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Global survey of stigma among physicians and patients with nonalcoholic fatty liver disease

Patients with fatty liver disease may experience stigma from the disease or comorbidities. In this cross-sectional study, we aimed to understand stigma among patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and healthcare providers. Members of the Global NASH Council created two surveys about experiences/attitudes toward NAFLD and related diagnostic terms: a 68-item patient and a 41-item provider survey. Surveys were completed by 1,976 patients with NAFLD across 23 countries (51% Middle East/North Africa [MENA], 19% Europe, 17% USA, 8% Southeast Asia, 5% South Asia) and 825 healthcare providers (67% gastroenterologists/hepatologists) across 25 countries (39% MENA, 28% Southeast Asia, 22% USA, 6% South Asia, 3% Europe). Of all patients, 48% ever disclosed having NAFLD/NASH to family/friends; the most commonly used term was "fatty liver" (88% at least sometimes); "metabolic disease" or "MAFLD" were rarely used (never by >84%). Regarding various perceptions of diagnostic terms by patients, there were no substantial differences between "NAFLD", "fatty liver disease (FLD)", "NASH", or "MAFLD". The most popular response was being neither comfortable nor uncomfortable with either term (56%-71%), with slightly greater discomfort with "FLD" among the US and South Asian patients (47-52% uncomfortable). Although 26% of patients reported stigma related to overweight/obesity, only 8% reported a history of stigmatization or discrimination due to NAFLD. Among providers, 38% believed that the term "fatty" was stigmatizing, while 34% believed that "nonalcoholic" was stigmatizing, more commonly in MENA (43%); 42% providers (gastroenterologists/hepatologists 45% vs. 37% other specialties, p= 0.03) believed that the name change to metabolic dysfunction-associated steatotic liver disease (or MASLD) might reduce stigma. Regarding the new nomenclature, the percentage of providers reporting "steatotic liver disease" as stigmatizing was low (14%). The perception of NAFLD stigma varies among patients, providers, geographic locations and sub-specialties. Over the past decades, efforts have been made to change the nomenclature of nonalcoholic fatty liver disease (NAFLD) to better align with its underlying pathogenetic pathways and remove any potential stigma associated with the name. Given the paucity of data related to stigma in NAFLD, we undertook this global comprehensive survey to assess stigma in NAFLD among patients and providers from around the world. We found there is a disconnect between physicians and patients related to stigma and related nomenclature. With this knowledge, educational programs can be developed to better target stigma in NAFLD among all stakeholders and to provide a better opportunity for the new nomenclature to address the issues of stigma.

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Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. MAESTRO-NAFLD-1 was a 52-week randomized, double-blind, placebo-controlled phase 3 trial evaluating the safety of resmetirom in adults with nonalcoholic fatty liver disease and presumed NASH. Patients were randomized to three double-blind arms (100 mg resmetirom (n = 325), 80 mg resmetirom (n = 327) or placebo (n = 320)) or open-label 100 mg resmetirom (n = 171). The primary end point was incidence of treatment-emergent adverse events (TEAEs) over 52 weeks and key secondary end points were LDL-C, apoB, triglycerides (over 24 weeks), hepatic fat (over 16 and 52 weeks) and liver stiffness (over 52 weeks). Resmetirom was safe and well tolerated. TEAEs occurred in 86.5% (open-label 100 mg resmetirom), 86.1% (100 mg resmetirom), 88.4% (80 mg resmetirom) and 81.8% (placebo) of patients. TEAEs in excess of placebo included diarrhea and nausea at the initiation of treatment. Key secondary end points included least square means difference from placebo at 80 mg, 100 mg resmetirom: LDL-C (−11.1%, −12.6%), apoB (−15.6%, −18.0%), triglycerides (−15.4%, −20.4%), 16-week hepatic fat (−34.9%, −38.6%), (P < 0.0001) and liver stiffness (−1.02, −1.70) and 52-week hepatic fat (−28.8, −33.9). These findings demonstrate resmetirom was safe and well tolerated in adults with presumed NASH, supporting a role for further clinical development. (ClinicalTrials.gov identifier NCT04197479).

