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EPIDEMIOLOGY AND SOCIAL

Rates of hospitalizations and associated diagnoses in a large multisite cohort of HIV patients in the United States, 1994–2005

Buchacz, Katea; Baker, Rose Kb; Moorman, Anne Ca; Richardson, James Tb; Wood, Kathleen Cb; Holmberg, Scott Da; Brooks, John Taand the HIV Outpatient Study (HOPS) Investigators

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doi: 10.1097/QAD.0b013e328304b38b
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Abstract

Introduction

Widespread use of highly active antiretroviral therapy (HAART) in the United States and other industrialized countries since 1996 has resulted in marked reductions in mortality and morbidity among HIV-infected patients [1–5] and a shift in causes of death from predominately AIDS-defining opportunistic infections to chronic diseases [5–9]. In parallel, studies of HIV-infected patients in these countries have found reductions in the overall rates of hospitalization and duration of hospital stays [10–20], and some have documented increasing contribution of non-AIDS-defining chronic illnesses to causes of hospitalization in the HAART era [12,14,21–24].

Observational studies of hospitalizations among HIV-infected patients continue to be relevant today for several reasons. First, they are useful for monitoring the effectiveness and durability of HAART in preventing opportunistic infections and other AIDS-defining illnesses [25]. Increase in hospitalization rates for these conditions could herald rising rates of antiretroviral treatment failure and exhaustion of treatment options among treated patients [26] earlier than the less-common outcome of death. Second, studies of hospitalizations may detect potential increases in chronic illnesses that represent complications or toxicities of HAART, late HIV disease, or both, such as cardiovascular, renal and hepatic disorders, osteopenia, and endocrine and metabolic abnormalities (including insulin resistance with consequent hyperglycemia, hyperlipidemia, diabetes, and lipodystrophy) [24,27–34]. Third, findings from these studies can inform cost-effectiveness analyses in the HAART era [35] to allocate optimally limited healthcare resources [36,37].

Existing large studies documenting the incidence rates of hospitalizations and the spectrum of hospitalization-associated diagnoses in the adult US populations in the HAART era [12,16,21,22] extend through 2001; more recent data from large diverse HIV-infected populations are scarce. We analyzed data from 7155 HIV-infected patients seen during 1994–2005 in 10 HIV clinics (private, public, and university) in the United States to describe risk factors for hospitalization, temporal trends in the rates of hospitalizations for major categories of medical conditions, and changes in immunologic status of hospitalized and nonhospitalized HIV-infected patients.

Methods

The HIV Outpatient Study

The HIV Outpatient Study (HOPS) [1] is an ongoing, open prospective cohort study in which patients have been continuously recruited and followed since 1993. Current study sites include 10 clinics (six university, two public, two private) in eight US cities that provide care for about 3000 HIV-infected patients per year. Over 8000 HOPS patients have been seen in over 31 000 person-years of observation since 1993. The study protocol is approved and renewed annually by each participating institution's ethical review board. All study participants provide written, informed consent.

All HOPS clinicians have extensive experience of treating HIV-infected patients. The HOPS medical record abstractors have backgrounds in nursing or other healthcare-related fields, are familiar with HIV disease and its manifestations, and have been trained in chart abstraction for the HOPS. Information is abstracted from outpatient charts at each visit, entered electronically by trained staff, compiled centrally, and reviewed and edited before being analyzed. Abstracted information includes demographic characteristics and risk factors for HIV infection; diagnoses (both definitive and presumptive); symptoms; prescribed medications, including dose and duration; laboratory values, including CD4+ cell counts and plasma HIV viral loads; mortality; and hospitalizations. Hospitalization data are abstracted from medical records and discharge summaries and include diagnoses and dates of admission and discharge when available. Data quality assurance measures include supervisory reviews of randomly selected charts to ascertain accuracy and completeness of abstracted data, and centralized checks of data files to resolve discrepancies in diagnosis start and stop dates, and in diagnosis codes versus descriptive text field information.

