Chronic viral hepatitis is common among persons living with HIV (PLWH). In the United States, Europe, and Australia, approximately 4.8%–9.0% of PLWH are also chronically infected with hepatitis B virus (HBV), 20%–33% are chronically infected with hepatitis C virus (HCV), and 0.5%–4.0% are chronically infected with both.1–5 Patients with HIV/HBV coinfection experience faster progression to cirrhosis, more hepatocellular carcinoma, and higher risk of liver-related mortality than patients with either infection alone.5–8 Similarly, liver disease progression and its complications are more common in HIV/HCV coinfected patients than in HIV monoinfected patients.2,8,9 Viral hepatitis, particularly HCV, has also been associated with extrahepatic complications that can include renal disease, cardiovascular disease, diabetes, autoimmunity, metabolic bone disease, and neurocognitive decline.10–16
In the era of potent and widely available antiretroviral therapy (ART), hospitalization rates have become an important outcome measure and an important health care cost among PLWH.17–19 Comparing rates and reasons for hospitalizations among PLWH with and without hepatitis coinfection will be important to clinicians and policy-makers trying to understand the health care needs of these populations. Differences across these populations could suggest areas of unique clinical need and may influence the allocation of health care resources and the construction of health care delivery models. The purpose of this study was to characterize the impact of hepatitis coinfection on inpatient health care utilization among HIV-infected patients in a multi-site, multi-state consortium of HIV care sites.
Site Selection and Data Collection
The HIV Research Network (HIVRN) is a consortium of 17 sites providing longitudinal adult and pediatric HIV care in 11 US cities. Sites abstract comprehensive demographic, laboratory, and treatment data from clinical records, then deidentify and submit them to a data-coordinating center where they are reviewed and combined into a uniform database.20 In 2010, 9 of the participating sites submitted details of hospital admissions for adult patients (3 Northeast, 3 West, 2 South, and 1 Midwest). Seven of these sites have academic affiliations and 2 are community-based. Inclusion in this retrospective cohort study was restricted to patients who enrolled in care before July 1, 2010, and were in active care during 2010. Active care was defined as having at least 1 outpatient HIV provider visit and 1 CD4 cell count during the calendar year. Institutional review boards at each site and at the data-coordinating center at Johns Hopkins University approved the collection and use of these data for analysis and publication.
Definitions of Variables
Hepatitis serostatus was assessed by detection of hepatitis B surface antigen (HBsAg) and/or hepatitis C antibody (anti-HCV) at any time before or during 2010. At each site, patients are screened for chronic HBV and chronic HCV at the discretion of their providers. If a patient had multiple serologies performed over time, a single positive test was considered sufficient to categorize the patient as positive for that assay. HBV DNA and HCV RNA levels were not available. Patients were assigned to 1 of 5 hepatitis serostatus categories. Patients with negative results for both hepatitis serologies were categorized as HIV monoinfected. Patients with a positive HBsAg and negative anti-HCV were categorized as HIV/HBV coinfected. Patients with a negative HBsAg and positive anti-HCV were categorized as HIV/HCV coinfected. Patients with positive results for both hepatitis serologies were categorized as HIV/HBV/HCV tri-infected. Patients without known results from one or both tests were categorized as unknown hepatitis serostatus.
Age was assessed on July 1, 2010 and divided into 4 categories: 18–34, 35–49, 50–64, and 65 or more years. Race/ethnicity was categorized based on self-report as white, black, Hispanic, or other/unknown. HIV transmission risk factor was classified as one of 4 mutually exclusive categories: injection drug use (IDU), men who have sex with men (MSM), heterosexual transmission, or other/unknown. Patients who reported IDU in addition to any other risk factor were categorized as IDU. Men who reported sex with both men and women were categorized as MSM.
The CD4 T-cell count and HIV-1 RNA values used in this analysis were the first available measurements in 2010. CD4 count was categorized as ≤50, 51–200, 201–500, or >500 cells per cubic millimeter. HIV-1 RNA was categorized as <400 or ≥400 copies per milliliter. ART was defined as the concurrent use of 3 or more antiretroviral medications from at least 2 classes at any time during calendar year 2010. Insurance status was categorized as Medicaid, Medicare, Private, Ryan White/Uninsured, or missing. Patients with dual eligibility for Medicaid and Medicare were included in the Medicare category.
