A global survey on the use of the international classification of diseases codes for metabolic dysfunction-associated fatty liver disease.

BACKGROUND: With the implementation of the 11th edition of the International Classification of Diseases (ICD-11) and the publication of the metabolic dysfunction-associated fatty liver disease (MAFLD) nomenclature in 2020, it is important to establish consensus for the coding of MAFLD in ICD-11. This will inform subsequent revisions of ICD-11. METHODS: Using the Qualtrics XM and WJX platforms, questionnaires were sent online to MAFLD-ICD-11 coding collaborators, authors of papers, and relevant association members. RESULTS: A total of 890 international experts in various fields from 61 countries responded to the survey. We also achieved full coverage of provincial-level administrative regions in China. 77.1% of respondents agreed that MAFLD should be represented in ICD-11 by updating NAFLD, with no significant regional differences (77.3% in Asia and 76.6% in non-Asia, p = 0.819). Over 80% of respondents agreed or somewhat agreed with the need to assign specific codes for progressive stages of MAFLD (i.e. steatohepatitis) (92.2%), MAFLD combined with comorbidities (84.1%), or MAFLD subtypes (i.e., lean, overweight/obese, and diabetic) (86.1%). CONCLUSIONS: This global survey by a collaborative panel of clinical, coding, health management and policy experts, indicates agreement that MAFLD should be coded in ICD-11. The data serves as a foundation for corresponding adjustments in the ICD-11 revision.

Review of current and new drugs for the treatment of metabolic-associated fatty liver disease.

In the past 3 decades, metabolic-associated fatty liver disease (MAFLD) has emerged as a widespread liver condition, with its global prevalence on the rise. It ranks as a leading contributor to hepatocellular carcinoma (HCC) and necessitates liver transplantation. Under the multiple parallel hits model, the pathogenesis of MAFLD stems from various liver stressors, notably nutrient overload and sedentary lifestyles. While medical management for MAFLD is well-established, encompassing non-pharmaceutical and pharmaceutical interventions, determining the most effective pharmaceutical therapy has remained elusive. This review discusses diabetic medications for MAFLD treatment, emphasizing recent studies and emerging drugs while reviewing other nondiabetic agents. Emerging evidence suggests that combination therapies hold promise for resolving MAFLD and metabolic steatohepatitis (MASH) while managing side effects. Ongoing trials play a pivotal role in elucidating the effects of mono, dual, and triple receptor agonists in individuals with MASH. With the rising burden of MAFLD/MASH and its severe consequences, the need for effective treatments is more pressing than ever. This review provides a comprehensive overview of the current landscape of pharmaceutical interventions for MAFLD and MASH, shedding light on the potential of newer drugs especially diabetic medications and the importance of ongoing research in this field.

Low HBV knowledge is associated with low HBV vaccination uptake in general adult population despite incentivization of HBV vaccination.

BACKGROUND: Hepatitis B virus (HBV) vaccination in Vietnamese adults remains low and unequally distributed. We conducted a study on HBV-naïve adults living in Ho Chi Minh City, Viet Nam, to determine barriers associated with HBV vaccination uptake after removing the financial barrier by providing free coupons for HBV vaccination. METHODS: After being screened for HBsAg, anti-HBs, and anti-HBc, 284 HBV-naïve study participants aged 18 and over (i.e., negative for HBsAg, anti-HBs, and anti-HBc total) were provided free 3-dose HBV vaccine coupons. Next, study participants' receipt of 1st, 2nd, and 3rd doses of HBV vaccine was documented at a pre-specified study healthcare facility, where HBV vaccines were distributed at no cost to the participants. Upon study entry, participants answered questionnaires on sociodemographics, knowledge of HBV and HBV vaccination, and related social and behavioral factors. The proportions of three doses of HBV vaccine uptake and their confidence intervals were analyzed. Associations of HBV vaccine initiation with exposures at study entry were evaluated using modified Poisson regression. RESULTS: 98.9% (281 of 284) of study participants had complete data and were included in the analysis. The proportion of participants obtaining the 1st, 2nd, and 3rd doses of HBV vaccine was 11.7% (95% Confidence Interval [95% CI] 8.0-15.5%), 10.7% (95%CI 7.1-14.3%), and 8.9% (95%CI 5.6-12.2%), respectively. On the other hand, participants were more likely to initiate the 1st dose if they had adequate knowledge of transmission (adjusted relative risk [aRR] = 2.58, 95% CI 1.12-5.92), adequate knowledge of severity (aRR = 6.75, 95%CI 3.38-13.48), and annual health-checking seeking behavior (aRR = 2.04, 95%CI 1.07-3.87). CONCLUSION: We documented a low HBV vaccination uptake despite incentivization. However, increased vaccine initiation was associated with better HBV knowledge and annual health check-up adherence. When considering expanding HBV vaccination to the general adult population, we should appreciate that HBV knowledge is an independent predictor of vaccine uptake.

