JAIDS Journal of Acquired Immune Deficiency Syndromes:
Trends and Causes of Hospitalizations Among HIV-Infected Persons During the Late HAART Era: What Is the Impact of CD4 Counts and HAART Use?
Crum-Cianflone, Nancy F MD, MPH*†; Grandits, Greg MS*‡; Echols, Sara RN*†; Ganesan, Anuradha MD*§; Landrum, Michael MD*‖; Weintrob, Amy MD*¶; Barthel, Robert MD*#; Agan, Brian MD*; the Infectious Disease Clinical Research Program
From the *Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD; †Infectious Disease Clinic, Naval Medical Center San Diego, San Diego, CA; ‡Division of Biostatistics, University of Minnesota, Minneapolis, MN; §Infectious Disease Clinic, National Naval Medical Center, Bethesda, MD; ‖Infectious Disease Clinic, San Antonio Military Medical Center, San Antonio, TX; ¶Infectious Disease Clinic, Walter Reed Army Medical Center, Washington, DC; and #Infectious Disease Clinic, Naval Medical Center Portsmouth, Portsmouth, VA.
Received for publication August 11, 2009; accepted October 5, 2009.
Support for this work (IDCRP #028) was provided by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense program executed through the Uniformed Services University of the Health Sciences. This project has been funded in whole, or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under Inter-Agency Agreement Y1-AI-5072.
This work is original and has not been published elsewhere. Part of these data was presented at the 47th Infectious Diseases Society of America Annual Meeting, October 29 to November 1, 2009, Philadelphia, PA.
All authors have reviewed and approved this article.
N.F.C.C and G.G. had full access to all the data and take responsibility for the accuracy of the data.
The content of this publication is the sole responsibility of the authors and does not necessarily reflect the views or policies of the National Institutes of Health or the Department of Health and Human Services, the Department of Defense, or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the US Government.
Correspondence to: Dr. Nancy F. Crum-Cianflone, MD, MPH, c/o Clinical Investigation Department (KCA), Naval Medical Center San Diego, 34800 Bob Wilson Drive, Ste. 5, San Diego, CA 92134-1005 (e-mail: firstname.lastname@example.org).
Background: Declining rates of hospitalizations occurred shortly after the availability of highly active antiretroviral therapy (HAART). However, trends in the late HAART era are less defined, and data on the impact of CD4 counts and HAART use on hospitalizations are needed.
Methods: We evaluated hospitalization rates from 1999 to 2007 among HIV-infected persons enrolled in a large US military cohort. Poisson regression was used to compare hospitalization rates per year and to examine factors associated with hospitalization.
Results: Of the 2429 participants, 822 (34%) were hospitalized at least once with 1770 separate hospital admissions. The rate of hospitalizations (137 per 1000 person-years) was constant over the study period [relative rate (RR) 1.00 per year change, 95% confidence interval: 0.98 to 1.02]. The hospitalization rates due to skin infections (RR: 1.50, P = 0.02), methicillin-resistant staphylococcus aureus (RR: 3.19, P = 0.03), liver disease (RR: 1.71, P = 0.04), and surgery (RR: 1.17, P = 0.04) significantly increased over time, whereas psychological causes (RR: 0.60, P < 0.01) and trauma (RR: 0.54, P < 0.01) decreased. In the multivariate model, higher nadir CD4 (RR: 0.92 per 50 cells, P < 0.01) and higher proximal CD4 counts (RR of 0.71 for 350-499 vs. <350 cells/mm3 and RR 0.67 for ≥500 vs. <350 cells/mm3, both P < 0.01) were associated with lower risk of hospitalization. Risk of hospitalization was constant for proximal CD4 levels above 350 (RR: 0.94 P = 0.51, CD4 ≥500 vs. 350-499). HAART was associated with a reduced risk of hospitalization among those with a CD4 <350 (RR: 0.72, P = 0.02) but had smaller estimated and nonsignificant effects at higher CD4 levels (RR: 0.81, P = 0.33 and 1.06, P = 0.71 for CD4 350-499 and ≥500, respectively).
Conclusions: Hospitalizations continue to occur at high rates among HIV-infected persons with increasing rates for skin infections, methicillin-resistant staphylococcus aureus, liver disease, and surgeries. Factors associated with a reduced risk of hospitalization include CD4 counts >350 cells per cubic millimeter and HAART use among patients with a CD4 count <350 cells per cubic millimeter.
Declining rates of hospitalizations occurred shortly after the availability of highly active antiretroviral therapy (HAART)1-8 along with significant reductions in both the length of stay and hospital mortality rates.2,9,10 These dramatic shifts were largely attributed to the effects of HAART, which decreased the incidence of AIDS events and improved the immune status of HIV-infected persons. Trends in hospitalization rates during the late HAART era are less defined, with some studies suggesting stabilization or increasing rates of hospitalizations.11-13 The potential reasons for the lack of continued decline in hospitalization rates include aging of the HIV population, development of chronic end-organ diseases, toxicity from long-term antiretroviral (ARV) use, development of multidrug-resistant viruses, and high prevalence of lifestyle-related factors such as illicit drug use and smoking.
