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Outcome of hospital care of liver disease associated with hepatitis C in the United States
Outcome of Hospital Care of Liver Disease Associated With Hepatitis C in the United States W. RAY KIM, JOHN B. GROSS, JR., JOHN J. POTERUCHA, G. RICHARD LOCKE, III, AND E. ROLLAND DICKSON
We describe mortality and resource utilization for inpatient care of hepatitis C (HCV) in comparison to alcohol-induced liver disease (ALD) in the United States and identify factors that affect outcomes. The Healthcare Cost and Utilization Project database, a national inpatient sample was used to identify hospitalization records with diagnoses related to liver disease from HCV and ALD. Outcome of hospitalizations was analyzed in terms of inhospital deaths and health care resource utilization. For 1995, we estimate that there were 26,700 hospitalizations and 2,600 deaths in acute, nonfederal hospitals in the United States for liver diseases caused by HCV. Total charges for these hospitalizations were $514 million. In comparison, ALD was associated with 101,200 hospitalizations, 13,400 deaths, and $1.8 billion in charges. Simultaneous HCV and alcohol abuse was associated with younger ages at the time of hospitalization and death compared with HCV or ALD alone. In a logistic regression analysis, alcohol abuse (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.2-1.5) and human immunodeficiency virus (HIV) infection (OR, 4.5; 95% CI, 4.0-4.9) were associated with an increased risk of death among those with HCV. Liver transplantation and patient death were associated with the largest increase in hospitalization charges. Major complications of cirrhosis, such as variceal bleeding, encephalopathy, and hepatorenal syndrome, and sociodemographic factors, such as race and health insurance, were also significantly associated with the risk of death and hospitalization charges, which were similar in HCV and ALD. This study provides new estimates regarding the public health impact of HCV, for use in health policy decisions and cost-effectiveness analyses of preventive and therapeutic interventions. (HEPATOLOGY 2001;33:201-206.) Hepatitis C (HCV) is the most common chronic bloodborne infection in the United States.1 The Centers for Disease Control and Prevention (CDC) estimates that as many as 2.7 million Americans are chronically infected with HCV.1 Cur-
rently, end-stage liver disease associated with HCV is the leading indication for liver transplantation in the United States, accounting for approximately 30% of cases.2 In addition, the CDC estimates that 8 to 10,000 deaths are related to HCV each year in the United States. Furthermore, this figure is expected to triple during the next 10 to 20 years.3 Since the discovery of HCV merely 10 years ago, significant progress has been made in our knowledge about the virus and the disease that it causes. However, the natural history and overall disease burden in the country remain uncertain. Because many infected people are asymptomatic and unaware of their infection, the magnitude of HCV as a potential public health problem may be underestimated.4-6 Available data have usually been obtained from tertiary care centers, which may not be representative of the entire nation.7-9 Data on the economic impact of hepatitis C are sparse.10 The total economic burden of hepatitis C in this country has been estimated to be approximately $600 million a year, although the source of this estimate is, to the best of our knowledge, unclear.3 In this study, we used a large administrative database to study the impact of hepatitis C in the United States. To put the hepatitis C data into perspective, hospitalizations for alcoholinduced liver disease (ALD) in the same database were analyzed in a similar fashion. ALD is the most common cause of cirrhosis in this country and is responsible for 12 to 13,000 deaths annually. Although liver disease–specific estimates are not well established, the cost of hospital care of alcohol-related illness in the country was estimated at $5.3 billion in 1992.11 The aims of this study were (1) to describe demographic and clinical characteristics of inpatient care of HCV- and ALD-related morbidity, (2) to provide nationwide estimates for the outcome of inpatient care, namely in-hospital deaths and resource utilization for these diagnoses, and (3) to identify demographic, clinical, and socioeconomic factors that may affect the in-hospital mortality and resource utilization. MATERIALS AND METHODS
Abbreviations: HCV, hepatitis C virus; ALD, alcohol-induced liver disease; HCUP, Healthcare Cost and Utilization Project; HBV, hepatitis B virus; HIV, human immunodeficiency virus. From the Outcomes Research Unit Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN. Received March 23, 2000; accepted October 2, 2000. Supported in part by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (DK34238). W.R.K. is a recipient of the Career Development Award in Epidemiology and Outcomes from Hepatitis Foundation International. Address reprint requests to: W. Ray Kim, M.D., Division of Gastroenterology and Hepatology (Ch 10), Mayo Clinic and Foundation, 200 First Street, SW, Rochester, MN 55905. E-mail: [email protected]; fax: 507-266-2810. Copyright © 2001 by the American Association for the Study of Liver Diseases. 0270-9139/01/3301-0026$3.00/0 doi:10.1053/jhep.2001.20798
Description of Database. The Healthcare Cost and Utilization Project (HCUP) is a multistate health care database, sponsored by the Agency for Healthcare Research and Quality (AHRQ, formerly the Agency for Health Care Policy and Research, AHCPR).12 The nationwide inpatient sample (NIS) of the HCUP data contains patient- as well as hospital-level information for inpatient hospital stays from over 900 hospitals in 19 states. These hospitals represented a 20% sample of nonfederal, acute-care hospitals, which altogether house 85% of hospital beds and admit 94% of hospitalizations in the United States. To ensure that the sample was representative of the United States as a whole, the AHRQ used a stratified sampling method based on the following criteria: (1) ownership control, (2) bed size, (3) teaching status, (4) urban/rural location, and (5) region of the United States. The AHRQ provided discharge weights for individual records
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202 KIM ET AL. according to the sampling strata, so that information in the database could be extrapolated to the national level. We used the fourth release of the NIS of the HCUP data from calendar year 1995, which contained 6.5 million hospital discharges. The variables in this database included patient demographics; clinical information, including principal and secondary diagnoses, procedures, diagnosis-related group (DRG) code, and patient disposition; and measures of resource utilization, including total charges and length of stay. Sociodemographic variables included age, gender, race (white, black, Hispanic, Asian, Native American, and other), expected primary payer (Medicare, Medicaid, private insurance/ HMO, and other including self-pay), and median income by the zip code area in which the patient resided. Since race was not reported by all states, case records with missing data on race were classified as unknown race. Hospital characteristics were based on location and teaching status (rural, urban nonteaching, and urban teaching) and geographic region (Northeast, South, Midwest, and West). Case Ascertainment. Case records with a diagnosis related to hepatitis C were identified using the diagnostic codes (ICD-9-CM) for hepatitis C infection (070.41, 070.44, 070.51, 070.54). We also extracted hospitalizations related to ALD (571.0-571.3). In addition, since concomitant alcohol abuse is a well-known cofactor in the progression of liver disease in patients with chronic hepatitis C, individuals with alcohol dependence (303), alcohol abuse (305.0), and mental disorders associated with alcohol (291) were identified (collectively referred to as “alcohol abuse” in this report). The hospitalizations were divided into 3 groups: (1) those with hepatitis C alone (HCV group), (2) those with concurrent hepatitis C and alcohol abuse or ALD (HCV/ETOH group), and (3) those with ALD without hepatitis C (ALD group). Because of the overlapping risk factors and potential influence on outcome, we identified hospitalizations that included hepatitis B (HBV: 070.2-070.3) and human immunodeficiency virus (HIV) diagnoses (042, 079.53). To take into account extrahepatic