The introduction of highly active antiretroviral therapy (HAART) has markedly decreased the rates of opportunistic infections, the progression to AIDS, and the overall mortality for HIV-infected patients . In the mid-1990s, clinicians noticed that certain patients deteriorated after starting HAART despite having decreasing HIV-1 RNA levels and rising CD4 cell counts [2–5]. In these patients, receipt of HAART results in a pathological inflammatory response to either previously treated infections or subclinical infections [6–8]. This inflammation could result in deleterious clinical outcomes, such as culture-negative meningitis or necrotizing lymphadenitis; it has been labeled as immune reconstitution disease (IRD) or immune reconstitution inflammatory syndrome (IRIS) [9–11].
The best described associations between particular infectious agents and IRIS include ophthalmic cytomegalovirus (CMV) disease, disseminated infection with Mycobacterium tuberculosis or Mycobacterium avium complex, and central nervous system involvement with Cryptococcus neoformans[8,10–15]. To date, the information regarding the incidence of IRIS is derived from small samples with widely varying estimates [16,17]. Similarly, information regarding risk factors for developing IRIS and long-term clinical outcomes of patients with IRIS has been scant .
The present study was undertaken to determine the incidence of IRIS in high-risk patients, the risk factors at baseline for developing IRIS, and the long-term outcome of patients with IRIS. We hypothesized that patients who started HAART in closer proximity to the diagnosis of their underlying opportunistic infection and who had a more robust response to HAART in terms of declining HIV-1 RNA levels would be at an increased risk for developing IRIS.
This retrospective cohort study was performed at the Harris County Hospital District and the Houston Veterans Affairs Medical Center in Houston, Texas. HIV-infected patients who were coinfected with M. tuberculosis, M. avium complex, or C. neoformans were studied because these are the three pathogens other than CMV most frequently associated with IRIS. CMV was excluded over concern that there was no reliable, comprehensive source for case finding. The Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals approved the protocol, and all aspects of the study were done in compliance with HIPAA guidelines.
Patients with M. tuberculosis, M. avium complex, or C. neoformans infection diagnosed between 1997 and 2000 were identified using preexisting population-based surveillance networks for monitoring infections with these pathogens [19,20]. The networks record all incident cases of these specific diseases in Harris County, Texas, which includes the city of Houston. The case lists were then cross-referenced with computerized databases of patients seen at the Houston Veterans Affairs Medical Center HIV clinic and the Thomas Street Clinic. Requirements for inclusion in the study were infection with HIV and coinfection with these microbial agents. Coinfection was defined by a positive culture of M. tuberculosis, culture of M. avium complex from a sterile site, culture of C. neoformans from a sterile site, or a positive C. neoformans antigen from the cerebrospinal fluid (CSF). In addition, to be included in the final dataset, patients had to have been prescribed HAART, defined as at least three antiretroviral agents, to have a measurement for either a baseline CD4 cell count or an HIV-1 RNA level prior to being prescribed HAART, and to have at least one follow-up CD4 cell count or HIV-1 RNA level after being prescribed HAART. The laboratory data were required in order to investigate the hypothesis that a robust response to HAART was associated with an increased risk of IRIS. Patients who were never prescribed HAART or did not return for follow-up were excluded from the final analysis.
All available inpatient and outpatient records of patients who met inclusion criteria were reviewed from the time of diagnosis with HIV until the patient died, was lost to follow-up, or until the end of the study, 4 January 2003. Data collected included patient demographics, pre- and post-HAART CD4 cell count and HIV-1 RNA levels, specifics regarding diagnosis and treatment of the opportunistic infection, and clinical outcome, including development of IRIS. The diagnosis of IRIS was based on a previously published definition . In brief, the patient had to be receiving HAART, to have clinical evidence of an inflammatory process that was not consistent with the usual course of an established infection or a new infectious process, and to have a rising CD4 cell count and a falling HIV-1 RNA level.
