Risk factors for fibrosis progression in non-alcoholic steatohepatitis: Analysis of the European cohort in the real-world GAIN study.

OBJECTIVE: To better understand drivers of disease progression in non-alcoholic steatohepatitis (NASH), we assessed clinical and sociodemographic markers of fibrosis progression in adults with NASH. PATIENTS AND METHODS: Physician-reported patient demographics and clinical characteristics were utilised from the real-world Global Assessment of the Impact of NASH (GAIN) study. Factors associated with likelihood of fibrosis progression since NASH diagnosis were identified using a logistic regression model. RESULTS: Overall, 2349 patients in Europe from the GAIN study were included; mean age was 54.6 years and 41% were women. Significant covariates included age, years since diagnosis, employment status, fibrosis stage at diagnosis, type 2 diabetes mellitus, hypertension, liver transplant and liver biopsy at diagnosis. Risk of progression was 1.16 (95% confidence interval 1.12-1.20; p<0.001) times higher for each additional year since NASH diagnosis and 5.43 (2.68-11.37; p<0.001) times higher when physicians proposed a liver transplant at diagnosis. Compared with full-time employed patients, risk of progression was 1.77 (1.19-2.60; p=0.004) times higher for unemployed patients and 3.16 (1.30-7.63; p=0.010) times higher for those unable to work due to NASH. CONCLUSIONS: Disease duration, NASH severity and presence of other metabolic comorbidities could help to assess risk of progression in patients with NASH.

De Novo Cost-Effectiveness Model Framework for Nonalcoholic Steatohepatitis-Modeling Approach and Validation.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with hepatic morbidity and mortality and extra-hepatic comorbidities. Published NASH cost-effectiveness models (CEMs) are heterogeneous and consistently omit comorbid conditions that frequently co-exist alongside NASH. We aimed to develop a de novo CEM framework that incorporates extra-hepatic disease states and outcomes alongside hepatic components to enable future estimation of the cost-effectiveness of NASH interventions. METHODS: Patient-level simulation and cohort-level Markov models were implemented in the same framework. Model inputs included fibrosis progression; late-stage liver disease outcomes; comorbidity outcomes for cardiovascular disease, type 2 diabetes, and obesity; mortality; health-related quality of life; and direct medical costs. The prototype analysis assessed the cost-effectiveness of obeticholic acid versus standard of care from a US payer perspective over a lifetime horizon with costs and effects discounted at 3% per annum. However, the CEM was designed for easy adaptation to other countries, time horizons, and other considerations. Efficacy and adverse event parameters were obtained from the 18-month interim analysis of the REGENERATE trial. Outputs include total and incremental costs, total life years, and quality-adjusted life years. RESULTS: In this model, total costs, total life years, and quality-adjusted life years were all higher with obeticholic acid compared with standard of care. Cross-validation of this model with the 2016 and 2020 Institute for Clinical and Economic Review models revealed marked differences, mainly driven by mortality inputs, transition probability estimates, and incorporation of the effect of treatment and comorbidities. CONCLUSION: This is the first CEM in NASH to incorporate the clinical consequences of several comorbidities. The flexible yet standardized framework permits estimation of the cost-effectiveness of NASH interventions in a variety of settings. The model currently includes several assumptions and will be further developed as more relevant data become available.

The burden of non-alcoholic steatohepatitis: A systematic review of health-related quality of life and patient-reported outcomes.

