Intention-to-treat outcomes of patients with hepatocellular carcinoma receiving immunotherapy before liver transplant: the multicenter VITALITY study.

BACKGROUND AND AIMS: The use of immune checkpoint inhibitors (ICI) in patients with advanced hepatocellular carcinoma (HCC) has become widespread with encouraging outcomes in the neoadjuvant setting. Safety and intention to treat (ITT) outcomes in the peri transplant setting are currently based on small and heterogenous single center reports. METHODS: This first multiregional US study (2016-2023) included 117 consecutive HCC patients assessed for LT and treated preoperatively with ICIs. Intention to treat ITT and survival analyses were conducted with evaluation of post LT rejection rates. RESULTS: In total, 86 (73.5%) patients exceeded MC and 65 (75.6%) were successfully downstaged (DS) within a median of 5.6 months. 43 (36.7%) underwent transplantation, including 18 (15.4%) within MC and 23 (19.7%) initially beyond and DS. Overall, 94% of the cohort received concurrent ICIs and locoregional therapies. No grade 4-5 adverse events occurred on the waiting list. The 3-year cumulative probability of dropout was 28% for those within MC and 48% for those beyond. Independent predictors of dropout included: being beyond MC (p<0.001), AFP doubling from baseline (p=0.014) and radiographic responses (p<0.001). The 3-year ITT survival was 71.1% (73.5% within MC vs 69.7% beyond MC, p=0.329), with 3-year post LT survival rate of 85%. Post-LT rejection occurred in 7 patients, six received their last dose of ICI less than 3 months prior to LT, resulting in one graft loss. CONCLUSIONS: The first multicenter evaluation of HCC patients receiving ICI pre-LT demonstrates favorable survival and safety outcomes, justifying continued utilization and further evaluation of this strategy in clinical practice. High tumor burden, doubling of AFP levels, and radiographic response were identified as predictors of unfavorable oncologic outcomes. IMPACT AND IMPLICATIONS: The first multicenter evaluation of pre-transplant immune-checkpoint-inhibitors in hepatocellular carcinoma to show promising intention-to-treat survival, safety and rejection rates. Immune-checkpoint-inhibitors, either alone or combined with LRT, demonstrate reliable efficacy. This preoperative strategy could be particularly beneficial for high-risk patients, including those requiring downstaging or with elevated AFP levels despite locoregional treatment. These findings fill current knowledge gaps and offer reassuring evidence for the feasibility of pre-transplant use of immune-checkpoint-inhibitors, pending results from ongoing trials.

Development and Validation of a Noninvasive Model for the Detection of High-Risk Varices in Patients with Unresectable HCC.

BACKGROUND & AIMS: Noninvasive variceal risk stratification systems have not been validated in patients with hepatocellular carcinoma (HCC), which presents logistical barriers for patients in the setting of systemic HCC therapy. We aimed to develop and validate a noninvasive algorithm for the prediction of varices in patients with unresectable HCC. METHODS: We performed a retrospective cohort study in 21 centers in the United States including adult patients with unresectable HCC and Child-Pugh A5-B7 cirrhosis diagnosed between 2007 and 2019. We included patients who completed an esophagogastroduodonoscopy (EGD) within 12 months of index imaging but before HCC treatment. We divided the cohort into a 70:30 training set and validation set, with the goal of maximizing negative predictive value (NPV) to avoid EGD in low-risk patients. RESULTS: We included 707 patients (median age, 64.6 years; 80.6% male; 74.0% White). Median time from HCC diagnosis to EGD was 47 (interquartile range, 114) days, with 25.0% of patients having high-risk varices. A model using clinical variables alone achieved an NPV of 86.3% in the validation cohort, whereas a model integrating clinical and imaging variables had an NPV 97.4% in validation. The clinical and imaging model would avoid EGDs in more than half of low-risk patients while misclassifying 7.7% of high-risk patients. CONCLUSIONS: A model incorporating clinical and imaging data can accurately predict the absence of high-risk varices in patients with HCC and avoid EGD in many low-risk patients before the initiation of systemic therapy, thus expediting their care and avoiding treatment delays.

The impact of surging transplantation of alcohol-associated liver disease on transplantation for HCC and other indications.

