Faculty Bibliography

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.

Primary biliary cholangitis (PBC) is a chronic, cholestatic, autoimmune disease with a variable progressive course. PBC can cause debilitating symptoms including fatigue and pruritus and, if left untreated, is associated with a high risk of cirrhosis and related complications, liver failure, and death. Recent changes to the PBC landscape include a name change, updated guidelines for diagnosis and treatment as well as new treatment options that have recently become available. Practicing clinicians face many unanswered questions when managing PBC. To assist these healthcare providers in managing patients with PBC, the American College of Gastroenterology (ACG) Institute for Clinical Research & Education, in collaboration with the Chronic Liver Disease Foundation (CLDF), organized a panel of experts to evaluate and summarize the most current and relevant peer-reviewed literature regarding PBC. This, combined with the extensive experience and clinical expertise of this expert panel, led to the formation of this clinical guidance on the diagnosis and management of PBC.

BACKGROUND:While hepatitis B and C have been the main drivers of hepatocellular carcinoma (HCC), non-alcoholic steatohepatitis (NASH) has recently become an important cause of HCC. The aim of this study was to assess the causes of HCC among liver transplant (LT) candidates in the U.S. METHODS:The Scientific Registry of Transplant Recipients (2002-2016) was used to estimate the trends in prevalence of HCC in LT candidates with the most common types of chronic liver disease: alcoholic liver disease (ALD), chronic hepatitis B (CHB), chronic hepatitis C, and NASH. RESULTS:158,347 adult LT candidates were included. Of these, 26,121 (16.5%) had HCC; this proportion increased from 6.4% (2002) to 23.0% (2016) (trend p<0.0001). Over the study period, CHC remained the most common etiology for HCC (65%). The proportions of HCC accounted for by CHC and ALD remained stable (both trend p>0.10), the proportion of CHB decreased 3.1-fold (p<0.0001), while the proportion of NASH in HCC increased 7.7-fold (from 2.1% to 16.2%, p<0.0001). Furthermore, since 2002, the prevalence of HCC in LT candidates with NASH increased 11.8-fold, while this rate increased 6.0-fold in CHB, 3.4-fold in ALD and 2.3-fold in CHC (all p<0.0001); the increasing trend in NASH was steeper than that for any other etiology (p<0.0001 in a trend regression model). The proportion of LT candidates with HCC who were ultimately transplanted or died while waiting did not differ between etiologies (p>0.05). CONCLUSIONS:Non-alcoholic steatohepatitis is the most rapidly growing cause of HCC among U.S. patients listed for liver transplantation.

Type 2 diabetes mellitus (T2DM) has been identified as an extrahepatic manifestation of chronic HCV infection. Conversely, in the context of chronic HCV infection, T2DM can accelerate the course of HCV-induced liver disease leading to increased risk of fibrosis, cirrhosis and hepatocellular carcinoma. The presence of T2DM negatively impacts the efficacy of interferon-based antiviral therapy, but real-world data with high-efficacy direct-acting antiviral therapies suggest high viral clearance rates in T2DM patients. In HCV-infected individuals, viral eradication is associated with a reduced risk of de novo T2DM in non-diabetic patients and beneficial metabolic changes in patients with T2DM, highlighting the importance of antiviral treatment and physician awareness of this association.