As HIV-infected persons are surviving and experiencing longer life expectancies, hospitalizations have become an important outcome measure and are an important component of excess health care costs among this population. Hence, data on the rates of hospitalizations in the late HAART era are useful for both health care planning and the development of strategies to improve the health of HIV patients. Although higher CD4 counts and HAART use are known to decrease AIDS-defining events and death,14 their impact on hospitalizations is less certain, especially because many hospitalizations are now due to non-AIDS-defining comorbidities.6,15 Further investigation into the effects of treatment approaches16 on hospitalization rates are needed.1
We evaluated prospectively collected data from an observational HIV Natural History Study (NHS) to investigate the trends and causes of hospitalizations among HIV-infected persons during the late HAART era. In addition, we assessed the impact of time-updated CD4 cell counts and ARV medication use on hospitalization events during the late HAART era.
We examined data collected from participants in the US Military NHS, an ongoing, multicenter, prospective, observational study of military personnel and beneficiaries with HIV infection, as previously described.17,18 All active duty US military personnel are confirmed HIV negative before enlistment and undergo routine HIV screening every 1-5 years. Participants in the NHS are evaluated every 6 months by an HIV specialist as part of the study, in addition to receiving routine clinical care. Data collected include demographics (age, gender, and self-reported ethnicity), markers of HIV progression, ongoing medical history, and HAART use as previously defined.18 Chronic hepatitis B was defined as 2 positive surface antigen tests over time and chronic hepatitis C as a positive antibody test. Standardized collection of hospitalization data in the NHS began in 1999. This substudy evaluated data from 1999 to 2007 among 2429 HIV-infected persons.
Hospitalization Data Collection
Hospitalizations were defined as a ≥24 hours admission to an inpatient hospital ward and were captured among both discharged patients and those who died during admission. Data on hospitalizations were collected at each 6-month visit using admission records and discharge summaries. Because participants were military beneficiaries, most admissions were to a military facility, which were collected via computerized medical review. In addition, participants were asked about any other hospitalizations including at civilian facilities, and these data were collected to ensure complete hospitalization data. For this study, the primary cause of hospitalization was used and was categorized based on an organ and disease system coding scheme as shown in the Appendix I. Diseases not within 1 of these categories or when the diagnosis was unknown were coded as “other.” Each hospitalization was placed into a single category.
In addition to these categories, a review of each discharge diagnosis was performed to assess for other clinically relevant medical diagnoses, and these were assigned an additional nonmutually exclusive reason for hospitalization. These diagnoses included AIDS-defining illnesses excluding solely a CD4 count <200 cells per cubic millimeter,19 infection, skin/soft tissue infections, culture-confirmed methicillin-resistant staphylococcus aureus (MRSA) infection, trauma, drug-related (illicit drug use, alcohol, or overdose), suicide attempt, and chronic end-organ diseases (chronic obstructive lung disease, asthma, congestive heart failure, cardiomyopathy, arrhythmia, coronary artery disease, cerebrovascular disease, hypertension, pancreatitis, chronic liver disease, or chronic renal disease).6 We also assessed each hospitalization if a surgical procedure was performed, and if so, whether the procedure was the primary reason for admission.
The number of hospitalizations, person-years at risk, and rates of hospitalization (per 1000 person-years of follow-up) were calculated for the overall study period, individual study years, and the following a priori determined study periods: 1999-2001, 2002-2004, and 2005-2007. Each participant contributed person-years at risk from their date of documented HIV diagnosis or January 1, 1999 (whichever was later), to their last follow-up visit or December 31, 2007 (whichever was earlier). Participants could be included in multiple periods and could contribute more than 1 hospitalization per period. Hospitalization rates per period (year or year interval) were computed as total hospitalizations occurring during the period divided by total person-years of follow-up in the period.
Comparisons of rates across periods were assessed using Poisson regression (with offset for person years) with a compound symmetry covariance structure to account for participants contributing to multiple periods. Analyses were done for total hospitalizations and for selected causes. Relative rates (RRs) were estimated from the model using calendar year as a continuous variable entered either as a single year (1999-2007) or as an ordinal variable for the 3 year categories. Thus, RR presented is per-year or per-period difference (approximately 3 years). We utilized and reported 1 degree of freedom (df) tests for linear trends over time; this strategy was chosen to be most clinically relevant and the most powerful test to determine if linear trends existed; however, 2 df tests were also examined for differences among any of the 3 periods.