BACKGROUND: Liver transplantation (LT) for alcohol-associated liver disease (ALD) is increasing and may impact LT outcomes for patients listed for HCC and other indications. METHODS: Using US adults listed for primary LT (grouped as ALD, HCC, and other) from October 8, 2015, to December 31, 2021, we examined the impact of center-level ALD LT volume (ATxV) on waitlist outcomes in 2 eras: Era 1 (6-month wait for HCC) and Era 2 (MMaT-3). The tertile distribution of ATxV (low to high) was derived from the listed candidates as Tertile 1 (T1): <28.4%, Tertile 2 (T2): 28.4%-37.6%, and Tertile 3 (T3): >37.6% ALD LTs per year. Cumulative incidence of waitlist death and LT within 18 months from listing by LT indication were compared using the Gray test, stratified on eras and ATxV tertiles. Multivariable competing risk regression estimated the adjusted subhazard ratios (sHRs) for the risk of waitlist mortality and LT with interaction effects of ATxV by LT indication (interaction p). RESULTS: Of 56,596 candidates listed, the cumulative waitlist mortality for those with HCC and other was higher and their LT probability was lower in high (T3) ATxV centers, compared to low (T1) ATxV centers in Era 2. However, compared to ALD (sHR: 0.92 [0.66-1.26]), the adjusted waitlist mortality for HCC (sHR: 1.15 [0.96-1.38], interaction p = 0.22) and other (sHR: 1.13 [0.87-1.46], interaction p = 0.16) were no different suggesting no differential impact of ATxV on the waitlist mortality. The adjusted LT probability for HCC (sHR: 0.89 [0.72-1.11], interaction p = 0.08) did not differ by AtxV while it was lower for other (sHR: 0.82 [0.67-1.01], interaction p = 0.02) compared to ALD (sHR: 1.04 [0.80-1.34]) suggesting a differential impact of ATxV on LT probability. CONCLUSIONS: The high volume of LT for ALD does not impact waitlist mortality for HCC and others but affects LT probability for other in the MMAT-3 era warranting continued monitoring.

Increasing risk of hepatocellular carcinoma with successive generations in the United States among Mexican American adults: The Multiethnic Cohort.

BACKGROUND: US-born Latinos have a higher incidence of hepatocellular carcinoma (HCC) than foreign-born Latinos. Acculturation to unhealthy lifestyle behaviors and an immigrant self-selection effect may play a role. In this study, the authors examined the influence of generational status on HCC risk among Mexican American adults. METHODS: The analytic cohort included 31,377 self-reported Mexican Americans from the Multiethnic Cohort Study (MEC). Generational status was categorized as: first-generation (Mexico-born; n = 13,382), second-generation (US-born with one or two parents born in Mexico; n = 13,081), or third-generation (US-born with both parents born in the United States; n = 4914). Multivariable Cox proportional hazards regression was performed to examine the association between generational status and HCC incidence. RESULTS: In total, 213 incident HCC cases were identified during an average follow-up of 19.5 years. After adjusting for lifestyle and neighborhood-level risk factors, second-generation and third-generation Mexican Americans had a 37% (hazard ratio [HR], 1.37; 95% confidence interval [CI], 0.98-1.92) and 66% (HR, 1.66; 95% CI, 1.11-2.49) increased risk of HCC, respectively, compared with first-generation Mexican Americans (p for trend = 0.012). The increased risk associated with generational status was mainly observed in males (second-generation vs. first-generation: HR, 1.60 [95% CI, 1.05-2.44]; third-generation vs. first-generation: HR, 2.08 [95% CI, 1.29-3.37]). CONCLUSIONS: Increasing generational status of Mexican Americans is associated with a higher risk of HCC. Further studies are needed to identify factors that contribute to this increased risk.

Care for Vulnerable Populations with Chronic Liver Disease: A Safety-Net Perspective.

Safety-net hospitals (SNHs) and facilities are the cornerstone of healthcare services for the medically underserved. The burden of chronic liver disease-including end-stage manifestations of cirrhosis and liver cancer-is high and rising among populations living in poverty who primarily seek and receive care in safety-net settings. For many reasons related to social determinants of health, these individuals often present with delayed diagnoses and disease presentations, resulting in higher liver-related mortality. With recent state-based policy changes such as Medicaid expansion that impact access to insurance and critical health services, an overview of the body of literature on SNH care for chronic liver disease is timely and informative for the liver disease community. In this narrative review, we discuss controversies in the definition of a SNH and summarize the known disparities in the cascade of the care and management of common liver-related conditions: (1) steatotic liver disease, (2) liver cancer, (3) chronic viral hepatitis, and (4) cirrhosis and liver transplantation. In addition, we review the specific impact of Medicaid expansion on safety-net systems and liver disease outcomes and highlight effective provider- and system-level interventions. Lastly, we address remaining gaps and challenges to optimizing care for vulnerable populations with chronic liver disease in safety-net settings.