Estimating the prevalence of hepatitis delta virus infection among adults in the United States: A meta-analysis.

BACKGROUND AND AIMS: Suboptimal awareness and low rates of hepatitis delta virus (HDV) testing contribute to underdiagnosis and gaps in accurate estimates of U.S. HDV prevalence. We aim to provide an updated assessment of HDV prevalence in the U.S. using a comprehensive literature review and meta-analysis approach. METHODS: A comprehensive literature review of articles reporting HBsAg seroprevalence and anti-HDV prevalence was conducted to calculate country-specific rates and pooled prevalence of CHB and HDV using meta-analyses. Country-specific CHB and HDV rate estimates were combined with number of foreign-born (FB) persons in the U.S. in 2022 from U.S. Census Bureau to estimate total numbers of FB with CHB and HDV, respectively. These estimates were further combined with updated estimates of U.S.-born persons with CHB and HDV to yield the total number of persons with CHB and HDV. RESULTS: In 2022, we estimated 1.971 million (M) (95% CI 1.547-2.508) persons with CHB; 1.547 M (95% CI 1.264-1.831) were FB and 0.424 M (95% CI: 0.282-0.678) were U.S.-born. The weighted average HDV prevalence among FB persons in the U.S. was 4.20% (64 938 [95% CI 33055-97 392] persons), among whom 45% emigrated from Asia, 25% from Africa, and 14% from Europe. When combined with updated estimates of U.S.-born persons with HDV, we estimate 75 005 (95% CI: 42187-108 393) persons with HDV in the U.S. CONCLUSIONS: Including both FB and U.S.-born persons, we estimated that 1.971 M and 75 005 persons were living with CHB and HDV, respectively, in the U.S. in 2022.

An updated assessment of hepatitis delta prevalence among adults in Canada: A meta-analysis.

Foreign-born (FB) persons represent a large proportion of adults with chronic hepatitis B (CHB) in Canada due to higher prevalence rates in countries of birth for FB persons. Suboptimal awareness and low rates of hepatitis delta virus (HDV) testing contribute to underdiagnosis and gaps in accurate estimates of Canada HDV prevalence. We aim to provide an assessment of CHB and HDV prevalence in Canada using a comprehensive literature review and meta-analysis. A comprehensive literature review of articles reporting HBsAg seroprevalence and anti-HDV prevalence was conducted to calculate country-specific rates and pooled prevalence of CHB and HDV using meta-analyses. Country-specific CHB and HDV rate estimates were combined with number of FB persons in Canada in 2021 from Statistics Canada to estimate total numbers of FB with CHB and HDV, respectively. These estimates were combined with estimates of Canada-born persons with CHB and HDV to yield the total number of persons with CHB and HDV. In 2021, we estimated 0.550 million (M) (95% CI 0.488-0.615) persons with CHB; 0.344 M (95% CI 0.288-0.401) were FB and 0.206 M (95% CI: 0.200-0.214) were Canada-born. The weighted average HDV prevalence among FB persons in Canada was 5.19% (17,848 [95% CI 9611-26,052] persons), among whom 50% emigrated from Asia and 31% from Africa. When combined with estimates of Canada-born persons with HDV, we estimate 35,059 (95% CI: 18,744-52,083) persons with HDV in Canada. In conclusion, we estimate 0.550 M and 35,059 persons living with CHB and HDV, respectively, in Canada in 2021.

The Forgotten Virus, Hepatitis D: A Review of Epidemiology, Diagnosis, and Current Treatment Strategies.

