There is growing concern that racial and ethnic minority communities around the world are experiencing a disproportionate burden of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ...infection and coronavirus disease 2019 (COVID-19). We investigated racial and ethnic disparities in patterns of COVID-19 testing (i.e., who received testing and who tested positive) and subsequent mortality in the largest integrated healthcare system in the United States.
This retrospective cohort study included 5,834,543 individuals receiving care in the US Department of Veterans Affairs; most (91%) were men, 74% were non-Hispanic White (White), 19% were non-Hispanic Black (Black), and 7% were Hispanic. We evaluated associations between race/ethnicity and receipt of COVID-19 testing, a positive test result, and 30-day mortality, with multivariable adjustment for a wide range of demographic and clinical characteristics including comorbid conditions, health behaviors, medication history, site of care, and urban versus rural residence. Between February 8 and July 22, 2020, 254,595 individuals were tested for COVID-19, of whom 16,317 tested positive and 1,057 died. Black individuals were more likely to be tested (rate per 1,000 individuals: 60.0, 95% CI 59.6-60.5) than Hispanic (52.7, 95% CI 52.1-53.4) and White individuals (38.6, 95% CI 38.4-38.7). While individuals from minority backgrounds were more likely to test positive (Black versus White: odds ratio OR 1.93, 95% CI 1.85-2.01, p < 0.001; Hispanic versus White: OR 1.84, 95% CI 1.74-1.94, p < 0.001), 30-day mortality did not differ by race/ethnicity (Black versus White: OR 0.97, 95% CI 0.80-1.17, p = 0.74; Hispanic versus White: OR 0.99, 95% CI 0.73-1.34, p = 0.94). The disparity between Black and White individuals in testing positive for COVID-19 was stronger in the Midwest (OR 2.66, 95% CI 2.41-2.95, p < 0.001) than the West (OR 1.24, 95% CI 1.11-1.39, p < 0.001). The disparity in testing positive for COVID-19 between Hispanic and White individuals was consistent across region, calendar time, and outbreak pattern. Study limitations include underrepresentation of women and a lack of detailed information on social determinants of health.
In this nationwide study, we found that Black and Hispanic individuals are experiencing an excess burden of SARS-CoV-2 infection not entirely explained by underlying medical conditions or where they live or receive care. There is an urgent need to proactively tailor strategies to contain and prevent further outbreaks in racial and ethnic minority communities.
The term acute‐on‐chronic liver failure (ACLF) is intended to identify patients with chronic liver disease who develop rapid deterioration of liver function and high short‐term mortality after an ...acute insult. The two prominent definitions (European Association for the Study of the Liver EASL and Asian Pacific Association for the Study of the Liver APASL) differ, and existing literature applies to narrow patient groups. We sought to compare ACLF incidence and mortality among a diverse cohort of patients with compensated cirrhosis, using both definitions. This was a retrospective cohort study of patients with incident compensated cirrhosis in the Veterans Health Administration from 2008 to 2016. First ACLF events were identified for each definition. Incidence rates were computed as events per 1,000 person‐years, and mortality was calculated at 28 and 90 days. Among 80,383 patients with cirrhosis with 3.35 years median follow‐up, 783 developed EASL and APASL ACLF, 4,296 developed EASL ACLF alone, and 574 developed APASL ACLF alone. The incidence rate of APASL ACLF was 5.7 per 1,000 person‐years (95% confidence interval CI: 5.4‐6.0), and the incidence rate of EASL ACLF was 20.1 (95% CI: 19.5‐20.6). The 28‐day and 90‐day mortalities for APASL ACLF were 41.9% and 56.1%, respectively, and were 37.6% and 50.4% for EASL ACLF. The median bilirubin level at diagnosis of EASL‐alone ACLF was 2.0 mg/dL (interquartile range: 1.1‐4.0). Patients with hepatitis C or nonalcoholic fatty liver disease had among the lowest ACLF incidence rates but had the highest short‐term mortality. Conclusion: There is significant discordance in ACLF events by EASL and APASL criteria. The majority of patients with EASL‐alone ACLF have preserved liver function, suggesting the need for more liver‐specific ACLF criteria.
The impact of proton pump inhibitory (PPI) medications on adverse outcomes in cirrhosis remains controversial. We aimed to evaluate the association between PPI exposure and all-cause mortality, ...infection, and decompensation in a large national cohort.
