With the advent of highly active combination antiretroviral therapy (cART) in the mid-1990s and routine use of antimicrobial prophylaxis, the rates of AIDS-defining opportunistic illnesses among HIV-infected adults [1–9] and children [10,11] have declined dramatically in the US and other industrialized countries. Nonetheless, opportunistic illnesses remain a leading cause of hospitalization [12–14] and death [15–20] among HIV-infected persons in these settings; late HIV diagnoses and acute opportunistic illnesses at first presentation to care remain common [21,22].
There have been few comprehensive studies of incidence of opportunistic infections and malignancies in the last decade in North America or Europe [7–9]. Although chronic non-AIDS-defining conditions are key determinants of morbidity and mortality on cART [15,23], opportunistic illnesses remain important markers of HIV disease progression; it is useful to monitor whether opportunistic illness rates have continued to fall or have stabilized, and whether the spectrum of opportunistic illness diagnoses has changed over time, so to inform HIV treatment guidelines, including thresholds for opportunistic illness prophylaxis initiation. Opportunistic illness rates could increase if more patients experience cART failure, if remaining therapeutic drug options are exhausted, or if HIV disease progresses for other reasons . Studies suggest that some opportunistic illnesses [25,26], notably Kaposi's sarcoma , are occurring at higher than expected CD4+ T-lymphocyte cell counts (CD4 cell counts) among otherwise healthy virally suppressed patients; however, Kaposi's sarcoma at CD4 cell counts at least 200 has been documented both before and after the introduction of cART [20,28,29].
We examined the rates and patterns of opportunistic illness occurrence, and CD4 cell counts at opportunistic illness diagnoses, among HIV Outpatient Study (HOPS) patients seen during 1994–2007.
The HIV Outpatient Study
The HOPS is an ongoing, prospective cohort study of HIV-infected patients since 1993 . The study protocol is approved annually by each participating clinic's institutional review board. All study participants provide written, informed consent. HOPS clinicians have extensive experience treating HIV-infected patients. Trained staff abstract data (including treatments, diagnoses, and laboratory values) from outpatient medical records at each visit, as well as hospitalizations and deaths. These data are compiled centrally, and reviewed and edited before analyses.
We analyzed data from 8070 HOPS participants who were seen at least twice from 1 January 1994 to 31 December 2007, using HOPS data updated as of 30 June 2008. We excluded patients seen only once because we could not define observation time for such patients to compute opportunistic illness incidence rates. The study sites included 12 clinics (university-based, public, and private) in ten US cities: Tampa, Florida; Washington, DC; Denver, Colorado (two sites); Atlanta, Georgia; Portland, Oregon; San Leandro, California; Chicago, Illinois (two sites); Stony Brook, New York; Philadelphia, Pennsylvania; Oakland, California.
Start of observation (baseline) was 1/1/1994 or first HOPS visit thereafter. We defined three time periods for analyses: 1994–1997 (pre-cART), 1998–2002 (early cART), and 2003–2007 (contemporary cART). We used accepted definitions for medications comprising cART and Pneumocystis pneumonia (PCP) prophylaxis and Mycobacterium avium complex (MAC) prophylaxis , as detailed in Appendix 2 (http://links.lww.com/QAD/A27). We studied all AIDS-defining opportunistic illnesses using the CDC revised 1993 AIDS case definition , except recurrent pneumonia (because we were unable to distinguish viral from bacterial pneumonia in the HOPS database), Salmonella septicemia (because there was only one case), and HIV-wasting syndrome (because of lack of a standardized case definition and diagnostic specificity across HOPS clinics). Outcomes of interest were opportunistic illness diagnoses made during HOPS clinic visits or hospitalizations, using supporting laboratory or diagnostic tests when required or available. We excluded the small fraction of opportunistic illnesses newly diagnosed at death in primary analyses. We considered Kaposi's sarcoma, non-Hodgkin's lymphoma, CNS lymphoma and cervical cancer as opportunistic malignancies. All other AIDS-defining opportunistic illnesses were classified as opportunistic infections. We considered as major opportunistic illnesses those for which at least 15 events had occurred during the contemporary cART period.