Background & Aims: Non-alcoholic steatohepatitis (NASH) is associated with increased mortality and a high clinical burden. NASH adversely impacts patients' health-related quality of life (HRQoL), but published data on the humanistic burden of disease are limited. This review aimed to summarise and critically evaluate studies reporting HRQoL or patient-reported outcomes (PROs) in populations with NASH and identify key gaps for further research. Methods: Medline, EMBASE, the Cochrane Library and PsycINFO were searched for English-language publications published from 2010 to 2021 that reported HRQoL/PRO outcomes of a population or subpopulation with NASH. Results: Twenty-five publications covering 23 unique studies were identified. Overall, the data showed a substantial impact of NASH on HRQoL, particularly in terms of physical functioning and fatigue, with deterioration of physical and mental health as NASH progresses. Prevalent symptoms, including fatigue, abdominal pain, anxiety/depression, cognition problems, and poor sleep quality, adversely impact patients' ability to work and perform activities of daily living and the quality of relationships. However, some patients fail to attribute symptoms to their disease because of a lack of patient awareness and education. NASH is associated with high rates of comorbidities such as obesity and type 2 diabetes, which contribute to reduced HRQoL. Studies were heterogeneous in terms of diagnostic methods, population, outcomes, follow-up time, and measures of HRQoL/utility. Most studies were rated 'moderate' at quality assessment, and all evaluable studies had inadequate control of confounders. Conclusions: NASH is associated with a significant HRQoL burden that begins early in the disease course and increases with disease progression. More robust studies are needed to better understand the humanistic burden of NASH, with adequate adjustment for confounders that could influence outcomes. Lay summary: Non-alcoholic steatohepatitis (NASH) has a significant impact on quality of life, with individuals experiencing worse physical and mental health compared with the general population. NASH and its symptoms, which include tiredness, stomach pain, anxiety, depression, poor focus and memory, and impaired sleep, affect individuals' relationships and ability to work and perform day-to-day tasks. However, not all patients are aware that their symptoms may be related to NASH. Patients would benefit from more education on their disease, and the importance of good social networks for patient health and well-being should be reinforced. More studies are needed to better understand the patient burden of NASH.

The Economic Burden of Non-Alcoholic Steatohepatitis: A Systematic Review.

BACKGROUND: The global prevalence of non-alcoholic steatohepatitis (NASH) is increasing, such that NASH is predicted to become the leading cause of liver transplantation (LT) in the US by 2025. Despite this, data on the economic burden of NASH are limited. OBJECTIVES: This systematic literature review aimed to summarise and critically evaluate studies reporting on the economic burden of NASH and identify evidence gaps for subsequent research. METHODS: Medline, EMBASE, the Cochrane Library and EconLit were searched up to 6 January 2021 for English language articles published from January 2010 to January 2021 inclusive that reported economic outcomes of a NASH population or subpopulation. Evidence was presented and synthesised using narrative data analysis, and quality was assessed by two reviewers using an 11-item checklist developed for economic evaluations and adapted to cost of illness. RESULTS: Fourteen studies were included, of which five presented data on costs and resource use, four on costs only and five on resource use only. Overall, NASH is associated with a significant and increasing economic burden in terms of healthcare resource utilisation (HCRU) and direct and indirect costs. This burden was higher among NASH patients with advanced (fibrosis stage 3-4) versus early (fibrosis stage 0-2) disease, symptomatic versus asymptomatic disease and for patients with complications or comorbidities versus those without. In LT patients, those with NASH as the primary indication had greater HCRU and higher costs compared with non-NASH indications such as hepatitis B and C viruses. Considerable variability in HCRU and costs was seen across the US and Europe, with the highest costs seen in the US. The quality of the included studies was variable, and the studies themselves were heterogeneous in terms of study methodology, patient populations, comorbidities, follow-up time and outcomes measured. CONCLUSIONS: This review highlights a general scarcity of NASH-specific economic outcomes data. Despite this, the identified studies show that NASH is associated with a significant economic burden in terms of increased HCRU, and high direct medical and non-medical costs and societal burden that increases with disease severity or when patients have complications or comorbidity. More national-level NASH prevalence data are needed to generate accurate forecasts of HCRU and costs in the coming decades. FUNDING: Novo Nordisk A/S, Søborg, Denmark.

