Health-related quality of life (HRQL) assessments in a 52-week, double-blind, randomized, placebo-controlled phase III study of resmetirom (MGL-3196) in patients with metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis.

BACKGROUND AND AIMS: Resmetirom, liver-directed thyroid-hormone receptor-ß agonist, received approval for metabolic dysfunction-associated steatohepatitis (MASH) treatment. We assessed health-related quality of life (HRQL) in patients with MASH treated with resmetirom. APPROACH AND RESULTS: Patients with MASH/NASH without cirrhosis and with confirmed/suspected fibrosis were enrolled in a 54-month double-blind randomized placebo-controlled phase III clinical trial with serial biopsy assessments at baseline and week 52 (MAESTRO-NASH, NCT03900429). HRQL was assessed using Chronic Liver Disease Questionnaire-NASH (CLDQ-NAFLD) and Liver Disease Quality of Life (LDQOL). Baseline HRQL score changes by treatment group (resmetirom 80 mg, resmetirom 100 mg, or placebo) and histological response (improvement of fibrosis without worsening of NAS or resolution of MASH/NASH without worsening of fibrosis) were compared after 52 weeks. Included were 966 intention-to-treat patients: 323 received resmetirom 100 mg, 322 resmetirom 80 mg, and 321 placebo. By weeks 24 and 52, patients receiving 80 or 100 mg resmetirom experienced HRQL improvement in CLDQ-NAFLD Worry domain (mean +0.21 to +0.24, p < 0.05). At week 52, subjects who met histologic endpoints after treatment with resmetirom (100 mg and 80 mg pooled) experienced HRQL improvement in CLDQ-NAFLD Worry +0.46 (41% met minimal clinically important difference [MCID]), LDQOL domains: Role Emotional +3.0 (28% met MCID), Health Distress +8.1 (38% MCID), Stigma +3.5 (39% MCID), and total LDQOL +2.2 (35% MCID) (all p < 0.05). Similar improvements were noted in histologic responders from 100 mg or 80 mg resmetirom groups when separated-no improvements in placebo or nonresponders. Baseline F3 histologic responders had similar/more pronounced HRQL improvements. CONCLUSIONS: Patients with MASH/NASH with fibrosis improvement or the resolution of MASH with resmetirom experienced clinically meaningful and statistically significant HRQL improvements.

Sarcopenia Among Patients With Nonalcoholic Fatty Liver Disease (NAFLD) Is Associated With Advanced Fibrosis.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) and sarcopenia can be associated with advanced liver disease. Our aim was to assess the association between sarcopenia and the risk of fibrosis among patients with NAFLD. METHODS: We used the National Health and Nutrition Examination Survey (2017-2018). NAFLD was defined by transient elastography without other causes of liver disease or excessive alcohol use. Significant fibrosis (SF) and advanced fibrosis (AF) were defined by liver stiffness greater than 8.0 kPa and greater than 13.1 kPa, respectively. Sarcopenia was defined using the Foundation for the National Institutes of Health definition. RESULTS: Of the total cohort (N = 2422), 18.9% had sarcopenia, 9.8% had obese sarcopenia, 43.6% had NAFLD, 7.0% had SF, and 2.0% had AF. Moreover, 50.1% had neither sarcopenia nor NAFLD, 6.3% had sarcopenia without NAFLD, 31.1% had NAFLD without sarcopenia, and 12.5% had NAFLD with sarcopenia. Compared with individuals without NAFLD or sarcopenia, individuals with sarcopenic NAFLD had higher rates of SF (18.3% vs 3.2%) and AF (7.1% vs 0.2%). In the absence of sarcopenia, compared with individuals without NAFLD, individuals with NAFLD have a significantly increased risk of SF (odds ratio, 2.18; 95% CI, 0.92-5.19). In the presence of sarcopenia, NAFLD was associated with an increased risk of SF (odds ratio, 11.27; 95% CI, 2.79-45.56). This increase was independent of metabolic components. The proportion of SF that is attributable to the interaction of NAFLD and sarcopenia was 55% (attributable proportion, 0.55; 95% CI, 0.36-0.74). Increased leisure time physical activity was associated with a lower risk of sarcopenia. CONCLUSIONS: Patients with sarcopenic NAFLD are at risk for SF and AF. Increased physical activity and a healthy diet targeted to improve sarcopenic NAFLD could reduce the risk of significant fibrosis.

Clinical and patient-reported outcome profile of patients with hepatitis B viral infection from the Global Liver Registry™.

