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Hospitalization Rates Differ by Hepatitis C Status in an Urban HIV Cohort
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--5-fold increase observed in hospitalizations for liver-related diagnosis in HIV
--further increases in cirrhosis expected
--we need increased efforts to prevent the spread of HCV and perhaps to treat HIV/HCV-coinfected patients
JAIDS Journal of Acquired Immune Deficiency Syndromes 2003; 34(2):165-173
Kelly A. Gebo, MD, MPH; Marie Diener-West, PhD; Richard D. Moore, MD, MHS
From the Department of Medicine, Johns Hopkins University School of Medicine, Baltimore (Dr Gebo and Dr Moore), and Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University School of Medicine, Baltimore (Dr Diener-West), Maryland
This study was supported by the National Institute of Drug Abuse (K 23 DA 00523, R 01 DA 11602, and K24 DA 00432).
“………there should be increased efforts to prevent the spread of HCV and perhaps to treat HIV/HCV-coinfected patients. The rates of hospitalization have important implications for the potential costs of medical care in the HIV/HCV-coinfected patient that will need to be considered…..”
“……..hospitalization discharges where a liver-related diagnosis was included as a diagnosis increased approximately 5-fold between 1995 and 2000 for patients infected with HCV………. HCV/HIV-coinfected patients had higher utilization of the intensive care unit, indicating more critical illness that required more intensive health care……. several significant risk factors for hospitalization, including female sex, African American race/ethnicity, lower CD4 counts, high viral loads, and HCV coinfection…… In multivariate analysis, HCV coinfection was a stronger predictor of hospitalization than history of IDU…… Patients who were more immunosuppressed, as measured by lower CD4 counts, had higher hospitalization rates……. Chronic HCV adopts a more aggressive course in the setting of HIV infection and has been thought to increase the risk of developing cirrhosis greater than the 20% risk observed in HIV-negative patients. As the chance of opportunistic illness (OI) is reduced and longevity increases in HIV patients treated with antiretroviral therapy, the cumulative incidence of cirrhosis and complications of hepatic disease in those coinfected with HCV is likely to continue to increase…..
…….. Treatment of HCV has been shown to decrease rates of cirrhosis, hepatocellular carcinoma, and mortality……patients with HIV should be assessed for treatment”.
ABSTRACT
Objective: To determine whether hepatitis C virus (HCV) infection status affected hospitalization rates, intensive care utilization rates, and discharge diagnoses between 1995 and 2000 in patients with HIV.
Methods: We conducted a prospective cohort study of 3730 HIV patients who were longitudinally followed between 1995 and 2000. All hospitalizations of these patients were classified as an opportunistic illness (OI) using the 1993 indicator diagnoses in the case definition of AIDS, complication of injection drug use (IDU) (abscess, cellulitis, osteomyelitis, bacteremia, endocarditis, and poisoning by analgesics), liver-related complication (acute and subacute necrosis of the liver, chronic liver disease and cirrhosis, liver abscess, hepatic coma, portal hypertension, hepatorenal syndrome, hepatocellular carcinoma, and gastrointestinal bleed), or other. Negative binomial regression was used to assess for risk factors for hospitalization.
Main Outcome Measures: Inpatient hospitalization and intensive care utilization rates and discharge diagnoses.
Results: Nearly half (42.8%) of our cohort was infected with HCV. Between 1995 and 2000, hospitalization rates for HCV-negative patients decreased from 61.9 to 33.9 per 100 patient-years (PY) of follow-up (P = 0.007). Hospitalization rates decreased between 1995 and 1997 for HCV-positive patients from 55.4 to 43.5 per 100 PY but increased between 1997 and 2000 from 43.5 to 62.9 per 100 PY (P = 0.001). When stratified by diagnostic category, IDU-related complications increased from 13.6 to 18.4 admissions per 100 PY and liver-related complications increased from 5.4 to 26.7 admissions per 100 PY between 1995 and 2000 in HCV-positive patients (P < 0.001); however, OIs remained relatively unchanged from 1995 to 2000, with 14.6 to 13.0 hospitalizations per 100 PY. In multivariate analysis, HCV infection (incidence rate ratio [IRR] = 1.75, 95% confidence interval [CI]: 1.47, 2.07), female gender (IRR = 1.56, 95% CI: 1.32, 1.85), age <37 years (IRR = 1.19, 95% CI: 1.01, 1.41), African American ethnicity (IRR= 1.30, 95% CI: 1.05, 1.61), and CD4 cell count <50 cells mm3 (IRR = 2.20, 95% CI: 1.72, 2.83) were predictive of hospitalization.
Conclusions: Our data indicate that hospitalization rates decreased significantly between 1995 and 2000 for HCV-negative patients but increased significantly for HCV-positive patients. Hospitalization rates for IDU- and liver-related complications increased during this time interval in coinfected patients. In the era of highly active antiretroviral therapy, HIV/HCV-coinfected patients are more likely to suffer from higher hospitalization rates, which will require more health care resources.
