Clinical Infectious Diseases Advance Access published November 17, 2011

Clinical Infectious Diseases Advance Access published November 17, 2011 MAJOR ARTICLE HIV/AIDS Paradoxical Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients Treated With Combination Antiretroviral Therapy After AIDS-Defining Opportunistic Infection Chad J. Achenbach, 1 Robert D. Harrington, 2,3 Shireesha Dhanireddy, 2 Heidi M. Crane, 2,3 Corey Casper, 2,3,4,5 and Mari M. Kitahata 2,3 1 Department of Medicine, Feinberg School of Medicine, Division of Infectious Diseases and Center for Global Health, Northwestern University, Chicago, Illinois; 2 Department of Medicine, 3 Center for AIDS Research, and 4 Department of Epidemiology, University of Washington, and 5 Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Background. The incidence of immune reconstitution inflammatory syndrome (IRIS) when antiretroviral therapy (ART) is initiated after an AIDS-defining opportunistic infection (OI) is uncertain and understudied for the most common OIs. Methods. We examined patients in the University of Washington Human Immunodeficiency Virus Cohort initiating potent ART subsequent to an AIDS-defining OI. IRIS was determined through retrospective medical record review and adjudication using a standardized data collection process and clinical case definition. We compared demographic and clinical characteristics, and immunologic changes in patients with and without IRIS. Results. Among 196 patients with 260 OIs, 21 (11%; 95% confidence interval, 7% 16%) developed paradoxical IRIS in the first year on ART. The 3 most common OIs among study patients were Pneumocystis pneumonia (PCP, 28%), Candida esophagitis (23%), and Kaposi sarcoma (KS, 16%). Cumulative 1-year incidence of IRIS was 29% (12/41) for KS, 16% (4/25) for tuberculosis, 14% (1/7) for Cryptococcus, 10% (1/10) for Mycobacterium avium complex, and 4% (3/72) for PCP. Morbidity and mortality were highest in those with visceral KS-IRIS compared with other types of IRIS (100% [6/6] vs 7% [1/15], P,.01). Patients with mucocutaneous KS and tuberculosis-iris experienced greater median increase in CD4 1 cell count during the first 6 months of ART compared with those without IRIS (1158 vs 153 cells/ll, P 5.04, mucocutaneous KS; 1261 vs 1113, P 5.04, tuberculosis). Conclusions. Cumulative incidence and features of IRIS varied depending on the OI. IRIS occurred in.10% of patients with KS, tuberculosis, or Cryptococcus. Visceral KS-IRIS led to considerable morbidity and mortality. Potent combination antiretroviral therapy (ART) has dramatically decreased mortality and the incidence of AIDS-defining opportunistic infections (OIs) among persons infected with human immunodeficiency virus Received 10 June 2011; accepted 23 September 2011. Correspondence: Chad Achenbach, MD, MPH, Center for Global Health, Feinberg School of Medicine, Northwestern University, 645 N. Michigan Ave., Ste. 1058, Chicago, IL 60611 (c-achenbach@northwestern.edu). Clinical Infectious Diseases Ó The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. DOI: 10.1093/cid/cir802 (HIV) [1, 2]. Nevertheless, OIs continue to occur, particularly in patients who present late for medical care or delay ART initiation [3, 4]. Profoundly immunodeficient individuals who develop OIs and then initiate ART may experience a paradoxical worsening or recurrence of OI symptoms, termed the immune reconstitution inflammatory syndrome (IRIS). IRIS has been described as an intense inflammatory reaction to foreign antigens after rapid immunologic recovery [5] that is associated with a greater burden of disease, a low CD4 1 T-cell nadir, and, for Mycobacterium tuberculosis, a shorter time period between OI diagnosis and initiation of ART [6 17]. Reports of the occurrence rates HIV/AIDS d CID d 1