Entry values for CD4 cell count and HIV viral load for each time period were those measured within 6 months prior through 3 months after the beginning of observation in the period. CD4 cell count at opportunistic illness diagnosis was the closest CD4 cell count within 6 months prior through 3 months after the date of opportunistic illness diagnosis.
Determination of opportunistic illness rates
Annual rates of first opportunistic illness events (1994–2007) were calculated for patients with at least one HOPS contact in a given year and without the specific opportunistic illness previously. Start of observation for each year was 1 January (if the patient was already enrolled in the HOPS) or the date of first HOPS visit during that year. For each opportunistic illness, end of observation was the earlier of 31 December of that year, date of incident opportunistic illness diagnosis (patient removed from the risk set), or last (alive) HOPS contact. In an analogous fashion, we calculated opportunistic illness incidence rates in each calendar period.
Incidence rate calculations for each opportunistic illness excluded patients with a history of that opportunistic illness at the start of observation, and considered patients no longer at risk for that opportunistic illness (censored observation time) after it was diagnosed in follow-up. Likewise, we calculated rates of any first opportunistic infection and any first opportunistic malignancy, after excluding patients with the history of either, respectively, from the analyses. Thus persons with a prior diagnosis of a given opportunistic illness were excluded from analyses of incidence of that opportunistic illness, but are included in the analyses of incidence of another opportunistic illness (also see Appendix 2, http://links.lww.com/QAD/A27).
Determination of opportunistic illness prophylaxis rates
We examined the annual percentage of eligible patients who were prophylaxed for at least 30 days for PCP or MAC during 1994–2007. Patients were considered eligible for primary PCP prophylaxis when their CD4 cell count was below 200 cells/μl and for MAC prophylaxis when their CD4 cell count was below 50 cells/μl . We restricted analyses to patients with a documented CD4 cell count below the eligible threshold in a given year and with at least 90 days of subsequent observation to ensure adequate opportunity to have received prophylaxis.
We calculated annual incidence rates per 1000 person-years with 95% confidence intervals (CIs) using a Poisson distribution for the first opportunistic infection, first opportunistic malignancy, and first occurrence of each individual opportunistic illness. Using stratified (by period) multivariable Poisson regression, we modeled annual percentage changes in opportunistic illness incidence rates within the three time periods for major opportunistic illnesses. We first explored with univariate regression models associations between major incident opportunistic illnesses and age, sex, race/ethnicity and HIV risk category. In the final multivariable models, we adjusted for sex, race, and HIV risk category, but omitted age as it was not associated with opportunistic illness rates. We further evaluated factors predictive of incident opportunistic illnesses in the contemporary cART era by considering entry CD4 cell count, HIV viral load, and type of health insurance as independent variables. We report rate ratios and 95% CIs. Finally, we assessed changes in CD4 cell count distribution at opportunistic illness diagnosis, by calendar period, using the nonparametric Jonckheere–Terpstra test. We performed analyses using SAS version 9.1 (SAS Institute Inc., Cary, North Carolina, USA).
Of 8517 patients who were seen in the HOPS between 1 January 1994 and 31 December 2007, we excluded 447 (5%) who were seen only once and for whom follow-up could not be defined. Excluded patients were not statistically different from included patients with respect to sex and age distribution, history of AIDS at first HOPS visit (45 vs. 48%) or baseline median CD4 cell count (273 vs. 303 cells/μl), but were significantly more likely to be non-white (62 vs. 43%) and have public insurance (59 vs. 37%) at HOPS entry.
Of 8070 patients analyzed (median age at baseline 38 years; median CD4 cell count 298 cells/μl), 81% were men, 57% white, 59% men who had sex with men (MSM) and 13% injection drug users (IDUs) (Table 1). During 1994–2007, the percentages of women, non-white persons, and persons with heterosexual risk for HIV infection increased, as did median age. The median duration of follow-up in the study was 2.9 years [interquartile range (IQR) 1.1–6.9]. The percentage of patients who received cART (≥1 day) within each time period increased from 56% during 1994–1997 to 88% during 2003–2007, with the corresponding increase in the percentage of total observation time on cART from 28.7 to 78.5%, respectively (Table 1). The percentage of eligible patients (CD4 cell count <200 cells/μl) who received primary PCP prophylaxis each year (annual range 75.8–93.7%) decreased from 93.7% in 1994 to 78.6% during 2007 (univariate P < 0.001). The percentage of eligible patients (CD4 cell count <50 cells/μl) who received primary MAC prophylaxis each year (annual range 53.2–74.3%) did not change (53.2% in 1994 to 66.7% in 2007, univariate P = 0.25).