It is important to know the cost of treating different diseases because this helps to guide how healthcare resources and funds are used. Non-alcoholic steatohepatitis (NASH) is a serious liver disease that can lead to liver scarring (cirrhosis), liver transplantation and early death, and the number of people with NASH is growing around the world. Fourteen studies published over the past 10 years have investigated the costs of treating patients with NASH. Patients with NASH generally use more healthcare services with a higher cost than the general population or patients with type 2 diabetes. In people with more serious liver disease, such as liver transplant patients, NASH tends to be more expensive and use more healthcare services than other serious liver diseases such as hepatitis. Costs and use of health services are particularly high in patients with more severe NASH, or those who have other diseases or complications in addition to NASH (such as type 2 diabetes or kidney failure).

MAMMALS IN PORTUGAL: A data set of terrestrial, volant, and marine mammal occurrences in Portugal.

Mammals are threatened worldwide, with ~26% of all species being included in the IUCN threatened categories. This overall pattern is primarily associated with habitat loss or degradation, and human persecution for terrestrial mammals, and pollution, open net fishing, climate change, and prey depletion for marine mammals. Mammals play a key role in maintaining ecosystems functionality and resilience, and therefore information on their distribution is crucial to delineate and support conservation actions. MAMMALS IN PORTUGAL is a publicly available data set compiling unpublished georeferenced occurrence records of 92 terrestrial, volant, and marine mammals in mainland Portugal and archipelagos of the Azores and Madeira that includes 105,026 data entries between 1873 and 2021 (72% of the data occurring in 2000 and 2021). The methods used to collect the data were: live observations/captures (43%), sign surveys (35%), camera trapping (16%), bioacoustics surveys (4%) and radiotracking, and inquiries that represent less than 1% of the records. The data set includes 13 types of records: (1) burrows | soil mounds | tunnel, (2) capture, (3) colony, (4) dead animal | hair | skulls | jaws, (5) genetic confirmation, (6) inquiries, (7) observation of live animal (8), observation in shelters, (9) photo trapping | video, (10) predators diet | pellets | pine cones/nuts, (11) scat | track | ditch, (12) telemetry and (13) vocalization | echolocation. The spatial uncertainty of most records ranges between 0 and 100 m (76%). Rodentia (n =31,573) has the highest number of records followed by Chiroptera (n = 18,857), Carnivora (n = 18,594), Lagomorpha (n = 17,496), Cetartiodactyla (n = 11,568) and Eulipotyphla (n = 7008). The data set includes records of species classified by the IUCN as threatened (e.g., Oryctolagus cuniculus [n = 12,159], Monachus monachus [n = 1,512], and Lynx pardinus [n = 197]). We believe that this data set may stimulate the publication of other European countries data sets that would certainly contribute to ecology and conservation-related research, and therefore assisting on the development of more accurate and tailored conservation management strategies for each species. There are no copyright restrictions; please cite this data paper when the data are used in publications.

The Burden of Nonalcoholic Steatohepatitis: A Systematic Review of Epidemiology Studies.

Background and Aims: Nonalcoholic steatohepatitis (NASH) is associated with increased mortality and risk of complications but is often asymptomatic and under-recognized. A systematic review of NASH epidemiology was conducted to provide information on the burden of NASH and highlight important evidence gaps for future research. Methods: Medline, EMBASE, and Cochrane Library databases were searched for English-language publications published from 2010 to January 2022 that reported on natural history, risk factors, comorbidities, and complications of a NASH population or subpopulation. Results: Overall, 173 publications were included. NASH was shown to have a variable disease course and high prevalence of comorbid disease. Although many patients progressed to cirrhosis and end-stage liver disease, disease regression or resolution was reported in up to half of patients in some studies. Reported risk factors for disease progression or resolution included levels of (or changes in) serum fibrosis markers, liver enzymes, and platelets. The presence of NASH increased the risk of liver cirrhosis and other serious diseases such as hepatocellular carcinoma, colorectal cancer, chronic kidney disease, and cardiovascular disease. In 2017, NASH was responsible for ∼118,000 cirrhosis deaths globally, and an increasing proportion of patients are receiving liver transplantation for NASH in Europe and the United States. Consolidation of data was hampered by heterogeneity across the studies in terms of patient populations, follow-up time, and outcomes measured. Conclusion: NASH is associated with significant morbidity and mortality, an increased risk of comorbidities, and imposes an increasing burden among liver transplantation recipients. Longer studies with harmonized study criteria are required to better understand the impact of NASH on patient outcomes.