RESULTS
This analysis is based on 3730 patients with 9275 PY of follow-up. The population was predominantly African American (76.9%) and male (67.5%), with a mean age of 37 years. Nearly half (42.8%) were HCV infected. IDU was the principal risk factor for HIV transmission across time, although the percentage of injection drug users dropped slightly between 1995 and 2000. Nearly 30% of our cohort had an HIV risk factor of MSM, whereas only 6% of our patients had "other" as their HIV risk factor. There was a statistically significant decrease in the number of injection drug users from 53.5% to 44.6%, and the patients who were HCV-positive decreased from 45.0% to 43.7% between 1995 and 2000. There were no other statistically significant differences in any demographic characteristic over time.
HCV-positive patients were more likely to be injection drug users. Mean viral load was not statistically significantly different between HCV-infected and -uninfected patients. There were no other statistically significant differences in any demographic characteristic between HCV-infected and -uninfected patients. During the study period, only 9 patients who were HCV-negative on original screen at entry in the clinic subsequently seroconverted.
Over the study period, the most common reasons for hospitalization for OIs were Pneumocystis carinii pneumonia, cytomegalovirus (CMV) infection, and cryptococcal meningitis. The most common diagnoses for IDU-related admissions were endocarditis; infections of the soft tissues, including cellulitis, and narcotic overdose.
Crude hospitalization rates for HCV-negative patients decreased by a third between 1995 and 1996 (P < 0.001) and have remained relatively constant between 1998 and 2000. Overall hospitalization rates for IDU-related complications have remained constant between 4.6 and 6.8 per 100 PY (P = 0.78) during this interval. Hospitalization rates for OIs significantly decreased from 35.5 to 12.0 per 100 PY during this interval (P < 0.001). Overall hospitalization rates increased significantly between 1995 and 2000 in this population from 55.4 to 62.9 hospitalizations per 100 PY (P = 0.001) (see Fig. 2). The hospitalization rates for IDU-related complications increased between 1995 and 2000 from 13.6 to 18.4 per 100 PY (P < 0.001), and the admission rates for liver-related complications during this time period increased approximately 5-fold (5.4 to 26.7 per 100 PY) in this cohort. Rates of hospitalization for OIs did not change significantly during this interval for HCV-positive patient.
The mean lengths of stay were 7.1 days for HCV-negative patients (range: 0-150 days) and 7.0 days for HCV-positive patients (range: 0-71 days; P = 0.52). The distribution of hospitalizations per person was nonnormally distributed, with approximately 90% of patients having 0 or 1 admission in a given year. The number of admissions in a single year per patient ranged from 0 to 11.
In multivariate analysis, risk factors for admission included coinfection with HCV (adjusted incidence rate ratio [IRR] = 1.75, 95% CI: 1.47, 2.07), female gender (IRR = 1.56, 95% CI: 1.32, 1.85), African American race (IRR = 1.30, 95% CI: 1.05, 1.61), age <37 years (IRR = 1.19, 95% CI: 1.01, 1.41), and CD4 count in 1998 <200 cells/mm3 (IRR = 1.32, 95% CI: 1.07, 1.63). Mean viral load <100,000 copies/mL (P < 0.001) was protective against admission.
Intensive care unit admissions occurred in 7.3% of all hospitalizations. There was a nonsignificant trend toward more use of the intensive care unit by HCV-infected patients than by HCV-uninfected patients between 1998 and 2000 (P = 0.07). In univariate analysis, African American race (IRR = 1.76; P = 0.03) was significantly associated with intensive care unit utilization, as was viral load >100,000 copies/mL (IRR =1.49; P = 0.02). After adjustment for viral load, however, the associations of race and hepatitis status with intensive care unit utilization were no longer significant.
DISCUSSION
Our analysis of hospitalization rates in an inner-city HIV clinic population has several important findings. Hospitalization rates in our HCV-negative cohort fell dramatically between 1995 and 1997 and have remained approximately half that of the rates in the pre-HAART era. Hospitalization rates for HCV-infected patients decreased between 1995 and 1997 and then increased significantly to exceed pre-HAART levels by 2000. Hospitalization rates for IDU-related complications in this HIV/HCV-coinfected cohort have remained approximately 3 times the rates of those who are HCV-negative.
The decline in hospitalization rates between 1995 and 1997 is consistent with findings at other institutions. Evaluating hospitalization rates over the longer term shows that although hospitalization rates appear to have reached a plateau between 1996 and 1997, they increased between 1997 and 2000 for those infected with HCV. There was a small increase in hospitalizations due to complications of IDU. Consistent with data from other studies, the increase in admissions in our HCV/HIV-coinfected patients is partially due to increases in liver-related complications.
The increasing frequency of chronic viral liver disease as a cause of morbidity and mortality in HIV-infected patients is a growing concern. In our cohort, prior to the introduction of HAART in 1996, approximately 7.5% of hospitalizations were due to complications of liver disease. Our results suggest that hospitalization discharges where a liver-related diagnosis was included as a diagnosis increased approximately 5-fold between 1995 and 2000 for patients infected with HCV. Although mean lengths of stay were similar, HCV/HIV-coinfected patients had higher utilization of the intensive care unit, indicating more critical illness that required more intensive health care. This is consistent with the many liver-related complications that often require intensive and expensive medical procedures such as endoscopy and radiologic scanning and also has important implications for the costs of care.