Trends in rates of opportunistic illnesses
Seven opportunistic illnesses met our definition for major incident opportunistic illnesses (>15 cases in the contemporary cART era): esophageal candidiasis (n = 67), PCP (n = 46), disseminated MAC (n = 32), cytomegalovirus (CMV) disease, including retinitis (n = 23), Kaposi's sarcoma (n = 16), non-Hodgkin's lymphoma [(NHL) n = 21], and HIV encephalopathy (n = 18).
We observed 2027 incident opportunistic illness events during 35 236 person-years of observation. In analyses of incidence of first opportunistic infection and first opportunistic malignancy, we excluded, respectively, 1313 and 282 patients with a prior diagnosis of these events at baseline. Among seven major individual opportunistic illnesses, the following were excluded from the analyses of that opportunistic illness: 136 patients with a history of esophageal candidiasis, 760 with PCP, 148 with MAC, 179 with CMV disease; 228 with Kaposi's sarcoma, 46 with NHL and 27 with HIV encephalopathy.
All opportunistic illness incidence rates fell during 1994–2007 (Table 2), most notably during 1994–1997, coinciding with cART introduction (Fig. 1a, b). Overall opportunistic illness incidence rates (per 1000 person-years) were 92.4 (95% CI 84.5–100.8) in 1994–1997, 29.6 (95% CI 26.4–33.1) in 1998–2002, and 16.6 (95% CI 14.2–19.3) in 2003–2007. In crude analyses, rates of first opportunistic infection and first opportunistic malignancy (Kaposi's sarcoma, NHL and CNS lymphoma) in the contemporary cART period were each significantly lower than in earlier periods (Table 2). Rates of first opportunistic infection and first opportunistic malignancy (per 1000 person-years) decreased for all patients and those receiving cART in a similar fashion (Fig. 2).
Opportunistic illnesses with the highest incidence rates during 1994–1997 were CMV disease, including retinitis (33.0), PCP (29.9), MAC (26.9), esophageal candidiasis (21.6), and Kaposi's sarcoma (16.4); during 2003–2007 they were esophageal candidiasis (5.2), PCP (3.9), cervical cancer (3.5), MAC (2.5), and CMV disease (1.8) (Table 2). Thus, opportunistic infections with the highest incidence rates in the first period remained among the most frequently observed in the last period.
In multivariable Poisson regression models adjusted for sex, race and HIV risk category (variables associated with opportunistic illness events in crude analyses; Supplemental online Table A, http://links.lww.com/QAD/A28), there were significant annual percentage reductions during 1994–1997 in incidence of first opportunistic infection, first opportunistic malignancy, and each major individual opportunistic illness, except for HIV encephalopathy and esophageal candidiasis (Table 3). During 1998–2002, declines continued, but were of lesser magnitude, for opportunistic infections overall and individual opportunistic illnesses: CMV, PCP, MAC and Kaposi's sarcoma. During 2003–2007, only MAC rates continued to fall; no opportunistic illness rates increased. Adjustment for current CD4 cell count, a critical determinant of opportunistic illness risk and also a laboratory marker affected by cART use (and thus associated with calendar period), tended to attenuate the percentage reductions in opportunistic illness rates over time (see footnote to Table 3).
Absolute rates and trends in opportunistic illness rates also did not change substantially when opportunistic illnesses first diagnosed at death (within 60 days of last patient contact with the HOPS) were included in analyses (only 33 events or 1.6% of all opportunistic illness events, data not shown). Results were also not meaningfully affected by analyzing all (first and repeat) opportunistic illness events for two of the major opportunistic illnesses that frequently recur: PCP and esophageal candidiasis (data not shown).