The primary outcome of this study was all-cause hospitalization in 2010. We also investigated cause-specific hospitalization rates using 18 diagnostic categories, including non–AIDS-defining infection, cardiovascular, gastrointestinal/liver, and AIDS-defining illness (ADI) (for complete list, see Table, Supplemental Digital Content,https://links.lww.com/QAI/A487). Using a previously published algorithm, several steps were taken to assign each hospitalization to a single diagnostic category.18,21 First, the primary diagnostic code for the hospitalization was assigned using the first-listed ICD-9 code that did not refer to HIV (042, V08, 795.71, V01.79), chronic HBV (070.22, 070.23, 070.32, 070.33), chronic HCV (070.44, 070.54, 070.70, 070.71), or oral candidiasis (112.0). These codes represent comorbidities that are frequently recorded for billing purposes but are not, by themselves, sufficient to justify hospitalization. Second, Clinical Classifications Software (CCS) developed by the Agency for Healthcare Research and Quality was used to assign the primary ICD-9 code into 1 of 18 “first-level” CCS categories.22 Finally, we modified the CCS diagnostic categories in 3 ways: we reassigned infections from organ system categories to the infection category (for example, pneumonia was reassigned from pulmonary to infection); we combined congenital, perinatal, and unclassified (together <1% of admissions) into a single category; and we created an ADI category according to the 1993 Centers for Disease Control and Prevention criteria.23 After the ADI category was created, we renamed the remaining infection category as “non–AIDS-defining” and the remaining malignancy category as “non–AIDS-defining.”
Within each diagnostic category, ICD-9 codes were used to identify the most frequently occurring individual diagnoses. Highly similar ICD-9 codes were grouped (Table, Supplemental Digital Content, https://links.lww.com/QAI/A487). The most common individual diagnoses were tallied and reported as percentages of admissions within the corresponding diagnostic category.
Hospitalization rates were calculated as total number of admissions divided by the number of years of patient follow-up and multiplied by 100 to obtain rates per 100 person-years (PY). Patients who enrolled in care or died during the observation period contributed less than 1 year of follow-up, so a variable person-time denominator was used in rate calculations.
Preliminary exploration of the hospitalization count data revealed that the variance was not equal to the mean of the distribution, making negative binomial regression a more robust analytic method than Poisson regression. Unadjusted negative binomial regression was therefore used to estimate incidence rate ratios for all-cause and diagnostic category-specific hospitalization rates associated with hepatitis serostatus and other predefined clinical and demographic variables.
Adjusted negative binomial models compared incidence rates for all-cause hospitalization and diagnostic category-specific hospitalizations between each of the hepatitis serostatus groups (including the unknown group), controlling for age, race, sex, HIV risk factor, CD4, HIV RNA, ART use, and insurance. Adjusted models also included categorical indicators for each clinical care site to control for site-specific variability in health care utilization (results suppressed).
A sensitivity analysis was performed in which patients with 1 positive hepatitis serology and 1 missing hepatitis serology were recategorized from the unknown hepatitis status group into either the HIV/HBV or HIV/HCV group. A 2-sided type I error of 5% was considered statistically significant. All analyses were performed using Stata 12.0 (StataCorp LP, College Station, TX).
Demographic and clinical characteristics of the study population are presented in Table 1. Of the 12,819 patients included in this analysis, 49.3% had HIV monoinfection, 4.2% HIV/HBV coinfection, 15.4% HIV/HCV coinfection, 2.5% HIV/HBV/HCV tri-infection, and 28.7% had unknown hepatitis serostatus. IDU was reported in 17.4% of patients overall with higher percentages in the HIV/HCV (59.4%) and HIV/HBV/HCV (32.7%) groups. MSM comprised 39.4% of patients overall with higher percentages in the HIV/HBV (56.6%) and HIV-monoinfected (47.5%) groups. MSM was relatively less common as a sole HIV risk factor in the HIV/HCV (15.7%) and HIV/HBV/HCV (26.1%) groups. Median CD4 counts and percentages of patients with HIV RNA <400 copies per milliliter were similar across all the hepatitis serostatus groups. There were 117 deaths and 885 new enrollments in care during the study period, resulting in less than 1 year of observation time for these individuals. Median follow-up of these patients was 230 days among patients in the HIV/HBV group and 245 days in all other hepatitis serostatus groups.