Study population

We analyzed data from 7155 participants in the HOPS who were seen at least twice from 1 January 1994 to 31 December 2005, using HOPS data updated as of 30 June 2007. The 10 clinics included in the analyses were located in Tampa, Florida, USA; Washington, District of Columbia, USA; Denver, Colorado, USA (two sites); San Leandro, California, USA; Chicago, Illinois, USA (two sites); Stony Brook, New York, USA; Philadelphia, Pennsylvania, USA; Oakland, California, USA. End of follow-up was defined as the earliest of the following: last patient contact, date of status change (e.g., death, lost to follow-up), or 31 December 2005.

Classification of diagnoses at hospitalization

We analyzed all diagnoses that were documented as at least a contributing reason for the hospitalization. We classified diagnoses into categories to characterize broad trends in rates of conditions associated with hospitalizations during the 12-year period as follows: AIDS opportunistic infections, AIDS-defining and non-AIDS-defining cancers, cardiovascular, endocrine, gastrointestinal, hematologic, hepatic, nonopportunistic infections, neurologic, psychologic/psychiatric, pulmonary, renal, and all other conditions. In addition, we evaluated trends in chronic end-organ diseases, a category that comprised chronic renal disease, chronic obstructive pulmonary disease (COPD)/asthma, congestive heart failure (CHF), cardiomyopathy and cardiomegaly, coronary artery disease (CAD), hypertension, pancreatitis, hepatitis C infection (HCV), hepatitis B infection (HBV), cirrhosis, and chronic hepatitis.

Broad diagnostic categories (e.g., cardiovascular) were divided into subcategories [e.g., ‘acute coronary syndrome (ACS)’ and ‘cerebrovascular accident (CVA) or transient ischemic attack (TIA)’]. If a patient had multiple diagnoses in the same organ system (e.g., cardiovascular, pulmonary, or hepatic) at a given hospitalization, we reviewed them and assigned the hospitalization to the subcategory of greatest clinical significance or severity. For example, if both hypertension and ACS were recorded at hospitalization, then that hospitalization was classified as linked to ACS. If conditions in the same broad category were either of similar severity or different etiologies or both, each one was counted in the appropriate subcategory, but both represented only one hospitalization in the broad diagnostic category (e.g., one hospitalization for both CAD and TIA would be attributed to both subcategories but counted only once under the ‘cardiovascular’ total). If a patient had multiple diagnoses at hospitalization affecting different organ systems (e.g., sepsis and pneumonia; HCV; and nephrolithiasis), this hospitalization was attributed to each relevant broad diagnostic category (respectively, nonopportunistic infections and pulmonary; hepatic; and renal). We reviewed diagnoses that comprised symptoms (e.g., chest pain, abdominal pain) or signs (e.g., shortness of breath, fever) and attributed a hospitalization to those causes only if an underlying pathologic reason for the hospitalization could not be found (e.g., acute coronary syndrome, chronic active viral hepatitis, sepsis). Within each major diagnostic category, the ‘other’ subcategory included less frequent diagnoses (those that did not exceed the total count of any one diagnosis within that major category shown in the table).

Classification of predictor variables

Age was determined as of the beginning of each of the four time periods: 1994–1996, 1997–1999, 2000–2002, and 2003–2005. Current and nadir CD4+ cell counts were based on values closest to the hospitalization within 180 days prior to the hospitalization. For nonhospitalized patients, current and nadir CD4+ cell counts were chosen from values closest to the middle of the time period. The CD4+ cell count prior to the start of antiretroviral therapy (ART) was the closest one to the start of ART, ranging from 6 months prior through 7 days after the start of ART.

Statistical analyses

We calculated the rates of hospitalization per 100 person-years overall and for categories of medical conditions in each of the four 3-year time periods: pre-HAART (1994–1996), early HAART (1997–1999), mid-HAART (2000–2002), and late HAART (2003–2005). In calculations of incidence rates, patients could be included in multiple time periods, and could contribute more than one hospitalization in each time period.

We evaluated patient sociodemographic and clinical factors associated with hospitalization in each time period using multiple logistic regression models; we reported univariate relative risks with 95% confidence intervals (CIs) and adjusted odds ratios (aOR) with 95% CIs. In these analyses, patients were classified as hospitalized in a given time period if they had at least one hospitalization in that period. All patient characteristics examined in Table 1 were included in the multiple logistic regression models, except that we chose current CD4+ cell count and history of AIDS to describe patient's immune and clinical status (and we did not include nadir CD4+ cell count or CD4+ cell count at the start of ART in the models, as these variables correlated with the above factors).

