Faculty Bibliography

BACKGROUND & AIMS:Chronic liver disease (CLD) and cirrhosis are associated with immune dysregulation, leading to concerns that affected patients may be at risk of adverse outcomes following SARS-CoV-2 infection. We aimed to determine the impact of COVID-19 on patients with pre-existing liver disease, which currently remains ill-defined. METHODS:Between 25th March and 8th July 2020, data on 745 patients with CLD and SARS-CoV-2 (including 386 with and 359 without cirrhosis) were collected by 2 international registries and compared to data on non-CLD patients with SARS-CoV-2 from a UK hospital network. RESULTS:Mortality was 32% in patients with cirrhosis compared to 8% in those without (p <0.001). Mortality in patients with cirrhosis increased according to Child-Pugh class (A [19%], B [35%], C [51%]) and the main cause of death was from respiratory failure (71%). After adjusting for baseline characteristics, factors associated with death in the total CLD cohort were age (odds ratio [OR] 1.02; 1.01-1.04), Child-Pugh A (OR 1.90; 1.03-3.52), B (OR 4.14; 2.4-7.65), or C (OR 9.32; 4.80-18.08) cirrhosis and alcohol-related liver disease (OR 1.79; 1.03-3.13). Compared to patients without CLD (n = 620), propensity-score-matched analysis revealed significant increases in mortality in those with Child-Pugh B (+20.0% [8.8%-31.3%]) and C (+38.1% [27.1%-49.2%]) cirrhosis. Acute hepatic decompensation occurred in 46% of patients with cirrhosis, of whom 21% had no respiratory symptoms. Half of those with hepatic decompensation had acute-on-chronic liver failure. CONCLUSIONS:In the largest such cohort to date, we demonstrate that baseline liver disease stage and alcohol-related liver disease are independent risk factors for death from COVID-19. These data have important implications for the risk stratification of patients with CLD across the globe during the COVID-19 pandemic. LAY SUMMARY:This international registry study demonstrates that patients with cirrhosis are at increased risk of death from COVID-19. Mortality from COVID-19 was particularly high among patients with more advanced cirrhosis and those with alcohol-related liver disease.

OBJECTIVE:Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are first-line agents for the treatment of chronic hepatitis B (CHB). Recent studies have challenged the assumption that these agents are equally effective at preventing hepatocellular carcinoma (HCC). We aimed to determine whether the risk of HCC and mortality differ in patients with CHB treated with ETV and TDF. DESIGN:We performed a retrospective cohort study of Veterans Affairs patients with CHB in the USA who initiated treatment with ETV or TDF between the dates of Food and Drug Administration approval of these medications and 1 January 2017. Multivariable Cox proportional hazards regression was used to determine the association between antiviral therapy and HCC risk as well as the risk of death or liver transplantation. Propensity score adjustment and competing risks analysis were performed. RESULTS:We identified 2193 ETV-treated and 1094 TDF-treated patients who were followed for a mean of 5.4 years. We found no difference in the risk of HCC in ETV-treated versus TDF-treated patients (adjusted HR (aHR) 1.00, 95% CI 0.76 to 1.32). Results were similar in propensity score adjusted and competing risks analysis, and in multiple sensitivity analyses. We also found no difference in the risk of death or liver transplantation (aHR 1.16, 95% CI 0.98 to 1.39). CONCLUSIONS:We found no difference in the risk of HCC between patients with CHB treated with ETV versus TDF. Our results support current guideline recommendations that both agents are appropriate first-line options for the treatment of CHB.

BACKGROUND:Fibroscan-derived liver stiffness decreases after anti-viral treatment for hepatitis C virus (HCV) infection, which may affect the associations and interpretation of liver stiffness. AIMS:To assess whether liver stiffness pre- or post-anti-viral therapy is associated with the development of decompensated cirrhosis, hepatocellular carcinoma (HCC) or death. METHODS:In this retrospective cohort study, we identified US veterans who initiated HCV treatment and had at least one liver stiffness before (n = 492) or after (n = 877) HCV therapy. We used Cox proportional hazards regression (adjusting for age, race/ethnicity, history of cirrhosis, body mass index, diabetes, FIB-4 score, Charlson comorbidity index, alcohol use disorder, Model for end-stage liver disease score and sustained virological response status) to determine the associations between pre- or post-treatment liver stiffness values and the development of decompensated cirrhosis, HCC, death or liver transplant. RESULTS:In the post-treatment liver stiffness cohort, during a mean follow-up of 27.3 months, 21 (2.4%) developed decompensated cirrhosis, 26 (3.0%) developed HCC and 57 (6.5%) died or underwent liver transplant. Compared to patients with post-treatment liver stiffness ≤12.5 kPa, those with post-treatment liver stiffness >20 kPa, had higher rates of developing decompensated cirrhosis (adjusted HR 3.85, 95% CI 1.29-11.50) and the composite outcome of death, liver transplant, decompensated cirrhosis or HCC (adjusted HR 1.95, 95% CI: 1.07-3.56). There were no significant associations between pre-treatment liver stiffness and any outcomes on multivariable analysis. CONCLUSIONS:Post-treatment liver stiffness >20 kPa, but not pre-treatment liver stiffness, was independently associated with the development of decompensated cirrhosis and the composite outcome in multivariable analyses. Measuring liver stiffness should be considered after anti-viral treatment because it predicts adverse outcomes even beyond routinely available clinical predictors.

Outcomes related to alcohol use after hepatitis C virus (HCV) treatment are unknown in the direct-acting antiviral (DAA) era. We assessed levels of alcohol use before and after HCV treatment and their association with long-term outcomes in a cohort of U.S. veterans. In this retrospective cohort analysis, 29,037 patients who initiated DAA regimens between 2013 and 2015 were followed for a mean of 3.04 years. We categorized alcohol use into three categories (nondrinking, low-level drinking, and unhealthy drinking) using Alcohol Use Disorders Identification Test-Consumption questionnaires administered within 1 year before (baseline) and after treatment. Multivariable Cox proportional hazards regression was used to determine the associations between alcohol use and mortality or liver-related outcomes. Before DAA treatment, 68% of veterans reported nondrinking, 22.9% reported low-level drinking, and 9.1% reported unhealthy drinking. Compared to patients with baseline non-drinking, those with unhealthy drinking had a higher risk of mortality (adjusted hazard ratio [HR] 1.53, 95% confidence interval [CI]: 1.34-1.75) and decompensated cirrhosis (adjusted HR 1.30, 95% CI: 1.06-1.59) and lower likelihood of liver transplantation (adjusted HR 0.24, 95% CI: 0.06-0.92). These associations were greater in patients without sustained virologic response than in those with sustained virologic response. When alcohol use before and after treatment was modeled as a time-varying covariate, similar associations were observed. Survival analysis also found that unhealthy drinking was significantly associated with a lower probability of survival compared with nondrinking. Low-level alcohol use was not associated with increased risk of adverse outcomes. Conclusion: In this large cohort of U.S. veterans with HCV who received DAAs, unhealthy drinking was common and associated with a higher risk of posttreatment mortality. Interventions to achieve alcohol cessation before and during antiviral treatment should be encouraged.