Loralee B. Rupp

Baseline Characteristics and Mortality Among People in Care for Chronic Viral Hepatitis: The Chronic Hepatitis Cohort Study

BACKGROUND The Chronic Hepatitis Cohort Study (CHeCS), a dynamic prospective, longitudinal, observational cohort study, was created to assess the clinical impact of chronic viral hepatitis in the United States. This report describes the cohort selection process, baseline demographics, and insurance, biopsy, hospitalization, and mortality rates. METHODS Electronic health records of >1.6 million adult patients seen from January 2006 through December 2010 at 4 integrated healthcare systems in Detroit, Michigan; Danville, Pennsylvania; Portland, Oregon; and Honolulu, Hawaii were collected and analyzed. RESULTS Of 2202 patients with chronic hepatitis B virus (HBV) infection, 50% were aged 44-63 years, 57% male, 58% Asian/Pacific Islander, and 13% black; and 5.1% had Medicaid, 16.5% Medicare, and 76.3% private insurance. During 2001-2010, 22.3% had a liver biopsy and 37.9% were hospitalized. For the 8810 patients with chronic hepatitis C virus (HCV) infection, 75% were aged 44-63 years, 60% male, 23% black; and 12% had Medicaid, 23% Medicare, and 62% private insurance. During 2001-2010, 38.4% had a liver biopsy and 44.3% were hospitalized. Among persons in care, 9% of persons with HBV and 14% of persons with HCV infection, mainly those born during 1945-1964, died during the 2006-2010 five-year period. CONCLUSIONS Baseline demographic, hospitalization, and mortality data from CHeCS highlight the substantial US health burden from chronic viral hepatitis, particularly among persons born during 1945-1964.

Noninvasive Serum Fibrosis Markers for Screening and Staging Chronic Hepatitis C Virus Patients in a Large US Cohort

BACKGROUND Liver biopsy remains critical for staging liver disease in hepatitis C virus (HCV)-infected persons, but is a bottleneck to evaluation, follow-up, and treatment of HCV. Our analysis sought to validate APRI (aspartate aminotransferase [AST]-to-platelet ratio index) and FIB-4, an index from serum fibrosis markers (alanine aminotransferase [ALT], AST, and platelets plus patient age) to stage liver disease. METHODS Biopsy results from HCV patients in the Chronic Hepatitis Cohort Study were mapped to an F0-F4 equivalent scale; APRI and FIB-4 scores at the time of biopsy were then mapped to the same scale. RESULTS We identified 2372 liver biopsies from HCV-infected patients with contemporaneous laboratory values for imputing APRI and FIB-4. Fibrosis stage distributions by the equivalent biopsy scale were 267 (11%) F0; 555 (23%) F1; 648 (27%) F2; 394 (17%) F3; and 508 (21%) F4. Mean APRI and FIB-4 values significantly increased with successive fibrosis levels (P < .05). The areas under the receiver operating characteristic curve (AUROC) analysis distinguishing severe (F3-F4) from mild-to-moderate fibrosis (F0-F2) were 0.80 (95% confidence interval [CI], .78-.82) for APRI and 0.83 (95% CI, .81-.85) for FIB-4. There was a significant difference between the AUROCs of FIB-4 and APRI (P < .001); 88% of persons who had a FIB-4 score ≥2.0 were at stage F2 or higher. CONCLUSIONS In a large observational cohort, FIB-4 was good at differentiating 5 stages of chronic HCV infection. It can be useful in screening patients who need biopsy and therapy, for monitoring patients with less advanced disease, and for longitudinal studies.

Antiviral Therapy for Chronic Hepatitis B Virus Infection and Development of Hepatocellular Carcinoma in a US Population