Hepatitis D virus (HDV) is an RNA subvirus that infects patients with co-existing hepatitis B virus (HBV) infections. HDV burden is estimated to be approximately 15-20 million people worldwide. Despite HDV severity, screening for HDV remains inadequate. HDV screening would benefit from a revamped approach that automatically reflexes testing when individuals are diagnosed with HBV if HBsAg-positive, to total anti-HDV, and then to quantitative HDV-RNA polymerase chain reaction (PCR) rather than only testing those at high risk sequentially. There are no current treatments in the United States that are Food and Drug Administration (FDA)-approved for the treatment of HDV; however, bulevirtide (BLV) is approved in the European Union conditionally and is under review with the United States FDA. Current treatment strategies in many countries are centered on the use of pegylated-interferon-alfa-2a (PEG-IFNa-2a). There are other therapies in development globally that have shown promise, including BLV, pegylated-interferon-lambda (PEG-IFN-lambda), and lonafarnib (LNF). LNF has shown substantial response in the LOWR trials. BLV is a well-tolerated drug, but it is not finite therapy and has shown significant on-treatment responses in the MYR clinical trials, and the FDA cited concerns with the manufacturing and patient preparation of the drug that have delayed approval. The PDUFA date for BLV in the United States is mid-2024. Current studies with both BLV and LNF are limited in providing sustained virological response (SVR); future trials will need to demonstrate more substantial SVR with possible triple combination trials as options.

Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here?

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of ursodeoxycholic acid. Up to 40% of patients do not, however, respond adequately to ursodeoxycholic acid and therefore still remain at risk of disease progression to cirrhosis. The introduction of obeticholic acid as a second-line therapy for patients failing ursodeoxycholic acid has improved outcomes for patients with PBC. There remains, however, a need for better treatment for patients at higher risk. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorization for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcome trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with obeticholic acid, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcome trials when a licensed drug is commercially available. New PBC therapies in development, such as the peroxisome proliferator-activated receptor agonists, face even greater challenges in demonstrating outcome benefit through randomized placebo-controlled studies once following conditional marketing authorization, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognize the importance of real-world data in providing evidence of outcome benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through real-world data collection.

Experience and impact of stigma in people with chronic hepatitis B: a qualitative study in Asia, Europe, and the United States.

BACKGROUND: People with chronic hepatitis B (CHB) commonly experience social and self-stigma. This study sought to understand the impacts of CHB-related stigma and a functional cure on stigma. METHODS: Adults with CHB with a wide range of age and education were recruited from 5 countries and participated in 90-minute qualitative, semi-structured interviews to explore concepts related to CHB-associated stigma and its impact. Participants answered open-ended concept-elicitation questions regarding their experience of social and self-stigma, and the potential impact of reduced CHB-related stigma. RESULTS: Sixty-three participants aged 25 to 71 years (15 from the United States and 12 each from China, Germany, Italy, and Japan) reported emotional, lifestyle, and social impacts of living with CHB, including prejudice, marginalization, and negative relationship and work experiences. Self-stigma led to low self-esteem, concealment of CHB status, and social withdrawal. Most participants stated a functional cure for hepatitis B would reduce self-stigma. CONCLUSIONS: CHB-related social and self-stigma are widely prevalent and affect many aspects of life. A functional cure for hepatitis B may reduce social and self-stigma and substantially improve the health-related quality of life of people with CHB. Incorporating stigma into guidelines along with infectivity considerations may broaden the patient groups who should receive treatment.

Prevalence and characteristics of hepatitis delta virus infection in patients with hepatitis B in the United States: An analysis of the All-Payer Claims Database.