This was a retrospective study of patients with cirrhosis in the Veterans Health Administration. PPI exposure was classified as a time-updating variable from the index time of the cirrhosis diagnosis. Inverse probability treatment weighting–adjusted Cox regression was performed with additional adjustment for key time-varying covariates, including cardiovascular comorbidities, gastrointestinal bleeding (GIB), and statin exposure.
The study included 76,251 patients, 23,628 of whom were on a PPI at baseline. In adjusted models, binary (yes/no) PPI exposure was associated with reduced hazard of all-cause mortality in patients with hospitalization for GIB (hazard ratio HR, 0.88; 95% confidence interval CI, 0.84–0.91; P < .001) but had no significant association in all others (HR, 0.99; 95% CI, 0.97–1.02; P = .58). However, cumulative PPI exposure was associated with increased mortality in patients without hospitalization for GIB (HR, 1.07 per 320 mg-months omeprazole equivalents; 95% CI, 1.06–1.08; P < .001). PPI exposure was significantly associated with severe infection (HR, 1.21; 95% CI, 1.18–1.24; P < .001) and decompensation (HR, 1.64; 95% CI, 1.61–1.68; P < .001). In a cause-specific mortality analysis, PPI exposure was associated with increased liver-related mortality (HR, 1.23; 95% CI, 1.19–1.28) but with decreased nonliver-related mortality (HR, 0.88; 95% CI, 0.85–0.91).
PPI exposure is associated with increased risk of infection and decompensation in cirrhosis, which may mediate liver-related mortality. However, PPI use was associated with reduced all-cause mortality in those with prior GIB, suggesting benefit in the presence of an appropriate indication.
Proton pump inhibitor use in cirrhosis is associated with increased risk of liver-related adverse outcomes, but may reduce mortality in patients hospitalized with gastrointestinal bleeding.
Two mRNA-based vaccines against coronavirus disease 2019 (COVID-19) were found to be highly efficacious in phase 3 clinical trials in the US. However, patients with chronic illnesses, including ...cirrhosis, were excluded from clinical trials. Patients with cirrhosis have immune dysregulation that is associated with vaccine hyporesponsiveness.
To study the association of receipt of the Pfizer BNT162b2 mRNA or the Moderna mRNA-1273 vaccines in patients with cirrhosis compared with a propensity-matched control group of patients at similar risk of infection and severe disease from COVID-19.
We performed a retrospective cohort study of patients with cirrhosis who received at least 1 dose of a COVID-19 mRNA vaccine at the Veterans Health Administration. Patients who received at least 1 dose of the vaccine (n = 20 037) were propensity matched with 20 037 controls to assess the associations of vaccination with new COVID-19 infection and COVID-19 hospitalization and death.
Receipt of at least 1 dose of the BNT162b2 mRNA or the mRNA-1273 vaccines between December 18, 2020, and March 17, 2021.
COVID-19 infection as documented by a positive result for COVID-19 by polymerase chain reaction, hospitalization, and death due to COVID-19 infection.
The median (interquartile range) age of the vaccinated individuals in the study cohort was 69.1 (8.4) years and 19 465 (97.2%) of the participants in each of the vaccinated and unvaccinated groups were male, consistent with a US veteran population. The mRNA-1273 vaccine was administered in 10 236 (51%) and the BNT162b2 mRNA in 9801 (49%) patients. Approximately 99.7% of patients who received the first dose of either vaccine with a follow-up of 42 days or more received a second dose. The number of COVID-19 infections in the vaccine recipients was similar to the control group in days 0 to 7, 7 to 14, 14 to 21, and 21 to 28 after the first dose. After 28 days, receipt of 1 dose of an mRNA vaccine was associated with a 64.8% reduction in COVID-19 infections and 100% protection against hospitalization or death due to COVID-19 infection. The association of reduced COVID-19 infections after the first dose was lower among patients with decompensated (50.3%) compared with compensated cirrhosis (66.8%). Receipt of a second dose was associated with a 78.6% reduction in COVID-19 infections and 100% reduction in COVID-19-related hospitalization or death after 7 days.
This cohort study of US veterans found that mRNA vaccine administration was associated with a delayed but modest reduction in COVID-19 infection but an excellent reduction in COVID-19-related hospitalization or death in patients with cirrhosis.
Background
The natural history of patients with anti‐mitochondrial antibody (AMA)‐negative Primary Biliary Cholangitis (PBC) cirrhosis has not been well defined, with prior studies showing discordant ...results. Furthermore, most studies of AMA‐negative PBC have limited numbers of patients with cirrhosis and liver‐related outcomes.