Table 1
Table 1:
Characteristics of the patient population in the four analysis periods, HIV Outpatient Study, 1994–2005.

We computed crude incidence rates of conditions associated with hospitalization in each of the four time periods. We further evaluated temporal trends in the rates of hospitalizations for these conditions using general estimating equations (GEE) models with autoregressive correlation structure and assuming a Poisson distribution. These models adjusted for age, race/ethnicity, HIV risk group, and type of health insurance coverage, to account for shift in these characteristics in our cohort over time. To safeguard against the overall studywise type I error rate, we considered the temporal trends for the 14 major disease categories to be statistically significant if their P values were below the Bonferroni-adjusted significance level of 0.05/14 that is equal to 0.0036.

We also examined trends in the mean nadir CD4+ cell counts and the mean CD4+ cell counts closest to the time of hospitalization using general linear modeling. We performed these analyses after transforming the CD4+ cell count data on square-root scale to normalize the distribution, and we plotted back-transformed mean values for both variables over time [38].

All analyses were done using SAS version 8.2 (SAS Institute, Cary, North Carolina, USA).

Results

The 7155 HOPS patients included in this analysis contributed 30 642 person-years of observation during 1994–2005, had a median age of 40 years, were predominately male (80.5%), white (56.2%), men who had sex with men (MSM) (58.5%), and privately insured (56.6%). Patient sociodemographic characteristics in the three time periods during 1997–2005 were largely similar, whereas patients in 1994–1996 period included fewer women, fewer nonwhite individuals, and fewer heterosexually infected individuals (Table 1). Patients' median age increased 2 years with each progressive later time period. The percentage of patients with injection drug use (IDU) history as an HIV risk factor decreased from 13.5% in the first period to 10.6% in the last period, whereas the proportion who had history of tobacco use (current or former cigarette smokers) remained level over time at approximately 56%. The median current CD4+ cell count of the population almost doubled from 225 cells/μl in the first period to 433 cells/μl in the last period, consistent with increased use of HAART over time (Table 1).

Of the 7155 HOPS patients analyzed, 2141 (29.9%) unique patients were hospitalized, resulting in a total of 4735 hospitalizations in the 12-year period. The overall rates of hospitalizations (per 100 person-years) declined from 24.6 in 1994 to 11.8 in 2005 (P < 0.0001 for trend; Fig. 1). Statistically significant reductions in rates of hospitalizations were observed for both men and women, across all major racial/ethnic groups (black, Hispanic, and white), across all HIV risk groups [MSM, high-risk heterosexual (HRH), and IDU], and for publicly and privately insured patients (data not shown).

Fig. 1
Fig. 1:
Incidence rate of hospitalization per 100 person-years, by year, the HIV Outpatient Study, 1994–2005. py, person-years.

The 2141 hospitalized patients had a median follow-up of 4.7 years [interquartile range (IQR) 2.0–8.5], whereas the 5014 nonhospitalized patients had a median follow-up of 2.6 years (IQR 0.9–5.8), P < 0.0001. During 1994–1996, of 660 hospitalized patients, 61.2% were hospitalized once, 19.4% were hospitalized twice, and 19.4% were hospitalized three or more times. During 2003–2005, the respective percentages were 68.8, 18.2, and 13.0%.

In the multivariable logistic regression models (Table 2), public insurance and having AIDS were associated with increased odds of hospitalization in both the pre-HAART and HAART eras; however, AIDS was no longer associated with hospitalization in the last analysis period, after adjusting for other factors. Higher current CD4+ cell count was associated with reduced odds of hospitalization across all time periods. Older age and history of substance abuse were independently associated with hospitalization only in the HAART era, whereas race/ethnicity, HIV risk group, and history of smoking were not associated with hospitalization after controlling for other factors in the models. Female gender was independently associated with increased odds of hospitalization only in one period of the HAART era (Table 2).

Table 2
Table 2:
Demographic and clinical patient characteristics associated with hospitalization, HIV Outpatient Study, 1994–2005.