Association of nativity with survival among adults with hepatocellular carcinoma.

INTRODUCTION: Immigrants comprise a considerable proportion of those diagnosed with hepatocellular carcinoma (HCC) in the United States. Nativity or birthplace affects incidence and risk factors for HCC, but little is known about its influence on survival after diagnosis. METHODS: We identified 51 533 adults with HCC with available birthplace in the California Cancer Registry between 1988 and 2017. HCC cases were categorized as foreign born or US born and stratified by mutually exclusive race and ethnicity groups. Primary outcome was all-cause mortality. Race and ethnicity-specific Cox regression propensity score-weighted models evaluated the relationship between nativity and death as well as region of birth among foreign-born patients. RESULTS: A total of 40% of all HCC cases were foreign born, and 92.2%, 45.2%, 9.1%, and 5.8% of Asian/Pacific Islander (API), Hispanic, White, and Black patients were foreign born, respectively. Five-year survival rates were higher in foreign-born patients compared with US-born patients: 12.9% vs 9.6% for White patients, 11.7% vs 9.8% for Hispanic patients, 12.8% vs 8.1% for Black patients, and 16.4% vs 12.4% for API patients. Nativity was associated with survival, with better survival in foreign-born patients: White patients: hazard ratio (HR) = 0.86 (95% confidence interval [CI] = 0.81 to 0.90), Hispanic patients: HR = 0.90 (95% CI = 0.86 to 0.93), Black patients: HR = 0.89 (95% CI = 0.76 to 1.05), and API patients: HR = 0.94 (95% CI = 0.88 to 1.00). Among foreign-born patients, lower mortality was observed in those from Central and South America compared with Mexico for Hispanic patients, East Asia compared with Southeast Asia for API patients, and East Europe and Greater Middle East compared with West/South/North Europe for White patients. CONCLUSION: Foreign-born patients with HCC have better survival than US-born patients. Further investigation into the mechanisms of this survival disparity by nativity is needed.

Population-attributable risk of modifiable lifestyle factors to hepatocellular carcinoma: The multi-ethnic cohort.

BACKGROUND AND AIMS: Lifestyle factors are well associated with risk of hepatocellular carcinoma (HCC). However, the impact of reducing adverse lifestyle behaviours on population-level burden of HCC is uncertain. METHODS: We conducted prospective analysis of the population-based multi-ethnic cohort (MEC) with linkage to cancer registries. The association of lifestyle factors (smoking, alcohol, diet quality assessed by alternate Mediterranean diet score, coffee drinking, physical activity and body mass index) with HCC incidence was examined using Cox regression. Population-attributable risk (PAR, %) for the overall, lean and overweight/obese populations was determined. RESULTS: A total of 753 incident cases of HCC were identified in 181,346 participants over median follow-up of 23.1 years. Lifestyle factors associated with elevated HCC risk included former/current smoking, heavy alcohol use, poor diet quality, lower coffee intake and obesity, but not physical activity. The lifestyle factor with highest PAR was lower coffee intake (21.3%; 95% CI: 8.9%-33.0%), followed by current smoking (15.1%; 11.1%-19.0%), obesity (14.5%; 9.2%-19.8%), heavy alcohol use (7.1%; 3.5%-10.6%) and lower diet quality (4.1%; 0.1%-8.1%). The combined PAR of all high-risk lifestyle factors was 51.9% (95% CI: 30.1%-68.6%). A higher combined PAR was observed among lean (65.2%, 26.8%-85.7%) compared to overweight/obese (37.4%, 11.7%-58.3%) participants. Adjusting for viral hepatitis status in a linked MEC-Medicare dataset resulted in similar PAR results. CONCLUSIONS: Modifying lifestyle factors, particularly coffee intake, may have a substantial impact on HCC burden in diverse populations, with greater impact among lean adults. Diet and lifestyle counselling should be incorporated into HCC prevention strategies.

Recall patterns and risk of primary liver cancer for subcentimeter ultrasound liver observations: a multicenter study.