Background: NAFLD and AFLD are overlapping liver diseases in which both metabolic syndrome (MS) and alcohol consumption contribute to progressive liver disease. Aim: To assess the impact of alcohol consumption and MS on mortality of individuals with NAFLD and AFLD. Methods: National Health and Nutrition and Examination Survey III (1988-1994)-National Death Index linked files were used to select participants with at least mild hepatic steatosis on an ultrasound. All other causes of liver disease (HBV, HCV, iron overload) were excluded. Alcohol consumption was selfreported as mean number of drinks per day for 1 year prior to data collection. Using alcohol consumption data, study cohort was divided into 5 groups: no alcohol use, minimal (<=3 and <=1.5 drinks/week for men and women), moderate (>minimal but <=2 and <=1 drinks/day for men and women), substantial (>moderate but <=3 and <=1.5 drinks/day for men and women), and excessive (>3 and 1.5 drinks/day for men and women). Association of alcohol consumption with mortality was quantified using Cox proportional hazard model while accounting for the survey design. Results: The study cohort included 4,309 individuals with hepatic steatosis: mean age 46.0 years, 51% male, 76% white, 46% with MS (ATPIII Criteria). Of the study cohort, 55.8% reported no, 18.4%-minimal, 16.7%-moderate, 3.7%-substantial, and 5.4%-excessive alcohol use. After mean follow-up of 20 years, 23% of participants died. Individuals with steatosis who reported excessive alcohol consumption were more commonly male and smokers (both p<0.05). Despite similar age (p=0.69), they had significantly higher mortality rate in comparison to those with steatosis and non-excessive alcohol use (33.0% vs. 22.5%, p=0.001), especially after 5 years of follow-up. In multivariate analysis, presence of MS [adjusted hazard ratio (aHR)=1.38 (1.09-1.76)], older age [aHR=1.094 (1.080-1.108)], smoking [aHR=2.101 (1.628-2.710)] and male gender [aHR=1.315 (1.125-1.538)] were independently associated with an increased risk of mortality in individuals with hepatic steatosis. In addition, excessive alcohol consumption was independently associated with mortality after adjustment for confounders: aHR=1.61 (1.12-2.33), p=0.01; lower average amounts of alcohol consumption were not associated with mortality (all p>0.20). In a subgroup analysis, association of excessive alcohol use with mortality was significant in individuals with MS [aHR=2.45 (1.37-4.39)] but not without MS (p=0.86). Conclusion: Excessive alcohol consumption is associated with increased mortality in the presence of MS, suggesting an important overlap between NAFLD and AFLD

Nonalcoholic steatohepatitis (NASH)-related cirrhosis and cryptogenic cirrhosis (CC) have become leading indications for liver transplantation (LT) in the US. Our aim was to compare the trends, clinical presentation, and outcomes for transplant candidates with NASH and CC.The Scientific Registry of Transplant Recipients (1994-2016) was used to select adult LT candidates and recipients with primary diagnoses of NASH and CC without hepatocellular carcinoma.Two lakh twenty-three thousand three hundred ninety-one LT candidates were listed between 1994 and 2016. Of these, 16,214 (7.3%) were listed for CC and 11,598 (5.2%) for NASH. Before 2004, NASH was seldom coded for an indication for LT, but became more common after 2009. Averaged across the study period, CC candidates compared with NASH candidates were younger and had fewer conditions of metabolic syndrome (MS). CC patients were more likely to have MS components in comparison to candidates with other chronic liver diseases (CLDs) (all P < .0001). For most of the study period, patients with CC or NASH were similarly more likely to be taken off the list due to deterioration or death, with to patients with other CLDs. Post-LT data were available for 14,052 transplant recipients with NASH or CC. With the exception of post-transplant diabetes, the outcomes of patients transplanted for CC and NASH were similar to those of other CLD patients.Number of LT due to CC and NASH cirrhosis is increasing. In the past decade, there is a shift from LT listing diagnosis from CC to NASH potentially related to increased awareness about NASH in transplant centers in the US.