BACKGROUND & AIMS Antiviral therapy could reduce the risk of hepatocellular carcinoma (HCC) among persons with chronic hepatitis B virus (HBV) infection. We evaluated the relationship between therapy for chronic HBV infection and HCC incidence using data from a longitudinal study of patients at 4 US healthcare centers. METHODS We analyzed electronic health records of 2671 adult participants in the Chronic Hepatitis Cohort Study who were diagnosed with chronic HBV infection from 1992 through 2011 (49% Asian). Data analyzed were collected for a median of 5.2 years. Propensity-score adjustment was used to reduce bias, and Cox regression was used to estimate the relationship between antiviral treatment and HCC. The primary outcome was time to event of HCC incidence. RESULTS Of study subjects, 3% developed HCC during follow-up period: 20 cases among the 820 patients with a history of antiviral HBV therapy and 47 cases among the 1851 untreated patients. In propensity-adjusted Cox regression, patients who received antiviral therapy had a lower risk of HCC than those who did not receive antiviral therapy (adjusted hazard ratio, 0.39; 95% confidence interval, 0.27-0.56; P < .001), after adjusting for abnormal level of alanine aminotransferase. In a subgroup analysis, antiviral treatment was associated with a lower risk of HCC after adjusting for serum markers of cirrhosis (adjusted hazard ratio, 0.24; 95% confidence interval, 0.15-0.39; P < .001). In a separate subgroup analysis of patients with available data on HBV DNA viral load, treated patients with viral loads >20,000 IU/mL had a significantly lower risk of HCC than untreated patients with viral loads >20,000 IU/mL. CONCLUSIONS In a large geographically, clinically, and racially diverse US cohort, antiviral therapy for chronic HBV infection was associated with a reduced risk for HCC.

Mortality Among Persons in Care With Hepatitis C Virus Infection: The Chronic Hepatitis Cohort Study (CHeCS), 2006–2010

BACKGROUND The number of deaths in hepatitis C virus (HCV)-infected persons recorded on US death certificates has been increasing, but actual rates and causes of death in these individuals have not been well elucidated. METHODS Disease-specific, liver-related, and non-liver-related mortality data for HCV-infected patients in an observational cohort study, the Chronic Hepatitis Cohort Study (CHeCS) at 4 US healthcare systems, were compared with multiple cause of death (MCOD) data in 12 million death certificates in 2006-2010. Premortem diagnoses, liver biopsies, and FIB-4 scores (a noninvasive measure of liver damage) were examined. RESULTS Of 2 143 369 adult patients seen at CHeCS sites in 2006-2010, 11 703 (0.5%) had diagnosed chronic HCV infection, and 1590 (14%) died. The majority of CHeCS decedents were born from 1945 to 1965 (75%), white (50%), and male (68%); mean age of death was 59 years, 15 years younger than MCOD deaths. The age-adjusted mortality rate for liver disease in CHeCS was 12 times higher than the MCOD rate. Before death, 63% of decedents had medical record evidence of chronic liver disease, 76% had elevated FIB-4 scores, and, among those biopsied, 70% had moderate or worse liver fibrosis. However, only 19% of all CHeCS decedents and only 30% of those with recorded liver disease had HCV listed on their death certificates. CONCLUSIONS HCV infection is greatly underdocumented on death certificates. The 16 622 persons with HCV listed in 2010 may represent only one-fifth of about 80 000 HCV-infected persons dying that year, at least two-thirds of whom (53 000 patients) would have had premortem indications of chronic liver disease.

Increased incidence of cancer and cancer-related mortality among persons with chronic hepatitis C infection, 2006–2010

BACKGROUND & AIMS Persons chronically infected with the hepatitis C virus (HCV) may be at higher risk for developing and dying from non-liver cancers than the general population. METHODS 12,126 chronic HCV-infected persons in the Chronic Hepatitis Cohort Study (CHeCS) contributed 39,984 person-years of follow-up from 2006 to 2010 and were compared to 133,795,010 records from 13 Surveillance, Epidemiology and End Results Program (SEER) cancer registries, and approximately 12 million U.S. death certificates from Multiple Cause of Death (MCOD) data. Measurements included standardized rate ratios (SRR) and relative risk (RR). RESULTS The incidence of the following cancers was significantly higher among patients with chronic HCV infection: liver (SRR, 48.6 [95% CI, 44.4-52.7]), pancreas (2.5 [1.7-3.2]), rectum (2.1 [1.3-2.8]), kidney (1.7 [1.1-2.2]), non-Hodgkin lymphoma (NHL) (1.6 [1.2-2.1]), and lung (1.6 [1.3-1.9]). Age-adjusted mortality was significantly higher among patients with: liver (RR, 29.6 [95% CI, 29.1-30.1]), oral (5.2 [5.1-5.4]), rectum (2.6 [2.5-2.7]), NHL (2.3 [2.2-2.31]), and pancreatic (1.63 [1.6-1.7]) cancers. The mean ages of cancer diagnosis and cancer-related death were significantly younger among CHeCS HCV cohort patients compared to the general population for many cancers. CONCLUSIONS Incidence and mortality of many types of non-liver cancers were higher, and age at diagnosis and death younger, in patients with chronic HCV infection compared to the general population.