Risk factors for increased incidence of opportunistic illnesses
In univariate analyses, incidence rates of first opportunistic infection were generally higher for women (vs. men); non-whites (vs. whites); heterosexuals and IDUs (vs. MSM); publicly insured (vs. privately insured); and persons with lower CD4 cell counts, lower nadir CD4 cell counts and higher HIV viral loads at the start of observation in each analysis period (Supplemental online Table A, http://links.lww.com/QAD/A28). For opportunistic malignancies (excluding cervical cancer, which only affects women), incidence rates were higher for men in the first period, MSM (vs. heterosexuals) and persons of white race (vs. non-white) in the second period, and were generally higher in patients with lower CD4 cell counts, lower nadir CD4 cell counts, and higher HIV viral loads at the start of each period (i.e., entry measurements).
In multivariable analyses of the contemporary cART period (2003–2007), factors independently associated with higher opportunistic infection rates included public insurance, lower entry CD4 cell counts and higher entry HIV viral load (Supplemental online Table B, http://links.lww.com/QAD/A29). Viremia was associated most strongly with higher incidence of opportunistic infections among patients with entry CD4 cell count above 200 cells/μl: for log10 viral load 3–4 vs. less than 3 [adjusted relative risk (RR), 95% CI 2.17, 1.50–3.12]; for log10 viral load at least 5 vs. less than 3 (5.61, 3.48–9.04). Higher HIV viral load, but not lower CD4 cell count, was independently associated with higher rates of opportunistic malignancy (Supplemental online Table B, http://links.lww.com/QAD/A29). When nadir CD4 cell count, instead of entry CD4 cell count, was included in these models, the findings were not markedly different, although associations with CD4 cell count were weaker (data not shown).
Finally, when we limited analyses to patients who were on cART as they entered contemporary cART period, lower CD4 cell count (cells/μl) and higher viral load (copies/ml) remained independently associated with increased rates of opportunistic infections: for CD4 cell count 50–199 vs. at least 200 (RR, 95% CI 2.70, 1.41–5.17), for CD4 cell count below 50 vs. at least 200 (11.12, 5.00–24.74); for log10 viral load 3–4 vs. less than 3 (3.37, 1.73–6.52); for log10 viral load at least 5 vs. less than 3 (3.02, 1.29–7.08). For malignant opportunistic illnesses, only log10 HIV viral load at least 5 vs. less than 3 (4.76, 1.65–13.72) was independently associated with higher event rates on cART.
Trends in CD4 cell counts at opportunistic illness diagnosis
Of all opportunistic illness events with documented CD4 cell counts at diagnosis (measured a median of 28 days after diagnosis, IQR 8–62 days), 13% of events occurred at CD4 cell counts at least 200 cells/μl during 1994–1997 (122/929), 22% during 1998–2002 (116/539), and 35% during 2003–2007 (94/268), univariate test for trend P < 0.0001. These findings corresponded with increases in the percentage of all active HOPS patients who had CD4 cell counts at least 200 cells/μl over time (see Table 1).
Among major opportunistic illnesses, CD4 cell counts at opportunistic illness diagnosis increased significantly (P < 0.05) over time for CMV, esophageal candidiasis, Kaposi's sarcoma, NHL, and HIV encephalopathy (Table 4). Except for NHL and CMV, these findings persisted in analyses limited to opportunistic illnesses diagnosed among patients receiving cART. Notably, the range of CD4 cell count (5th–95th percentile) at diagnosis was wide for many opportunistic illnesses both before and after the widespread cART use (Table 4).
Opportunistic illnesses in the contemporary combination antiretroviral therapy period
Among 300 total opportunistic illness diagnoses (250 opportunistic infections, 50 opportunistic malignancies) during 2003–2007 (Table 2), 32 (11%) were among antiretoviral-naive persons and 42 (14%) among patients diagnosed with HIV infection during the previous year. Of 268 opportunistic illnesses with CD4 cell counts recorded at diagnosis, 94 (35%) occurred at CD4 cell counts at least 200 cells/μl (including 19 esophageal candidiasis, 13 NHL, 11 PCP, nine HIV encephalopathy and eight Kaposi's sarcoma). Of the 94, 14% met AIDS criteria based on associated CD4% less than 14. Finally, among 259 opportunistic illness diagnoses with recorded CD4 cell counts and HIV viral loads at opportunistic illness diagnosis in this period, 45 (17%) were documented in patients with CD4 cell count at least 200 cells/μl and HIV viral load less than 1000 copies/ml; some of these events might have represented immune reconstitution inflammatory syndrome (IRIS) , an area of ongoing investigation in the HOPS .