BACKGROUND: Patients with cirrhosis and subcentimeter lesions on liver ultrasound are recommended to undergo short-interval follow-up ultrasound because of the presumed low risk of primary liver cancer (PLC). AIMS: The aim of this study is to characterize recall patterns and risk of PLC in patients with subcentimeter liver lesions on ultrasound. METHODS: We conducted a multicenter retrospective cohort study among patients with cirrhosis or chronic hepatitis B infection who had subcentimeter ultrasound lesions between January 2017 and December 2019. We excluded patients with a history of PLC or concomitant lesions ≥1 cm in diameter. We used Kaplan Meier and multivariable Cox regression analyses to characterize time-to-PLC and factors associated with PLC, respectively. RESULTS: Of 746 eligible patients, most (66.0%) had a single observation, and the median diameter was 0.7 cm (interquartile range: 0.5-0.8 cm). Recall strategies varied, with only 27.8% of patients undergoing guideline-concordant ultrasound within 3-6 months. Over a median follow-up of 26 months, 42 patients developed PLC (39 HCC and 3 cholangiocarcinoma), yielding an incidence of 25.7 cases (95% CI, 6.2-47.0) per 1000 person-years, with 3.9% and 6.7% developing PLC at 2 and 3 years, respectively. Factors associated with time-to-PLC were baseline alpha-fetoprotein >10 ng/mL (HR: 4.01, 95% CI, 1.85-8.71), platelet count ≤150 (HR: 4.90, 95% CI, 1.95-12.28), and Child-Pugh B cirrhosis (vs. Child-Pugh A: HR: 2.54, 95% CI, 1.27-5.08). CONCLUSIONS: Recall patterns for patients with subcentimeter liver lesions on ultrasound varied widely. The low risk of PLC in these patients supports short-interval ultrasound in 3-6 months, although diagnostic CT/MRI may be warranted for high-risk subgroups such as those with elevated alpha-fetoprotein levels.

Geographic hotspot detection for late-stage hepatocellular carcinoma: novel approach to cancer control.

IMPORTANCE: As hepatocellular carcinoma (HCC)-associated mortality continues to rise in the United States, there is a crucial need for strategies to shift diagnoses from late to early stage in order to improve survival. OBJECTIVE: To describe a population-based geospatial approach to identifying areas with high late-stage HCC burden for intervention. DESIGN: Cross-sectional study between 2008 and 2017. SETTING: Los Angeles County. PARTICIPANTS: All incident cases of HCC with residential address at diagnosis in Los Angeles County were identified from a population-based cancer registry. Late stage included AJCC 7th Edition stages III-IV and unstaged cases. EXPOSURE: Sociodemographic factors. MAIN OUTCOME(S): Geographic "hotspots" or areas with a high density of late-stage HCC, identified using kernel density estimation in ArcMap 10.3.1. RESULTS: 51.8% of 7,519 incident cases of HCC were late stage. We identified a total of 23 late-stage hotspots, including 30.0% of all late-stage cases. Cases within hotspots were more often racial/ethnic minorities, foreign-born, under or uninsured, and of lower socioeconomic status. The age-adjusted incidence rate of late-stage HCC was twofold higher within hotspots (6.85 per 100,000 in hotspots vs 3.38 per 100,000 outside of hotspots). The calculated population-attributable risk was 43%, suggesting that a substantial proportion of late-stage HCC burden could be averted by introducing interventions in hotspot areas. We mapped the relationship between hotspots and federally qualified health centers primary care clinics and subspecialty clinics in Los Angeles County to demonstrate how clinic partnerships can be selected to maximize impact of interventions and resource use. Hotspots can also be utilized to identify "high-risk" neighborhoods that are easily recognizable by patients and the public and to facilitate community partnerships. CONCLUSION AND RELEVANCE: Reducing late-stage HCC through geographic late-stage hotspots may be an efficient approach to improving cancer control and equity.

Provider Attitudes Toward Risk-Based Hepatocellular Carcinoma Surveillance in Patients With Cirrhosis in the United States.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) surveillance rates are suboptimal in clinical practice. We aimed to elicit providers' opinions on the following aspects of HCC surveillance: preferred strategies, barriers and facilitators, and the impact of a patient's HCC risk on the choice of surveillance modality. METHODS: We conducted a web-based survey among gastroenterology and hepatology providers (40% faculty physicians, 21% advanced practice providers, 39% fellow-trainees) from 26 US medical centers in 17 states. RESULTS: Of 654 eligible providers, 305 (47%) completed the survey. Nearly all (98.4%) of the providers endorsed semi-annual HCC surveillance in patients with cirrhosis, with 84.2% recommending ultrasound ± alpha fetoprotein (AFP) and 15.4% recommending computed tomography (CT) or magnetic resonance imaging (MRI). Barriers to surveillance included limited HCC treatment options, screening test effectiveness to reduce mortality, access to transportation, and high out-of-pocket costs. Facilitators of surveillance included professional society guidelines. Most providers (72.1%) would perform surveillance even if HCC risk was low (≤0.5% per year), while 98.7% would perform surveillance if HCC risk was ≥1% per year. As a patient's HCC risk increased from 1% to 3% to 5% per year, providers reported they would be less likely to order ultrasound ± AFP (83.6% to 68.9% to 57.4%; P < .001) and more likely to order CT or MRI ± AFP (3.9% to 26.2% to 36.1%; P < .001). CONCLUSIONS: Providers recommend HCC surveillance even when HCC risk is much lower than the threshold suggested by professional societies. Many appear receptive to risk-based HCC surveillance strategies that depend on patients' estimated HCC risk, instead of our current "one-size-fits all" strategy.