Methods
We investigated the association of AMA‐negative PBC and the development of death, liver‐related death, decompensation and hepatocellular carcinoma (HCC), in a large cohort of predominantly male patients with PBC cirrhosis assembled from the Veterans Health Administration.
Results
In a cohort of 521 patients with PBC cirrhosis (65 AMA‐negative) with a total follow‐up of 2504.3 person‐years (PY) from cirrhosis diagnosis, patients with AMA‐negative PBC were younger and more likely to be black but had similar rates of UDCA response. AMA‐negative PBC cirrhosis was associated with similar unadjusted rates of liver‐related death (4.6 vs 5.9 per 100 PY, P = .44), overall death (7.7 vs 9.6 per 100 PY, P = .31), decompensation (7.3 vs 5.1 per 100 PY, P = .12) and HCC (0.6 vs 1.0 per 100 PY, P = .63) to AMA‐positive PBC. After adjusting for confounders, AMA‐negative PBC cirrhosis was associated with similar rates of liver‐related death (sub‐Hazard Ratio sHR 1.27, 95% CI 0.71‐2.28, P = .42, death sHR 1.24, 95% CI 0.81‐1.90, P = .32), decompensation (sHR 1.05, 95% CI 0.56‐1.98, P = .87) and HCC (sHR 0.48, 95% CI 0.11‐2.10, P = .33) to AMA‐positive patients.
Conclusion
In a cohort of predominantly male patients, AMA‐negative PBC cirrhosis was associated with similar rates of overall or liver‐related death, HCC or decompensation compared with AMA‐positive disease.
Hepatocellular carcinoma (HCC) arises from a number of cirrhosis-related and non-cirrhosis-related exposures and is one of the leading causes of cancer-related deaths worldwide. Achieving a durable ...cure currently relies on either resection or transplantation, but since most patients will be diagnosed with inoperable disease, there is great interest in achieving more effective systemic therapies. At a molecular level, HCC is heterogeneous, but initial treatment strategies, including the use of multi-targeted tyrosine kinase inhibitors and checkpoint inhibitors, have been fairly homogenous, depending on general host factors and overall tumor burden rather than specific molecular signatures. Over the past 2 decades, however, there has been significant success in identifying key molecular targets, including driver mutations involving the telomerase reverse transcriptase, p53, and beta-catenin genes, and significant work is now being devoted to translating these discoveries into the development of robust and well-tolerated targeted therapies. Furthermore, multi-modal therapies have also begun to emerge, harnessing possible synergism amongst a variety of different treatment classes. As the findings of these landmark trials become available over the next several years, the landscape of the systemic management of advanced HCC will change significantly.
Background and Aims
Acute on chronic liver failure (ACLF) results in extremely high short‐term mortality in patients with underlying cirrhosis. The European Association for the Study of the Liver ...criteria grade ACLF severity from 1 (least severe) to 3 (most severe) based on organ failures (OFs) that develop after an acute decompensation (AD). However, the implications of surviving low‐grade ACLF in terms of risk of subsequent high‐grade ACLF are unclear.
Approach and Results
We conducted a retrospective cohort study of patients with compensated cirrhosis in the Veterans Health Administration database from January 2008 to June 2016. Propensity matching for grade 1 (G1) ACLF, followed by Cox regression, was used to model risk of subsequent grade 3 (G3) ACLF. Stratified analyses of different ADs and OFs were also performed. We identified 4,878 patients with well‐matched propensity scores. G1 ACLF events conferred a significantly increased risk of subsequent G3 ACLF relative no previous G1 ACLF (hazard ratio, 8.69; P < 0.001). When stratified by AD, patients with ascites or hepatic encephalopathy were significantly more likely to develop G3 ACLF relative to those with gastrointestinal bleed or infection as an AD (P < 0.001). Risk of G3 ACLF also varied significantly by type of OF characterizing previous G1 ACLF, with liver, coagulation, and circulatory failure posing the highest increased risk.
Conclusions
Patients who recover from G1 ACLF have substantially increased risk of later developing G3 ACLF as compared to those who never have G1 ACLF. Moreover, reversible decompensations for G1 ACLF have a lower risk of G3 ACLF, and liver‐intrinsic OFs confer a much higher risk of G3 ACLF. These findings have implications for prognosis, future surveillance, and triaging early transplant evaluation.
It is unclear if hepatocellular carcinoma (HCC) risk declines over time after hepatitis C virus (HCV) eradication. We analyzed changes in HCC annual incidence over time following HCV eradication and ...identified dynamic markers of HCC risk.