In our HOPS cohort, the incidence rates of opportunistic illnesses fell sharply during 1994–1997, either remained stable or declined more gradually during 1998–2002, and stabilized at low levels during 2003–2007. In general, opportunistic illnesses with the highest incidence in the pre-cART era were also the most frequently diagnosed in the cART eras. In the contemporary cART era, opportunistic illnesses occurred predominately among antiretroviral-experienced patients, and approximately one-third occurred among persons with CD4 cell counts at least 200 cells/μl. Among patients on cART, opportunistic illness rates were significantly lower in 2003–2007 than 1998–2002, a finding consistent with improved potency and tolerability of newer cART regimens. However, higher HIV viral loads and lower CD4 cell counts remained associated with opportunistic illnesses among cART recipients; these factors could represent patients with more recent cART initiation, suboptimal responses to cART or medication nonadherence. The decreasing rates of PCP prophylaxis and fluctuations in rates of MAC prophylaxis over time raise the possibility that some opportunistic illnesses might have occurred because prophylaxis was not restarted promptly among cART-experienced patients when their CD4 cell counts fell below the threshold for prophylaxis initiation, a phenomenon documented in other studies .
Although direct comparisons of our observed opportunistic illness rates to those reported from other cohorts are difficult because of multiple cross-cohort differences, including degree of immunosuppression and differences in analytic methods, our absolute opportunistic illness rates were generally of the same magnitude as in other studies of opportunistic infections and malignancies both before and during cART era [2,8,9,34].
In addition to low CD4 cell counts and high HIV viral loads [3,35], certain demographic factors are associated with increased risk for specific opportunistic illnesses [2,3,9,26]: older age (e.g. for opportunistic malignancies ), male sex (e.g. for Kaposi's sarcoma ), and HIV risk (e.g. IDU and MSM for a variety of opportunistic infections [2,9]). In our adjusted analyses for 2003–2007, publicly insured HOPS patients were significantly more likely than privately insured patients to experience opportunistic infections (public insurance being associated with lower socioeconomic status and later entry to HIV care in the HOPS), and women were less likely than MSM to experience opportunistic malignancies (likely explained, at least in part, by higher rates of Kaposi's sarcoma among MSM and the exclusion of cervical cancer from consideration in this comparison). We did not detect significant differences in opportunistic illness rates by race/ethnicity or age in the contemporary cART period, but our study population had a narrow age range (IQR 33–44 years). Having a CD4 cell count <50 cells/μl remained the strongest predictor of an incident opportunistic infection in that period, whereas an HIV viral load above 100 000 copies/ml (vs. <1000 copies/ml) was associated with increased risk for an opportunistic malignancy among all patients and those on cART.
The finding that median CD4 cell counts at opportunistic illness diagnosis for CMV, esophageal candidiasis, Kaposi's sarcoma, NHL and HIV encephalopathy have increased during 1994–2007 is intriguing. A considerable variability in CD4 cell counts at diagnosis of opportunistic illnesses has been documented before and after introduction of cART [9,20,26]. Two principal hypotheses exist to explain observed trends [4,26,34,36]. First, the increase in median CD4 cell count at diagnosis, for the few opportunistic illness events that still occur, is likely a reflection of increased CD4 cell counts of the entire HOPS population followed after introduction of cART (see Table 1). Second, cART-associated immune restoration is functionally incomplete, particularly among persons who had experienced profound CD4+ T-cell depletion, resulting in opportunistic illness occurrence at higher CD4 cell counts.