There were 2793 hospitalizations in total. Unadjusted all-cause hospitalization rates stratified by hepatitis serostatus are presented in Figure 1A. Rates were highest among HIV/HCV coinfected patients [41.1 hospitalizations per 100 PY (95% confidence interval: 35.7 to 47.2)], followed by HIV/HBV coinfected [35.4/100 PY (26.6 to 47.0)], then HIV/HBV/HCV tri-infected [28.2/100 PY (19.4 to 40.9)]. All-cause hospitalization rates were similar among HIV-monoinfected patients [19.5/100 PY (17.9 to 21.3)] and patients with unknown hepatitis serostatus [18.2/100 PY (16.2 to 20.5)].
Analyses of factors associated with all-cause hospitalization are presented in Table 2. Decreasing CD4 count was the strongest predictor of all-cause hospitalization with an adjusted incidence rate ratio (aIRR) of 8.14 (95% confidence interval: 6.27 to 10.58) for persons with CD4 <50 cells per cubic millimeter, compared with CD4 >500 cells per cubic millimeter. Risk of hospitalization increased in those with HIV/HBV [aIRR, 1.55 (1.17 to 2.06)], HIV/HCV [aIRR, 1.45 (1.21 to 1.74)], and HIV/HBV/HCV [aIRR, 1.52 (1.04 to 2.22)] compared with HIV monoinfection. Other factors independently associated with hospitalization included age, gender, HIV transmission risk factor, HIV-1 RNA, and insurance.
In unadjusted analyses, non–AIDS-defining infections accounted for significantly more hospitalizations per 100 PY in each of the hepatitis coinfected groups than in the HIV monoinfected group (Fig. 1B). Gastrointestinal/liver-related hospitalizations were more common in the HIV/HBV [5.6 per 100 PY (2.9 to 10.7)], and HIV/HCV [4.0 per 100 PY (2.9 to 5.6)] groups than in the HIV monoinfected group [1.6 per 100 PY (1.3 to 2.0)]. Compared with HIV monoinfected patients, patients with HIV/HCV had significantly higher unadjusted hospitalization rates in the cardiovascular, renal, psychiatric, pulmonary, and injury/poisoning categories (P < 0.001).
Adjusted relative rates of hospitalization for the 10 most common diagnostic categories are presented in Figure 2. Compared with HIV monoinfection, the relative rate of hospitalization for non–AIDS-defining infection was higher among patients with HIV/HBV [aIRR, 2.07 (1.38 to 3.11)], HIV/HCV [aIRR, 1.81 (1.36 to 2.40)], and HIV/HBV/HCV [aIRR, 1.96 (1.11 to 3.46)]. The relationship between hepatitis coinfection and hospitalization for gastrointestinal/liver disease was attenuated in multivariate analysis, with only HIV/HBV remaining independently associated with risk of hospitalization for this reason [aIRR, 2.55 (1.30 to 5.01)]. Patients with HIV/HCV had higher risk of hospitalization for psychiatric illness [aIRR, 1.89 (1.11 to 3.26)], and patients with HIV/HBV had higher risk of hospitalization for non–AIDS-defining cancers [aIRR, 4.75 (1.52 to 14.88)] than the HIV monoinfected reference group.
Table 3 lists the most common diagnostic categories and individual diagnoses within these categories. Among non–AIDS-defining infections, bacterial pneumonia was the most common diagnosis overall and among most hepatitis serostatus groups. Complications of cirrhosis (including admissions for cirrhosis, hepatic encephalopathy, portal hypertension, and ascites) were the most common reason for GI/liver admissions overall, although the proportion of admissions did not differ significantly from the proportions for pancreatitis or diarrhea. Complications of cirrhosis accounted for only 4.12% of GI/liver admissions in the HIV monoinfected group. Among ADIs, Pneumocystis jiroveci was the most common diagnosis overall and among most hepatitis serostatus groups.