More specifically, for patients to be diagnosed with IRIS, there had to have been an initial clinical response to therapy for M. tuberculosis/M. avium complex/cryptococcal infection as defined by their physician providers based on some combination of cessation of fever, relief of pulmonary symptoms, decrease in the size of lymph nodes, or termination of meningeal symptoms, depending on the original presentation. Following the initiation of HAART, the patient had to have either recurrence of their initial symptoms or new symptoms compatible with an inflammatory process such as fever, dyspnea, painful swelling of lymph nodes, abdominal pain caused by enlarged retroperitoneal nodes, or headache. Among those with crytococcal meningitis, analysis of CSF had to be consistent with an inflammatory condition (e.g., elevated white blood cell count and/or increase in CSF protein); the intracranial pressure needed to be elevated; all stains and cultures needed to be negative; and cryptococcal antigen, if still present, had to have decreased at least fourfold from that documented at the initial infection. As dictated by the clinical situation, appropriate radiological examinations had to have worsened since the initiation of HAART, as judged by independent radiological review, with such findings as increasing pulmonary infiltrates, accumulating pleural effusions, worsening mediastinal lymphadenopathy, new or increasing abdominal lymph nodes, or hepatosplenomegaly. Finally, all cultures or other work-up (antigen assays, serology, etc.) carried out for the recurrent clinical presentation had to be negative.
For all three pathogens, there had been unmasking of subclinical disease described shortly after starting HAART [8,13,21]. For the purposes of this study, the unmasking variant of IRIS related to M. tuberculosis infection was defined as a positive culture for M. tuberculosis from a focal, inflammatory process in an atypical location for M. tuberculosis, such as the bowel, in the absence of pulmonary, lymphatic, blood, or central nervous system involvement . Similarly, the unmasking form of IRIS related to M. avium complex infection was defined as M. avium complex cultured from a site-limited inflammatory process, such as unilateral cervical lymphadenopathy, in the presence of negative systemic cultures, the so-called immune reconstitution localized M. avium complex infection [22–24]. To be diagnosed with latent meningeal cryptococcal infection uncovered by HAART required clinical symptoms compatible with meningitis, negative CSF stains and cultures, very low levels of CSF cryptococcal antigen (between 1:1 and 1:8), and CSF white blood cell levels ≥ 75 × 106 cells/l .
Most importantly, the agreement of two investigators was necessary for a diagnosis of IRIS; when there was disagreement or the diagnosis was unclear, then the patient was declared not to have IRIS. All available information including radiographs, pathological specimens, and microbiological data was utilized in the decision to diagnose IRIS. The majority of IRIS cases (> 70%) already carried a diagnosis of IRIS in their chart, while the remainder were diagnosed during the course of the study.
Statistical analysis was performed using the NCSS statistical package, 2000 version (NCSS Statistical Software, Kaysville, Utah, USA). Student's t-test was used for analysis of continuous data with parametric distributions (e.g., age), while the Wilcoxon rank-sum test was used for analysis of non-parametric data (e.g., CD4 cell count, HIV-1 RNA levels). Categorical data were analyzed using the chi-square test. Stepwise logistic regression was employed for multivariate analysis of categorical variables found to be significant by univariate analysis at a level of 0.05. Test results were considered significant for a two-sided P value of < 0.05.
A group of 259 patients with HIV who were coinfected with M. tuberculosis, M. avium complex, or C. neoformans were identified between 1997 and 2000. Of these, 180 (69.5%) met the definition for inclusion in the final data analysis. Of the 79 (30.5%) who did not qualify, 25 (31.6%) had died at the time of diagnosis of the opportunistic infection; 41 (51.9%) were not prescribed HAART in the study centers, usually because they were receiving outpatient care elsewhere; and 13 (16.5%) did not return for any follow-up after being prescribed HAART.