Our study has several limitations. First, we analyzed chart-abstracted data collected in the course of routine clinical care. Although most opportunistic infections present acutely and thereby bring affected patients into clinical care, some opportunistic illnesses might have gone undetected due to presentation and care provided outside of a HOPS facility, subclinical presentation or incomplete screening (e.g. cervical cancer); thus leading to potential underestimation of opportunistic illness incidence in our population. Conversely, overestimation of opportunistic illness incidence rates could have resulted from inadvertent inclusion of patients with opportunistic illness histories that were not documented in available medical records. Provider feedback and exploratory analyses suggest that the extent of this misclassification was modest and constant over time. Second, our study excludes recurrent bacterial pneumonia, a relatively frequent opportunistic illness , because differentiation between bacterial and viral pneumonia was often undocumented, and excludes HIV-wasting syndrome, a condition lacking diagnostic specificity and standardized definition across HOPS clinics. Third, we performed an ecological analysis of trends rates of opportunistic illnesses, cART usage and opportunistic illness prophylaxis and therefore cannot draw causal inferences; however, it has been well established that cART and opportunistic illness prophylaxis reduce opportunistic illness rates [1,3,6,9,37]. Fourth, due to relatively small numbers of events, particularly in the contemporary cART period, we may have failed to detect some significant annual changes in individual opportunistic illness rates due to low statistical power. Finally, our findings are drawn from a convenience sample of patients receiving care at 12 select private and public HIV specialty US clinics, and are likely generalizable only to diagnosed patients in care in industrialized countries.
In conclusion, in our diverse cohort of HIV-infected patients in the US, rates of the major AIDS-defining opportunistic illnesses in the cART era have fallen 5–20-fold to approximately five cases per 1000 person-years or less for each opportunistic illness, and have remained stable during 2003–2007. Opportunistic illnesses that predominated in the pre-cART period have remained prominent in the contemporary cART period. Low CD4 count and high HIV viral load remain associated with incident opportunistic illnesses. However, a minority of patients have opportunistic illnesses diagnosed at higher-than-expected CD4 cell counts and possibly while virally suppressed. Healthcare providers need to maintain vigilance in looking for incident opportunistic illnesses, and ensure that all patients are appropriately screened for opportunistic malignancies and prescribed antimicrobial prophylaxis for opportunistic infections as recommended , to further reduce rates of AIDS and mortality  among contemporary HIV-infected patients.
Disclaimers: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
Data presented previously at the joint 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy and 46th Annual Meeting of the Infectious Diseases Society of America, Washington, DC, October 25–28, 2008 (abstract H-2330).
Funding source Contracts 200-2001-00133 and 200-2006-18797 – Centers for Disease Control and Prevention.
Competing interests: All authors declare that no competing interests exist.
HIV Outpatient Study Investigators
The current HIV Outpatient Study (HOPS) Investigators include the following persons and sites: John T. Brooks, Kate Buchacz, Marcus Durham, Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention (NCHSTP), Centers for Disease Control and Prevention (CDC), Atlanta, Georgia; Kathleen C. Wood, Rose K. Baker, James T. Richardson, Darlene Hankerson, and Carl Armon, Cerner Corporation, Vienna, Virginia; Frank J. Palella, Joan S. Chmiel, Carolyn Studney, and Onyinye Enyia, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Kenneth A. Lichtenstein and Cheryl Stewart, National Jewish Medical and Research Center Denver, Colorado; John Hammer, Benjamin Young, Kenneth S. Greenberg, Barbara Widick, and Joslyn D. Axinn, Rose Medical Center, Denver, Colorado; Bienvenido G. Yangco and Kalliope Halkias, Infectious Disease Research Institute, Tampa, Florida; Douglas J. Ward and Jay Miller, Dupont Circle Physicians Group, Washington, DC; Jack Fuhrer, Linda Ording-Bauer, Rita Kelly, and Jane Esteves, State University of New York (SUNY), Stony Brook, New York; Ellen M. Tedaldi, Ramona A. Christian, Faye Ruley and Dania Beadle, Temple University School of Medicine, Philadelphia, Pennsylvania; Richard M. Novak and Andrea Wendrow, University of Illinois at Chicago, Chicago, Illinois.
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