Posted: 08/26/2010; J Acquir Immune Defic Syndr. 2010;54(3):248-257. © 2010 Lippincott Williams & Wilkins
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, 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 approaches on hospitalization rates are needed.
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.
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 (Cited Here…). 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.