Of the 180 patients included in the final analysis, 86 (47.8%) were infected with M. tuberculosis, 35 (19.4%) with M. avium complex, and 59 (32.8%) with C. neoformans. IRIS developed during follow-up in 57 of the 180 [31.7%; 95% confidence interval (CI), 24.9–39.0). The absolute number and percentage of patients that developed IRIS while on HAART were 26 out of 86 (30.2%; 95% CI, 20.8–41.1) for M. tuberculosis infection, 11 out of 35 (31.4%; 95% CI, 16.9–49.3) for M. avium complex infection, and 20 out of 59 (33.9%; 95% CI, 22.0–47.4) for C. neoformans infection. There was no difference in the risk of developing IRIS by underlying opportunistic infection (P = 0.897). With 2.17 person-years of HAART in follow-up, on average, the incidence of IRIS in the total cohort was 15.1/100 patient-years HAART (95% CI, 11.0–18.9). The incidence of IRIS by infectious agents was 13.6/100 patient-years HAART (95% CI, 9.5–20.0) for M. tuberculosis, 15.1/100 patient-years HAART (95% CI, 7.5–27.0) for M. avium complex, and 15.7/100 patient-years HAART (95% CI, 9.6–26.1) for C. neoformans.
The 26 patients with IRIS associated with M. tuberculosis had 19 cases of worsening, localized lymphadenitis, usually cervical; five cases of increasing pulmonary infiltrates; four cases of accumulating pleural effusions; two cases of prolonged fever; and one case of increased intracranial pressure in a patient previously diagnosed with M. tuberculosis meningitis. The 11 patients with IRIS associated with M. avium complex consisted of 10 with localized lymphadenitis, usually cervical or abdominal, and one with prolonged fever associated with hepatosplenomegaly. There were two patients with IRIS associated with M. avium complex, presenting as lymphadenitis and also pronounced hypercalcemia. In two patients, HAART was started prior to the diagnosis of M. avium complex infection; in both, marked, localized cervical lymphadenitis developed that grew M. avium complex on biopsy, although work-up for disseminated M. avium complex disease was negative. There were 20 patients with C. neoformans-associated IRIS, 16 of whom had culture-negative meningitis. In two of these, HAART was started approximately 14 days prior to the diagnosis of C. neoformans infection. In these instances, there were low values for C. neoformans antigen in the CSF (1:2 and 1:4, respectively) in association with elevated CSF white blood cell counts (188 and 81 × 106 cells/l, respectively) compared with typical cases of AIDS-associated cryptococcal meningitis . There were two patients with C. neoformans-associated lymphadenitis, one cervical and one abdominal, one of whom had HAART initiated prior to diagnosis of the C. neoformans infection; there was one case of culture-negative, inflammatory, disseminated lung nodules in this group.
For the 57 patients who developed IRIS, treatments administered included non-steroidal anti-inflammatory drugs in 12 (21%), corticosteroids in 16 (28%), mechanical measures such as lumbar puncture or lymph node drainage in 44 (77%), intensification of opportunistic infection therapy in 23 (40%), and cessation of HAART in 4 (7%). The low rate of complications precluded any conclusions regarding the relative efficacy of therapy. No superinfections were noted as a result of steroid use.
For the 57 patients who developed IRIS, the duration between the initiation of HAART and the diagnosis of IRIS is shown in Fig. 1. The median time between starting HAART and diagnosing IRIS was 46 days, with the shortest time being 3 days and the longest 658 days. Presentation was within 60 days for 34 (60%) and within 90 days for 41 (72%) of beginning HAART. There were no significant differences between the underlying opportunistic infection and the time to onset of IRIS (data not shown) after commencing HAART.
After excluding the five patients with IRIS where HAART was started prior to the diagnosis of the underlying opportunistic infection, the remainder were used to examine how the timing of initiating HAART relative to starting therapy for the opportunistic infection influenced the subsequent development of IRIS. The median number of days between beginning treatment for the opportunistic infection and commencing HAART in patients who developed IRIS was 27 days, while for patients who did not develop IRIS it was 50 days (P < 0.001). Patients who began HAART within 30 days of initiating treatment for the opportunistic infection had a relative risk (RR) of 2.01 (95% CI, 1.25–3.22; P = 0.003) for the development of IRIS compared with those who had an interval of longer than 30 days.