Poisson regression was also used to assess risk factors for hospitalization. For these analyses, risk factors were updated for each calendar year, and the hospitalization rate for the subsequent year was modeled as a function of the current level of covariates. CD4 levels used were the last recorded value in the prior year (referred to as “proximal CD4” and categorized in 3 levels) and the lowest CD4 recorded up through the prior year (referred to as “nadir CD4”). HAART was examined in the models using time-updated variables accounting for time on and off of ARV medications and was recorded as the status at the beginning of the year. To assess if the effect of HAART use on hospitalization differed by CD4 level an interaction term (CD4 level × HAART use) was added to the model. Longitudinal models were used to compare characteristics of patients hospitalized across periods. All analyses were conducted using SAS (version 9.1, Cary, NC); PROC GENMOD was used for Poisson regression modeling.
Baseline Characteristics of Study Population
During the study period (1999-2007), 2429 participants were followed for a total of 12,923 person years. The median length of follow-up during this period was 5.6 years. Mean age of participants at HIV diagnosis was 30 (SD: 8) years; 91% were male; 46% reported to be African-American, and 41% white/non-Hispanic. Documented HIV-positive date was before 1996 for 48% of participants. Median CD4 count at HIV diagnosis was 488 cells per cubic millimeter (interquartile range: 344-644 cells/mm3).
Table 1 shows the characteristics of the population during the overall study period and over the 3 periods. The mean age during the study period was 37 (SD: 10) years, mean duration of HIV infection was 7 (SD: 5) years, and 62% were receiving HAART for a mean duration of 4 (SD: 2) years. The mean CD4 count at HAART initiation was 352 cells per cubic millimeter (SD: 207). The mean CD4 count throughout the study period was 554 (SD: 286) cells per cubic millimeter with a nadir of 327 (SD: 200) cells per cubic millimeter, and 52% had a suppressed (<400 copies/mL) HIV RNA level. Characteristics of the cohort were similar over the periods except for duration factors reflecting the aging of the cohort.
Rates and Causes of Hospitalizations
Of the 2429 participants, 822 (33.8%) were hospitalized at least once during 1999-2007 with 1770 separate hospital admissions. Of those hospitalized, 53% had 1 admission, 24% had 2, 10% had 3, and 13% had 4 or more admissions. The mean duration of hospitalization was 6.3 (SD: 9.2) days and did not significantly vary over the study periods [6.6 (SD: 5.6), 7.1 (8.2), and 5.1 (3.6) from earliest to latest periods]. The longest hospitalizations were due to drug-related and psychiatric causes with a mean duration of 15 (SD 13.5) and 10 (20.2) days, respectively.
The overall rate of hospitalizations during the study period was 137 [95% confidence interval (CI): 131 to 143] per 1000 person-years (Table 2). Rates during the 3 time periods were 137 (95% CI: 126 to 148), 148 (95% CI: 137 to 159), and 125 (95% CI: 115 to 137), respectively. The estimated RR slope was 1.00 per year (95% CI: 0.98 to 1.02). Age-adjusted hospitalization rates over the study period also showed no significant change over time (RR: 0.98, 95% CI: 0.96 to 1.01).
The unadjusted rates of the primary causes of hospitalization based on organ and disease system categories are shown in Table 3. The most common reason for hospitalization was gastrointestinal (rate 23.8 per 1000 person-years), followed by bacterial infection (17.8 per 1000 person-years), respiratory (15.8 per 1000 person-years), and cardiovascular (12.0 per 1000 person-years). The most frequent gastrointestinal cause was pancreatitis (Appendix I). There was 40% reduction (RR: 0.60, 95% CI: 0.46 to 0.77) from period to period in the rate of hospitalizations due to psychological causes, which were most commonly a major depressive disorder. There were trends for rising rates of hospitalization for cancer (RR: 1.50, P = 0.06) and cardiovascular disease (RR: 1.24, P = 0.06), and decreasing trends for neurological disease (RR: 0.75, P = 0.05). We also examined the data using 2 df and found no additional categories with significant P values beyond that found with 1 df.
We also examined rates of selected clinically relevant individual causes of hospitalizations (Table 4). AIDS-defining conditions occurred at a rate of 10.3 admissions per 1000 person-years and did not significantly change over the study period (RR: 0.95, 95% CI: 0.71 to 1.27). Infections accounted for the highest rate of hospitalizations (rate 49.2 per 1000 person-years) and also did not change over time (RR: 0.94, 95% CI: 0.84 to 1.05). However, some non-AIDS-defining infections occurred at higher rates over time: hospitalizations for MRSA infections, although infrequent, increased 300% over time (RR: 3.19, 95% CI 1.10 to 9.20); and skin/soft tissue infections increased by 50% (RR: 1.50, 95% CI: 1.07 to 2.09). Liver disease due to hepatitis B or C infection, cirrhosis, or other forms of hepatitis also accounted for an increasing rate of admissions (RR: 1.71, 95% CI: 1.03 to 2.83). Surgery as the primary reason for admission occurred at a rate of 21.9 per 1000 person-years and increased over time (RR: 1.17, 95% CI: 1.01 to 1.35), as did any surgery being performed during admission (RR: 1.14, 95% CI: 1.01 to 1.29). Decreasing rates for trauma-related admissions were noted (RR: 0.54, 95% CI: 0.35 to 0.83).