Chronic hepatitis B (CHB) infection is one of the most common causes of cirrhosis and liver cancer worldwide. Our aim was to assess clinical and patient-reported outcome (PRO) profile of CHB patients from different regions of the world using the Global Liver Registry. The CHB patients seen in real-world practices are being enrolled in the Global Liver Registry. Clinical and PRO (FACIT-F, CLDQ, WPAI) data were collected and compared to baseline data from CHB controls from clinical trials. The study included 1818 HBV subjects (48 ± 13 years, 58% male, 14% advanced fibrosis, 7% cirrhosis) from 15 countries in 6/7 Global Burden of Disease super-regions. The rates of advanced fibrosis varied (3-24%). The lowest PRO scores across multiple domains were in HBV subjects from the Middle East/North Africa (MENA), the highest - Southeast/East and South Asia. Subjects with advanced fibrosis had PRO impairment in 3 CLDQ domains, Activity of WPAI (p < 0.05). HBV subjects with superimposed fatty liver had more PRO impairments. In multivariate analysis adjusted for location, predictors of PRO impairment in CHB included female sex, advanced fibrosis, and non-hepatic comorbidities (p < 0.05). In comparison to Global Liver Registry patients, 242 controls from clinical trials had better PRO scores (Abdominal, Emotional, and Systemic scores of CLDQ, all domains of WPAI) (p < 0.05). In multivariate analysis with adjustment for location and clinicodemographic parameters, the associations of PROs with the enrollment setting (real-life Global Liver Registry vs. clinical trials) were no longer significant (all p > 0.10). The clinico-demographic portrait of CHB patients varies across regions of the world and enrollment settings. Advanced fibrosis and non-hepatic comorbidities are independently associated with PRO impairment in CHB patients.

Neutralizing Monoclonal Antibody Treatment Reduces Hospitalization for Mild and Moderate Coronavirus Disease 2019 (COVID-19): A Real-World Experience.

BACKGROUND: Neutralizing monoclonal antibody (NmAb) treatments have received Emergency Use Authorization to treat patients with mild or moderate COVID-19 infection. To date, no real- world data on the efficacy of NmAbs have been reported from clinical practice. We assessed the impact of NmAb treatment given in the outpatient clinical practice setting on hospital utilization. METHODS: Electronic medical records were used to identify adult COVID-19 patients who received NmAbs (bamlanivimab [BAM] or casirivimab and imdevimab [REGN-COV2]) and historic COVID-19 controls. Post-index hospitalization rates were compared. RESULTS: 707 confirmed COVID-19 patients received NmAbs and 1709 historic COVID-19 controls were included; 553 (78%) received BAM, 154 (22%) received REGN-COV2. Patients receiving NmAb infusion had significantly lower hospitalization rates (5.8% vs 11.4%, P < .0001), shorter length of stay if hospitalized (mean, 5.2 vs 7.4 days; P = .02), and fewer ED visits within 30 days post-index (8.1% vs 12.3%, P = .003) than controls. Hospitalization-free survival was significantly longer in NmAb patients compared with controls (P < .0001). There was a trend towards a lower hospitalization rate among patients who received NmAbs within 2-4 days after symptom onset. In multivariate analysis, having received an NmAb transfusion was independently associated with a lower risk of hospitalization after adjustment for age, sex, race, BMI, and referral source (adjusted HR [95% CI], .54 [0.38-0.79]; P = .0012). Overall mortality was not different between the 2 groups. CONCLUSIONS: NmAb treatment reduced hospital utilization, especially when received within a few days of symptom onset. Further study is needed to validate these findings.

Long-term Patient-Centered Outcomes in Cirrhotic Patients With Chronic Hepatitis C After Achieving Sustained Virologic Response.

BACKGROUND & AIMS: Achieving sustained virologic response (SVR) among patients with hepatitis C virus (HCV) leads to patient reported outcome (PRO) improvement. We aimed to assess the long-term post-SVR PRO trends in HCV patients with cirrhosis. METHODS: Patients with HCV and cirrhosis treated in clinical trials with direct acting antiviral agents (DAAs) who achieved SVR-12 were prospectively enrolled in a long-term registry (clinicaltrials.gov #NCT02292706). PROs were collected every 24 weeks using the Short Form-36v2 (SF-36), CLDQ-HCV, and WPAI-HCV. RESULTS: Pre-treatment baseline data were available for 854 cirrhotic patients who achieved SVR after DAAs. Of these, 730 had compensated (CC) and 124 had decompensated cirrhosis (DCC) before treatment- patients with DCC reported severe impairment in their PROs in comparison to CC patients (by mean -5% to -16% of a PRO range size; p < .05 for 16 out of 20 studied PROs]. After achieving SVR and registry enrollment, significant PRO improvements were noted from pre-treatment levels in 11/20 domains for those with DCC (+4% to +21%) and 19/20 PRO domains in patients with CC (+3% to +17%). Patients with baseline DCC had higher rates of hepatocellular carcinoma and mortality (P < .05). In patients with CC, the PRO gains persisted up to 168 weeks (3.5 years) of registry follow-up. In patients with DCC, the improvements lasted for at least 96 weeks but a declining trend after year 2. CONCLUSIONS: Patients with HCV cirrhosis experience severe PRO impairment at baseline with sustainable improvement after SVR. Though those with DCC experience improvement, there is a decline after 2 years.