Lower Alpha-Fetoprotein Threshold of 500 ng/mL for Liver Transplantation May Improve Posttransplant Outcomes in Patients With Hepatocellular Carcinoma.

Under current United Network for Organ Sharing (UNOS) policy, patients with hepatocellular carcinoma (HCC) and alpha-fetoprotein (AFP) levels ≥1000 ng/mL are required to show a reduction in AFP level to <500 ng/mL before liver transplantation (LT). However, effects of AFP reduction on post-LT HCC outcomes among patients with HCC with moderately elevated AFP levels between 100 and <1000 ng/mL are unclear. Adults in the UNOS registry who underwent LTs from January 2005 to September 2015 with initial AFP levels of 100 to 999 ng/mL at listing for Model for End-Stage Liver Disease exceptions were included. Primary predictor was AFP level at LT, categorized as <100, 100 to 499, or ≥500 ng/mL, and patients with only 1 recorded pre-LT AFP value (AFP 1-value). Survival was compared using the Kaplan-Meier curve method. Factors associated with post-LT survival and HCC recurrence were assessed in a multivariable Cox regression model. Among 1766 included patients, 50.2% had AFP 1-value, followed by 24.7%, 18.9%, and 6.2% with AFP levels <100, 100 to 499, and ≥500 ng/mL, respectively. The 5-year post-LT survival rate was lowest in the AFP ≥500 category, at 56.1%, compared with 72.7%, 70.4%, and 65.6% in the AFP <100, 100 to 499 ng/mL, and AFP 1-value categories, respectively. In multivariable analysis, AFP ≥500 ng/mL at LT was associated with a greater risk of post-LT death (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.1-2.1) and HCC recurrence (HR, 1.9; 95% CI, 1.1-3.1) when compared with the AFP <100 ng/mL category; other significant variables included donor risk index, age, race/ethnicity, Child-Turcotte-Pugh class, and tumor diameter. Among AFP levels ≥500 ng/mL at LT, 40.4% had AFP levels ≥1000, but no difference in post-LT survival or recurrence was seen between those patients with AFP levels < or ≥1000 ng/mL. Mandating AFP <500 ng/mL at LT for all patients, not only for those with initial AFP levels ≥1000 ng/mL, may improve post-LT outcomes and can be considered in future UNOS policy.

Diverging Incidence Trends for Hepatocellular Carcinoma in Rural and Urban Settings in the United States.

In the United States, hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related deaths and was the 5th most common cause in 2020.1 One in 5 Americans lives in a rural area,2 yet little is known about temporal changes in HCC incidence by rural-urban residence. Area-specific data are critical to guide public health strategies and clinical interventions. Our study compared the overall and subgroup incidence trends for HCC across rural and urban communities in the United States over the past 20 years using the North American Association of Central Cancer Registries database, which covers 93% of the United States and well-represents the rural United States (North American Association of Central Cancer Registries 14.6% rural vs United States 14.8% rural).3.

Etiology and Outcomes of Hepatocellular Carcinoma in an Ethnically Diverse Population: The Multiethnic Cohort.

BACKGROUNDS: HCC incidence varies by race/ethnicity. We characterized racial differences in underlying etiology, presentation, and survival in the linkage of Multiethnic Cohort Study with SEER and Medicare claims. METHODS: HCC characteristics, treatment, and underlying etiology in participants were obtained. Deaths were ascertained using state death certificates and the National Death Index. Risk factors were collected via questionnaires. Cox models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for death. RESULTS: Among 359 cases, the average age at diagnosis was 75.1. The most common etiology was hepatitis C (HCV) (33%), followed by nonalcoholic fatty liver disease (NAFLD) (31%), and different by ethnicity (p < 0.0001). African Americans (AA) (59.5%) and Latinos (40.6%) were more likely to be diagnosed with HCV-related HCC. In Japanese Americans (33.1%), Native Hawaiians (39.1%), and whites (34.8%), NAFLD was the most common etiology. Receipt of treatment varied across ethnic groups (p = 0.0005); AA had the highest proportion of no treatment (50.0%), followed by Latinos (45.3%), vs. whites (15.2%). HCC (72.2%) was the most common cause of death. In a multivariate analysis, AA (HR = 1.87; 95% CI: 1.06-3.28) had significantly higher mortality compared to whites. CONCLUSIONS: We found significant ethnic differences in HCC underlying etiology, receipt of treatment, and outcome. The findings are important for reducing disparities.