comorbidity status that may influence the outcome of hospitalizations, 4 additional diagnostic categories were considered for risk adjustment.13 These were based on underlying comorbidity factors used in the APACHE-III system,14 including diabetes mellitus, ischemic heart disease, cerebrovascular disease, and malignancies other than hepatocellular carcinoma. Hospitalizations in the 3 groups were divided into 2 categories, liver-related and liver-unrelated hospitalizations. A liver-related hospitalization was defined by the following criteria: (1) a principal diagnosis of HCV or ALD; (2) cirrhosis, portal hypertension, or other sequelae of chronic liver disease; (3) specific individual complications of chronic liver disease, including hepatic encephalopathy, variceal bleeding, ascites, hepatorenal syndrome, and hepatocellular carcinoma; or (4) hospitalization of a liver transplant recipient. Hospitalizations that included liver transplantation procedures were identified using the procedure code. Hospitalizations that did not meet these criteria were considered liver-unrelated hospitalizations. These mostly represented cases in which HCV or ALD was an incidental notation and the primary reason for hospitalization was another illness, including chemical dependency. Data Analysis. Hospitalizations that belonged to each of the 3 groups (HCV, HCV/ETOH, and ALD) were identified and the numbers were extrapolated to yield nationwide estimates. These estimates were rounded to the nearest hundred. Age and sex distribution as well as clinical characteristics including encephalopathy, variceal bleeding, ascites, hepatorenal syndrome, and hepatocellular carcinoma were described for the 3 groups. For liver-related hospitalizations, we compared additional sociodemographic variables, including race, primary payer, geographic region, income level by the ZIP code area of residence, and hospital characteristics. The outcome of hospitalizations was evaluated by in-hospital death, length of stay, and total charges. National estimates of these
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parameters were obtained based on sampling weights as outlined above. Patients were considered to have died of liver-related causes if the death occurred during a liver-related hospitalization. Logistic regression analyses were used to identify factors associated with in-hospital death in the HCV and ALD groups. The HCV/ ETOH group was included in both analyses noting the overlap of two conditions as a covariate. Additional predictor variables included (1) age and sex, (2) clinical events (gastrointestinal bleeding, encephalopathy, ascites, hepatorenal syndrome, hepatocellular carcinoma, liver transplantation), (3) extrahepatic comorbid conditions, (4) socioeconomic variables (race, payer, income level), and (5) hospital characteristics (region, hospital category). Discharge weights were taken into account in the regression models. The results of the models were expressed as odds ratios with 95% confidence intervals. Determinants of hospitalization charges for the HCV and ALD groups were investigated using multiple linear regression analyses. Because the charge data were skewed, models were created for charges after logarithmic transformation. Identical sets of predictor variables were used in the model. The results of the model were expressed as percent increase in charges associated with the given factor. RESULTS Overall Description. Among the 6.5 million records in the database, 12,900 hospitalizations (0.5%) listed HCV in one of the 15 available diagnostic fields. When the appropriate discharge weight was applied for each hospitalization record, it was estimated that there were 64,800 hospitalizations in acute, nonfederal hospitals in the United States in 1995 for individuals with hepatitis C, including 53,200 in the HCV group and 11,700 in the HCV/ETOH group (Table 1). By comparison, there were 218,100 hospitalizations in the ALD group. Of these hospitalizations, 19,300 of the HCV group (36%), 7,400 of the HCV/ETOH group (63%), and 101,200 of the ALD group (46%) met the criteria for liver-related hospitalization. The age distribution of the 3 groups is summarized in Table 1. The median age in the HCV group was 44 years, compared with 51 years in the ALD group. Within the HCV group, the median age for liver-related hospitalizations was 53 years compared with 42 years in the liver-unrelated hospitalizations. The median age for liver-related hospitalizations in the HCV/ETOH group was 9 years younger than the other 2 groups. Clinical characteristics of the 3 groups are shown in Table 2. The proportion of men was higher in the alcohol-related groups (HCV/ETOH and ALD). Complications of portal hypertension were seen most frequently in the HCV/ETOH
TABLE 1. Age Distribution and Number of Hospitalizations for (1) Hepatitis C Without Concomitant Alcohol Dependence (HCV Alone), (2) Hepatitis C With Alcohol Dependence (HCV/ETOH), and (3) ALD Alone Median Age (Interquartile Range)
Liver-related Liver-unrelated Total
HCV
HCV/ETOH
ALD
53 (42-67) N ⫽ 19,300 42 (36-51) N ⫽ 33,900 44 (38-59) N ⫽ 53,200
44 (39-50) N ⫽ 7,400 42 (37-47) N ⫽ 4,300 43 (39-49) N ⫽ 11,700
53 (43-64) N ⫽ 101,200 50 (41-63) N ⫽ 117,000 51 (42-63) N ⫽ 218,100
NOTE. The median age of each group is shown with the interquartile range in parentheses. (N ⫽ nationwide estimate of the number of hospitalizations in nonfederal acute-care hospitals in the respective category.)
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group, followed by the ALD group, and then the HCV group. Hepatocellular carcinoma, liver transplantation, and HIV or HBV coinfection were the least common in the ALD group. Sociodemographic characteristics of the liver-related hospitalizations are summarized in Table 3. The racial distribution was comparable among the 3 groups, with white patients accounting for approximately 60% of hospitalizations. Over 60% of hospitalizations for HCV-related liver problems were supported by public funding (Medicare and Medicaid). The majority of the hospitalizations occurred in urban hospitals. The proportion of hospitalizations in urban teaching hospitals was lower in the ALD group than the HCV group. The geographic distribution of hospitalizations was comparable among the 3 groups. Outcome of Inpatient Care for Hepatitis C. Among the 64,800 hospitalizations related to HCV, there were 3,900 in-hospital deaths, 2,600 of which occurred during liver-related hospitalizations (Table 4). This compared with 18,700 deaths from all causes and 13,400 from liver-related causes in the ALD group. Of the 3 groups, the median age at the time of death was the lowest in the HCV/ETOH group (46 years, compared with 60 and 57 in the other groups). We estimate the nationwide total charges associated with liver-related hospitalizations for HCV at $514 million, which includes $158 million for the HCV/ETOH group, and those for the ALD group at $1.8 billion (Table 4). The corresponding estimates for in-hospital days were 146,700 days for the HCV group, 60,900 for the HCV/ETOH group, and 802,000 days for the ALD group. Table 4 also includes median charges per hospitalization for the 3 groups, by liver transplantation. Table 5 summarizes the results of multivariate logistic regression analyses predicting in-hospital death, adjusting for age, sex, and extrahepatic comorbidity. Separate models were created for the HCV and ALD groups. As expected, all of the major complications of cirrhosis were associated with a significant increase in the risk of death. Of these, hepatorenal syndrome had the highest risk, followed by hepatic encephalopathy, hepatocellular carcinoma, and variceal bleeding. The odds ratios were similar in both groups. The addition of alcohol abuse to hepatitis C diagnosis (HCV/ETOH group) increased the risk of death by 40%,
TABLE 2. Clinical Characteristics of the Three Groups
Male Encephalopathy Gastrointestinal bleeding Ascites Hepatocellular carcinoma Hepatorenal syndrome Liver transplantation HIV HBV Diabetes Ischemic heart diseases Cerebrovascular diseases Malignancies (excluding hepatocellular carcinoma)
HCV N ⴝ 53,200
HCV/ETOH N ⴝ 11,700
ALD N ⴝ 218,100
57.6% 7.0% 3.6% 11.4% 1.6% 0.6% 2.0% 10.7% 9.6% 18.1% 8.9% 2.2% 4.4%
74.1% 18.0% 13.6% 29.5% 2.3% 1.9% 2.1% 4.4% 13.2% 10.6% 1.9% 1.0% 1.3%
72.3% 12.0% 8.4% 21.5% 0.8% 1.8% 0.4% 1.2% 1.0% 13.1% 6.7% 2.5% 3.7%
NOTE. The numbers represent the proportion with the given characteristic of all hospitalizations (liver-related and -unrelated combined) in the 3 categories.