Clinical and Patient-Reported Outcomes From Patients With Nonalcoholic Fatty Liver Disease Across the World: Data From the Global Non-Alcoholic Steatohepatitis (NASH)/ Non-Alcoholic Fatty Liver Disease (NAFLD) Registry.

BACKGROUND & AIMS: Globally, nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. We assessed the clinical presentation and patient-reported outcomes (PROs) among NAFLD patients from different countries. METHODS: Clinical, laboratory, and PRO data (Chronic Liver Disease Questionnaire-nonalcoholic steatohepatitis [NASH], Functional Assessment of Chronic Illness Therapy-Fatigue, and the Work Productivity and Activity Index) were collected from NAFLD patients seen in real-world practices and enrolled in the Global NAFLD/NASH Registry encompassing 18 countries in 6 global burden of disease super-regions. RESULTS: Across the global burden of disease super-regions, NAFLD patients (n = 5691) were oldest in Latin America and Eastern Europe and youngest in South Asia. Most men were enrolled at the Southeast and South Asia sites. Latin America and South Asia had the highest employment rates (>60%). Rates of cirrhosis varied (12%-21%), and were highest in North Africa/Middle East and Eastern Europe. Rates of metabolic syndrome components varied: 20% to 25% in South Asia and 60% to 80% in Eastern Europe. Chronic Liver Disease Questionnaire-NASH and Functional Assessment of Chronic Illness Therapy-Fatigue PRO scores were lower in NAFLD patients than general population norms (all P < .001). Across the super-regions, the lowest PRO scores were seen in Eastern Europe and North Africa/Middle East. In multivariate analysis adjusted for enrollment region, independent predictors of lower PRO scores included younger age, women, and nonhepatic comorbidities including fatigue (P < .01). Patients whose fatigue scores improved over time experienced a substantial PRO improvement. Nearly 8% of Global NAFLD/NASH Registry patients had a lean body mass index, with fewer metabolic syndrome components, fewer comorbidities, less cirrhosis, and significantly better PRO scores (P < .01). CONCLUSIONS: NAFLD patients seen in real-world practices in different countries experience a high comorbidity burden and impaired quality of life. Future research using global data will enable more precise management and treatment strategies for these patients.

A Global Survey of Physicians Knowledge About Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Despite rapidly increasing nonalcoholic fatty liver disease (NAFLD) prevalence, providers' knowledge may be limited. We assessed NAFLD knowledge and associated factors among physicians of different specialties globally. METHODS: NAFLD knowledge surveys containing 54 and 59 questions covering 3 domains (epidemiology/pathogenesis, diagnostics, and treatment) were completed electronically by hepatologists, gastroenterologists (GEs), endocrinologists (ENDOs), and primary care physicians (PCPs) from 40 countries comprising 5 Global Burden of Disease super-regions. Over 24 months, 2202 surveys were completed (488 hepatologists, 758 GEs, 148 ENDOs, and 808 PCPs; 50% high-income Global Burden of Disease super-region, 27% from North Africa and Middle East, 12% Southeast Asia, and 5% South Asian and Latin America). RESULTS: Hepatologists saw the greatest number of NAFLD patients annually: median 150 (interquartile range, 60-300) vs 100 (interquartile range, 35-200) for GEs, 100 (interquartile range, 30-200) for ENDOs, and 10 (interquartile range, 4-50) for PCPs (all P < .0001). The primary sources of NAFLD knowledge acquisition for hepatologists were international conferences (33% vs 8%-26%) and practice guidelines for others (39%-44%). The Internet was the second most common source of NAFLD knowledge for PCPs (28%). NAFLD knowledge scores were higher for hepatologists than GEs: epidemiology, 62% vs 53%; diagnostics, 80% vs 73%; and treatment, 61% vs 58% (P < .0001), and ENDOs scores were higher than PCPs: epidemiology, 70% vs 60%; diagnostics, 71% vs 64%; and treatment, 79% vs 68% (P < .0001). Being a hepatologist or ENDO was associated with higher knowledge scores than a GE or PCP, respectively (P < .05). Higher NAFLD knowledge scores were associated independently with a greater number of NAFLD patients seen (P < .05). CONCLUSIONS: Despite the growing burden of NAFLD, a significant knowledge gap remains for the identification, diagnosis, and management of NAFLD.

