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.
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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).
Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
complications; epidemiology; HIV; hospitalization; morbidity; MRSA infections; surgery