For 93.9% of hospitalizations, there was at least one recorded associated diagnosis, and this percentage was similar across the four time periods (range 92.7–95.7%). The rates of hospitalizations for AIDS opportunistic infections decreased from 7.59 per 100 person-years in the pre-HAART era to 0.97 per 100 person-years in 2003–2005 (P < 0.0001 for trend in multivariable models; Table 3). The rates of hospitalizations for non-AIDS-defining cancers, cardiovascular, endocrine, hepatic, and psychologic/psychiatric conditions did not change significantly over time (using the Bonferroni-adjusted significance level of P = 0.0036), whereas the rates of hospitalizations for all other major categories of medical conditions declined (Table 3). The rates of hospitalizations for the combined category of chronic end-organ conditions were, respectively, 1.75, 1.99, 2.08, and 1.45 per 100 person-years for the four time periods (P = 0.012 for trend in multivariable model). In crude univariate analyses, cardiovascular disease was the only category at hospitalization, which showed a trend toward an increase over time (1.20 per 100 person-years in 1994–1996 to 1.60 per 100 person-years in 2003–2005, P = 0.038 for trend). After adjusting for aging and other sociodemographic risk factors in the models, this trend was neither present for the whole category of cardiovascular disease (P = 0.747) nor for the subset of conditions representing CAD and its consequences (ACS and CHF) (P = 0.445).

Table 3
Table 3:
Incidence rates of hospitalizations for major disease categories, HIV Outpatient Study, 1994–2005.

The rates of hospitalizations for specific illnesses within each major diagnostic category are detailed in Table 3L (long version) available electronically on the journal website at http://www.aidsonline.com.

Although we detected no absolute increase in the rates of hospitalizations for chronic end-organ diseases, these diseases accounted for an increasing percentage of hospitalizations in the latter years due to steep declines over time in the rates of hospitalizations for AIDS opportunistic infections and other conditions (Fig. 2). AIDS opportunistic infections were present at 31% of hospitalizations during 1994–1996 compared with 9.5% of hospitalizations during 2003–2005. The respective percentages for chronic end-organ diseases were 7.3% compared with 14.3%.

Fig. 2
Fig. 2:
Rates of hospitalizations for major categories of medical conditions, the HIV Outpatient Study, 1994–2005. py, person-years.

Within our study population, the percentage of observation time on HAART increased from 14% in 1994–1996 to 75% in 2003–2005 [antiretroviral (ARV)-naïve time was 31 versus 21%, respectively]. The square-root back-transformed mean CD4+ cell counts closest to hospitalization increased over time from 115 cells/μl in 1994 to 310 cells/μl in 2005 and the mean current CD4+ cell counts of nonhospitalized patients rose from 245 to 464 cells/μl (P < 0.0001 for trend for both hospitalized and nonhospitalized patients, Fig. 3a). The square-root back-transformed mean nadir CD4+ cell count for hospitalized patients increased from 88 cells/μl in 1994 to 144 cells/μl in 2005 (P < 0.0001 for trend, Fig. 3b); however, it was consistently lower than the mean nadir CD4+ cell count for nonhospitalized patients, which ranged from 219 to 200 cells/μl in the same time period (P = 0.992).

Fig. 3
Fig. 3:
(a) Mean current CD4+ cell count, by year and hospitalization status, the HIV Outpatient Study, 1994–2005. (b) Mean nadir CD4+ cell count, by year and hospitalization status, the HIV Outpatient Study, 1994–2005.

Conclusion

Hospitalization rates among approximately 7000 HIV-infected patients followed in 10 clinics in the United States have decreased substantially after the introduction of HAART and have continued to decline through 2005, with reductions observed in all major sociodemographic subgroups. CD4+ cell counts improved among both hospitalized and nonhospitalized HOPS patients in the HAART era, but the mean CD4+ cell count of hospitalized patients remained well below the corresponding value for nonhospitalized counterparts. In addition, the spectrum of diagnoses associated with hospitalization has changed during 1994–2005: the rates of AIDS-defining opportunistic infections have decreased precipitously, and the rates of other conditions have either declined or remained unchanged. Consequently, chronic end-organ conditions have become more common as a percentage of all diagnoses associated with hospitalization.