Severe impairment of patient-reported outcomes in patients with chronic hepatitis C virus infection seen in real-world practices across the world: Data from the global liver registry.

Cure of chronic hepatitis C (CHC) can lead to improvement of health-related quality of life and other patient-reported outcomes (PROs). While extensive PRO data for CHC patients who were enrolled in clinical trials are available, similar data for patients seen in real-world practices are scarce. Our aim was to assess PROs of CHC patients enrolled from real-world practices from different regions and to compare them with those enrolled in clinical trials. CHC patients seen in clinical practices and not receiving treatment were enrolled in the Global Liver Registry (GLR). Clinical and PRO (FACIT-F, CLDQ-HCV, WPAI) data were collected and compared with the baseline data from CHC patients enrolled in clinical trials. N = 12,171 CHC patients were included (GLR n = 3146, clinical trial subjects n = 9025). Patients were from 30 countries from 6 out of 7 Global Burden of Disease (GBD) super-regions. Compared with clinical trial enrollees, patients from GLR were less commonly enrolled from High-Income GBD super-region, older, more commonly female, less employed, had more type 2 diabetes, anxiety and clinically overt fatigue but less cirrhosis (all p < 0.001). Out of 15 PRO domain and summary scores, 12 were lower in GLR patients than in subjects enrolled in clinical trials (p < 0.001). In multiple regression models, anxiety, depression, and fatigue were associated with significant PRO impairment in CHC patients (p < 0.05). After adjustment for the clinico-demographic confounders, the association of PRO scores of CHC patients with enrolment settings was no longer significant (all p > 0.05). In conclusion, hepatitis C patients seen in the real-world practices have PRO impairment driven by fatigue and psychiatric comorbidities.

Nonalcoholic Steatohepatitis Is the Most Rapidly Increasing Indication for Liver Transplantation in the United States.

BACKGROUND & AIMS: The profile of chronic liver disease (CLD) in the United States has changed due to obesity trends and advances in treatment of viral hepatitis. We assessed liver transplant listing trends by CLD etiology. METHODS: Adult candidates for liver transplantation were selected from the Scientific Registry of Transplant Recipients (2002 through 2019). We calculated proportion trends for common CLD etiologies at time of placement on the wait list, including chronic infection with hepatitis B virus, chronic infection with hepatitis C virus (HCV), nonalcoholic steatohepatitis (NASH, including cryptogenic cirrhosis), alcohol-related liver disease (ALD) without or with chronic HCV infection, autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis, in patients with and without hepatocellular carcinoma (HCC). RESULTS: From the 168,441 patients with known etiology and non-acute liver failure on the liver transplant waitlist, 27,799 patients (16.5%) had HCC. In 2002, the most common etiologies in patients without HCC were chronic HCV infection (37%) and ALD (16%), whereas only 5% had NASH. Among patients with HCC, 58% had chronic HCV infection and 10% had ALD and only 1% had NASH. In 2019, among patients without HCC, NASH was the second leading indication for liver transplantation (28% of patients), after ALD (38% of patients). Among patients with HCC, chronic HCV infection remained the leading indication (40% of patients) but NASH (24% of patients) surpassed ALD (16% of patients) to become the second leading indication. NASH was the leading indication in women without HCC (34%), in patients older than 54 years (36%), and in patients on Medicare (41%). In trend analysis, NASH was the most rapidly increasing indication for liver transplantation in patients without HCC (Kendall tau=0.97; P < .001) and in patients with HCC (tau=0.94; P < .0001). CONCLUSIONS: In an analysis of data from the Scientific Registry of Transplant Recipients (2002 through 2019), we found NASH to be the second most common indication for liver transplant in 2019, and the fastest increasing indication. In 2019, NASH was the leading indication for liver transplantation among women without HCC.

Development and validation of a hepatitis B-specific health-related quality-of-life instrument: CLDQ-HBV.