APRI and FIB-4 are good predictors of the stage of liver fibrosis in chronic hepatitis B: the Chronic Hepatitis Cohort Study (CHeCS)

We aim to determine the predictive ability of APRI, FIB‐4 and AST/ALT ratio for staging of liver fibrosis and to differentiate significant fibrosis (F2–F4) from none to minimal fibrosis (F0–F1) in chronic hepatitis B (CHB). Liver biopsy results were mapped to an F0–4 equivalent fibrosis stage. Mean APRI and FIB‐4 scores were significantly higher for each successive fibrosis level from F1 to F4 (P < 0.05). Based on optimized cut‐offs, the AUROCs in distinguishing F2–F4 from F0 to F1 were 0.81 (0.76–0.87) for APRI, 0.81 (0.75–0.86) for FIB‐4 and 0.56 (0.49–0.64) for AST/ALT ratio. APRI and FIB‐4 distinguished F2–F4 from F0 to F1 with good sensitivity and specificity and can be useful for treatment decisions and monitoring progression of fibrosis.

Predictors of Poor Mental and Physical Health Status Among Patients With Chronic Hepatitis C Infection: The Chronic Hepatitis Cohort Study (CHeCS)

Our objective was to assess the extent and risk factors for depression and poor physical health among patients with chronic hepatitis C virus (HCV) infection. We surveyed HCV‐infected patients seen at four large healthcare systems participating in the Chronic Hepatitis Cohort Study (CHeCS). Survey data included demographics, depression and physical health measures, substance use history, current social support, recent stressor exposures, and, from the electronic medical record, treatment history, and Charlson Comorbidity Index scores. There were 4,781 respondents, who were a mean of 56.7 years old, 71% White, and 57% male. Altogether, 51.4% reported past injection drug use, 33.9% were current smokers, and 17.7% had abused alcohol in the previous year. Additionally, 47.4% had been previously treated for HCV and 14.8% had a 12‐week sustained viral response (SVR) following HCV therapy. Overall, 29.7% of patients met criteria for current depression and 24.6% were in poor physical health. In multivariate analyses, significant predictors of depression and poor health included: male gender (versus female, odds ratios [ORs], 0.70 and 0.81), Black race (versus white, ORs, 0.60 and 0.61), having education less than high school (versus college, ORs, 1.81 and 1.54), being employed (versus not, ORs, 0.36 and 0.25), having high life stressors (versus low, ORs, 2.44 and 1.64), having low social support (versus high, ORs = 2.78 and 1.40), and having high Charlson scores (versus none, ORs = 1.58 and 2.12). Achieving a 12‐week SVR was found to be protective for depression. Conclusion: This large survey of U.S. HCV patients indicates the extent of adverse health behaviors and mental and physical comorbidities among these patients. (Hepatology 2015;61:802–811)

Prevalence of Cirrhosis in Hepatitis C Patients in the Chronic Hepatitis Cohort Study (CHeCS): A Retrospective and Prospective Observational Study