BACKGROUND AND AIMS: HDV leads to the most severe form of viral hepatitis; however, the prevalence of HDV is not well understood. Using real-world data from the All-Payer Claims Database, this study estimates the prevalence of HBV/HDV infection among the chronic HBV population and describes patient/clinical characteristics for adults with HBV/HDV infection in the United States. APPROACH AND RESULTS: Adults (≥18 years) with ≥1 inpatient claim or ≥2 outpatient claims for HDV infection or HBV in the All-Payer Claims Database from January 1, 2014, to December 31, 2020, were identified. HDV prevalence was calculated as the proportion of patients with HBV/HDV infection among total patients with HBV infection. Patient characteristics, socioeconomic status, advanced liver complications (eg, cirrhosis, HCC), and comorbidities were assessed. A total of 6719 patients were diagnosed with HBV/HDV among 144,975 with HBV and 12 months of continuous data, for a prevalence of 4.6%. At diagnosis, 31.7% of patients with HBV/HDV had advanced liver complications, including compensated cirrhosis (16.3%) and decompensated cirrhosis (10.4%). Diabetes (50.5%), hypertension (49.8%), and HIV infection (30.9%) were the top 3 comorbidities. CONCLUSIONS: In a large database capturing approximately 80% of the US-insured population, HBV/HDV infection prevalence was 4.6% among adults infected with HBV. Patients infected with HDV had high rates of baseline liver complications and other comorbidities at the time of diagnosis, suggesting potentially delayed diagnosis and/or treatment. Earlier identification of HBV/HDV infection among the population with HBV may provide opportunities to improve linkage to care and treatment, thereby reducing the risk of liver-related morbidity and mortality.

Association of hepatitis delta virus with liver morbidity and mortality: A systematic literature review and meta-analysis.

BACKGROUND AND AIMS: Studies have suggested that patients with chronic hepatitis B, either co- or superinfected, have more aggressive liver disease progression than those with the HDV. This systematic literature review and meta-analysis examined whether HDV RNA status is associated with increased risk of advanced liver disease events in patients who are HBsAg and HDV antibody positive. APPROACH AND RESULTS: A total of 12 publications were included. Relative rates of progression to advanced liver disease event for HDV RNA+/detectable versus HDV RNA-/undetectable were extracted for analysis. Reported OR and HRs with 95% CI were pooled using the Hartung-Knapp-Sidik-Jonkman method for random-effects models. The presence of HDV RNA+ was associated with an increased risk of any advanced liver disease event [random effect (95% CI): risk ratio: 1.48 (0.93, 2.33); HR: 2.62 (1.55, 4.44)]. When compared to the patients with HDV RNA- status, HDV RNA+ was associated with a significantly higher risk of progressing to compensated cirrhosis [risk ratio: 1.74 (1.24, 2.45)] decompensated cirrhosis [HR: 3.82 (1.60, 9.10)], HCC [HR: 2.97 (1.87, 4.70)], liver transplantation [HR: 7.07 (1.61, 30.99)], and liver-related mortality [HR: 3.78 (2.18, 6.56)]. CONCLUSIONS: The patients with HDV RNA+ status have a significantly greater risk of liver disease progression than the patients who are HDV RNA-. These findings highlight the need for improved HDV screening and linkage to treatment to reduce the risk of liver-related morbidity and mortality.

Test All for Hepatitis B Virus: Link to Care and Treatment if Quantitative DNA Positive, Vaccinate if Susceptible.

Hepatitis B infection affects approximately 262 million people worldwide and is responsible for 900,000 deaths annually. This article reviews the major factors limiting HBV elimination, which includes limited linkage to care and complicated HBV testing and treatment guidelines. The article then provides solutions to these pressing issues.

On-treatment risks of cirrhosis and hepatocellular carcinoma among a large cohort of predominantly non-Asian patients with non-cirrhotic chronic hepatitis B.

