrhosis.
Aim(s): To compare HRQL scores in patients with cirrhosis due to CHC to NASH.
Method(s): Patients with CHC and NASH and compensated cirrhosis completed SF-36, CLDQ, and Work Productivity and Activity questionnaires while off-treatment.
Result(s): We included 1460 patients with NASH or CHC and cirrhosis: 57.4 +/- 8.2 years, 44% male, 40% history of psychiatric disorders, 50% employed (all p>0.05 between NASH and CHC). Cirrhotic patients with NASH had higher BMI (mean 33.8 vs. 28.2) and more type 2 diabetes (77% vs. 18%) (p<0.01). Patients with NASH had lower HRQL in Physical Functioning, Bodily Pain, General Health domains, and Physical Summary of SF-36 (by 3.6-4.4 points on a 0-100 scale, all p<0.01). Despite this, patients with CHC had lower Mental Health score of SF-36 (mean 69.5 vs. 73.0) and Emotional score of CLDQ (mean 4.9 vs. 5.3 on a 1-7 scale), and higher Activity Impairment score of WPAI (0.27 vs. 0.19) (all p<0.002). In multivariate regression analysis, after adjustment for demographic and clinical parameters, having NASH was independently associated with lower physical HRQL scores (beta - 3.6 to - 4.3 for SF-36 domains) and higher mental health-related scores (beta +3.8 for Mental Health of SF-36, +0.33 for Emotional of CLDQ) (all p<0.01).
Conclusion(s): Patients with NASH and cirrhosis have more impairment of their physical health-related scores than demographically similar patients with hepatitis C

European treatment guidelines for hepatitis C virus (HCV) infection recommend that people with genotype (GT) 1a infection and baseline viral load ≤800 000 IU/mL receive elbasvir/grazoprevir (EBR/GZR) for 12 weeks, and those with baseline viral load >800 000 IU/mL receive EBR/GZR plus ribavirin for 16 weeks. This analysis was conducted to clarify whether baseline viral load can serve as an accurate, sensitive or specific stratification factor for defining EBR/GZR regimens. In this post hoc, integrated analysis, participants with GT1a infection who received EBR 50 mg/GZR 100 mg for 12 weeks were stratified according to baseline viral load. Sustained virologic response at 12 weeks post-treatment was achieved by 95.2% (911/957) of participants and was higher among participants with baseline viral load ≤800 000 IU/mL vs >800 000 IU/mL (98.5% vs 93.9%). The 800 000 IU/mL threshold had a positive predictive value of 98.5%, a negative predictive value of 6.1%, a specificity of 91.3%, a sensitivity of 28.4% and an overall accuracy of 31.5%. A baseline viral load cutpoint of 800 000 IU/mL had high positive predictive value and specificity but poor negative predictive value, sensitivity and accuracy in predicting treatment outcomes in this population. Baseline NS5A resistance-associated substitutions (RASs) were detected in 25% (1/4) of virologic failures with baseline viral load ≤800 000 IU/mL and 59.5% (25/42) of those with baseline viral load >800 000 IU/mL. Overall, these data suggest that, compared with the use of a baseline viral load cutpoint, baseline testing for NS5A RASs enables more individuals to receive the 12-week EBR/GZR regimen without compromising the opportunity for SVR.