Clinical and sociodemographic determinants of disease progression in patients with nonalcoholic steatohepatitis in the United States.

ABSTRACT: One fifth of patients with nonalcoholic fatty liver disease (NAFLD) may progress to nonalcoholic steatohepatitis (NASH), which can increase the risk of cirrhosis, cancer, and death. To date, reported predictors of NASH progression have been heterogeneous.We identified determinants of fibrosis progression in patients with NASH in the United States using physician-reported data from the real-world Global Assessment of the Impact of NASH (GAIN) study, including demographics and clinical characteristics, NASH diagnostic information, fibrosis stage, comorbidities, and treatment. We developed a logistic regression model to assess the likelihood of fibrosis progression since diagnosis, controlling for sociodemographic and clinical variables. An iterative nested model selection approach using likelihood ratio test determined the final model.A total of 989 patients from the GAIN US cohort were included; 46% were women, 58% had biopsy-proven NAFLD, and 74% had fibrosis stage F0-F2 at diagnosis. The final multivariable model included age, years since diagnosis, sex, employment status, smoking status, obesity, fibrosis stage, diagnostic biopsy, Vitamin E, and liver transplant proposed at diagnosis. Odds of progression were 17% higher (odds ratio, 1.17 [95% CI: 1.11-1.23]; P < .001) with each year since NASH diagnosis, 41% lower (0.59 [0.38-0.90]; P = .016) for women than men, 131% higher (2.31 [1.30-4.03]; P = .004) for smokers versus non-smokers, and 89% higher (1.89 [1.26-2.86]; P = .002) with obesity. Odds of progression were also higher with part-time, retired, unemployed, and unable to work due to NASH status versus full-time employment, and when a liver transplant was proposed at diagnosis.Disease duration and severity, obesity, smoking, and lack of full-time employment were significant determinants of fibrosis progression. These findings can support clinical and health-policy decisions to improve NASH management in the US.

Budget impact analysis of long-acting injectable aripiprazole once-monthly 400 mg in bipolar I disorder in the USA.

AIM: To estimate the budget impact (BI) of introducing aripiprazole once-monthly 400 mg/300 mg (AOM 400) in the maintenance monotherapy treatment of bipolar I disorder versus long-acting injectables, oral antipsychotics and best supportive care. METHODS: A BI model was developed from a US-payer perspective using treatment-related, hospitalization and adverse event management cost estimates for a hypothetical 1,000,000-member health plan over a 5-year period. RESULTS: Market share of AOM 400 was predicted to increase from 0.6% in Year 1 (current scenario) to 1.3% in Year 5 (predicted scenario), with predicted increases for paliperidone palmitate, asenapine and cariprazine. Treatment-related costs explained the BI increase, while adverse event and hospitalization costs were reduced. The per member per month incremental cost ranged from US$0.06 to US$0.26 in Years 1-5. The largest increases were predicted for paliperidone palmitate. CONCLUSION: As market shares of atypical antipsychotics are predicted to increase, payers may wish to re-evaluate their use.

Cost-effectiveness of long-acting injectable aripiprazole once-monthly 400 mg in bipolar I disorder in the USA.