Objectives:The severity of liver disease in the hepatitis C virus (HCV)-infected population in the United States remains uncertain. We estimated the prevalence of cirrhosis in adults with chronic hepatitis C (CHC) using multiple parameters including liver biopsy, diagnosis/procedure codes, and a biomarker.Methods:Patients enrolled in the Chronic Hepatitis Cohort Study (CHeCS) who received health services during 2006–2010 were included. Cirrhosis was identified through liver biopsy reports, diagnosis/procedure codes for cirrhosis or hepatic decompensation, and Fibrosis-4 (FIB-4) scores ≥5.88. Demographic and clinical characteristics associated with cirrhosis were identified through multivariable logistic modeling.Results:Among 9,783 patients, 2,788 (28.5%) were cirrhotic by at least one method. Biopsy identified cirrhosis in only 661 (7%) patients, whereas FIB-4 scores and diagnosis/procedure codes for cirrhosis and hepatic decompensation identified cirrhosis in 2,194 (22%), 557 (6%), and 482 (5%) patients, respectively. Among 661 patients with biopsy-confirmed cirrhosis, only 356 (54%) had an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for cirrhosis. Older age, male gender, Asian race, Hispanic ethnicity, genotype 3 infection, HIV coinfection, diabetes, history of antiviral therapy, and history of alcohol abuse were independently associated with higher odds of cirrhosis (all, P<0.05). Conversely, private health insurance coverage, black race, and HCV genotype 2 were associated with lower odds of cirrhosis.Conclusions:A high proportion of patients with biopsy-confirmed cirrhosis are not assigned ICD-9 codes for cirrhosis. Consequently, ICD-9 codes may not be reliable as the sole indicator of the prevalence of cirrhosis in cohort studies. Use of additional parameters suggests a fourfold higher prevalence of cirrhosis than is revealed by biopsy alone. These findings suggest that cirrhosis in CHC patients may be significantly underdocumented and underdiagnosed.

Late diagnosis of hepatitis C virus infection in the Chronic Hepatitis Cohort Study (CHeCS): Missed opportunities for intervention.

To determine the stage of liver disease at initial diagnosis of hepatitis C virus (HCV) infection, we analyzed data from the Chronic Hepatitis Cohort Study (CHeCS), a large U.S. observational study. We examined the temporal relationships of initial HCV infection diagnosis with cirrhosis—defined by liver biopsy or mean FIB‐4 score >5.88—and time to onset of cirrhotic decompensation in electronic medical records. We determined time in the health system prior to HCV diagnosis and rates of hospitalization and death following HCV diagnosis. Of 14,717 patients with chronic HCV seen during 2006‐2011, 6,166 (42%) had a definable time of initial HCV diagnosis. Of these, 1,056 (17%) patients met our definition for “late diagnosis” with either cirrhosis concurrent with initial HCV diagnosis (n = 550), a first diagnosis of hepatic decompensation before or within 12 months after initial HCV diagnosis (n = 506), or both (n = 314). Patients with late diagnosis had an average of 6 years in the health system before their HCV diagnosis. In a comparison with patients without late diagnosis, hospitalization (59% versus 35%) and death (33% versus 9%) were more frequent among patients with late diagnosis. Among all who died, mean (median) time from initial HCV diagnosis to death was 4.8 (4.2) years. Conclusion: Many CHeCS patients had advanced liver disease concurrent with their initial HCV diagnosis despite many years of engagement with the healthcare system, and these patients had high rates of hospitalization and mortality. (Hepatology 2015;61:1479–1484)

Hepatitis C treatment failure is associated with increased risk of hepatocellular carcinoma.

Sustained virological response (SVR) to antiviral therapy for hepatitis C (HCV) reduces risk of hepatocellular carcinoma (HCC), but there is little information regarding how treatment failure (TF) compares to lack of treatment. We evaluated the impact of treatment status on risk of HCC using data from the Chronic Hepatitis Cohort Study (CHeCS–an observational study based in four large US health systems, with up to 7 years of follow‐up on patients). Multivariable analyses were used to adjust for bias in treatment selection, as well as other covariates, followed by sensitivity analyses. Among 10 091 HCV patients, 3681 (36%) received treatment, 2099 (57%) experienced treatment failure (TF), and 1582 (43%) of these achieved sustained virological response (SVR). TF patients demonstrated almost twice the risk of HCC than untreated patients [adjusted hazard ratio (aHR) = 1.95, 95% confidence interval (CI) 1.50–2.53]; this risk persisted across all stages of fibrosis. Several sensitivity analyses validated these results. Although African Americans were at increased risk of treatment failure, they were at lower risk for HCC and all‐cause mortality compared to White patients. SVR patients had lower risk of HCC than TF patients (aHR = 0.48, CI 0.31–0.73), whereas treatment – regardless of outcome – reduced all‐cause mortality (aHR = 0.45, CI 0.34–0.60 for SVR patients; aHR = 0.78, CI 0.65–0.93 for TF patients).