Our analysis demonstrated several significant risk factors for hospitalization, including female sex, African American race/ethnicity, lower CD4 counts, high viral loads, and HCV coinfection. In other studies, HIV-infected injection drug users have been shown to have higher hospitalization rates than patients who are not injection drug users. In multivariate analysis, HCV coinfection was a stronger predictor of hospitalization than history of IDU. Interestingly, unlike HCV coinfection, IDU was not a predictor of intensive care unit admission, perhaps indicating that patients hospitalized for complications of IDU have less severe diagnoses that require less intensive health care consumption. In our analysis, we defined IDU based on a history of IDU as a risk factor for HIV transmission. Analysis of our data indicates that a history of IDU does not imply continued drug use. Nevertheless, approximately 80% of patients who have a history of IDU are using injection drugs at any given time. Therefore, further research will need to evaluate the impact of active IDU as opposed to a history of IDU on hospitalization rates.
African American ethnicity and female gender were strong predictors of hospitalization in our analysis. Like other studies that have shown higher hospitalization rates in HIV-seropositive nonwhites compared with whites, race was correlated with overall hospitalization rate after adjustment for other demographic and laboratory features in our analysis. Consistent with previous data collected since the introduction of HAART, women had higher overall hospitalization rates than men. These results remained unchanged even after removing admissions for pregnancy, childbirth, and the puerperium, which accounted for <1% of all admissions. The reasons for the significantly higher hospitalization rates in women than in men will need to be evaluated in future studies.
Patients who were more immunosuppressed, as measured by lower CD4 counts, had higher hospitalization rates. In addition, high viral load was associated with higher hospitalization rates and more frequent intensive care utilization. Interestingly, use of HAART did not reduce hospitalization rates, perhaps indicating that patients who achieved viral suppression were more likely to reap the benefits of HAART than patients who were prescribed HAART but did not achieve a reduction in viral load.
Chronic HCV adopts a more aggressive course in the setting of HIV infection and has been thought to increase the risk of developing cirrhosis greater than the 20% risk observed in HIV-negative patients. As the chance of opportunistic illness (OI) is reduced and longevity increases in HIV patients treated with antiretroviral therapy, the cumulative incidence of cirrhosis and complications of hepatic disease in those coinfected with HCV is likely to continue to increase.
Treatment of HCV has been shown to decrease rates of cirrhosis, hepatocellular carcinoma, and mortality. Although coinfected patients were previously excluded from most HCV treatment trials and treatment of HCV in HIV-coinfected patients remains complicated due to medication toxicities, patients with HIV should be assessed for treatment. Preliminary data indicate that interferon is equally effective in HIV-negative and HIV-positive patients with CD4 cell counts >500 cells/mL, and new studies with pegylated interferon are underway. We were unable to demonstrate an increase in hepatotoxicity due to antiretroviral medications or hepatic complications due to hepatocellular carcinoma; however, this will need future monitoring, because long-term complications of cirrhosis may not have been detectable in our study time frame.
Our study has some potential limitations. Our data are drawn from a single inner-city clinic that treats predominantly indigent patients and has a high proportion of injection drug users. Although our results may not generalize to all HIV-infected populations, they are likely to be representative of HIV disease in many urban settings. Also, in our analysis, any patient who had a positive screen for HCV antibody was classified as HCV infected. Although we do not have HCV RNA information on our patients, in another group of injection drug users in Baltimore, approximately 90% of patients with HCV antibodies have active viremia. In addition, in injection drug users, the seroconversion for HCV is generally within 2 years of the initiation of injection drugs, and our data revealed only 9 patients who had seroconverted during the study period. Therefore, patients identified as HCV infected are likely to have active HCV disease. Also, we do not have information on adherence to antiretroviral therapy; therefore, we used viral load as a surrogate for adequate adherence, because viral suppression is the ultimate goal of antiretroviral therapy. Finally, we were only able to analyze hospitalizations from our institution. Our patients reside predominantly in East Baltimore, where our hospital is located, and we enroll patients in our database who receive primary longitudinal care in our HIV clinic. Using statewide insurance claims data, we have determined that only 16% of hospital admissions occur at outside facilities. There were no statistically significant differences in rates of hospitalization at outside hospitals versus our hospital when evaluated by gender, HIV risk factor, race/ethnicity, or hepatitis status. Therefore, we believe that by only evaluating hospitalizations at our hospital, we are presenting conservative estimates of true hospitalization rates.
Our data suggest that overall hospitalization rates decreased significantly between 1995 and 1996 corresponding to the introduction of HAART; however, our results are intriguing in that they show an increase in overall hospitalization rates between 1998 and 2000 compared with the nadir from 1996 to 1997 in our HCV-coinfected patients. These results suggest that there should be increased efforts to prevent the spread of HCV and perhaps to treat HIV/HCV-coinfected patients. The rates of hospitalization have important implications for the potential costs of medical care in the HIV/HCV-coinfected patient that will need to be considered.
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