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TABLE 3. Sociodemographic Characteristics of Liver-Related Hospitalizations
Race White Black Other Unknown Primary payer Medicare Medicaid Private/HMO Self pay All other payer Median annual income ⱕ$25,000 ⬎$35,000 Hospital characteristics Rural Urban, nonteaching Urban, teaching Region Midwest West South Northeast
HCV N ⴝ 19,300
HCV/ETOH N ⴝ 7,400
ALD N ⴝ 101,200
58.1% 11.6% 13.7% 16.6%
59.8% 15.3% 12.1% 12.9%
60.7% 12.2% 12.9% 14.2%
40.3% 22.1% 28.0% 5.2% 4.4%
20.3% 40.0% 22.1% 10.1% 7.5%
32.9% 24.1% 25.9% 12.3% 4.8%
35.6% 27.6%
41.1% 26.6%
39.0% 25.1%
9.4% 47.9% 42.7%
8.1% 46.5% 45.5%
14.2% 51.2% 34.6%
16.6% 24.9% 38.9% 19.6%
16.0% 30.1% 34.1% 19.8%
18.5% 24.1% 37.9% 19.6%
whereas adding an HCV-related diagnosis in the ALD group had no effect. The addition of an HBV-related diagnosis increased the risk of death by about 30% in both the HCV and ALD groups. Not unexpectedly, HIV was associated with an increased risk of death in both groups, but the effect was more pronounced in the HCV group than in the ALD group. A number of sociodemographic factors were associated with the risk of in-hospital death, which were largely identical in both HCV and ALD groups. African American race and miscellaneous payers other than Medicare, Medicaid, or private insurance were associated with a 20% to 30% increase in the risk of death. Modest effects were noted for hospital characteristics and geographic regions, which were also similar in both groups. Table 6 summarizes the results of linear regression analyses predicting hospitalization charges. Because liver transplantation resulted in extraordinarily high charges for hospitalization (mean $183,900, compared with $14,700 without transplantation), models were created for hospitalizations that did not include transplantation. After adjustment for age, sex, extrahepatic morbidity, and geographic region, in-hospital death was associated with the largest increase in hospitalization charges in both groups. In addition, variceal bleeding, hepatorenal syndrome and HIV infection also increased the charges significantly. These effects were similar in both groups. With regard to other socioeconomic factors, private payers were associated with lower charges, whereas nonwhite, non-black race was associated with slightly higher charges. Compared with rural hospitals, urban hospitals had higher charges. DISCUSSION
In this study, we estimate the burden related to hospitalization care of hepatitis C in the United States. There were 26,700
204 KIM ET AL.
HEPATOLOGY January 2001 TABLE 4. Outcome of Hospital Care in the Three Groups HCV (N ⴝ 19,300)
HCV/ETOH (N ⴝ 7,400)
ALD (N ⴝ 101,200)
1,800 9.5 60 (46-72)
800 11.1 46 (41-54)
13,400 13.3 57 (47-66)
$356M 146,700
$158M 60,900
$1,771M 802,000
9,200 (4,900-17,400) 120,500 (92,900-174,800)
10,100 (5,600-19,500) 130,400 (94,400-220,200)
9,600 (5,400-17,800) 132,700 (87,900-204,800)
In-hospital deaths Nationwide estimate % of liver-related hospitalizations Median age (interquartile range) Nationwide resource utilization Total charges ($million) Total days in hospital Median charges per hospitalization ($ interquartile range) Without liver transplantation Liver transplantation
hospitalizations and 2,600 deaths in nonfederal acute-care hospitals for liver disease related to hepatitis C infection in 1995. By comparison, ALD was associated with 4 to 5 times as many hospitalizations and deaths as hepatitis C. Our estimate on hepatitis C and ALD accounts for approximately two thirds of all deaths from chronic liver disease reported in the United States.15 Putting the result of this analysis together with the estimate of Alter et al. that there are 2.7 million Americans infected with HCV,1 it appears that only a small fraction of people infected with HCV currently require inpatient care. This observation might be reassuring to patients newly diagnosed with HCV. From the standpoint of public health, however,
TABLE 5. Factors Associated With In-Hospital Death in Hepatitis C and ALD
hepatitis C poses an important public health burden in the form of premature deaths and health care resource utilization. The total economic burden of hepatitis C in this country has been previously estimated to be approximately $600 million a year.3 Our analysis suggests that this was likely to have been an underestimate, because the expenditure for inpatient care of liver-related problems associated with HCV alone was $514 million in 1995 and this did not include other important items, such as professional fees and outpatient expenses. Outpatient care for patients with hepatitis C may include antiviral treatment and periodic medical follow-up, particularly in patients with cirrhotic stage disease. Another aspect of the economic burden of hepatitis C includes indirect costs. These represent the cumulative effect of hepatitis C on lost earnings caused by sickness, hospitalization, and premature death, as well as decreased work productivity related to hepatitis C.16,17
Hepatitis C Odds Ratio (95% CI)
ALD Odds Ratio (95% CI)
2.1 (1.9-2.4) 3.0 (2.8-3.3) 1.9 (1.7-2.0) 10.3 (8.5-12.5) 2.4 (2.0-2.9) 4.4 (4.0-4.9) 1.3 (1.1-1.4)
2.3 (2.2-2.4) 3.1 (3.0-3.2) 1.6 (1.5-1.6) 14.0 (13.0-15.0) 3.2 (2.8-3.5) 2.2 (2.0-2.5) 1.3 (1.1-1.4)
Private payer Other payer Medicare/Medicaid*
0.9 (0.9-1.0) 1.2 (1.1-1.4) 1
1.1 (1.0-1.1) 1.3 (1.2-1.3) 1
Black race Other race White*
1.2 (1.1-1.3) 1.3 (1.2-1.5) 1
1.3 (1.2-1.3) 1.0 (0.9-1.0) 1
West South Northeast Midwest*
1.3 (1.1-1.4) 1.3 (1.2-1.5) 1.4 (1.3-1.6) 1
1.1 (1.1-1.2) 1.3 (1.2-1.4) 1.3 (1.2-1.3) 1
Urban nonteaching Urban teaching Rural*
0.8 (0.7-0.9) 0.9 (0.8-1.0) 1
0.9 (0.9-1.0) 1.1 (1.0-1.2) 1
Urban nonteaching Urban teaching Rural*
Alcohol abuse HCV
1.4 (1.2-1.5) —
— 1.0 (0.9-1.1)
Alcohol abuse HCV
Variceal bleeding Encephalopathy Ascites Hepatorenal syndrome Hepatocellular ca HIV HBV
NOTE. Odds ratios and 95% confidence intervals obtained from multiple logistic regression analyses incorporating all variables simultaneously, adjusting for age and extrahepatic comorbidity. *Baseline for comparison.
TABLE 6. Factors Associated With Hospitalization Charges in Hepatitis C and ALD Groups
Death Variceal bleeding Encephalopathy Ascites Hepatorenal syndrome Hepatocellular ca HIV HBV Private payer Other payer Medicare/Medicaid* Black race Other race White*
Hepatitis C % Increase (95% CI)
ALD % Increase (95% CI)
69% (57%-82%) 37% (28%-48%) 9% (2%-16%) 14% (8%-19%) 46% (21%-77%) 5% (⫺8%-19%) 26% (18%-33%) 3% (⫺2%-9%)
66% (61%-71%) 56% (51%-61%) 17% (14%-20%) 22% (20%-25%) 35% (26%-44%) ⫺3% (⫺11%-7%) 26% (17%-35%) 3% (⫺4%-11%)
⫺5% (⫺9%-⫺1%) 2% (⫺3%-8%) 0%
⫺4% (⫺6%-⫺2%) 0% (⫺3%-2%) 0%
4% (⫺1%-8%) 9% (3%-15%) 0%
3% (1%-6%) 6% (3%-10%) 0%
49% (41%-58%) 62% (53%-72%) 0%
40% (36%-43%) 54% (50%-58%) 0%
⫺4% (⫺8%-1%) —
— 8% (4%-13%)
NOTE. Percent increase in charges (95% confidence intervals) obtained from multiple linear regression analyses incorporating all variables simultaneously, adjusting for age, extrahepatic comorbidity, and geographic region. *Baseline for comparison.
