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.

Background: Standard of care nucleos(t)ide analogs (Nrtl) are effective in chronic HBV (CHB) infection, but achieve low rates of sustained responses off therapy. The combination of the HBV Core Inhibitor ABI-H0731 (731) with a Nrtl has demonstrated potent antiviral activity in prior clinical studies and is being evaluated in a long-term treatment study.
Method(s): Studies ABI-H0731-201 and ABI-H0731-202 were 24-wk double-blind, placebo (Pbo)-controlled studies in CHB patients (pts). After 24 wks of treatment, pts could enter the open-label extension study ABI-H0731-211 and receive 731+Nrtl for up to an additional 52 wks. The study diagram summarizes study design, patient flow and monitored parameters. This interim report summarizes data for HBeAg+ pts only.
Result(s): Final Wk 24 results confirmed greater mean Iog10 declines in HBV DNA (5.27 vs 3.99; p=0.017) and RNA (2.34 vs 0.61; p<0.001) are achieved with 731+ETV vs ETV in Study 202. By Wk 24 in Study 201, the proportion of pts on 731+Nrtl vs Nrtl achieving DNA "TND" was 69% vs 0% (p<0.001), and the proportion of pts achieving RNA <35 U/mL whose baseline RNA > 35 U/mL was 52% vs 0% (p=0.0013) respectively. There are 64 HBeAg+ pts currently on treatment in Study 211, having received an overall treatment duration of >32 wks. Among the 27 HBeAg+ pts receiving 731+Nrtl in Study 201, 41% (11/27) have now achieved DNA TND along with RNA <35 U/mL and HBeAg <1 lU/mL At their last timepoint, Study 202 (Rx naive) pts now in Study 211 (n=22) have demonstrated mean DNA and RNA declines of 6.1 and 3.0 logs, respectively, with observed mean log changes of >0.6 for HBeAg (11 pts >0.5, 4 pts >1.0), >0.8 log for HBcrAg (7 pts >1.0, 3 pts >2.0) and >0.4 log for HBsAg (7 pts >0.5, 3 pts >1.0). When, administered in combination with Nrtl for up to 1 year, 731 has been well-tolerated, with only mild/moderate adverse events and lab abnormalities, and only a single discontinuation due to a Grade 1 rash.
Conclusion(s): ABI-H0731 continues to exhibit a favorable safety and tolerability profile in pts treated for up to 1 yr. The combination of 731+Nrtl results in faster, deeper declines in HBV DNA and RNA than Nrtl alone, as well as subsequent declines in the surrogate markers of cccDNA (pgRNA, HBeAg and HBcrAg) predictive of cccDNA pool depletion, and HBsAg. The emergent data supports the continued development of ABI-H0731. Updated safety and efficacy data will be presented

INTRODUCTION/BACKGROUND:Although there is substantial evidence suggesting poor health-related quality of life (HRQL) in patients with chronic hepatitis C (CHC), similar data in nonalcoholic steatohepatitis (NASH) have not been fully assessed. The aim is to compare HRQL scores in patients with CHC to those with NASH. METHODS:Matched patients with advanced fibrosis (bridging fibrosis and compensated cirrhosis) due to CHC and NASH completed Short Form-36 (SF-36) questionnaire, Chronic Liver Disease Questionnaire (CLDQ), and Work Productivity and Activity Instrument questionnaire. RESULTS:We included 1,338 patients with NASH with advanced fibrosis (mean age 57.2 years, 47% men, 55% cirrhosis) and 1,338 matched patients with CHC. Patients with CHC and NASH had similar rates of employment and psychiatric disorders (P > 0.05). As expected, patients with NASH had higher body mass index (mean 33.7 vs 27.6) and more type 2 diabetes (74% vs 16%) (all P < 0.01). Patients with NASH had significantly lower HRQL scores related to physical health: Physical Functioning, Bodily Pain, General Health, Vitality, Physical Summary of SF-36, and Fatigue of CLDQ (P < 0.02). By contrast, patients with CHC had a lower Mental Health score of SF-36 and Emotional score of CLDQ and reported greater impairment in daily activities as measured by the Work Productivity and Activity Instrument questionnaire (P < 0.002). In multivariate analysis, after adjustment for demographic parameters, cirrhosis, and history of psychiatric disorders, having NASH was associated with lower physical HRQL scores and higher mental health-related scores (P < 0.05). DISCUSSION/CONCLUSIONS:Patients with NASH and advanced fibrosis have more impairment of their physical health-related scores than patients with CHC with advanced fibrosis. These data should dispel the misconception that NASH is an asymptomatic disease with little negative impact on patients' well-being.

The development of bacterial endocarditis as a result of endoscopic interventions within the gastrointestinal tract is exceedingly rare. Antibiotic prophylaxis for endoscopic procedures is generally not warranted, except for certain high-risk patients. Double-balloon enteroscopy (DBE) is a common endoscopic procedure for evaluation of the small bowel. Bacterial endocarditis secondary to DBE has not been previously described. We describe the first case of enterococcal endocarditis attributed to DBE in a patient with a history of stage 1 primary biliary cholangitis.

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.

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
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