We identified 48,135 patients who initiated HCV antiviral treatment from 2000 through 2015 and achieved a sustained virologic response (SVR) in the Veterans Health Administration (29,033 treated with direct-acting antiviral DAA agents and 19,102 treated with interferon-based regimens). Patients were followed after treatment until February 14, 2019 (average 5.4 years), during which 1509 incident HCCs were identified.
Among patients with cirrhosis before treatment with DAAs (n = 9784), those with pre-SVR fibrosis-4 (FIB-4) scores ≥3.25 had a higher annual incidence of HCC (3.66%/year) than those with FIB-4 scores <3.25 (1.16%/year) (adjusted hazard ratio 2.14; 95% confidence interval 1.66–2.75). In DAA-treated patients with cirrhosis and FIB-4 scores ≥3.25, annual HCC risk decreased from 3.8%/year in the first year after SVR to 2.4%/year by the fourth year (P=.01). In interferon-treated patients with FIB-4 scores ≥3.25, annual HCC risk remained above 2%/year, even 10 years after SVR. A decrease in FIB-4 scores from ≥3.25 pre-SVR to <3.25 post-SVR was associated with an approximately 50% lower risk of HCC, but the absolute annual risk remained above 2%/year. Patients without cirrhosis before treatment (n = 38,351) had a low risk of HCC, except for those with pre-SVR FIB-4 scores ≥3.25 (HCC risk 1.22%/year) and post-SVR FIB-4 scores ≥3.25 (HCC risk 2.39%/year); risk remained high for many years after SVR.
Patients with cirrhosis before an SVR to treatment for HCV infection continue to have a high risk for HCC (>2%/year) for many years, even if their FIB-4 score decreases, and should continue surveillance. Patients without cirrhosis but with FIB-4 scores ≥3.25 have a high enough risk to merit HCC surveillance, especially if FIB-4 remains ≥3.25 post-SVR.
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The Child-Turcotte-Pugh (CTP) score is a widely used and validated predictor of long-term survival in cirrhosis. The CTP score is a composite of 5 subscores, 3 based on objective clinical laboratory ...values and 2 subjective variables quantifying the severity of ascites and hepatic encephalopathy. To date, no system to quantify CTP score from administrative databases has been validated. The Veterans Outcomes and Costs Associated with Liver Disease study is a multicenter collaborative study to evaluate the outcomes and costs of hepatocellular carcinoma in the U.S. Veterans Health Administration. We developed and validated an algorithm to calculate electronic CTP (eCTP) scores by using data from the Veterans Health Administration Corporate Data Warehouse.
Multiple algorithms for determining each CTP subscore from International Classification of Diseases version 9, Common Procedural Terminology, pharmacy, and laboratory data were devised and tested in 2 patient cohorts. For each cohort, 6 site investigators (Boston, Bronx, Brooklyn, Philadelphia, Minneapolis, and West Haven VA Medical Centers) were provided cases from which to determine validity of diagnosis, laboratory data, and clinical assessment of ascites and encephalopathy. The optimal algorithm (designated eCTP) was then applied to 30,840 cirrhotic patients alive in the first quarter of 2008 for whom 5-year overall and transplant-free survival data were available. The ability of the eCTP score and other disease severity scores (Charlson-Deyo index, Veterans Aging Cohort Study index, Model for End-Stage Liver Disease score, and Cirrhosis Comorbidity) to predict survival was then assessed by Cox proportional hazards regression.
Spearman correlations for administrative and investigator validated laboratory data in the HCC and cirrhotic cohorts, respectively, were 0.85 and 0.92 for bilirubin, 0.92 and 0.87 for albumin, and 0.84 and 0.86 for international normalized ratio. In the HCC cohort, the overall eCTP score matched 96% of patients to within 1 point of the chart-validated CTP score (Spearman correlation, 0.81). In the cirrhosis cohort, 98% were matched to within 1 point of their actual CTP score (Spearman, 0.85). When applied to a cohort of 30,840 patients with cirrhosis, each unit change in eCTP was associated with 39% increase in the relative risk of death or transplantation. The Harrell C statistic for the eCTP (0.678) was numerically higher than those for other disease severity indices for predicting 5-year transplant-free survival. Adding other predictive models to the eCTP resulted in minimal differences in its predictive performance.
We developed and validated an algorithm to extrapolate an eCTP score from data in a large administrative database with excellent correlation to actual CTP score on chart review. When applied to an administrative database, this algorithm is a highly useful predictor of survival when compared with multiple other published liver disease severity indices.
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