Hepatitis B virus (HBV) carries a large global burden. Efforts abound to decrease the burden, which necessitates reporting of patient-reported outcomes (PROs). We aimed to develop and validate an HBV-specific PRO instrument using the Chronic Liver Disease Questionnaire (CLDQ). Data were obtained from patients enrolled in our HBV registries who completed the CLDQ, Short Form-36 (SF-36) and FACIT-F. The sample was split randomly 1:1 into training and testing groups. A standard PRO instrument validation pipeline was used to develop and validate the new CLDQ-HBV instrument. HBV patients (n = 1,339) were 48 ± 13 years old, 60% male, 8% cirrhosis, with 53% receiving oral antivirals (OAV). After reduction of 10 redundant items, exploratory factor analysis for the remaining 19 items found 95% of variance was explained by five factors-emotional function, fatigue, systemic symptoms, worry and sleep. Good-to-excellent internal consistency was found: Cronbach's alphas 0.70-0.90 and item-to-own-domain correlations >0.50 for 18/19 items. Known-group validity tests discriminated between HBV patients with and without cirrhosis, with FIB-4 ≥ 3.25 vs <3.25, with and without history of depression or clinically overt fatigue (all p < 0.0001), and treatment (all p < 0.05, all but one <0.0001). After 48-week follow-up, HBV patients receiving OAV (N = 144) with ≥2.7 log 10/mL decline in HBV viral load experienced significant improvements in fatigue, worry and total CLDQ-HBV scores (p < 0.05). The newly developed CLDQ-HBV is a short, disease-specific PRO instrument for HBV patients which was developed and validated using large data set and an established methodology showing excellent psychometric characteristics.

Health-related quality of life in Cuban patients with chronic liver disease: A real-world experience.

INTRODUCTION AND OBJECTIVES: Patient-reported outcomes (PROs) are important for comprehensive assessment of chronic liver disease (CLD). Latin America and the Caribbean have a high burden of CLD, but PROs are lacking. We assessed health-related quality of life (HRQL) in Cuban patients with compensated CLD. MATERIALS AND METHODS: A cross sectional study performed of adult patients with a diagnosis of chronic viral infection B and C (HBV, HCV), non-alcoholic fatty liver diseases (NAFLD) and autoimmune liver diseases (AILD) including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and overlap syndrome (AIH+PBC). PROs were collected using: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Work Productivity and Activity-Specific Health Problem (WPAI: SHP), and the Chronic Liver Disease Questionnaire (CLDQ)-disease-specific. RESULTS: 543 patients enrolled, n=91 (HBV), n=188 (HCV), n=221 (NAFLD), n=43 (AILD). Of those with AILD, 22 had AIH, 14 PBC, and 7 overlap AIH/PBC. Mean age was 53.5 years, 64.1% female, 69.2% white, and 58.0% employed. Patients with HCV and AILD had more severe liver disease. A significant impairment in PROs was observed in HCV group whereas the AILD patients had more activity impairment. CLDQ-HRQL scores were significantly lower for patients with NAFLD and AILD compared to HBV. Male gender and exercising ≥90min/week predicted better HRQL. The strongest independent predictors of HRQL impairment were fatigue, abdominal pain, anxiety, and depression (p<0.05). CONCLUSIONS: HRQL for Cuban patients with compensated CLD differs according to the CLD etiology. Patients with HCV and AILD had the worst PRO scores most likely related to severe underlying liver disease and/or extrahepatic manifestations.

Not Achieving Sustained Viral Eradication of Hepatitis C Virus After Treatment Leads to Worsening Patient-reported Outcomes.

BACKGROUND: The causative relationship between the clearance of infections and long-term, health-related quality-of-life (HRQL) improvements in patients with hepatitis C virus (HCV) has been generally accepted. The aim of this study was to assess long-term HRQL trends in HCV patients who did not achieve sustained virologic responses (SVRs) after treatment with direct-acting antivirals. METHODS: HCV patients who completed treatment in clinical trials and did not achieve SVRs were enrolled in a long-term registry (#NCT01457768). HRQL scores were prospectively collected using the short form-36 instrument (8 HRQL domains and 2 summary scores). RESULTS: There were 242 patients included: they had a median age of 54 years (standard deviation ± 8 years), 85% were male, and 38% had cirrhosis. Before treatment, patients' HRQL scores were similar to the general population norms (all 1-sided P > 0.05), but were followed by significant decreases by the end of treatment (-3.4 to -6.2 points; P < .05 for 5/8 HRQL domains and mental summary). By the time subjects entered the registry, all but 1 of the mean HRQL scores had returned to their pretreatment levels (P > .05). During subsequent periods in the registry, patients experienced further HRQL decrements: up to -9.2 points (P < .05 for all HRQL domains) at Week 24 and up to -8.3 points (P < .05 for 5/8 HRQL domains) at Week 48. Although these HRQL decrements were observed regardless of cirrhosis status, they were more pronounced in patients with cirrhosis (P < .05 for 3/8 HRQL domains). CONCLUSIONS: Patients who did not achieve an SVR after treatment experienced worsening HRQL scores in long-term follow-ups. Retreatment of these patients will be important not only to improve their clinical outcomes, but also their quality of life.