The reductions in hospitalization rates and the shift in diagnoses associated with hospitalization in the HOPS may be explained by several factors. Better opportunistic infection prophylaxis followed by HAART-associated improvements in immunologic function have progressively reduced incidence of AIDS-associated illnesses requiring hospitalization. Improved survival has permitted patients to live long enough to be affected by the sequelae of chronic HIV infection and its treatment, comorbidities, and aging [22,29–31,39]. However, with improved recognition and treatment of many of these non-AIDS-related conditions, they too have steadily declined in incidence. Finally, improvements in the clinical practice of HIV medicine have allowed many conditions for which patients were previously hospitalized to be treated on an outpatient basis.

Our findings of an increasing proportion of hospitalizations for chronic diseases among HIV-infected patients during the HAART era are consistent with and extend the results from earlier studies in the United States [12,22]. In a prospective cohort of 855 predominately inner-city HIV-infected women, Gardner et al.[12] found that the rates of hospitalization associated with diabetes, nonacute renal, and cardiovascular events were stable or increased slightly during 1993–1999, whereas the rates of hospitalization related to hepatitis increased more than 10-fold during the same period. In a 12-state hospital discharge data analysis, Gebo et al.[18,22] reported that hospitalizations for liver-related complications increased from 13 to 18% of all HIV hospitalizations (P < 0.001) during 1996–2000. In our study [40], only 13% of patients analyzed had IDU history, and the prevalence of hepatitis C among all active HOPS patients was approximately 22% during 2002–2005, which may explain the lower frequency of hospitalizations with hepatic diagnoses in our population compared with the results from other populations with greater fractions of IDU and HCV-coinfected individuals [12,13,22].

Furthermore, in the analyses adjusted for age and other sociodemographic factors, we found no increase in the incidence rates of hospitalizations with cardiovascular diseases, non-AIDS cancers, or chronic end-organ diagnoses in the HAART era. The findings for cardiovascular disease were consistent with more recent findings of level trends in hospitalizations for myocardial infarction (MI) from the U.S. Veterans Affairs cohort study [41] of 41 213 HIV-infected patients and the decreasing trends in hospitalizations for coronary artherosclerosis and MI in the National Hospital Discharge Survey of the US population [42]. Finally, the proportion of smokers among the HOPS patients we analyzed was high (about 56%) and relatively constant over time, and although cardiovascular disease and cancers have been associated with smoking in the HOPS [43,44], smoking, as charted, was not an independent predictor for hospitalizations overall or for hospitalizations for chronic end-organ conditions (data not shown).

A notable finding in our study was that hospitalized patients had lower mean nadir and current CD4+ cell counts compared with nonhospitalized patients, both in the pre-HAART and HAART eras. Although we cannot infer a causal relationship, this finding suggests that earlier diagnosis of HIV infection and initiation of antiretroviral treatment to preserve immune function may reduce hospitalizations in HIV-infected patients. In addition to current CD4+ cell count and AIDS, public insurance and history of substance abuse were independently associated with hospitalization in the HAART era. Thus, although the rates of hospitalizations have declined within each major sociodemographic subgroup of HOPS patients, our study suggests that there remain socioeconomic disparities in access to, utilization of, and possibly adherence to optimal care and antiretroviral treatment in the HAART era [12,17,21].