In addition to rates, the proportion of hospitalizations due to specific causes was examined. AIDS-defining conditions accounted for 133 (7.5%) of admissions and did not change from 1999 to 2007. Infections were the most common cause of admission and accounted for 637 (36%) admissions but also did not significantly change over time. Of infections, MRSA accounted for an increasing proportion of admissions (0.3%, 0.6%, and 2.9%, respectively). Likewise, the proportion of admissions due to skin/soft tissue infections increased from 3.6% and 4.5% to 8.3%. Surgery as the primary reason for admission accounted for 283 (16%) of hospitalizations, and this proportion increased over time: 12.8%, 16.0%, and 19.6%, respectively. By the last study period, any surgery (as either the primary reason or as a result of another reason) occurred among 28.5% of admissions. The most common type of surgery performed was orthopedic (n = 86), followed by appendectomy due to acute appendicitis (n = 37), abscess drainage procedure (n = 37), human papillomavirus procedure for anal disease including cancer (n = 30), hernia repair (n = 30), and cardiovascular disease-related procedures (n = 29).
Characteristics of Hospitalized HIV-Infected Persons and Trends in the HAART Era
We examined characteristics of HIV-infected persons who were hospitalized (Table 5). The mean age of hospitalized patients was 40.7 (SD: 10.2) years, with age steadily increasing over the study period from 39 to 43 years (P < 0.001). The percentage of hospitalized patients with hepatitis C increased over time from 8% to 14% (P < 0.01). Hospitalized HIV-infected persons had a mean duration of HIV of 10 (SD: 6) years, which progressively increased over the study period (8, 10, 11 years, P < 0.001). The mean proximal CD4 count of those hospitalized also increased, although this did not reach statistical significance: 409, 437, and 466 cells per cubic millimeter (P = 0.18); nadir CD4 counts did significantly increase over time (P < 0.01). The HIV RNA level was suppressed among 47% of hospitalized patients, which did not significantly change over time. Although the percentage of patients currently receiving HAART also did not significantly change over time (overall 70%), the cumulative duration of HAART use was higher over time: 3, 5, and 7 years, respectively (P < 0.001).
Factors Associated With Hospitalization
In a multivariate model, factors associated with a lower risk of hospitalization included higher nadir CD4 count (RR: 0.92 per 50 cells, 95% CI: 0.89 to 0.95, P < 0.01) and higher proximal CD4 count (RR: of 0.71 for 350-499 vs. <350 cells/mm3 and RR: 0.67 for >500 vs. <350 cells/mm3, both P < 0.01) (Table 6). The risk of hospitalization was further explored for proximal CD4 strata above 350 cells per cubic millimeter and found to be not significantly different (RR: 0.94, 95% CI: 0.88 to 1.14, P = 0.51, CD4 ≥500 vs. 350-499 cells/mm3). HAART use among those with a CD4 <350 cells/mm3 (RR: 0.72, 95% CI: 0.55 to 0.94, P = 0.02) was associated with a reduced risk of hospitalization but had a smaller estimated effect at CD4 levels of 350-499 cells per cubic millimeter (RR of 0.81, 95% CI: 0.53 to 1.24, P = 0.33) and no apparent effect at CD4 levels ≥500 cells per cubic millimeter (RR of 1.06, 95% CI: 0.79 to 1.41, P = 0.71). The test for CD4-HAART interaction was not significant (P = 0.13). Chronic hepatitis C infection was associated with a higher risk of hospitalization (RR: 1.46, 95% CI: 1.05 to 2.03, P = 0.02), with trends for female gender (RR: 1.34, 95% CI: 0.99 to 1.80, P = 0.05). HIV duration was also examined but was highly correlated with age. When HIV duration was included instead of age in the multivariate model, it had a borderline statistical significance (RR: 1.02 per year, 95% CI: 1.0 to 1.03, P = 0.05). We also repeated the multivariate analyses for each of the 3 periods; similar results were found, except that female was a risk factor for hospitalization early in the study period (1999-2001) but not significant in more recent years (data not shown). Multivariate analyses were repeated for non-AIDS-defining causes of hospitalizations, and similar findings were noted (Table 6).
In addition, multivariate analyses for factors associated with fewer hospitalizations due to an infectious cause were performed. Stronger associations were found for nadir CD4 count (RR: 0.86 per 50 cells, P < 0.01) and proximal CD4 count (RR of 0.67 for 350-499 vs. <350 cells/mm3 and RR: 0.56 for ≥500 vs. <350 cells/mm3, both P < 0.01). HAART also seemed beneficial at CD4 counts <350 cells/mm3 (RR: 0.62, 95% CI: 0.45 to 0.84, P < 0.01) and at CD4 counts 350-499 cells/mm3 (RR: 0.58, 95% CI: 0.34 to 0.99, P = 0.05) but not at CD4 counts >500 cells per cubic millimeter (RR: 1.34, 95% CI: 0.85 to 2.10, P = 0.21) (Table 6). Finally, factors associated with hospitalizations primarily due to a surgery procedure included increasing age (RR: 1.25, 95% CI: 1.06 to 1.48, P < 0.01) and race; African Americans compared with whites had a lower risk for hospitalization for surgery (RR: 0.58, 95% CI: 0.41 to 0.81, P < 0.01). Neither CD4 counts nor HAART use was associated with admission for a surgical procedure.