The association of baseline demographics on the subsequent development of IRIS is shown in Table 1. There was no difference based on age at initiation of HAART, race, baseline CD4 cell count or HIV-1 RNA level. However, men had an increased risk (RR, 2.65; 95% CI, 1.06–8.37; P = 0.018) of being diagnosed with IRIS compared with women. Also, patients who developed IRIS were more likely to be antiretroviral naive at the time of diagnosis of their underlying opportunistic infection (RR, 4.03; 95% CI, 1.57–12.80; P < 0.001). No differences in the risk of developing IRIS were observed when protease inhibitor-containing regimens were compared with regimens not containing a protease inhibitor, with regimens containing a non-nucleoside reverse transcriptase inhibitor, or with regimens containing triple nucleoside reverse transcriptase inhibitors (data not shown).
Data showing the association between response to HAART and diagnosis of IRIS are summarized in Table 2. The median times to obtaining first, second, and third CD4 cell count and HIV-1 RNA measurements after starting HAART were 36, 119, and 219 days, respectively. Therefore, unique patient laboratory data were analyzed in the following discrete intervals from the time of initiating HAART: 1–90, 91–150, and 151–270 days. Patients who developed IRIS had more marked reductions in HIV-1 RNA level both initially and persistently (see Fig. 2) versus patients who did not develop IRIS (P < 0.001). The CD4 cell count response did not differ significantly during the first interval, but by the time of the second and third interval, the patients with IRIS did have significantly greater increases in CD4 cell count versus patients who did not develop the syndrome (see Table 2).
The relative contributions of each factor towards the development of IRIS was assessed using multivariate analysis via stepwise logistic regression. Given that nearly 75% of cases of IRIS occurred within 90 days of starting HAART, the entries into the model were 2 log10 copies/ml decrease in HIV-1 RNA level at 90 days, gender, being antiretroviral naive, and starting HAART within 30 days of initiating therapy for the underlying opportunistic infection, all of which had been significant in univariate analysis. The variables that retained significance in the multivariate model were the 2 log10 copies/ml decrease in HIV-1 RNA level (RR, 3.66; 95% CI, 1.55–8.64; P = 0.003), the timing of initiation of HAART (RR, 2.83; 95% CI, 1.24–6.46; P = 0.014), and being antiretroviral naive (RR, 3.87; 95% CI, 1.008–14.88; P = 0.049).
In the first year following the initiation of HAART, patients diagnosed with IRIS had an average of 1.34 more hospital admissions and 2.52 more invasive procedures compared with those who did not develop the syndrome (P < 0.001; see Table 2): 39% of patients without IRIS were admitted to the hospital in the first year after starting HAART while 81% of patients with IRIS required hospitalization during this same time period (P < 0.001). The percentage of patients who needed an invasive procedure over this 12 month period was 24% for patients without IRIS and 86% for patients with IRIS (P < 0.001).
Successful immune reconstitution was defined as an increase in CD4 cell count of 100 × 106 cells/l over baseline and successful viral suppression was defined as an HIV-1 RNA level of < 400 copies/ml at 24 months (±3 months). When examining patients who were still actively followed during this time period, patients diagnosed with IRIS had a greater likelihood of successful immune reconstitution (RR, 2.24; 95% CI, 1.22–4.38; P = 0.003) and an increased rate of successful viral suppression (RR, 3.32; 95% CI, 1.73–6.89; P < 0.001) versus patients without IRIS (see Table 2). There was no statistical difference in mortality between the two groups 24 months after starting HAART (RR for being alive if diagnosed with IRIS, 1.95; 95% CI, 0.91–4.19; P = 0.061). There were two deaths considered directly attributable to IRIS.
In the largest study of IRIS to-date, 31.6% of HIV-infected patients who were coinfected with M. tuberculosis, M. avium complex, or C. neoformans developed IRIS while on HAART, with an incidence of 15.1/100 patient-years of HAART in this high-risk cohort. These numbers are consistent with published data from smaller case series in which IRIS was seen in approximately 25–35% of HIV-infected patients responding to HAART [3,26]. The majority of cases of IRIS occurred within the first 60 days of initiating HAART, which is in accord with prior individual reports and case series [26–28]. As described previously, the onset of IRIS continues for up to 2 years following the initiation of HAART .