Background & Aims: The vast majority of studies evaluating differences in on-treatment risks of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) have been conducted in Asia. Data on the course of CHB on antiviral therapy among predominantly non-Asian populations is less well described. We aimed to evaluate overall risks of cirrhosis and HCC and the influence of baseline factors on this risk among a predominantly non-Asian cohort of patients with CHB in the US. Methods: Using longitudinal data from the national Veterans Affairs database, we evaluated the incidence of cirrhosis or HCC among adults with non-cirrhotic CHB on continuous antiviral therapy. Cumulative incidence functions and adjusted Cox proportional hazards models employed competing risks methods and evaluated overall risk and predictors of developing cirrhosis or HCC while on treatment. Results: Among 2,496 patients with non-cirrhotic CHB (39.1% African American, 38.4% non-Hispanic White, 18.8% Asian, mean age 58.0 ± 13.4 years), the overall incidences of cirrhosis and HCC were 3.99 per 100 person-years (95% CI 3.66-4.35) and 0.43 per 100 person-years (95% CI 0.33-0.54), respectively. The highest incidences of cirrhosis and HCC were observed in non-Hispanic White patients (5.74 and 0.52 per 100 person-years, respectively), which were significantly higher than in Asian patients (1.93 and 0.17 per 100 person-years, respectively, p <0.0001). On multivariate regression, only baseline FIB-4 score was consistently associated with long-term risk of cirrhosis or HCC. Conclusions: Using a longitudinal cohort of predominantly non-Asian Veterans with non-cirrhotic CHB on antiviral therapy (an understudied population), we provide important epidemiological data to describe long-term risks of cirrhosis and HCC. Impact and implications: In one of the largest studies to date of a predominantly non-Asian cohort of patients with non-cirrhotic chronic hepatitis B, we provide important epidemiological data describing the long-term risks of cirrhosis and hepatocellular carcinoma among patients on antiviral therapies. Among this understudied population, the overall incidence of cirrhosis was 3.99 per 100-person-years (95% CI 3.66-4.35) and of HCC was 0.43 per 100-person-years (95% CI 0.33-0.54). These data also emphasize the importance of continued monitoring and HCC surveillance among CHB patients who are maintained on antiviral therapies.

Advancing research, awareness, screening, and linkage to care to eliminate HDV in the U.S.

HDV, which coinfects individuals living with HBV, is the most aggressive form of viral hepatitis. Compared with hepatitis B monoinfection, hepatitis delta is associated with more rapid progression to cirrhosis and an increased risk of liver cancer and death. Despite being a major contributor to hepatitis B-associated liver disease, hepatitis delta remains largely unknown to the general public, health care providers, and at-risk communities. Given the widespread lack of awareness and underdiagnosis of hepatitis delta in the US, the American Liver Foundation (ALF) and the Hepatitis B Foundation (HBF) convened a virtual Hepatitis Delta Roundtable Meeting on April 21 and 22, 2022. The Roundtable Panel included persons living with hepatitis delta, caregivers, liver disease specialists, primary care providers, state and federal public health professionals, and community-based organizations. The Panel identified several major challenges surrounding hepatitis delta, including a lack of awareness of hepatitis delta among the public and health care providers; complex risk-based testing protocols; a lack of accurate prevalence data; limited data on linkage to care; and inadequate communications among stakeholders. Potential strategies to address these challenges include improving and expanding education for different audiences; advocating for simplified protocols for hepatitis B screening with hepatitis delta reflex testing; expanding surveillance for hepatitis delta; requiring automated reporting and national notification; improving data sharing for research; and enhancing communications around hepatitis delta. The recent CDC recommendations for universal adult screening and vaccination against hepatitis B and the anticipated availability of new therapies for hepatitis delta present a unique opportunity to focus attention on this dangerous virus. The Roundtable Panel calls for urgent action to make significant progress in addressing hepatitis delta among individuals living with hepatitis B.

Diagnosis and Management of Hepatitis Delta Virus Infection.

Hepatitis D virus (HDV) depends on hepatitis B virus (HBV) to enter and exit hepatocytes and to replicate. Despite this dependency, HDV can cause severe liver disease. HDV accelerates liver fibrosis, increases the risk of hepatocellular carcinoma, and hastens hepatic decompensation compared to chronic HBV monoinfection. The Chronic Liver Disease Foundation (CLDF) formed an expert panel to publish updated guidelines on the testing, diagnosis, and management of hepatitis delta virus. The panel group performed network data review on the transmission, epidemiology, natural history, and disease sequelae of acute and chronic HDV infection. Based on current available evidence, we provide recommendations for screening, testing, diagnosis, and treatment of hepatitis D infection and review upcoming novel agents that may expand treatment options. The CLDF recommends universal HDV screening for all patients who are Hepatitis B surface antigen-positive. Initial screening should be with an assay to detect antibodies generated against HDV (anti-HDV). Patients who are positive for anti-HDV IgG antibodies should then undergo quantitative HDV RNA testing. We also provide an algorithm that describes CLDF recommendations on the screening, diagnosis, testing, and initial management of Hepatitis D infection.