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Liver Transplant Outcomes in Young Adults with Cirrhosis Related to Nonalcoholic Fatty Liver Disease

The prevalence of nonalcoholic fatty liver disease (NASH) and cryptogenic cirrhosis (CC) is constantly increasing in adolescents and young adults (AYAs). In a retrospective UNOS database evaluation, we analyzed postoperative outcomes of AYAs with nonalcoholic NASH/CC undergoing LT between January 1st, 2003 and March 5th, 2021. After exclusions, 85,970 LT recipients, 393 (47.1%) AYAs with NASH/CC and 441 (52.9%) AYAs with other metabolic conditions, were analyzed. During the study period, the number of LTs performed for AYAs with NASH/CC increased from 4%-7% but decreased from 6.6%-5.3% compared to LTs performed for NASH/CC in all ages. In comparison to AYAs with other metabolic conditions, AYA LT recipients with NASH/CC had a higher prevalence of metabolic syndrome (MetS) components, including diabetes and increased body mass index (P < .0001 for both). Patient and graft survival in AYAs with NASH/CC were significantly lower in comparison to AYAs transplanted for other metabolic conditions (P < .0001) (Hazard Ratio=1.93, P < .001). Patient survival in AYAs with NASH/CC was significantly better in comparison to older (40-65-year-old) patients with the same diagnosis (P=.01). Our study found that the overall number of LTs in AYAs with NASH increased significantly, but to a lesser degree compared to the older population with the same diagnosis. Outcomes after LT in AYAs with NASH/CC were worse compared to LT for other metabolic conditions, but significantly better in comparison to older patients. The prevalence of LT for NASH/CC in AYAs is growing. MetS may contribute to worse outcomes in AYAs.

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A randomized, double-blind, placebo-controlled trial of aldafermin in patients with NASH and compensated cirrhosis.

Aldafermin, an engineered analog of the human hormone FGF19, improves liver histology in patients with noncirrhotic NASH; however, its efficacy and safety in compensated cirrhosis is unknown. No drug has yet to demonstrate benefit in the compensated NASH population. In this multicenter, double-blind, placebo-controlled, phase 2b trial, 160 patients with compensated NASH cirrhosis were randomized to aldafermin 0.3mg (n = 7), 1mg (n = 42), 3mg (n = 55), or placebo (n = 56) for 48 weeks. The 0.3mg group was discontinued to limit exposure to suboptimal doses. The primary end point was a change in Enhanced Liver Fibrosis from baseline to week 48. The analyses were performed in the intention-to-treat population. At week 48, the least-squares mean difference in the change in Enhanced Liver Fibrosis was -0.5 (95% CI, -0.7 to -0.2; p = 0.0003) between the 3mg group and the placebo group. 15%, 21%, and 23% of patients in the placebo, 1mg, and 3mg group, respectively, achieved fibrosis improvement ≥ 1 stage; and 13%, 16%, and 20% achieved fibrosis improvement ≥ 1 stage without NASH worsening. Improvement in alanine aminotransferase, aspartate aminotransferase, neoepitope-specific N-terminal pro-peptide of type III collagen, and liver stiffness favored aldefermin groups over placebo. Diarrhea was the most frequent adverse event, occurring at 26% and 40% in the 1mg and 3mg groups, respectively, compared to 18% in the placebo group. Overall, 0%, 2%, and 9% of patients in the placebo, 1mg, and 3mg group, respectively, discontinued due to treatment-related adverse events. Aldafermin 3mg resulted in a significant reduction in Enhanced Liver Fibrosis in patients with compensated NASH cirrhosis.

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The Prevalence of Nonalcoholic Steatohepatitis (NASH)-Related Advanced Fibrosis and Cirrhosis in the United States Population Utilizing AGILE 3+ and AGILE 4+ Scores: Analysis of the NHANES 2017-2018 Cycle