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Given the long natural history of the disease and the age of the patient population, the indirect costs incurred by HCV-related morbidity are likely to be considerable. A previous study of viral hepatitis estimated that the proportion of inpatient care was one third of all costs including inpatient and outpatient care and indirect costs.18 Using this figure, our inpatient estimates would extrapolate to $1.5 billion for all costs attributable to morbidity related to hepatitis C in 1995. The overall economic burden related to the long-term consequences of chronic hepatitis C underscores the importance of prevention of infection transmission and disease progression. In our previous analysis, the cost of treating hepatic decompensation was one of the important factors influencing the cost-effectiveness of interferon treatment.19 By eradicating the viral infection at an early stage of disease, downstream costs may be reduced substantially. Because publicly funded health care programs (Medicare and Medicaid) provide more than a half of the care of liver-related problems caused by hepatitis C, expansion of governmental programs to fund research aimed at prevention and treatment certainly appears to be justified. The comparison between hepatitis C and ALD is sobering, in that the overall impact of ALD was still several times that of hepatitis C. In light of the fact that this analysis is a crosssectional study based on data from 5 years ago and that the prevalence of chronic liver disease from hepatitis C appears to be rising, the relative impact of hepatitis C may be larger now. Nonetheless, our analysis underscores the need to continue to emphasize alcohol as the major cause of chronic liver disease in this country. In particular, patients with hepatitis C and alcohol abuse seem to have worse outcome, as assessed by the ages at the time of hospitalization and death. The median ages at the time of liver-unrelated and -related hospitalization and death were 42, 44, and 46 years in the HCV/ETOH group, compared with 43, 52, and 59 years in the HCV group. These differences may suggest that the time course at the end of disease progression of hepatitis C may be accelerated in people with concomitant alcohol problems. This effect was also borne out in the multiple regression analysis in which the addition of an alcohol-related diagnosis was associated with a 40% increase in the risk of death among patients with HCV (odds ratio, 1.4). Our regression analyses identified a number of other factors that were associated with the outcome of hospitalizations for HCV and ALD. HBV infection increased the risk of in-hospital death in both HCV and ALD groups. On the other hand, the impact of HIV infection on mortality was greater in the HCV group than in the ALD group. This is in agreement with previous studies showing that the outcome of HCV infection is significantly worse among immunocompromised individuals such as those with HIV infection or previous organ transplantation.20 Certain socioeconomic variables were associated with poorer outcome, such as race, type of insurance, hospital characteristics, and geographic region. Although the effects of these factors were similar in the HCV and ALD groups, indicating that these are not hepatitis C–specific effects, further investigation of these associations seems warranted. For example, there is evidence that African Americans are less likely to respond to antiviral treatment.21 Potential biologic mechanisms for such a difference remain unknown. There are limitations to our study. First, as with all studies based on administrative data, our analysis relies on the accu-
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racy of the data provided by individual hospitals. Although we believe that the data that we used, the HCUP data, provide a representative cross-sectional sample of hepatitis C in the United States, health care in other sectors such as the VA system was not included in the study. Second, this analysis is based on data obtained 5 years ago. Although we believe that ascertainment of hepatitis C was probably complete by 1995, some of hepatitis C patients may have been misclassified as having other types of liver disease (such as ALD). Our results are, therefore, likely to represent minimum estimates of the national data. Third, the HCUP data do not allow cross-linking of records by individual identifier, for the purpose of patient confidentiality. We were not able to follow individual patients longitudinally or provide information on unique patients. We minimized the risk of introducing biases by restricting our analysis to one-time events such as death or individuals’ hospitalization charges and using a large number of covariates. These caveats notwithstanding, valid conclusions may be drawn from this analysis. As of 1995, only a small fraction of Americans chronically infected with hepatitis C required hospital care for liver-related morbidity. Nonetheless, the impact of hepatitis C on premature deaths and health care utilization was substantial, an effect that will likely become even greater as the number of patients with decompensated liver disease from hepatitis C rises. A longitudinal assessment of this trend is needed, to obtain accurate projections into the future. In the meantime, the estimates and analyses presented herein may be useful in making decisions about resource allocation and in analyzing the cost effectiveness of interventions for prevention and treatment of hepatitis C. REFERENCES 1. Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, Kaslow RA, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341:556-562. 2. Seaberg EC, Belle SH, Beringer KC, Schivins JL, Detre KM. Long-term patient and retransplantation-free survival by selected recipient and donor characteristics: an update from the Pitt-UNOS Liver Transplant Registry. Clinical Transplants 1997:15-28. 3. Satcher DA. Testimony to Congress, Committee on Government Reform and Oversight Subcommittee on Human Resources. 1998. 4. Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. HEPATOLOGY 1997;26(Suppl):15S-20S. 5. Di Bisceglie AM. Hepatitis C. Lancet 1998;351:351-355. 6. Gross JB, Jr. Clinician’s guide to hepatitis C. Mayo Clinic Proc 1998;73: 355-360; quiz 361. 7. Seeff LB, Buskell-Bales Z, Wright EC, Durako SJ, Alter HJ, Iber FL, Hollinger FB, et al. Long-term mortality after transfusion-associated non-A, non-B hepatitis. The National Heart, Lung, and Blood Institute Study Group. N Engl J Med 1992;327:1906-1911. 8. Tong MJ, el-Farra NS, Reikes AR, Co RL. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med 1995;332:1463-1466. 9. Serfaty L, Aumaitre H, Chazouilleres O, Bonnand AM, Rosmorduc O, Poupon RE, Poupon R, et al. Determinants of outcome of compensated hepatitis C virus-related cirrhosis. HEPATOLOGY 1998;27:1435-1440. 10. Kondro W. Revised estimates of hepatitis C from tainted blood published [news]. Lancet 1998;352:466. 11. Harwood HFD, Livermore G. The economic costs of alcohol and drug abuse in the United States 1992. Washington, DC: US Government Printing Office, 1998. 12. Anonymous. Comparative Analysis of HCUP and NHDS Inpatient Discharge Data. Technical Supplement 13, NIS Release 5. Rockville, MD: Agency for Health Care Policy and Research, 1999. 13. Iezzoni L. Risk Adjustment for Measuring Healthcare Outcomes. Chicago: Health Administration Press, 1997. 14. Knaus WA, Wagner DP, Draper EA, Zimmerman JE, Bergner M, Bastos PG, Sirio CA, et al. The APACHE III prognostic system. Risk prediction of
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15. 16. 17. 18.
hospital mortality for critically ill hospitalized adults. Chest 1991;100: 1619-1636. Hoyert DL KK, Murphy SL. Death: Final Data for 1997. National Vital Statistics Reports. Vol. 47. Hyattsville, MD: National Center for Health Statistics, 1999. Bonkovsky HL, Woolley JM. Reduction of health-related quality of life in chronic hepatitis C and improvement with interferon therapy. The Consensus Interferon Study Group. HEPATOLOGY 1999;29:264-270. Foster GR, Goldin RD, Thomas HC. Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis. HEPATOLOGY 1998;27:209-212. Brown DM. Cost of Digestive Diseases in the United States. In: JE Ever-
HEPATOLOGY January 2001 hart, ed. Digestive Diseases in the United States: Epidemiology and Impact. Washington, DC: US Government Printing Office, 1994:67-76. 19. Kim WR, Poterucha JJ, Hermans JE, Therneau TM, Dickson ER, Evans RW, Gross JB, Jr, et al. Cost-effectiveness of 6 and 12 months of interferon-alpha therapy for chronic hepatitis C . Ann Int Med 1997;127:866874. 20. Collier J, Heathcote J. Hepatitis C viral infection in the immunosuppressed patient. HEPATOLOGY 1998;27:2-6. 21. Reddy KR, Hoofnagle JH, Tong MJ, Lee WM, Pockros P, Heathcote EJ, Albert D, et al. Racial differences in responses to therapy with interferon in chronic hepatitis C. Consensus Interferon Study Group. HEPATOLOGY 1999;30:787-793.