Presentation, Management, and Outcomes Across the Rural-Urban Continuum for Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma is 1 of few cancers with rising incidence and mortality in the United States. Little is known about disease presentation and outcomes across the rural-urban continuum. Methods: Using the population-based Surveillance, Epidemiology, and End Results registry, we identified adults with incident hepatocellular carcinoma between 2000 and 2016. Urban, suburban, and rural residence at time of cancer diagnosis were categorized by the Census Bureau's percent of the population living in nonurban areas. We examined association between place of residence and overall survival. Secondary outcomes were late tumor stage and receipt of therapy. Results: Of 83 368 incident cases of hepatocellular carcinoma, 75.8%, 20.4%, and 3.8% lived in urban, suburban, and rural communities, respectively. Median survival was 7 months (interquartile range = 2-24). All stage and stage-specific survival differed by place of residence, except for distant stage. In adjusted models, rural and suburban residents had a respective 1.09-fold (95% confidence interval [CI] = 1.04 to 1.14; P < .001) and 1.08-fold (95% CI = 1.05 to 1.10; P < .001) increased hazard of overall mortality as compared with urban residents. Furthermore, rural and suburban residents had 18% (odds ratio [OR] = 1.18, 95% CI = 1.10 to 1.27; P < .001) and 5% (OR = 1.05, 95% CI = 1.02 to 1.09; P = .003) higher odds of diagnosis at late stage and were 12% (OR = 0.88, 95% CI = 0.80 to 0.94; P < .001) and 8% (OR = 0.92, 95% CI = 0.88 to 0.95; P < .001) less likely to receive treatment, respectively, compared with urban residents. Conclusions: Residence in a suburban and rural community at time of diagnosis was independently associated with worse indicators across the cancer continuum for liver cancer. Further research is needed to elucidate the primary drivers of these rural-urban disparities.

Predictors of Outcomes of COVID-19 in Patients With Chronic Liver Disease: US Multi-center Study.

BACKGROUND & AIMS: Chronic liver disease (CLD) represents a major global health burden. We undertook this study to identify the factors associated with adverse outcomes in patients with CLD who acquire the novel coronavirus-2019 (COVID-19). METHODS: We conducted a multi-center, observational cohort study across 21 institutions in the United States (US) of adult patients with CLD and laboratory-confirmed diagnosis of COVID-19 between March 1, 2020 and May 30, 2020. We performed survival analysis to identify independent predictors of all-cause mortality and COVID-19 related mortality, and multivariate logistic regression to determine the risk of severe COVID-19 in patients with CLD. RESULTS: Of the 978 patients in our cohort, 867 patients (mean age 56.9 ± 14.5 years, 55% male) met inclusion criteria. The overall all-cause mortality was 14.0% (n = 121), and 61.7% (n = 535) had severe COVID-19. Patients presenting with diarrhea or nausea/vomiting were more likely to have severe COVID-19. The liver-specific factors associated with independent risk of higher overall mortality were alcohol-related liver disease (ALD) (hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.29-4.55), decompensated cirrhosis (HR 2.91 [1.70-5.00]) and hepatocellular carcinoma (HCC) (HR 3.31 [1.53-7.16]). Other factors were increasing age, diabetes, hypertension, chronic obstructive pulmonary disease and current smoker. Hispanic ethnicity (odds ratio [OR] 2.33 [1.47-3.70]) and decompensated cirrhosis (OR 2.50 [1.20-5.21]) were independently associated with risk for severe COVID-19. CONCLUSIONS: The risk factors which predict higher overall mortality among patients with CLD and COVID-19 are ALD, decompensated cirrhosis and HCC. Hispanic ethnicity and decompensated cirrhosis are associated with severe COVID-19. Our results will enable risk stratification and personalization of the management of patients with CLD and COVID-19. Clinicaltrials.gov number NCT04439084.