Our study demonstrates that hospitalizations continue to occur at high rates among HIV-infected persons and that these rates have not changed during the late HAART era. The causes of hospitalizations have diversified with non-AIDS-related comorbidities currently being the most common cause of admission. Our study has shown that CD4 counts >350 cells per cubic millimeter and the use HAART among persons with a CD4 count <350 cells per cubic millimeter are associated with reduced rates of hospitalization. These data suggest that HAART use by the treatment guidelines16 seems to be protective of hospitalizations due to non-AIDS-related causes.
Our study investigated the rates of hospitalization during the late HAART era and found that rates have stabilized and occurred at 137 per 1000 person-years, a rate higher than both in general and military population.13,20-22 In fact, one third of HIV-infected persons required hospitalized at least once during our study period. In addition, the length of stay for hospitalizations also remained constant during the late HAART era. These data suggest that hospitalizations remain an important issue among HIV-infected persons and provide useful information for planning future resource allocation and providing areas of focus to improve health among HIV-infected persons.
Infections were the most common cause of admission, although most were non-AIDS-defining. We noted increasing hospitalization rates due to skin and soft tissue infections and MRSA infections. These increases may reflect trends seen in the general population.23 Another study also noted the importance of MRSA as a cause for hospitalizations among HIV-infected persons, although that study was among injection drug users.24 Our military population consists mostly of non-drug users, suggesting that hospitalizations due to MRSA infections among these HIV patients are also occurring at increasing rates.
Chronic end-organ diseases are an important cause of hospitalizations among HIV-infected persons.6,25 Our study suggests that liver disease, and perhaps cardiovascular diseases and cancers, are increasingly important reasons for hospitalization. Other studies have demonstrated the increasing impact of chronic viral hepatitis and liver disease on admission rates,2,5,25-28 including one study that showed nearly 10% of admissions and one third of in-hospital deaths were due to liver disease.29 Many studies focused on the importance of hepatitis C virus on the increasing hospitalization rates of liver disease2,28; of note, we found increasing rates of liver disease despite an overall low prevalence of hepatitis C among our cohort. Together, these data emphasize the importance of the prevention of hepatitis coinfection, treatment of chronic viral hepatitis, and avoidance of other causes of hepatic injury as potential methods in reducing liver-related complications including hospitalizations.
Surgery as the cause of hospitalization occurred at an increasing rate, and by the last period, was the primary reason for 20% of admissions. The most common surgeries were orthopedic in nature and were usually the result of degenerative disease or injury. The rising rate of surgery likely is a reflection of the aging of the HIV population and the military population served who may experience work-related injuries.20 It may also reflect the increased willingness to perform surgical procedures as HIV patients are less often succumbing to opportunistic diseases.30,31
We evaluated factors associated with hospitalizations and found that higher nadir and proximal CD4 counts were associated with a reduced rate of hospitalizations. A CD4 count of >350 cells per cubic millimeter was significantly related to a lower rate of admissions. Other studies have also noted the relationship between lower CD4 counts and hospitalizations.2,5,6,13,32 These data emphasize the need for early diagnosis and treatment to maintain robust CD4 counts to further reduce hospitalization events.
Previous studies suggest that reductions in hospitalizations during the HAART era may be reaching its threshold.13 In a study examining trends between 1996 and 2000 in 12 States, hospitalization rates substantially dropped after the introduction of HAART (by 25% between 1996 and 1998), but the subsequent decline was less robust (6% between 1998 and 2000).32 Similarly, a recent study showed that although rates continued to decline, they did so only modestly during the most recent period.6 Most of the decrease in these hospitalization rates, especially during the early HAART era, was attributed to a reduction in AIDS-defining conditions. More recently, however, there has been an increase in hospitalizations due to non-AIDS-related diagnoses (eg, liver disease)32 suggesting that hospitalization rates could stabilize or increase over time. Our study showed stable admission rates over the late HAART era, perhaps due to the more recent period examined (1999-2007), the early diagnosed and treated cohort evaluated who had few AIDS-defining events, and aging of our population during the study period.