In our sensitivity analysis, 67 participants from the unknown hepatitis serostatus group were recategorized as HIV/HBV coinfected and 291 as HIV/HCV coinfected on the basis of 1 positive serology and an unknown second hepatitis serology. Multivariable models using this definition of hepatitis serostatus yielded similar results to our original analysis. Compared with HIV monoinfection, the relative rate of all-cause hospitalization was again increased in those with HIV/HBV [aIRR, 1.50 (1.15 to 1.97)], HIV/HCV [aIRR, 1.38 (1.16 to 1.65)], and HIV/HBV/HCV [aIRR, 1.52 (1.04 to 2.22)]. Inferences about the relationship between hepatitis serostatus and risk of diagnostic category-specific hospitalizations were also unchanged (data not shown).
This study is the first to demonstrate, in a contemporary cohort of PLWH, that hospitalization rates are higher among patients with HBV and/or HCV coinfection. This finding is consistent with previous studies demonstrating high rates of morbidity and mortality in coinfected populations.2,5–13,16 Because hospitalizations are a significant driver of health care costs among PLWH, the higher frequency of hospitalization in hepatitis-coinfected populations results in increased health care costs for these populations.19 Policy-makers should be aware of the financial implications of coinfection among PLWH as they allocate scarce health care resources and establish capitated costs for accountable care organizations.
Non–AIDS-defining infections accounted for about a quarter of all hospital admissions, and the relative risk of hospitalization for this reason was elevated among patients in all the hepatitis-infected categories. Consistent with previous studies, the most common non–AIDS-defining infection in our study was bacterial pneumonia.24–26 Chronic viral hepatitis is known to be associated with dysregulation of hepatitis-specific immune responses, but further investigation is needed to explore potential mechanisms underlying an increased risk of bacterial infections.27,28 Preventable infections such as influenza and pneumococcal pneumonia should be proactively addressed in PLWH with appropriate vaccinations to potentially reduce morbidity and hospitalizations.29,30
While complications of cirrhosis among PLWH with viral hepatitis coinfection deserve attention because of their seriousness and their associations with mortality, such hospitalizations accounted for only 2.8% (28 of 999; Table 3) of all hospitalizations among the 3 viral hepatitis groups combined.5–9 We did not perform formal diagnostic tests specifically on complications of cirrhosis because of small sample sizes. By way of comparison, however, they accounted for 0.3% (4 of 1160) of all hospitalizations among HIV monoinfected persons.
The increased risk for hospitalization due to psychiatric disease in the HIV/HCV coinfected group highlights the need for mental health care in this population. The most common diagnosis among psychiatric admissions was depression. Although drug use may also play a role in hospitalizations related to depression, this finding is consistent with existing evidence that HIV/HCV coinfection is associated with higher prevalence and severity of neuropsychiatric disease than either infection alone.16,31 Integrated mental health and HIV care programs have been shown to improve rates of HIV viral suppression, retention in care, substance abuse and psychiatric symptoms, and decrease hospitalization costs.32,33 Colocation of mental health services may offer particular benefit to the HIV/HCV coinfected population.
Interestingly, we did not observe significantly increased risk of hospitalization for renal, cardiovascular, or endocrine diagnoses among HIV/HCV coinfected patients, despite the evidence that morbidity and mortality related to such diagnoses are increased with HCV coinfection.10–13 Our study may not have included enough cardiovascular events to detect a statistically significant difference. Our adjusted relative risk estimates for renal and endocrine hospitalizations, however, suggested no trend toward increased hospitalizations for these diagnoses. One possible explanation for this discrepancy is that these complications are being successfully managed in the outpatient setting and, while present, are not contributing to excess hospitalizations.