Abstract Background Studies attempted to estimate NASH-related advanced fibrosis (AF) and cirrhosis (NC) prevalence utilized tests with low positive predictive value (PPV) which overestimates prevalence. AGILE3+ and 4+ scores were developed to increase the PPV of both; respectively. In this study, w used these scores to assess the prevalence of AF and NC. Methods Participants aged ≥18 years with VCTE exam in the NHANES 2017-2018 cycle were included. We excluded pregnant women, patients with excessive alcohol intake, hepatitis B/C, and ALT or AST &gt;500 IU/L. NAFLD was defined with CAP score &gt;248 dB/m. NAFLD subjects with AGILE 3+ score of ≥0.68 and AGILE4+ score of ≥0.57 were considered to have advanced fibrosis and cirrhosis; respectively. AGILE3+ of 0.45-0.67 and AGILE4+ of 0.25-0.57 were grey zone, whereas AGILE 3+ &lt;0.45 and AGILE4+ &lt;0.25 were considered a rule-out. Results 1244 subjects were included in the final analysis. The Median age was 53 (51.4-54.6) years, 55.6% were male, median BMI was 33.8 kg/m2 and 41.1% had T2DM. Based on AGILE3+, 80.3% of the NAFLD population were at low risk for AF and 11.5% were in grey zone. The prevalence of AF due to NAFLD was 8.1% corresponding to 4.5M Americans. Based on AGILE4+ score, 96.5% of the NAFLD population were at low risk for cirrhosis and 2.4% were in the grey zone. The prevalence of NASH-cirrhosis was 1.1% corresponding to 610,000 Americans. Conclusion Our results suggest that approximately 4.5 million people in the U.S. have AF and 0.6 million have cirrhosis due to NASH.

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A global action agenda for turning the tide on fatty liver disease.

Fatty liver disease is a major public health threat due to its very high prevalence and related morbidity and mortality. Focused and dedicated interventions are urgently needed to target disease prevention, treatment, and care. We developed an aligned, prioritized action agenda for the global fatty liver disease community of practice. Following a Delphi methodology over 2 rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the action priorities using Qualtrics XM, indicating agreement using a 4-point Likert-scale and providing written feedback. Priorities were revised between rounds, and in R2, panelists also ranked the priorities within 6 domains: epidemiology, treatment and care, models of care, education and awareness, patient and community perspectives, and leadership and public health policy. The consensus fatty liver disease action agenda encompasses 29 priorities. In R2, the mean percentage of "agree" responses was 82.4%, with all individual priorities having at least a super-majority of agreement (> 66.7% "agree"). The highest-ranked action priorities included collaboration between liver specialists and primary care doctors on early diagnosis, action to address the needs of people living with multiple morbidities, and the incorporation of fatty liver disease into relevant non-communicable disease strategies and guidance. This consensus-driven multidisciplinary fatty liver disease action agenda developed by care providers, clinical researchers, and public health and policy experts provides a path to reduce the prevalence of fatty liver disease and improve health outcomes. To implement this agenda, concerted efforts will be needed at the global, regional, and national levels.

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Intramuscular vs Intravenous SARS-CoV-2 Neutralizing Antibody Sotrovimab for Treatment of COVID-19 (COMET-TAIL): A Randomized Noninferiority Clinical Trial.

Convenient administration of coronavirus disease 2019 (COVID-19) treatment in community settings is desirable. Sotrovimab is a pan-sarbecovirus dual-action monoclonal antibody formulated for intravenous (IV) or intramuscular (IM) administration for early treatment of mild/moderate COVID-19. This multicenter phase 3 study based on a randomized open-label design tested the noninferiority of IM to IV administration according to an absolute noninferiority margin of 3.5%. From June to August 2021, patients aged ≥12 years with COVID-19, who were neither hospitalized nor receiving supplemental oxygen but were at high risk for progression, were randomized 1:1:1 to receive sotrovimab as a single 500-mg IV infusion or a 500- or 250-mg IM injection. The primary composite endpoint was progression to (1) all-cause hospitalization for >24 hours for acute management of illness or (2) all-cause death through day 29. Sotrovimab 500 mg IM was noninferior to 500 mg IV: 10 (2.7%) of 376 participants vs 5 (1.3%) of 378 met the primary endpoint, respectively (absolute adjusted risk difference, 1.06%; 95% CI, -1.15% to 3.26%). The 95% CI upper limit was lower than the prespecified noninferiority margin of 3.5%. The 250-mg IM group was discontinued early because of the greater proportion of hospitalizations vs the 500-mg groups. Serious adverse events occurred in <1% to 2% of participants across groups. Four participants experienced serious disease-related events and died (500 mg IM, 2/393, <1%; 250 mg IM, 2/195, 1%). Sotrovimab 500-mg IM injection was well tolerated and noninferior to IV administration. IM administration could expand outpatient treatment access for COVID-19. ClinicalTrials.gov: NCT04913675.

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