We describe mortality and resource utilization for inpatient care of hepatitis C (HCV) in comparison to alcohol-induced liver disease (ALD) in the United States and identify factors that affect outcomes. The Healthcare Cost and Utilization Project database, a national inpatient sample was used to identify hospitalization records with diagnoses related to liver disease from HCV and ALD. Outcome of hospitalizations was analyzed in terms of inhospital deaths and health care resource utilization. For 1995, we estimate that there were 26,700 hospitalizations and 2,600 deaths in acute, nonfederal hospitals in the United States for liver diseases caused by HCV. Total charges for these hospitalizations were $514 million. In comparison, ALD was associated with 101,200 hospitalizations, 13,400 deaths, and $1.8 billion in charges. Simultaneous HCV and alcohol abuse was associated with younger ages at the time of hospitalization and death compared with HCV or ALD alone. In a logistic regression analysis, alcohol abuse (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.2-1.5) and human immunodeficiency virus (HIV) infection (OR, 4.5; 95% CI, 4.0-4.9) were associated with an increased risk of death among those with HCV. Liver transplantation and patient death were associated with the largest increase in hospitalization charges. Major complications of cirrhosis, such as variceal bleeding, encephalopathy, and hepatorenal syndrome, and sociodemographic factors, such as race and health insurance, were also significantly associated with the risk of death and hospitalization charges, which were similar in HCV and ALD. This study provides new estimates regarding the public health impact of HCV, for use in health policy decisions and cost-effectiveness analyses of preventive and therapeutic interventions. (HEPATOLOGY 2001;33:201-206.) Hepatitis C (HCV) is the most common chronic bloodborne infection in the United States.1 The Centers for Disease Control and Prevention (CDC) estimates that as many as 2.7 million Americans are chronically infected with HCV.1 Cur-
rently, end-stage liver disease associated with HCV is the leading indication for liver transplantation in the United States, accounting for approximately 30% of cases.2 In addition, the CDC estimates that 8 to 10,000 deaths are related to HCV each year in the United States. Furthermore, this figure is expected to triple during the next 10 to 20 years.3 Since the discovery of HCV merely 10 years ago, significant progress has been made in our knowledge about the virus and the disease that it causes. However, the natural history and overall disease burden in the country remain uncertain. Because many infected people are asymptomatic and unaware of their infection, the magnitude of HCV as a potential public health problem may be underestimated.4-6 Available data have usually been obtained from tertiary care centers, which may not be representative of the entire nation.7-9 Data on the economic impact of hepatitis C are sparse.10 The total economic burden of hepatitis C in this country has been estimated to be approximately $600 million a year, although the source of this estimate is, to the best of our knowledge, unclear.3 In this study, we used a large administrative database to study the impact of hepatitis C in the United States. To put the hepatitis C data into perspective, hospitalizations for alcoholinduced liver disease (ALD) in the same database were analyzed in a similar fashion. ALD is the most common cause of cirrhosis in this country and is responsible for 12 to 13,000 deaths annually. Although liver disease–specific estimates are not well established, the cost of hospital care of alcohol-related illness in the country was estimated at $5.3 billion in 1992.11 The aims of this study were (1) to describe demographic and clinical characteristics of inpatient care of HCV- and ALD-related morbidity, (2) to provide nationwide estimates for the outcome of inpatient care, namely in-hospital deaths and resource utilization for these diagnoses, and (3) to identify demographic, clinical, and socioeconomic factors that may affect the in-hospital mortality and resource utilization. MATERIALS AND METHODS
Abbreviations: HCV, hepatitis C virus; ALD, alcohol-induced liver disease; HCUP, Healthcare Cost and Utilization Project; HBV, hepatitis B virus; HIV, human immunodeficiency virus. From the Outcomes Research Unit Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN. Received March 23, 2000; accepted October 2, 2000. Supported in part by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (DK34238). W.R.K. is a recipient of the Career Development Award in Epidemiology and Outcomes from Hepatitis Foundation International. Address reprint requests to: W. Ray Kim, M.D., Division of Gastroenterology and Hepatology (Ch 10), Mayo Clinic and Foundation, 200 First Street, SW, Rochester, MN 55905. E-mail: [email protected]; fax: 507-266-2810. Copyright © 2001 by the American Association for the Study of Liver Diseases. 0270-9139/01/3301-0026$3.00/0 doi:10.1053/jhep.2001.20798
Description of Database. The Healthcare Cost and Utilization Project (HCUP) is a multistate health care database, sponsored by the Agency for Healthcare Research and Quality (AHRQ, formerly the Agency for Health Care Policy and Research, AHCPR).12 The nationwide inpatient sample (NIS) of the HCUP data contains patient- as well as hospital-level information for inpatient hospital stays from over 900 hospitals in 19 states. These hospitals represented a 20% sample of nonfederal, acute-care hospitals, which altogether house 85% of hospital beds and admit 94% of hospitalizations in the United States. To ensure that the sample was representative of the United States as a whole, the AHRQ used a stratified sampling method based on the following criteria: (1) ownership control, (2) bed size, (3) teaching status, (4) urban/rural location, and (5) region of the United States. The AHRQ provided discharge weights for individual records
201
202 KIM ET AL. according to the sampling strata, so that information in the database could be extrapolated to the national level. We used the fourth release of the NIS of the HCUP data from calendar year 1995, which contained 6.5 million hospital discharges. The variables in this database included patient demographics; clinical information, including principal and secondary diagnoses, procedures, diagnosis-related group (DRG) code, and patient disposition; and measures of resource utilization, including total charges and length of stay. Sociodemographic variables included age, gender, race (white, black, Hispanic, Asian, Native American, and other), expected primary payer (Medicare, Medicaid, private insurance/ HMO, and other including self-pay), and median income by the zip code area in which the patient resided. Since race was not reported by all states, case records with missing data on race were classified as unknown race. Hospital characteristics were based on location and teaching status (rural, urban nonteaching, and urban teaching) and geographic region (Northeast, South, Midwest, and West). Case Ascertainment. Case records with a diagnosis related to hepatitis C were identified using the diagnostic codes (ICD-9-CM) for hepatitis C infection (070.41, 070.44, 070.51, 070.54). We also extracted hospitalizations related to ALD (571.0-571.3). In addition, since concomitant alcohol abuse is a well-known cofactor in the progression of liver disease in patients with chronic hepatitis C, individuals with alcohol dependence (303), alcohol abuse (305.0), and mental disorders associated with alcohol (291) were identified (collectively referred to as “alcohol abuse” in this report). The hospitalizations were divided into 3 groups: (1) those with hepatitis C alone (HCV group), (2) those with concurrent hepatitis C and alcohol abuse or ALD (HCV/ETOH group), and (3) those with ALD without hepatitis C (ALD group). Because of the overlapping risk factors and potential influence on outcome, we identified hospitalizations that included hepatitis B (HBV: 070.2-070.3) and human immunodeficiency virus (HIV) diagnoses (042, 079.53). To take into account extrahepatic comorbidity status that may influence the outcome of hospitalizations, 4 additional diagnostic categories were considered for risk adjustment.13 These were based on underlying comorbidity