Long-term Benefits of Sustained Virologic Response for Patient-Reported Outcomes in Patients With Chronic Hepatitis C Virus Infection.

BACKGROUND & AIMS: Patients with hepatitis C virus (HCV) infections who achieve a sustained virologic response (SVR) to treatment have improved patient-reported outcomes (PROs). We compared post-treatment PRO scores between patients with chronic HCV infection who did and did not achieve an SVR to treatment. METHODS: Patients who completed treatment in clinical trials were enrolled in 2 registries, depending on the treatment outcome (NCT01457755, NCT01457768), from 2016 to 2017 in 17 countries in North America, Europe, and the Asia-Pacific region. PRO scores (scale, 0-100) were collected at pretreatment (baseline); the last day of treatment; the post-treatment week 12 follow-up visit (in patients with SVR only); the registry baseline; and on registry weeks 12, 24, 36, 48, and 96 (the non-SVR registry) or every 24 weeks until week 96 (SVR registry), using the Short Form-36 (SF-36) instrument. RESULTS: Our analysis included 4234 patients with an SVR and 242 without an SVR from whom pretreatment PRO data were available (mean age, 54 ± 10 y; 63% male; 65% enrolled in the United States; 17% with cirrhosis; 12% with human immunodeficiency virus co-infection). Upon registry enrollment, patients with an SVR had significant increases in all PRO scores compared with pretreatment baseline levels (all P < .05). Patients without an SVR had mean reductions of 9.2 points or less in PRO scores while followed up on the registry (P < .05 for 4-8 of 8 PRO domains measured by the SF-36). In contrast, patients with an SVR had sustained increases in PRO scores (mean increase, ≤7.0 points) while on the registry. In multivariate analysis, achieving an SVR was associated independently with superior scores in all SF-36 domains at all registry time points (ß, +4.8 to +15.9 points, all P ≤ .01). CONCLUSIONS: In a follow-up analysis of participants in clinical trials, we found that those with an SVR to treatment for HCV infection had significant increases in well-being, based on PRO scores. Patients without an SVR had decreasing PRO scores over the follow-up period.

Primary Biliary Cholangitis in Medicare Population: The Impact on Mortality and Resource Use.

Primary biliary cholangitis (PBC) is a disease of small bile ducts, which can lead to morbidity and mortality. Our aim was to assess recent trends in mortality and healthcare use of PBC patients in the Medicare program. Data from Medicare beneficiaries between 2005 and 2015 (5% random samples) were used. The diagnosis of PBC was established with International Classification of Diseases-9 code 571.6 used for both primary and secondary diagnoses. Mortality was assessed by Medicare-linked death registry. Healthcare use included episodes of care, length of stay, and total charges/payments. Independent predictors of outcomes were evaluated in multiple generalized linear or logistic regression models. The study cohort included a total of 6,375 inpatient/outpatient Medicare beneficiaries (mean age 69.8 years, 17% male, 88% white, and 18% with disability). Over the study period, 1-year mortality remained stable (9.1% to 14.3%, P = 0.11). Independent predictors of 1-year mortality were older age, male gender, black race, the presence of ascites, encephalopathy, hepatocellular carcinoma, and higher Charlson score. Outpatient total yearly charges and payments per beneficiary with PBC increased from $3,065 and $777 (2005) to $5,773 and $967 (2014), respectively. Similarly, inpatient total yearly charges and payments per beneficiary with PBC increased from $59,765 and $19,406 (2007), to $98,941 and $27,948 (2013), respectively (P < 0.05). The presence of ascites, portal hypertension, and higher Charlson score were independent predictors of higher payments for both inpatient and outpatient resource use, and the presence of hepatic encephalopathy was an additional predictor of higher inpatient resource use (all P < 0.02). Conclusion: The prevalence of PBC among the Medicare beneficiaries has increased. Despite stable mortality rates, resource use for Medicare patients with PBC continues to rise.

Burden of Illness and Economic Model for Patients With Nonalcoholic Steatohepatitis in the United States.

Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease. Our aim was to estimate the total economic burden of NASH and advanced NASH in the United States. We constructed lifetime Markov models for all stages of NASH and a separate model to specifically identify the increased burden of advanced NASH (fibrosis stage >3). The models comprised patients aged 18+, who moved through seven different health states. We used a lifetime horizon with 1-year cycles for each transition. Cohort size was estimated using US population data, and prevalence and incidence rates were obtained from the literature. Transition probabilities between states were derived from meta-analyses. Costs included inpatient, outpatient, professional services, emergency department, and drug costs, which were obtained from the Center for Medicare and Medicaid Services Fee Schedule 2017 and published data. All future costs were discounted at an annual rate of 3%. Our models estimated that there are 6.65 million adults (18+ years old) with NASH in the United States and that there were 232,000 incident cases in 2017. Lifetime costs of all NASH patients in the United States in 2017 will be $222.6 billion, and the cost of the advanced NASH population will be $95.4 billion. Conclusion: NASH, especially advanced NASH, is associated with high lifetime economic burden; in the absence of treatment, the total direct costs of illness for these patients will continue to grow, and these costs would be even greater if the societal costs are included.

Hypothetical treatment of patients with non-alcoholic steatohepatitis: Potential impact on important clinical outcomes.

BACKGROUND & AIMS: Currently, standard of care (SOC) treatment for NASH is limited to lifestyle modifications. Drug regimens are being evaluated currently. We assessed the impact of a short-term hypothetical treatment on clinical outcomes of NASH. METHODS: Markov models estimated differences in outcomes between SOC and 2 hypothetical NASH treatments (A and B). We modelled 10 000 50-year-old biopsy-proven NASH patients over lifetime horizon. Health states included NASH with fibrosis (F1-F3), cirrhosis, hepatocellular carcinoma, liver transplant and mortality. Fibrosis Regression Factor (FRF) variable modelled the probability of 1-3 stage fibrosis improvement with treatment. Annual probability of treatment (ATP) ranged from 10%-70%. Treatment success was defined as regression to fibrosis, whereas failure was defined as progression to stages beyond cirrhosis. In treatment-A, successful treatment was followed by a maintenance regimen which stopped disease progression. After a successful treatment-B, patients remained at risk of disease progression. Differences in outcomes were calculated between both treatments and SOC models. We conducted a probabilistic sensitivity analysis. RESULTS: At 10% to 70% ATP, treatment-A averts 353 to 782 liver transplants and 1277 to 2381 liver-related deaths relative to SOC. Treatment-B averts 129 to 437 liver transplants and 386 to 1043 liver-related deaths. Sensitivity analysis shows our model is robust in estimating liver-related mortality and LTs averted, but is sensitive when estimating QALYs gained. CONCLUSIONS: With a small annual probability of treatment and FRF = 1, a 2-year treatment followed by maintenance of histologic improvement for patients would be highly beneficial relative to short-term treatment alone.

Outcomes of Liver Transplant Candidates with Primary Biliary Cholangitis: The Data from the Scientific Registry of Transplant Recipients.

BACKGROUND: Primary biliary cholangitis (PBC) is progressive and can cause end-stage liver disease necessitating a liver transplant (LT). PBC patients may be disadvantaged on LT waitlist due to MELD-based priority listing or other factors. AIM: The aim was to assess waitlist duration, waitlist mortality, and post-LT outcomes of PBC patients. METHODS: The Scientific Registry of Transplant Recipients data for 1994-2016 was utilized. Adult patients with PBC without hepatocellular carcinoma (HCC) were selected. Their clinico-demographic parameters and waitlist and post-transplant outcomes were compared to those of patients with hepatitis C (HCV) without HCC. RESULTS: Out of 223,391 listings for LT in 1994-2016, 8133 (3.6%) was for PBC without HCC. Mean age was 55.5 years, 76.9% white, 86.2% female, mean MELD score 21, 6.6% retransplants. There were 52,017 patients with hepatitis C included for comparison. The mean waitlist mortality was 17.9% for PBC and 17.6% for HCV (p > 0.05). The average transplantation rate was 57.7% for PBC and 53.3% for HCV (p < 0.0001), while waitlist dropout (death or removal due to deterioration) rate was 25.0% for PBC and 25.4% for HCV (p > 0.05). There was no significant difference in median waiting duration till transplantation between PBC patients and HCV after 2002 (103 vs. 95 days, p > 0.05). Post-LT mortality and graft loss rates were significantly lower in PBC than in HCV patients (all p < 0.02). CONCLUSIONS: Despite no evidence of impaired waitlist outcomes and favorable post-transplant survival in patients with PBC, there is still a high waitlist dropout rate suggesting the presence of an unmet need for effective treatment.