In our study, patients diagnosed with IRIS initiated HAART in closer proximity to the diagnosis of their opportunistic infection compared with patients who did not develop IRIS. This is consistent with a previous report of 17 HAART-treated patients coinfected with M. tuberculosis and HIV . Biological reasons for this association are unclear at present, although we speculate that patients who receive prolonged therapy for their opportunistic infection prior to starting HAART will have decreased microbial antigen burdens when HAART is initiated. This, in turn, would provide less material to stimulate a reconstituting immune system once HAART is begun. These concerns may lend added support to the recent recommendations to consider delaying HAART for 4–8 weeks after starting M. tuberculosis therapy in coinfected patients .
As we hypothesized, having a more pronounced decrease in HIV-1 RNA levels within 90 days of starting HAART was associated with development of IRIS. The independent association of being antiretroviral drug naive and development of IRIS is likely related to having a more robust virological and immunological response to therapy in these group of subjects compared with those who were on prior therapy . A significant association between CD4 cell count increase and the diagnosis of IRIS was not seen until later in therapy. It has been noted that reductions in HIV-1 RNA levels in response to HAART result initially in redistribution of memory CD4 lymphocytes . This redistribution of activated CD4 lymphocytes may be, at least partly, responsible for the manifestations of IRIS, which could explain why the increase in measured CD4 cell count appears delayed compared with the viral load decrease.
To determine whether patients with IRIS require more interventions to prevent morbidity and mortality, data were collected regarding invasive procedures and hospitalizations during the first year following initiation of HAART as surrogate markers for healthcare utilization. In the 12 months after starting HAART, patients with IRIS required increased numbers of invasive procedures, such as lumbar punctures to relieve increased intracranial pressure, and had a higher number of hospitalizations. This implies that, in the short term, these patients require intensification of their healthcare, thereby suggesting that preventive strategies might be cost effective. Such strategies might be especially effective in developing countries where coinfection with C. neoformans or M. tuberculosis is relatively common and the ability to manage complex paradoxical reactions readily may be limited [33,34].
Although there may be short-term morbidity associated with IRIS, these patients appear to have comparably good long-term outcomes. After 24 months of HAART, patients with IRIS were more likely to have successful viral suppression and immune reconstitution than patients without the syndrome. In addition, there was no significant mortality difference between the two groups of patients. In fact, the survival trend was in favor of the IRIS patients, which is likely a reflection of the durable viral suppression and immune reconstitution seen in these patients.
Advantages of our study included that we used population-based surveillance networks to focus on a defined group of patients who were at increased risk for developing the syndrome of interest and, therefore, are able to report the largest number of IRIS patients in a single study to date. The patients served by the clinics and hospitals are indigent with limited options for care, allowing a good opportunity to view the entirety of their clinical course. The numbers of patients followed permitted valid comparisons to be made and conclusions drawn regarding incidence, risk factors, and long-term response to HAART.
The limitations of our study included its retrospective character and the inherently subjective nature of diagnosing a patient with IRIS. We attempted to minimize this issue by conforming to published guidelines, by accessing information from multiple sources, and by having multiple reviewers agree on a diagnosis. Finally, our databases were limited in that a cultured pathogen or positive antigen test was needed in order for a patient to be identified. Patients who developed culture- or antigen-negative inflammatory reactions after HAART would not have been identified; this may have led us to underestimate the true incidence of IRIS in patients with subclinical infection.
IRIS is a syndrome that occurs because a patient develops an exuberant response to appropriate therapy. The inclusion of IRIS in the differential diagnosis of a patient who presents with an inflammatory process after initiating HAART allows for a focused approach to diagnosis and therapy. These patients often require significant interventions to minimize short-term morbidity but their long-term outcome appears relatively good. Further studies looking at how to decrease the rate of IRIS in high-risk patients appear warranted by its prevalent nature and the association of IRIS with increased hospitalizations and invasive procedures.
Support for this work was provided by an HIV Fellowship Research Grant from Bristol-Myers Squibb to Samuel A. Shelburne and in part by the Department of Veterans Affairs, the National Institute of Allergy and Infectious Diseases (grant T32–AI055413) and the National Institute of Mental Health (grant K23–MH067505).
Conflicts of interest: This study was supported in part by an HIV fellowship training grant to SAS. The other authors have no conflicts of interest to declare.
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