Although it is known that HAART has played a critical role in decreasing opportunistic events,14,33 its role on the impact of other causes of hospitalization is less defined. Because most admissions in our study were due to non-AIDS-related causes, we were able to assess the relationship between HAART and non-AIDS hospitalizations. We found that HAART use was associated with approximately a 30% reduction in both all-cause and non-AIDS-defining hospitalization rates among those with CD4 counts <350 cells per cubic millimeter. Although the risk of all-cause hospitalizations was lower among those on HAART at CD4 counts 350-500 cells per cubic millimeter, this did not reach statistical significance. These data demonstrate that HAART use is beneficial in reducing hospitalizations when utilized at a threshold consistent with the treatment guidelines.16 Additionally, there may be potential benefits of HAART at higher CD4 counts (>350 cells/mm3) for reducing specific types (eg, infection related) hospitalizations; further studies to confirm this finding are needed.
Increasing age was also associated with trends for increased hospital admissions, especially for non-AIDS causes and surgical procedures. These data suggest that the aging of the HIV population may be contributing to hospitalization rates in this population and may continue to impact these rates in the upcoming years. We noted that females during some periods had a higher rate of hospitalization similar to other studies6,13,32,34; the exact nature of this finding is uncertain.
Like all studies, ours had potential limitations. Our cohort was comprised of mainly male patients; although this is similar to the male predominant HIV population in the United States, we could not assess the factors specifically associated with hospitalizations among women or the impact of obstetric diagnoses. Our study did not ascertain if the cause of hospitalization was related to ARV toxicities; another study showed that 7% of admissions were related to ARV toxicities.35 Although ARV toxicities probably accounted for some hospitalizations, it is likely that HAART is more apt to prevent, than cause, hospital admissions. Another potential limitation is that the diagnosis listed on discharge paperwork may not always accurately reflect the cause of admission; however, we reviewed the cases when the diagnosis was in question and verified the cause for these admissions. To maintain statistical power, we calculated rates based on broad categories of causes of hospitalization; however, we also performed a review of all hospitalization diagnoses and created other clinically relevant diagnosis categories. Regarding our findings of the protective benefit of HAART on hospitalizations, we acknowledge that HAART may also be a surrogate for better follow-up and healthier behaviors; however, only those who attended study and clinical care visits were included in our analyses. We also acknowledge the effect of HAART is difficult to assess in an observational study due the fact that discontinuation of HAART may be related to illness or other factors related to hospitalization. Finally, we did not have an HIV-negative comparator group for our study population.
Our study had several strengths including the availability of detailed and time-updated information on HIV-specific factors. We also had access to detailed information on the cause of hospitalization with ability to verify the diagnoses, a unique characteristic in comparison to several prior studies. Our population consisted of HIV patients who had equal access to care, stable socioeconomic status, little illicit drug use, and universal health care coverage-characteristics which are known to affect hospitalizations6,9,36,37 but were uniform in our population allowing for us to focus on the effect of HIV-specific factors on hospitalization rates. Our study cohort also was not affected by changing insurance policies, which can impact hospitalizations over time; to our knowledge, there were consistent decisions and policies regarding hospitalizations at our medical facilities during the study period.
In summary, HIV-infected persons continue to experience high rates of hospitalizations in the late HAART era. Non-AIDS-related comorbidities are currently the most common cause of hospitalizations, with increasing rates of hospitalizations due to skin and soft infections, MRSA, and liver disease. Maintaining CD4 counts >350 cells per cubic millimeter and the use HAART among persons with a CD4 count <350 cells per cubic millimeter are associated with reduced hospitalization rates. These data emphasize the importance of early diagnosis and entry into care in further reducing hospitalizations among HIV-infected persons.
We express our gratitude to Ken Svendsen, MS, for his assistance with the statistical analyses in this article. The Infectious Disease Clinical Research Program Working Group is comprised of Naomi Aronson, MD, Susan Banks, Mary Bavaro, MD, Helen Chun, MD, Cathy Decker, MD, Conner Eggleston, Heather Hairston, Cliff Hawkes, MD, Arthur Johnson, MD, Alan Lifson, MD, Grace Macalino, PhD, Jason Maguire, MD, Scott Merritt, Robert O'Connell, MD, Jason Okulicz, MD, Sheila Peel, PhD, Michael Polis, MD, John Powers, MD, Sybil Tasker, MD, Edmund Tramont, MD, Timothy Whitman, MD, Mark Wallace, MD, Glenn Wortmann, MD, and Michael Zapor, MD.
1. Mocroft A, Barry S, Sabin CA, et al. The changing pattern of admissions to a London hospital of patients with HIV: 1988-1997. Royal Free Centre for HIV Medicine. AIDS. 1999;13:1255-1261.
2. Mocroft A, Monforte A, Kirk O, et al, and EuroSIDA study group. Changes in hospital admissions across Europe: 1995-2003. Results from the EuroSIDA study. HIV Med. 2004;5:437-447.
3. Altés J, Guadarrama M, Force L, et al. The impact of highly active antiretroviral therapy on HIV-related hospitalizations in 17 county hospitals in Catalonia, Spain. Catalonian County Hospitals HIV Infection Study Group. AIDS. 1999;13:1418-1419.