Validation of Chronic Liver Disease Questionnaire for Nonalcoholic Steatohepatitis in Patients With Biopsy-Proven Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: The chronic liver disease questionnaire for nonalcoholic steatohepatitis (CLDQ-NASH) was developed in a systematic manner for assessment of patient-reported outcomes. This instrument collects data on 36 items grouped into 6 domains: abdominal symptoms, activity/energy, emotional health, fatigue, systemic symptoms, and worry. We aimed to validate the CLDQ-NASH in a large group of patients with NASH. METHODS: We collected data from patients with biopsy-proven NASH enrolled in 2 international phase 3 trials of selonsertib (NCT03053050 and NCT03053063). Our final analysis comprised 1667 patients who completed the CLDQ-NASH (age, 58 ± 9 y; 40% male; 52% with cirrhosis; and 69% with type 2 diabetes). The CLDQ-NASH was administered before treatment initiation. A standard patient-reported outcome instrument validation pipeline with internal consistency and validity assessment was applied. RESULTS: The domains of CLDQ-NASH showed good to excellent internal consistency: the Cronbach's α values were 0.80 to 0.94 and item-to-own-domain correlations were greater than 0.50 for 33 of 36 items. All items correlated to the greatest extent with their own domains (discriminant validity). Known-group validity tests indicated that the instrument consistently discriminated between patients with NASH based on the presence of cirrhosis (vs bridging fibrosis; all but 1 P value < .02), obesity (all but 1 P value < .001), psychiatric comorbidities (all P values < .0001), fatigue (all P values < .001), and type 2 diabetes (all but 1 P value < .01). Of the CLDQ-NASH domains, the highest correlated domains with the Short Form-36 were as follows: physical functioning for activity (rho = 0.70), mental health for emotional (rho = 0.72), vitality for fatigue (rho = 0.75), and body pain for systemic (rho = 0.72) (all P values < .0001). In contrast, the domains of abdominal and worry, which are disease-specific, did not correlate with the domains in the Short Form-36 (all rho ≤ 0.50). CONCLUSIONS: We validated the CLDQ-NASH by an analysis of data from 1667 patients with biopsy-proven NASH enrolled in phase 3 trials, observing excellent psychometric characteristics of the instrument.

Patients With Nonalcoholic Steatohepatitis Experience Severe Impairment of Health-Related Quality of Life.

INTRODUCTION: 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: 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.

Development and validation of a primary sclerosing cholangitis-specific patient-reported outcomes instrument: The PSC PRO.

Primary sclerosing cholangitis (PSC) is a chronic liver disease associated with inflammation and biliary fibrosis that leads to cholangitis, cirrhosis, and impaired quality of life. Our objective was to develop and validate a PSC-specific patient-reported outcome (PRO) instrument. We developed a 42-item PSC PRO instrument that contains two modules (Symptoms and Impact of Symptoms) and conducted an external validation. Reliability and validity were evaluated using clinical data and a battery of other validated instruments. Test-retest reliability was assessed in a subgroup of patients who repeated the PSC PRO after the first administration. One hundred two PSC subjects (44 ± 13 years; 32% male, 74% employed, 39% with cirrhosis, 14% with a history of decompensated cirrhosis, 38% history of depression, and 68% with inflammatory bowel disease [IBD]) completed PSC PRO and other PRO instruments (Short Form 36 V2 [SF-36], Chronic Liver Disease Questionnaire [CLDQ], Primary Biliary Cholangitis - 40 [PBC-40], and five dimensions [5-D Itch]). PSC PRO demonstrated excellent internal consistency (Cronbach alphas, 0.84-0.94) and discriminant validity (41 of 42 items had the highest correlations with their own domains). There were good correlations between PSC PRO domains and relevant domains of SF-36, CLDQ, and PBC-40 (R = 0.69-0.90; all P < 0.0001), but lower (R = 0.31-0.60; P < 0.001) with 5-D Itch. Construct validity showed that PSC PRO can differentiate patients according to the presence and severity of cirrhosis and history of depression (P < 0.05), but not by IBD (P > 0.05). Test-retest reliability was assessed in 53 subjects who repeated PSC PRO within a median (interquartile range) of 37 (27-47) days. There was excellent reliability for most domains with intraclass correlations (0.71-0.88; all P < 0.001). CONCLUSION: PSC PRO is a self-administered disease-specific instrument developed according to U.S. Food and Drug Administration guidelines. This preliminary validation study suggests good psychometric properties. Further validation of the instrument in a larger and more diverse sample of PSC patients is needed. (Hepatology 2018;68:155-165).