Immune reconstitution inflammatory syndrome (IRIS) is defined as the presentation or clinical deterioration of opportunistic infections (OI) in HIV-infected patients as a direct result of the enhancement of immune responses to those pathogens during HAART . Although 10–25% of patients who start HAART experience IRIS [2,3], little is known about the effect of IRIS on the long-term clinical outcome. We compared the clinical outcome of patients with IRIS-associated OI arising during the first year of HAART with patients who experienced non-IRIS OI and with patients without OI.
The study included all HIV patients who were at least 16 years old and were followed for at least one year after HAART was started at Seoul National University Hospital between January 1998 and December 2004. The hospital is a 1600-bed, university-affiliated teaching hospital and is the largest referral centre for HIV/AIDS in South Korea. HAART is defined as the use of at least three antiretroviral drugs, including protease inhibitors or non-nucleoside reverse transcriptase inhibitors. Baseline CD4 lymphocyte counts and HIV-RNA levels were the test results obtained closest to the time of HAART initiation.
OI that developed during one year after HAART were classified as IRIS or non-IRIS. The diagnosis of IRIS was based on the previously published definition . In brief, an IRIS event was defined as either a first presentation or a paradoxical worsening of a pre-existing infection after the initiation of HAART in the presence of a rising CD4 cell count and a falling HIV-1-RNA level, if measured. The agreement of two investigators was required for a diagnosis of IRIS.
For each patient with IRIS OI, two control patients without OI (OI-free group) were selected by matching age, sex, clinical category, and the baseline CD4 cell count. AIDS-defining event-free survival was compared among the groups by Kaplan–Meier survival analyses (log rank test), and adjusted hazard ratios were estimated using Cox's proportional hazards regression model. AIDS-defining illness and clinical categories were defined using 1993 Centers for Disease Control and Prevention classification criteria; diagnoses of AIDS-defining illness based on absolute CD4 lymphocyte counts less than 200 cells/μl were excluded . Categorical variables were compared using Fisher's exact tests and continuous variables using the Mann–Whitney U-test. Statistical analyses were performed with SPSS software (version 12.0; SPSS Inc., Chicago, Illinois, USA). All significance tests were two-sided.
In 45 of 387 HIV patients (12%) 52 OI were identified. Of these, 33 IRIS events occurred in 31 patients; however, four of these 31 patients also experienced a non-IRIS OI and were ultimately classified into the non-IRIS group. The IRIS group thus consisted of 27 of the original 45 patients and the non-IRIS group consisted of 18 patients, four of whom had both IRIS and non-IRIS OI.
In the IRIS group, the median age was 42 years [interquartile range (IQR) 35–45] and 96% were male. Before HAART, five of the IRIS group (19%) had undergone antiretroviral treatment, and 24 (89%) had a diagnosis of AIDS. Nine patients (33%) were classified as clinical category A and 18 (67%) as clinical category C at the start of HAART.
There was no significant difference in age (P = 0.89), previous history of antiretroviral treatment (P = 0.67), or diagnosis of AIDS (P = 1.00) between IRIS and non-IRIS groups. In the IRIS group, the most common OI was tuberculosis (27%) followed by herpes zoster (24%) and Pneumocystis jiroveci pneumonia (15%), whereas in the non-IRIS group, cytomegalovirus infection (26%) and herpes zoster (26%) were most common, followed by tuberculosis (11%).
The median baseline CD4 cell count (μl) was 43 (IQR 21–105) for the non-IRIS group (P = 0.79) and 53 (IQR 20–108) for the OI-free group (P = 0.98) compared with 40 (IQR 30–90) for the IRIS group. The median baseline viral load (log10/ml) was 5.5 (IQR 4.8–5.9) for the non-IRIS group (P = 0.96) and 5.4 (IQR 4.9–5.8) for the OI-free group (P = 0.99) compared with 5.5 (IQR 4.7–5.9) for the IRIS group.
At one year after the initiation of HAART, the median baseline CD4 cell count (μl) was 85 (IQR 35–189) for the non-IRIS group (P < 0.01) and 260 (IQR 220–370) for the OI-free group (P = 0.74) in contrast with 285 (IQR 200–375) for the IRIS group. The viral titre was undetectable for 50% of the patients in the non-IRIS group (P = 0.14) and 67% in the OI-free group (P = 0.39) compared with 78% in the IRIS group.
There was a median follow-up duration of 3.1 years (IQR 1.9–4.6) per individual after starting HAART. Patients in the IRIS group demonstrated a significantly better outcome than patients in the non-IRIS group (P = 0.007), and showed no significant difference in the AIDS event-free survival curve compared with the OI-free group (P = 0.81; Fig. 1).
After adjusting for age, baseline CD4 cell count, the number of antiretroviral drugs experienced before beginning HAART, non-infectious AIDS-defining illness, and the number of missed clinic appointments during one year after the initiation of HAART, the hazard ratio for AIDS-defining illness or death was 3.75 [95% confidence interval (CI)1.05–13.44, P = 0.04] for the non-IRIS group and 1.32 (95% CI 0.31–5.58, P = 0.70) for the OI-free group contrasting with the IRIS group.
The incidence of IRIS in this study was comparable with that of previous studies. Ratnam et al.  reported that 23% of patients who start HAART experience an IRIS event. Michelet et al.  showed that 18 out of 34 clinical events (53%) observed during the first 2 months of HAART were thought to be IRIS. The spectrum of IRIS in the present study was largely similar to that of non-IRIS in same period as well as that of OI in the era before HAART .
The clinical manifestation of IRIS may be very similar to that of non-IRIS OI . However, our study found that IRIS-associated OI have an entirely different prognosis from non-IRIS OI. This difference may be explained by the fact that IRIS indicates good compliance with and a successful response to HAART. It should also be noted that in the present study, IRIS did not result in a better clinical outcome than that of OI-free patients with a similar immune defect at the start of HAART.
To evaluate the long-term clinical outcome, this study population was confined to patients who were followed for at least one year; thus it did not include cases with early mortality. However, severe IRIS cases with mortality are known to be very rare .
In spite of the small case number and the retrospective nature of this study, to our knowledge this is first investigation to focus on the effect of IRIS on the long-term clinical outcome. Our results suggest that IRIS OI should be differentiated from non-IRIS OI because patients with IRIS have a significantly different prognosis.
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