4. Paul S, Gilbert HM, Ziecheck W, et al. The impact of potent antiretroviral therapy on the characteristics of hospitalized patients with HIV infection. AIDS. 1999;13:415-418.
5. Paul S, Gilbert HM, Lande L, et al. Impact of antiretroviral therapy on decreasing hospitalization rates of HIV-infected patients in 2001. AIDS Res Hum Retroviruses. 2002;18:501-506.
6. Buchacz K, Baker RK, Moorman AC, et al, and HIV Outpatient Study (HOPS) Investigators. Rates of hospitalizations and associated diagnoses in a large multisite cohort of HIV patients in the United States, 1994-2005. AIDS. 2008;22:1345-1354.
7. Baum SE, Morris JT, Gibbons RV, et al. Reduction in human immunodeficiency virus patient hospitalizations and nontraumatic mortality after adoption of highly active antiretroviral therapy. Mil Med. 1999;164:609-612.
8. Beck EJ, Mandalia S, Williams I, et al. Decreased morbidity and use of hospital services in English HIV-infected individuals with increased uptake of anti-retroviral therapy 1996-1997. National Prospective Monitoring System Steering Group. AIDS. 1999;13:2157-2164.
9. Fleishman JA, Hellinger FJ. Trends in HIV-related inpatient admissions from 1993 to 1997: a seven-state study. J Acquir Immune Defic Syndr. 2001;28:73-80.
10. Nuesch R, Geigy N, Schaedler E, et al. Effect of highly active antiretroviral therapy on hospitalization characteristics of HIV-infected patients. Eur J Clin Microbiol Infect Dis. 2002;21:684-687.
11. Gebo KA, Diener-West M, Moore RD. Hospitalization rates in an urban cohort after the introduction of highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2001;27:143-152.
12. Fleishman JA, Hellinger FH. Recent trends in HIV-related inpatient admissions 1996-2000: a 7-state study. J Acquir Immune Defic Syndr. 2003;34:102-110.
13. Krentz HB, Dean S, Gill MJ. Longitudinal assessment (1995-2003) of hospitalizations of HIV-infected patients within a geographical population in Canada. HIV Med. 2006;7:457-466.
14. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338:853-860.
15. Moore RD, Gebo KA, Lucas GM, et al. Rate of comorbidities not related to HIV infection or AIDS among HIV-infected patients, by CD4 cell count and HAART use status. Clin Infect Dis. 2008;47:1102-1104.
16. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
. Department of Health and Human Services; November 3, 2008: 1-139. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
. Accessed July 1, 2009.
17. Weintrob AC, Fieberg AM, Agan BK, et al. Increasing age at HIV seroconversion from 18 to 40 years is associated with favorable virologic and immunologic responses to HAART. J Acquir Immune Defic Syndr. 2008;49:40-47.
18. Crum-Cianflone N, Hullsiek KH, Marconi V, et al. Trends in the incidence of cancers among HIV-infected persons and the impact of antiretroviral therapy: a 20-year cohort study. AIDS. 2009;23:41-50.
19. Centers for Disease Control (CDC). 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep. 1992;41:961-962.
20. Hospitalizations among members of active components, U.S. Armed Forces, 2008. Medical Surveillance Monthly Report. 2009;16:2-8.
22. DeFrances CJ, Lucase CA, Bule VC, et al. 2006 National Hospital Discharge Survey. National Health Statistics Reports. Hyattsville, MD: US Department of Health and Humans Services; July 30, 2008.
23. Moran GJ, Krishnadasan A, Gorwitz RJ, et al, and EMERGEncy ID Net Study Group. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med. 2006;355:666-674.
24. Hsieh YH, Rothman RE, Bartlett JG, et al. HIV seropositivity predicts longer duration of stay and rehospitalization among nonbacteremic febrile injection drug users with skin and soft tissue infections. J Acquir Immune Defic Syndr. 2008;49:398-405.
25. Gardner LI, Klein RS, Szczech LA, et al, and HIV Epidemiology Research Study Group. Rates and risk factors for condition-specific hospitalizations in HIV-infected and uninfected women. J Acquir Immune Defic Syndr. 2003;34:320-330.
26. Martín-Carbonero L, Soriano V, Valencia E, et al. Increasing impact of chronic viral hepatitis on hospital admissions and mortality among HIV-infected patients. AIDS Res Hum Retroviruses. 2001;17:1467-1471.
27. del Valle J, Macías J, Mira JA, et al. Changes in liver-related hospital admissions and hospital mortality among HIV-infected patients (1998 to 2005). Enferm Infecc Microbiol Clin. 2008;26:500-501.
28. Gebo KA, Diener-West M, Moore RD. Hospitalization rates differ by hepatitis C status in an urban HIV cohort. J Acquir Immune Defic Syndr. 2003;34:165-173.