factors used in the APACHE-III system,14 including diabetes mellitus, ischemic heart disease, cerebrovascular disease, and malignancies other than hepatocellular carcinoma. Hospitalizations in the 3 groups were divided into 2 categories, liver-related and liver-unrelated hospitalizations. A liver-related hospitalization was defined by the following criteria: (1) a principal diagnosis of HCV or ALD; (2) cirrhosis, portal hypertension, or other sequelae of chronic liver disease; (3) specific individual complications of chronic liver disease, including hepatic encephalopathy, variceal bleeding, ascites, hepatorenal syndrome, and hepatocellular carcinoma; or (4) hospitalization of a liver transplant recipient. Hospitalizations that included liver transplantation procedures were identified using the procedure code. Hospitalizations that did not meet these criteria were considered liver-unrelated hospitalizations. These mostly represented cases in which HCV or ALD was an incidental notation and the primary reason for hospitalization was another illness, including chemical dependency. Data Analysis. Hospitalizations that belonged to each of the 3 groups (HCV, HCV/ETOH, and ALD) were identified and the numbers were extrapolated to yield nationwide estimates. These estimates were rounded to the nearest hundred. Age and sex distribution as well as clinical characteristics including encephalopathy, variceal bleeding, ascites, hepatorenal syndrome, and hepatocellular carcinoma were described for the 3 groups. For liver-related hospitalizations, we compared additional sociodemographic variables, including race, primary payer, geographic region, income level by the ZIP code area of residence, and hospital characteristics. The outcome of hospitalizations was evaluated by in-hospital death, length of stay, and total charges. National estimates of these
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parameters were obtained based on sampling weights as outlined above. Patients were considered to have died of liver-related causes if the death occurred during a liver-related hospitalization. Logistic regression analyses were used to identify factors associated with in-hospital death in the HCV and ALD groups. The HCV/ ETOH group was included in both analyses noting the overlap of two conditions as a covariate. Additional predictor variables included (1) age and sex, (2) clinical events (gastrointestinal bleeding, encephalopathy, ascites, hepatorenal syndrome, hepatocellular carcinoma, liver transplantation), (3) extrahepatic comorbid conditions, (4) socioeconomic variables (race, payer, income level), and (5) hospital characteristics (region, hospital category). Discharge weights were taken into account in the regression models. The results of the models were expressed as odds ratios with 95% confidence intervals. Determinants of hospitalization charges for the HCV and ALD groups were investigated using multiple linear regression analyses. Because the charge data were skewed, models were created for charges after logarithmic transformation. Identical sets of predictor variables were used in the model. The results of the model were expressed as percent increase in charges associated with the given factor. RESULTS Overall Description. Among the 6.5 million records in the database, 12,900 hospitalizations (0.5%) listed HCV in one of the 15 available diagnostic fields. When the appropriate discharge weight was applied for each hospitalization record, it was estimated that there were 64,800 hospitalizations in acute, nonfederal hospitals in the United States in 1995 for individuals with hepatitis C, including 53,200 in the HCV group and 11,700 in the HCV/ETOH group (Table 1). By comparison, there were 218,100 hospitalizations in the ALD group. Of these hospitalizations, 19,300 of the HCV group (36%), 7,400 of the HCV/ETOH group (63%), and 101,200 of the ALD group (46%) met the criteria for liver-related hospitalization. The age distribution of the 3 groups is summarized in Table 1. The median age in the HCV group was 44 years, compared with 51 years in the ALD group. Within the HCV group, the median age for liver-related hospitalizations was 53 years compared with 42 years in the liver-unrelated hospitalizations. The median age for liver-related hospitalizations in the HCV/ETOH group was 9 years younger than the other 2 groups. Clinical characteristics of the 3 groups are shown in Table 2. The proportion of men was higher in the alcohol-related groups (HCV/ETOH and ALD). Complications of portal hypertension were seen most frequently in the HCV/ETOH
TABLE 1. Age Distribution and Number of Hospitalizations for (1) Hepatitis C Without Concomitant Alcohol Dependence (HCV Alone), (2) Hepatitis C With Alcohol Dependence (HCV/ETOH), and (3) ALD Alone Median Age (Interquartile Range)
Liver-related Liver-unrelated Total
HCV
HCV/ETOH
ALD
53 (42-67) N ⫽ 19,300 42 (36-51) N ⫽ 33,900 44 (38-59) N ⫽ 53,200
44 (39-50) N ⫽ 7,400 42 (37-47) N ⫽ 4,300 43 (39-49) N ⫽ 11,700
53 (43-64) N ⫽ 101,200 50 (41-63) N ⫽ 117,000 51 (42-63) N ⫽ 218,100
NOTE. The median age of each group is shown with the interquartile range in parentheses. (N ⫽ nationwide estimate of the number of hospitalizations in nonfederal acute-care hospitals in the respective category.)
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group, followed by the ALD group, and then the HCV group. Hepatocellular carcinoma, liver transplantation, and HIV or HBV coinfection were the least common in the ALD group. Sociodemographic characteristics of the liver-related hospitalizations are summarized in Table 3. The racial distribution was comparable among the 3 groups, with white patients accounting for approximately 60% of hospitalizations. Over 60% of hospitalizations for HCV-related liver problems were supported by public funding (Medicare and Medicaid). The majority of the hospitalizations occurred in urban hospitals. The proportion of hospitalizations in urban teaching hospitals was lower in the ALD group than the HCV group. The geographic distribution of hospitalizations was comparable among the 3 groups. Outcome of Inpatient Care for Hepatitis C. Among the 64,800 hospitalizations related to HCV, there were 3,900 in-hospital deaths, 2,600 of which occurred during liver-related hospitalizations (Table 4). This compared with 18,700 deaths from all causes and 13,400 from liver-related causes in the ALD group. Of the 3 groups, the median age at the time of death was the lowest in the HCV/ETOH group (46 years, compared with 60 and 57 in the other groups). We estimate the nationwide total charges associated with liver-related hospitalizations for HCV at $514 million, which includes $158 million for the HCV/ETOH group, and those for the ALD group at $1.8 billion (Table 4). The corresponding estimates for in-hospital days were 146,700 days for the HCV group, 60,900 for the HCV/ETOH group, and 802,000 days for the ALD group. Table 4 also includes median charges per hospitalization for the 3 groups, by liver transplantation. Table 5 summarizes the results of multivariate logistic regression analyses predicting in-hospital death, adjusting for age, sex, and extrahepatic comorbidity. Separate models were created for the HCV and ALD groups. As expected, all of the major complications of cirrhosis were associated with a significant increase in the risk of death. Of these, hepatorenal syndrome had the highest risk, followed by hepatic encephalopathy, hepatocellular carcinoma, and variceal bleeding. The odds ratios were similar in both groups. The addition of alcohol abuse to hepatitis C diagnosis (HCV/ETOH group) increased the risk of death by 40%,
TABLE 2. Clinical Characteristics of the Three Groups
Male Encephalopathy Gastrointestinal bleeding Ascites Hepatocellular carcinoma Hepatorenal syndrome Liver transplantation HIV HBV Diabetes Ischemic heart diseases Cerebrovascular diseases Malignancies (excluding hepatocellular carcinoma)
HCV N ⴝ 53,200
HCV/ETOH N ⴝ 11,700
ALD N ⴝ 218,100
57.6% 7.0% 3.6% 11.4% 1.6% 0.6% 2.0% 10.7% 9.6% 18.1% 8.9% 2.2% 4.4%
74.1% 18.0% 13.6% 29.5% 2.3% 1.9% 2.1% 4.4% 13.2% 10.6% 1.9% 1.0% 1.3%
72.3% 12.0% 8.4% 21.5% 0.8% 1.8% 0.4% 1.2% 1.0% 13.1% 6.7% 2.5% 3.7%
NOTE. The numbers represent the proportion with the given characteristic of all hospitalizations (liver-related and -unrelated combined) in the 3 categories.