Therapy directed against hepatitis B and/or hepatitis C has been shown to decrease progression to cirrhosis among coinfected PLWH.34 Further investigation is needed to evaluate the effects of hepatitis therapy on all-cause and cause-specific hospitalization rates. Treatment of HBV is common among PLWH, and more than 75% of HIV/HBV coinfected patients in the HIVRN are prescribed agents with activity against both HIV and HBV (Moore RD, Personal Communication on May 31, 2013). Conversely, previous studies have reported treatment rates of only 20%–40% for HCV in the routine clinical care of PLWH, with less than half of these persons achieving sustained virologic response.35,36 With the development of more effective and better tolerated anti-HCV medications, increased utilization of anti-HCV therapy among coinfected patients is expected in the near future.37,38 If hepatitis therapy decreases hospitalization rates, this could provide an economic counterbalance to the high cost of treating hepatitis, especially with the newest anti-HCV medications.38,39
A potential limitation of this study is the reliance on hepatitis C antibodies as evidence of hepatitis C coinfection. Unfortunately, HCV RNA data were not available to confirm chronic infection. The bias introduced by misclassifying patients who cleared HCV viremia as being chronically infected would likely make the HIV monoinfected and HIV/HCV coinfected groups seem more similar. Inferences made based on significant differences between these groups should therefore be robust despite the misclassification. Also, HIV coinfection decreases spontaneous clearance of HCV to fewer than 10% of cases, so it is expected that most patients in this analysis with positive anti-HCV were chronically infected with HCV.40
The use of ICD-9 codes to determine cause for hospitalization may be less accurate than physician chart review, although validation studies within individual institutions have suggested high concordance with chart review.21 Hospitalizations occurring outside of each patient's HIV care institution may not be completely captured, though efforts are made by all HIVRN sites to capture utilization data from neighboring hospitals. The inclusion of relatively few patients with HIV/HBV/HCV tri-infection in this study limits our power to draw conclusions about this unique patient population. The population of patients at HIVRN sites is not nationally representative and our findings may not be generalizable to populations served by smaller clinics, located in more rural settings, or cared for by providers with less HIV subspecialty experience.
This study demonstrates that chronic viral hepatitis is associated with increased risk of hospitalization and therefore increased health care costs among PLWH. Policy-makers and third-party payers should be aware of the heightened risk of hospitalization associated with coinfection when allocating health care resources and considering models of health care delivery. Our findings also underscore the importance of targeting patients who are coinfected with HIV and viral hepatitis with preventive measures such as routine vaccinations and integrated mental health services that may help to curb their increased risk of hospitalization. Further investigation is needed to evaluate the effects of therapy against hepatitis on hospitalization rates.
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HIVRN Participating Sites: Alameda County Medical Center, Oakland, CA (Howard Edelstein, MD); Children's Hospital of Philadelphia, Philadelphia, PA (Richard Rutstein, MD); Community Health Network, Rochester, NY (Roberto Corales, DO); Drexel University, Philadelphia, PA (Jeffrey Jacobson, MD, Sara Allen, CRNP); Fenway Health, Boston, MA (Stephen Boswell, MD); Johns Hopkins University, Baltimore, MD (Kelly Gebo, MD, MPH, Richard Moore, MD, MHS, Allison Agwu, MD, ScM); Montefiore Medical Group, Bronx, NY (Robert Beil, MD); Montefiore Medical Center, Bronx, NY (Lawrence Hanau, MD); Oregon Health and Science University, Portland, OR (P. Todd Korthuis, MD); Parkland Health and Hospital System, Dallas, TX (Ank Nijhawan, MD, Muhammad Akbar, MD); St. Jude's Children's Hospital and University of Tennessee, Memphis, TN (Aditya Gaur, MD); St. Luke's Roosevelt Hospital Center, New York, NY (Victoria Sharp, MD, Stephen Arpadi, MD); Tampa General Health Care, Tampa, FL (Charurut Somboonwit, MD); University of California, San Diego, CA (W. Christopher Mathews, MD); Wayne State University, Detroit, MI (Jonathan Cohn, MD).
Sponsoring Agencies: Agency for Healthcare Research and Quality, Rockville, MD (Fred Hellinger, PhD, John Fleishman, PhD, Irene Fraser, PhD); Health Resources and Services Administration, Rockville, MD (Robert Mills, PhD, Faye Malitz, MS).
Data Coordinating Center: Johns Hopkins University (Richard Moore, MD, MHS, Jeanne Keruly, CRNP, Kelly Gebo, MD, MPH, Cindy Voss, MA).