29. Núñez-Fernández C, Martín-Carbonero L, Valencia ME, et al. Liver complications have reached a plateau as cause of hospital admission and death in HIV patients in Madrid. AIDS Res Hum Retroviruses. 2009;25:383-385.
30. Filsoufi F, Salzberg SP, Harbou KT, et al. Excellent outcomes of cardiac surgery in patients infected with HIV in the current era. Clin Infect Dis. 2006;43:532-536.
31. Dua RS, Wajed SA, Winslet MC. Impact of HIV and AIDS on surgical practice. Ann R Coll Surg Engl. 2007;89:354-358.
32. Gebo KA, Fleishman JA, Moore RD. Hospitalizations for metabolic conditions, opportunistic infections, and injection drug use among HIV patients: trends between 1996 and 2000 in 12 states. J Acquir Immune Defic Syndr. 2005;40:609-616.
33. Mocroft A, Ledergerber B, Katlama C, et al, and EuroSIDA study group. Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet. 2003;362:22-29.
34. Betz ME, Gebo KA, Barber E, et al, and HIV Research Network. Patterns of diagnoses in hospital admissions in a multistate cohort of HIV-positive adults in 2001. Med Care. 2005;43:III3-III14.
35. Núñez MJ, Martín-Carbonero L, Moreno V, et al. Impact of antiretroviral treatment-related toxicities on hospital admissions in HIV-infected patients. AIDS Res Hum Retroviruses. 2006;22:825-829.
36. Dray-Spira R, Gueguen A, Persoz A, et al, and PRIMO Cohort Study Group. Temporary employment, absence of stable partnership, and risk of hospitalization or death during the course of HIV infection. J Acquir Immune Defic Syndr. 2005;40:190-197.
37. Weber AE, Yip B, O'Shaughnessy MV, et al. Determinants of hospital admission among HIV-positive people in British Columbia. CMAJ. 2000;162:783-786.
Appendix I: Specific Diagnoses in Each Category and Number of Total Hospitalizations for Each Cause
Lymphoma-non-Hodgkins (28), lymphoma-Hodgkins (6), anal (12), melanoma (4), lung (3), prostate (3), Kaposi sarcoma (2), breast (1), and other (9).
Coronary artery disease/myocardial infarction (47), cerebrovascular disease/stroke (14), severe hypertension (13), deep vein thrombosis (10), peripheral artery disease (10), arrhythmia (7), pericarditis (3), congestive heart failure (2), myocarditis (2), cardiomyopathy (1), pericardial effusion (1), and other (45).
Pancreatitis (45), cholelithiasis/cholecystitis (21), cirrhosis (20), peptic ulcer disease/reflux (9), chronic diarrhea (6), oral ulcer (1), esophagitis (1), other (204). The other category represents diagnoses without a specific code in our dataset; on individual review these were appendicitis (37), hernia repair (30), gastrointestinal bleeding (22), nausea/vomiting/dehydration (17), gastroenteritis (16), small bowel obstruction (13), acute diarrhea (11), diverticular disease (9), and other (49).
Nephrolithiasis (29), acute renal failure (19), and other (17).
Inflammatory arthropathy (7), avascular necrosis (6), degenerative arthropathy (3), myopathy (1), and other (118). The other categories contained most commonly an orthopedic surgical procedure (84) including back, knee, hip, or shoulder surgeries and a variety of other diagnoses (34).
Meningitis-non bacterial (23), seizures (18), neuropathy (7), encephalitis (4), AIDS-dementia complex (2), myelopathy (1), and other (39).
Major depression (74), bipolar disorder (9), schizophrenia (10), suicide attempt (10), sleep disorder (9), anxiety disorder (8), post-traumatic stress (1).
Pneumonia (108), sinusitis (19), asthma exacerbation (11), pulmonary embolism (7), pneumothorax (6), chronic obstructive lung disease (2), lymphocytic interstitial pneumonia (1), and other (51).
Cutaneous abscess (34), cellulitis (30), perirectal abscess (26), syphilis (25), bacteremia (19), urinary tract infection/pyelonephritis (16), MRSA (10), C. difficile colitis (7), gonorrhea (5), Shigella (5), Salmonella (4), epididymitis (3), proctitis (2), MSSA (2), bacterial meningitis (1), endocarditis (1), and other (41).
Human papillomavirus (24), herpes zoster (16), herpes simplex (9), hepatitis B (8), hepatitis C (5), cytomegalovirus (3), progressive multifocal leukoencephalopathy (3), mononucleosis (1), hepatitis A (1), varicella (1), and other (15).
Pneumocystis (jiroveci) carinii (40), candidiasis (16), cryptococcus (4), coccidioidomycosis (1), and histoplasmosis (1). Cited Here...
This article has been cited 2 time(s).
Journal of InfectionCommunity-associated methicillin-resistant Staphylococcus aureus infections in HIV-infected patients in SpainJournal of Infection
Community Associated Methicillin-Resistant Staphylococcus Aureus in HIV-Infected Patients
AIDS Reviews, 12(3):
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