The Asian-American population is characterized by remarkable diversity. Studying Asians as an aggregate group may obscure clinically-meaningful heterogeneity. We performed a population-based study using data from the United States (US) National Vital Statistics System. We determined the trends in age-standardized mortality rates for chronic liver disease stratified by etiology among the most populous US-based Asian subgroups (Asian Indians, Chinese, Filipino, Japanese, Korean, and Vietnamese) and compared it to non-Hispanic whites. Annual percentage change was calculated to determine temporal mortality patterns using joinpoint analysis.Hepatitis C virus-related mortality rates were higher in non-Hispanic whites compared to individual Asian subgroups, but a sharp decline in mortality rates was noted in 2014 among non-Hispanic whites and all Asian subgroups. Age-standardized hepatitis B virus-related mortality rates were higher in all Asian subgroups as compared to non-Hispanic whites in 2016, with the highest mortality among Vietnamese followed by Chinese. Mortality rates for alcoholic liver disease have been steadily trending upwards in all Asian subgroups, with the highest mortality in Japanese. Overall, age-standardized cirrhosis-related mortality rates were highest in non-Hispanic whites, followed by Japanese, and more distantly by Vietnamese and other subgroups. However, hepatocellular carcinoma-related mortality rates were higher in most Asian subgroups led by Vietnamese, Japanese and Koreans compared to non-Hispanic whites. In this population-based study utilizing a nationally representative database, we demonstrated a marked heterogeneity in the mortality rates of etiology-specific chronic liver disease among Asian subgroups in the US.

Introduction: Chronic hepatitis C virus (HCV) infection is a systemic disease associated with insulin resistance and other extrahepatic met-abolic manifestations that can accelerate liver disease progression, increasing the risk of fibrosis and hepatocellular carcinoma. Curative treatment of HCV infection with direct-acting antivirals (DAAs) can reduce these risks. The pangenotypic DAA regimen G/P (glecaprevir [NS3/4A inhibitor discovered by AbbVie and Enanta] coformulated with pibrentasvir [NS5A inhibitor]) is approved to treat HCV infection and demonstrated a 98% overall cure rate in clinical trials. We pooled data from 7 phase 3 clinical trials conducted in over 2000 patients and performed an integrated analysis evaluating the safety and efficacy of G/P in patients with baseline metabolic syndrome. Materials-&-Methods: The analysis included patients with HCV genotype 1, 2, 3, 4, 5 or 6 infection and baseline metabolic syndrome de-fined according to the ATP III criteria who received G/P treatment for 8, 12 or 16 weeks. Patients with or without severe renal impairment, and without cirrhosis or with compensated cirrhosis, could be either treatment-naive or experienced with interferon (IFN) or pegIFN with or without ribavirin (RBV) or sofosbuvir and RBV with or without pegIFN. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). Adverse events and laboratory abnormalities were recorded in all patients to monitor safety and tolerability Results: The analysis included 349 patients, the majority of whom were male (208; 60%), white (265; 76%), HCV treatment-naive (244; 70%), and without cirrhosis (275; 79%). The most common HCV genotype among enrolled patients was genotype 1 (186/349; 53%), followed by genotype 2 (66/349; 19%) and 3 (62/349; 18%). The median BMI at baseline was 29.8 kg/m² and 54% (189/349) presented with elevated triglycerides. Efficacy is shown in Figure 1; the SVR12 rate was 98% (343/349), with 2 virologic failures. One adverse event led to treatment discontinuation (<1%); no serious adverse events were deemed related to study drug. One patient (<1%) experienced a Grade 3 alanine aminotransferase elevation. Conclusions: G/P is a once-daily DAA therapy with a favorable safety profile that yields high SVR12 rates in patients with comorbid conditions including baseline metabolic syndrome. [Figure Presented]

Treatment of chronic hepatitis C virus (HCV) infection has been revolutionized with the development of direct-acting antiviral agents (DAAs). Eight to twelve weeks of all-oral, once-daily treatments is now the standard of care and viral eradication can be achieved in >95% across different patient populations. Despite these advances, several unresolved issues remain, including treatment of HCV genotype 3, chronic kidney disease, and in patients in whom DAA therapy has failed. Glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) are the most recently approved DAA regimens. Given the overwhelming success of modern DAA-based therapies, GLE/PIB and SOF/VEL/VOX are also likely to represent the last DAAs to be approved. Both are pangenotypic, once-daily, all-oral DAA combinations that have the potential to close the gaps in the current DAA treatment portfolio. Here, we review the challenges associated with current DAAs and how these two regimens may be implemented in existing treatment algorithms.