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TABLE 3. Sociodemographic Characteristics of Liver-Related Hospitalizations
Race White Black Other Unknown Primary payer Medicare Medicaid Private/HMO Self pay All other payer Median annual income ⱕ$25,000 ⬎$35,000 Hospital characteristics Rural Urban, nonteaching Urban, teaching Region Midwest West South Northeast
HCV N ⴝ 19,300
HCV/ETOH N ⴝ 7,400
ALD N ⴝ 101,200
58.1% 11.6% 13.7% 16.6%
59.8% 15.3% 12.1% 12.9%
60.7% 12.2% 12.9% 14.2%
40.3% 22.1% 28.0% 5.2% 4.4%
20.3% 40.0% 22.1% 10.1% 7.5%
32.9% 24.1% 25.9% 12.3% 4.8%
35.6% 27.6%
41.1% 26.6%
39.0% 25.1%
9.4% 47.9% 42.7%
8.1% 46.5% 45.5%
14.2% 51.2% 34.6%
16.6% 24.9% 38.9% 19.6%
16.0% 30.1% 34.1% 19.8%
18.5% 24.1% 37.9% 19.6%
whereas adding an HCV-related diagnosis in the ALD group had no effect. The addition of an HBV-related diagnosis increased the risk of death by about 30% in both the HCV and ALD groups. Not unexpectedly, HIV was associated with an increased risk of death in both groups, but the effect was more pronounced in the HCV group than in the ALD group. A number of sociodemographic factors were associated with the risk of in-hospital death, which were largely identical in both HCV and ALD groups. African American race and miscellaneous payers other than Medicare, Medicaid, or private insurance were associated with a 20% to 30% increase in the risk of death. Modest effects were noted for hospital characteristics and geographic regions, which were also similar in both groups. Table 6 summarizes the results of linear regression analyses predicting hospitalization charges. Because liver transplantation resulted in extraordinarily high charges for hospitalization (mean $183,900, compared with $14,700 without transplantation), models were created for hospitalizations that did not include transplantation. After adjustment for age, sex, extrahepatic morbidity, and geographic region, in-hospital death was associated with the largest increase in hospitalization charges in both groups. In addition, variceal bleeding, hepatorenal syndrome and HIV infection also increased the charges significantly. These effects were similar in both groups. With regard to other socioeconomic factors, private payers were associated with lower charges, whereas nonwhite, non-black race was associated with slightly higher charges. Compared with rural hospitals, urban hospitals had higher charges. DISCUSSION
In this study, we estimate the burden related to hospitalization care of hepatitis C in the United States. There were 26,700
204 KIM ET AL.
HEPATOLOGY January 2001 TABLE 4. Outcome of Hospital Care in the Three Groups HCV (N ⴝ 19,300)
HCV/ETOH (N ⴝ 7,400)
ALD (N ⴝ 101,200)
1,800 9.5 60 (46-72)
800 11.1 46 (41-54)
13,400 13.3 57 (47-66)
$356M 146,700
$158M 60,900
$1,771M 802,000
9,200 (4,900-17,400) 120,500 (92,900-174,800)
10,100 (5,600-19,500) 130,400 (94,400-220,200)
9,600 (5,400-17,800) 132,700 (87,900-204,800)
In-hospital deaths Nationwide estimate % of liver-related hospitalizations Median age (interquartile range) Nationwide resource utilization Total charges ($million) Total days in hospital Median charges per hospitalization ($ interquartile range) Without liver transplantation Liver transplantation
hospitalizations and 2,600 deaths in nonfederal acute-care hospitals for liver disease related to hepatitis C infection in 1995. By comparison, ALD was associated with 4 to 5 times as many hospitalizations and deaths as hepatitis C. Our estimate on hepatitis C and ALD accounts for approximately two thirds of all deaths from chronic liver disease reported in the United States.15 Putting the result of this analysis together with the estimate of Alter et al. that there are 2.7 million Americans infected with HCV,1 it appears that only a small fraction of people infected with HCV currently require inpatient care. This observation might be reassuring to patients newly diagnosed with HCV. From the standpoint of public health, however,
TABLE 5. Factors Associated With In-Hospital Death in Hepatitis C and ALD
hepatitis C poses an important public health burden in the form of premature deaths and health care resource utilization. The total economic burden of hepatitis C in this country has been previously estimated to be approximately $600 million a year.3 Our analysis suggests that this was likely to have been an underestimate, because the expenditure for inpatient care of liver-related problems associated with HCV alone was $514 million in 1995 and this did not include other important items, such as professional fees and outpatient expenses. Outpatient care for patients with hepatitis C may include antiviral treatment and periodic medical follow-up, particularly in patients with cirrhotic stage disease. Another aspect of the economic burden of hepatitis C includes indirect costs. These represent the cumulative effect of hepatitis C on lost earnings caused by sickness, hospitalization, and premature death, as well as decreased work productivity related to hepatitis C.16,17
Hepatitis C Odds Ratio (95% CI)
ALD Odds Ratio (95% CI)
2.1 (1.9-2.4) 3.0 (2.8-3.3) 1.9 (1.7-2.0) 10.3 (8.5-12.5) 2.4 (2.0-2.9) 4.4 (4.0-4.9) 1.3 (1.1-1.4)
2.3 (2.2-2.4) 3.1 (3.0-3.2) 1.6 (1.5-1.6) 14.0 (13.0-15.0) 3.2 (2.8-3.5) 2.2 (2.0-2.5) 1.3 (1.1-1.4)
Private payer Other payer Medicare/Medicaid*
0.9 (0.9-1.0) 1.2 (1.1-1.4) 1
1.1 (1.0-1.1) 1.3 (1.2-1.3) 1
Black race Other race White*
1.2 (1.1-1.3) 1.3 (1.2-1.5) 1
1.3 (1.2-1.3) 1.0 (0.9-1.0) 1
West South Northeast Midwest*
1.3 (1.1-1.4) 1.3 (1.2-1.5) 1.4 (1.3-1.6) 1
1.1 (1.1-1.2) 1.3 (1.2-1.4) 1.3 (1.2-1.3) 1
Urban nonteaching Urban teaching Rural*
0.8 (0.7-0.9) 0.9 (0.8-1.0) 1
0.9 (0.9-1.0) 1.1 (1.0-1.2) 1
Urban nonteaching Urban teaching Rural*
Alcohol abuse HCV
1.4 (1.2-1.5) —
— 1.0 (0.9-1.1)
Alcohol abuse HCV
Variceal bleeding Encephalopathy Ascites Hepatorenal syndrome Hepatocellular ca HIV HBV
NOTE. Odds ratios and 95% confidence intervals obtained from multiple logistic regression analyses incorporating all variables simultaneously, adjusting for age and extrahepatic comorbidity. *Baseline for comparison.