AIM: To evaluate the cost-effectiveness of aripiprazole once-monthly 400/300 mg (AOM 400) in maintenance monotherapy treatment of bipolar I disorder (BP-I). METHODS: A de novo lifetime Markov model was developed for BP-I using available data for AOM 400 and relevant comparators. Base-case analysis considered costs and outcomes from the US payer perspective. RESULTS: The cost per quality-adjusted life year gained with AOM 400 versus comparators ranged from US$2007 versus oral asenapine to dominance (i.e., lower cost with quality-adjusted life gain) versus long-acting injectable risperidone, paliperidone palmitate, oral cariprazine and best supportive care. Patients treated with AOM 400 were estimated to have fewer mood episodes and hospitalizations per patient (5.37) than comparators (6.33, asenapine or cariprazine; 6.54, risperidone long-acting injectable; 7.64, paliperidone palmitate; and 8.93, best supportive care). Sensitivity analyses showed results were robust to parameter uncertainty. CONCLUSION: AOM 400 may be considered cost effective in the maintenance monotherapy treatment of BP-I in adults.

Burden of disease and cost of illness of atrial fibrillation in Portugal.

INTRODUCTION AND OBJECTIVES: Atrial fibrillation is the most prevalent sustained arrhythmia. This paper estimates the burden and cost of illness attributable to atrial fibrillation in Portugal based on demographic and health statistics. METHODS: Mortality data by cause of death came from the European Detailed Mortality Database of the World Health Organization (WHO). Hospital data were taken from the Portuguese diagnosis-related groups database. The burden of disease was measured using DALYs (disability-adjusted life years), a metric adopted by the WHO. Costs studied included resource use and lost productivity. The burden and cost of illness are those attributable to atrial fibrillation and its main complication, ischemic stroke. RESULTS: In Portugal, 4070 deaths were attributable to atrial fibrillation in 2010, corresponding to 3.8% of all deaths. In total, the burden of disease attributable to atrial fibrillation was estimated at 23,084 DALYs: 10,521 resulting from premature deaths (1.7% of the total DALYs due to death in 2010 in Portugal), and 12,563 resulting from disability. The total estimated direct costs attributable to atrial fibrillation at 2013 prices were €115 million: €34 million for inpatient care and €81 million for outpatient care. Indirect costs resulting from lost production due to disability were estimated at €25 million. CONCLUSIONS: Atrial fibrillation has an important social impact in Portugal due to its associated mortality and morbidity, and was responsible in 2013 for a total cost of €140 million, about 0.08% of gross domestic product.

[Antidiabetic drugs and in-patient admissions attributable to diabetes in Portugal]. / Antidiabéticos orais e internamentos atribuíveis à diabetes em Portugal.

INTRODUCTION: The growth of oral antidiabetic drugs spending has led to concerns questioning the health gains and benefits for the health system generated by these drugs. This study contributes to answering these questions. MATERIAL AND METHODS: Initially we present estimates of the three variables central to the analysis: 1) the prevalence of treated diabetes per year and health region, based on the consumption of oral antidiabetic drugs, 2) the number of hospitalization episodes and their costs attributable to diabetes, based on the relative risks and 3) a quantitative characterization of the consumption of oral antidiabetics by calculating average vintages by year and region. Through the use of observations for 10 years and five regions, a total of 50 observations,it was possible to estimate an econometric model explaining statistically both hospitalizations and hospital costs attributable to diabetes by regional characteristics, treated prevalence and the average vintage of oral antidiabetic drugs. RESULTS: The results of the multiple regression models show that hospital costs are proportional to the treated prevalence, all else constant, but that the more recent the oral antidiabetic drugs used, the lower are hospital costs. The effects on the number of hospitalizations are similar. DISCUSSION AND CONCLUSIONS: For an average observation in the sample, if the average vintage of oral hypoglycemic agents had one additional year, then hospital costs would have a 5.3% reduction (about 11 million € in 2009) and the number of admissions would suffer a 3.8% reduction (about 3965 less episodes in 2009). A counterfactual exercise allows us to estimate that for 2009 the introduction of the class of DPP IV inhibitors reduced the number of hospitalizations attributable to diabetes by 8480 and saved € 23.3 million in hospital costs.