Our study is subject to several limitations. First, we analyzed routinely collected medical chart data and reviewed diagnoses to characterize broad trends in the rates of conditions associated with hospitalizations during the 12-year period. Discharge summaries may list comorbidities present at hospitalization, which were not necessarily reasons for hospitalization. Diagnoses at hospitalization, as well as hospital admissions, may not always have been accurately or completely charted; for instance, there was no diagnosis for approximately 6% of hospitalizations. Although HOPS has multiple data quality control measures in place, we cannot rule out the possibility that some diagnoses were misclassified due to errors in data abstraction. Thus, we may have overestimated or underestimated the rates of hospitalizations for some conditions. However, we do not believe that there were systematic differences over time in the way that hospitalization-related information was recorded or abstracted in the HOPS. Second, although we present the rich data on the rates of specific diagnoses associated with hospitalizations over time (Table 3L on the journal website at http://www.aidsonline.com), we limited statistical inferences of temporal trends to the broad disease categories because the data in these categories are more robust and less subject to possible misclassification than individual diagnoses. Third, specific dates of hospital admission and discharge were not known for 40% of patients in this analysis, thus we could not reliably examine trends in length of hospital stay. Fourth, because of the ecological design of this study, we cannot infer causality between use of HAART and reduced rates of hospitalization, but this relationship is supported by many prior reports and by the fact that patients who had higher current or nadir CD4+ cell counts were less likely to be hospitalized. Fifth, being an HIV-clinic-based cohort, HOPS does not follow HIV-uninfected patients with similar demographics who could provide comparative data on the absolute rates and trends in rates of hospitalizations for chronic diseases. Sixth, our findings are based on a convenience sample of patients who are followed at 10 select private and public HIV clinics, and may not reflect national trends.

Notwithstanding, this study is, to our knowledge, the largest analysis of a prospective cohort of HIV-infected patients in the United States to report on recent temporal trends in hospitalization rates with detailed information on hospitalization-associated diagnoses. The strengths of our study include a 12-year span (1994–2005) comprising more than 30 000 person-years of observation and over 4700 hospitalizations with detailed information on patient clinical and sociodemographic variables and diagnoses associated with hospitalizations. Our study population was diverse: 19% were women, 41% were of nonwhite race/ethnicity, 24% had heterosexual behavior as their HIV risk, and 41% were publicly insured.

In conclusion, we found that the overall rates of hospitalization in a large cohort of HIV-infected patients in routine care declined substantially during 1994–2005, and these declines were observed in all major sociodemographic subgroups. In the HAART era, HOPS patients are increasingly hospitalized at higher CD4+ cell counts and more frequently for chronic end-organ conditions than for AIDS-defining opportunistic infections.

Acknowledgements

The present study is funded by Centers for Disease Control and Prevention (contract no. 200-2006-18797).

We thank the article referees and Dr Sherri Pals at the CDC for advice on data analyses.

Data presented previously at the XVI International AIDS Conference in Toronto; 13–18 August 2006 [Abstract MOPE0071].

The HOPS Investigators include the following investigators and sites: John T. Brooks, Kate Buchacz, Tony Tong, and Anne Moorman, Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention (NCHSTP), Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA; Kathleen C. Wood, Rose K. Baker, James T. Richardson, Darlene Hankerson, and Carl Armon, Cerner Corporation, Vienna, Virginia, USA; Frank J. Palella, Joan S. Chmiel, Aditya Chawla, and Onyinye Enyia, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA; Kenneth A. Lichtenstein and Cheryl Stewart, National Jewish Medical and Research Center Denver, Colorado, USA; John Hammer, Benjamin Young, Kenneth S. Greenberg, Barbara Widick, and Joslyn D. Axinn, Rose Medical Center, Denver, Colorado, USA; Bienvenido G. Yangco and Kalliope Halkias, Infectious Disease Research Institute, Tampa, Florida, USA; Douglas J. Ward and Charles A. Fiorentino, Dupont Circle Physicians Group, Washington, District of Columbia, USA; Jack Fuhrer, Linda Ording-Bauer, Rita Kelly, and Jane Esteves, State University of New York (SUNY), Stony Brook, New York, USA; Ellen M. Tedaldi, Ramona A. Christian, Faye Ruley and Atiya Nimmons, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Richard M. Novak and Andrea Wendrow, University of Illinois at Chicago, Chicago, Illinois, USA.

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

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Table 1
Table 1
Table 2
Table 2
Table 3
Table 3
44. Patel P, Novak R, Tony T, Behari P, Moorman A, Palela F, Holmberg D and the HOPS Investigators. Incidence of non-AIDS defining malignancies in the HIV Outpatient Study (HOPS). Eleventh Conference on Retroviruses and Opportunistic Infections; San Francisco, California, February 2004 [abstract 81].
Keywords:

chronic disease; highly active antiretroviral therapy; HIV; hospitalization; incidence; opportunistic infection; trends

© 2008 Lippincott Williams & Wilkins, Inc.