TABLE 6. Factors Associated With Hospitalization Charges in Hepatitis C and ALD Groups
Death Variceal bleeding Encephalopathy Ascites Hepatorenal syndrome Hepatocellular ca HIV HBV Private payer Other payer Medicare/Medicaid* Black race Other race White*
Hepatitis C % Increase (95% CI)
ALD % Increase (95% CI)
69% (57%-82%) 37% (28%-48%) 9% (2%-16%) 14% (8%-19%) 46% (21%-77%) 5% (⫺8%-19%) 26% (18%-33%) 3% (⫺2%-9%)
66% (61%-71%) 56% (51%-61%) 17% (14%-20%) 22% (20%-25%) 35% (26%-44%) ⫺3% (⫺11%-7%) 26% (17%-35%) 3% (⫺4%-11%)
⫺5% (⫺9%-⫺1%) 2% (⫺3%-8%) 0%
⫺4% (⫺6%-⫺2%) 0% (⫺3%-2%) 0%
4% (⫺1%-8%) 9% (3%-15%) 0%
3% (1%-6%) 6% (3%-10%) 0%
49% (41%-58%) 62% (53%-72%) 0%
40% (36%-43%) 54% (50%-58%) 0%
⫺4% (⫺8%-1%) —
— 8% (4%-13%)
NOTE. Percent increase in charges (95% confidence intervals) obtained from multiple linear regression analyses incorporating all variables simultaneously, adjusting for age, extrahepatic comorbidity, and geographic region. *Baseline for comparison.
HEPATOLOGY Vol. 33, No. 1, 2001
Given the long natural history of the disease and the age of the patient population, the indirect costs incurred by HCV-related morbidity are likely to be considerable. A previous study of viral hepatitis estimated that the proportion of inpatient care was one third of all costs including inpatient and outpatient care and indirect costs.18 Using this figure, our inpatient estimates would extrapolate to $1.5 billion for all costs attributable to morbidity related to hepatitis C in 1995. The overall economic burden related to the long-term consequences of chronic hepatitis C underscores the importance of prevention of infection transmission and disease progression. In our previous analysis, the cost of treating hepatic decompensation was one of the important factors influencing the cost-effectiveness of interferon treatment.19 By eradicating the viral infection at an early stage of disease, downstream costs may be reduced substantially. Because publicly funded health care programs (Medicare and Medicaid) provide more than a half of the care of liver-related problems caused by hepatitis C, expansion of governmental programs to fund research aimed at prevention and treatment certainly appears to be justified. The comparison between hepatitis C and ALD is sobering, in that the overall impact of ALD was still several times that of hepatitis C. In light of the fact that this analysis is a crosssectional study based on data from 5 years ago and that the prevalence of chronic liver disease from hepatitis C appears to be rising, the relative impact of hepatitis C may be larger now. Nonetheless, our analysis underscores the need to continue to emphasize alcohol as the major cause of chronic liver disease in this country. In particular, patients with hepatitis C and alcohol abuse seem to have worse outcome, as assessed by the ages at the time of hospitalization and death. The median ages at the time of liver-unrelated and -related hospitalization and death were 42, 44, and 46 years in the HCV/ETOH group, compared with 43, 52, and 59 years in the HCV group. These differences may suggest that the time course at the end of disease progression of hepatitis C may be accelerated in people with concomitant alcohol problems. This effect was also borne out in the multiple regression analysis in which the addition of an alcohol-related diagnosis was associated with a 40% increase in the risk of death among patients with HCV (odds ratio, 1.4). Our regression analyses identified a number of other factors that were associated with the outcome of hospitalizations for HCV and ALD. HBV infection increased the risk of in-hospital death in both HCV and ALD groups. On the other hand, the impact of HIV infection on mortality was greater in the HCV group than in the ALD group. This is in agreement with previous studies showing that the outcome of HCV infection is significantly worse among immunocompromised individuals such as those with HIV infection or previous organ transplantation.20 Certain socioeconomic variables were associated with poorer outcome, such as race, type of insurance, hospital characteristics, and geographic region. Although the effects of these factors were similar in the HCV and ALD groups, indicating that these are not hepatitis C–specific effects, further investigation of these associations seems warranted. For example, there is evidence that African Americans are less likely to respond to antiviral treatment.21 Potential biologic mechanisms for such a difference remain unknown. There are limitations to our study. First, as with all studies based on administrative data, our analysis relies on the accu-
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racy of the data provided by individual hospitals. Although we believe that the data that we used, the HCUP data, provide a representative cross-sectional sample of hepatitis C in the United States, health care in other sectors such as the VA system was not included in the study. Second, this analysis is based on data obtained 5 years ago. Although we believe that ascertainment of hepatitis C was probably complete by 1995, some of hepatitis C patients may have been misclassified as having other types of liver disease (such as ALD). Our results are, therefore, likely to represent minimum estimates of the national data. Third, the HCUP data do not allow cross-linking of records by individual identifier, for the purpose of patient confidentiality. We were not able to follow individual patients longitudinally or provide information on unique patients. We minimized the risk of introducing biases by restricting our analysis to one-time events such as death or individuals’ hospitalization charges and using a large number of covariates. These caveats notwithstanding, valid conclusions may be drawn from this analysis. As of 1995, only a small fraction of Americans chronically infected with hepatitis C required hospital care for liver-related morbidity. Nonetheless, the impact of hepatitis C on premature deaths and health care utilization was substantial, an effect that will likely become even greater as the number of patients with decompensated liver disease from hepatitis C rises. A longitudinal assessment of this trend is needed, to obtain accurate projections into the future. In the meantime, the estimates and analyses presented herein may be useful in making decisions about resource allocation and in analyzing the cost effectiveness of interventions for prevention and treatment of hepatitis C. REFERENCES 1. Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, Kaslow RA, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341:556-562. 2. Seaberg EC, Belle SH, Beringer KC, Schivins JL, Detre KM. Long-term patient and retransplantation-free survival by selected recipient and donor characteristics: an update from the Pitt-UNOS Liver Transplant Registry. Clinical Transplants 1997:15-28. 3. Satcher DA. Testimony to Congress, Committee on Government Reform and Oversight Subcommittee on Human Resources. 1998. 4. Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. HEPATOLOGY 1997;26(Suppl):15S-20S. 5. Di Bisceglie AM. Hepatitis C. Lancet 1998;351:351-355. 6. Gross JB, Jr. Clinician’s guide to hepatitis C. Mayo Clinic Proc 1998;73: 355-360; quiz 361. 7. Seeff LB, Buskell-Bales Z, Wright EC, Durako SJ, Alter HJ, Iber FL, Hollinger FB, et al. Long-term mortality after transfusion-associated non-A, non-B hepatitis. The National Heart, Lung, and Blood Institute Study Group. N Engl J Med 1992;327:1906-1911. 8. Tong MJ, el-Farra NS, Reikes AR, Co RL. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med 1995;332:1463-1466. 9. Serfaty L, Aumaitre H, Chazouilleres O, Bonnand AM, Rosmorduc O, Poupon RE, Poupon R, et al. Determinants of outcome of compensated hepatitis C virus-related cirrhosis. HEPATOLOGY 1998;27:1435-1440. 10. Kondro W. Revised estimates of hepatitis C from tainted blood published [news]. Lancet 1998;352:466. 11. Harwood HFD, Livermore G. The economic costs of alcohol and drug abuse in the United States 1992. Washington, DC: US Government Printing Office, 1998. 12. Anonymous. Comparative Analysis of HCUP and NHDS Inpatient Discharge Data. Technical Supplement 13, NIS Release 5. Rockville, MD: Agency for Health Care Policy and Research, 1999. 13. Iezzoni L. Risk Adjustment for Measuring Healthcare Outcomes. Chicago: Health Administration Press, 1997. 14. Knaus WA, Wagner DP, Draper EA, Zimmerman JE, Bergner M, Bastos PG, Sirio CA, et al. The APACHE III prognostic system. Risk prediction of
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