for IRIS range from 8% to over 30%; however, most previous studies have examined IRIS related to specific OIs [7 9, 11, 16, 18, 19]. Thus, it is unclear what proportion of patients with a broad range of OIs who are started on ART go on to develop IRIS. IRIS has been described in association with tuberculosis, Mycobacterium avium complex (MAC), cytomegalovirus (CMV) retinitis, and disseminated Cryptococcus. Little is known about the clinical characteristics and pathogenesis of IRIS among patients with other common OIs such as Candida esophagitis, Pneumocystis pneumonia (PCP), and Kaposi sarcoma (KS) [4]. Only a few studies have directly compared clinical characteristics and outcomes of IRIS across more than 1 AIDS-defining OI [6, 8, 10, 12, 13, 17]. We conducted this study to better understand predictors, outcomes, and immunologic changes associated with IRIS among a cohort of patients with a full spectrum of prior AIDS-defining OIs. METHODS Study Population This retrospective cohort study was conducted on the University of Washington (UW) HIV Cohort, a longitudinal observational study of HIV-infected patients receiving care in the UW Harborview Medical Center HIV Clinic and the UW Medical Center Virology Clinic from 1995 to the present, using standardized data collection methods as previously described [20]. We examined all patients in the UW HIV Cohort who: (1) had an initial visit after 1 January 1996, (2) initiated their first ART regimen (3 drugs containing at least 1 nonnucleoside reverse transcriptase inhibitor or protease inhibitor), (3) had HIV viral load suppression of at least 1 log 10 copies/ml within the first 6 months after initiating ART, (4) were diagnosed with at least 1 Centers for Disease Control and Prevention AIDS-defining OI, and (5) exhibited stability or improvement in the course of their OI prior to initiation of ART to exclude patients with worsening OIs due to treatment failure or resistance. Table 1. AIDS-defining diagnoses of recurrent pneumonia, salmonella septicemia, and chronic herpes simplex virus were excluded because of the difficulty in distinguishing IRIS from recurrent disease. The primary investigator (C. A.) reviewed comprehensive medical records for all patients meeting study criteria, and identified those who experienced clinical worsening or recurrence of a prior OI during the first year after ART initiation, or until discontinuation of therapy. For each case patient, a set of documents from the medical record was compiled for adjudication that contained the following: (1) clinician progress notes, including the 2 most recent visits prior to the initiation of ART and all visits during the worsening or recurrent OI event; and (2) laboratory data (excluding CD4 1 cell counts and HIV RNA levels); endoscopic, radiographic, and pathologic reports; and physical exam findings performed during the worsening or recurrent OI event. Paradoxical IRIS Case Definition The clinical case definition for IRIS included at least a 1 log 10 drop in HIV viral load as a measure of adherence and response to ART, similar to recently validated criteria [21], but different from older studies in not requiring a rise in CD4 1 cell count. The clinical criteria required to meet the definition of paradoxical IRIS are presented in Table 1. Cases of unmasking IRIS (underlying OI revealed and diagnosed with IRIS event) were excluded. IRIS Event Adjudication Two experienced HIV physicians (R. H. and S. D.) reviewed the set of deidentified medical record documents for each case to determine whether clinical worsening or recurrence of the OI was due to IRIS. If the 2 reviewers did not concur, then a third independent reviewer (H. C.) evaluated the document set using the same criteria to make the final determination. Definitive determination of a case of paradoxical IRIS required the agreement of 2 reviewers. Reviewers were blinded to CD4 1 /CD8 1 cell Definitive Determination of a Case of Paradoxical Immune Reconstitution Inflammatory Syndrome a Criteria (1) New, worsening, or recurrent signs or symptoms consistent with an exaggerated or atypical inflammatory reaction to the previously diagnosed OI (2) Exclusion of medication toxicity or other disease process as a cause of the clinical event (3) At least 1 piece of supportive evidence from the following: (a) Localized skin or lymph node inflammatory manifestation or lesion documented in a provider s physical examination (b) Inflammatory manifestation or lesion visualized and reported by radiology (X-ray, CT, or MR imaging), specialist examination (ophthalmology), or endoscopy (EGD, bronchoscopy, or colonoscopy) (c) Histopathologic or cytologic evaluation of tissue or fluid consistent with inflammation, granulomas or necrosis Abbreviations: CT, computed tomography; EGD, esophagogastroduodenoscopy; MR, magnetic resonance; OI, opportunistic infection. a All 3 criteria were assessed and required by each independent reviewer. 2 d CID d HIV/AIDS

Table 2. Distribution of Opportunistic Infection Diagnoses Among Study Patients, Nadir CD4 1 Cell Counts by Diagnosis, and Cumulative Incidence of Immune Reconstitution Inflammatory Syndrome During the First Year of Antiretroviral Therapy a Figure 1. Scheme of patient identification, review, and inclusion in the study analysis. Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; OI, opportunistic infection; IRIS, immune reconstitution inflammatory syndrome. counts, HIV RNA levels, date of prior OI diagnoses, and any documentation suggesting a diagnosis of IRIS in the medical record. Statistical Analysis We calculated cumulative incidence and 95% confidence intervals (CIs) as a percentage of all patients who developed IRIS over the first year of ART. Bivariate comparisons of dichotomous demographic, clinical, and treatment characteristics were performed using the Wilcoxon signed rank test for continuous variables and Fisher exact test for categorical variables. Adjusted analysis was performed using logistic regression. Factors included in the multivariable analysis were type of OI, multiple or widespread OIs, nadir CD4 1 cell count, and CD4 1 cell count increase in the first 6 months of ART. The Kaplan-Meier survival curves were used to display the time from starting ART to IRIS. Test results were considered statistically significant for a2-sidedp value of,.05. RESULTS Study Population and Type of OIs A total of 196 patients had an improving or stable OI, initiated ART, and then had at least 1 log 10 copies/ml drop in HIV RNA (Figure 1). Of the 260 OIs diagnosed in these 196 patients, the 3 most common were PCP (28%), Candida esophagitis (23%), and KS (16%) (Table 2). Within the first year of ART, 50 of 196 (26%) patients had clinical symptoms of OI worsening or recurrence (33/50 [66%] and 17/50 [34%], respectively). After independent case review, the 2 primary reviewers were in Opportunistic Infection Overall number (% of all diagnoses) Nadir CD4 1 cell count median (IQR) Cumulative IRIS incidence (1 year) number (% of OI; 95% CI) CMV 18 (7) 6 (4,29) 0 (0) Retinitis 8 (3) 7 (4,24) 0 (0) Visceral 10 (4) 6 (4,174) 0 (0) Candida esophagitis 60 (23) 40 (13,93) 0 (0) Cryptococcus, 7 (3) 5 (3,34) 1 (14; 0.4 58) disseminated Cryptosporidiosis 14 (5) 31 (16,203) 0 (0) KS 41 (16) 36 (5,89) 12 (29; 16 46) MC 27 (10) 51 (9,75) 6 (22; 9 42) Visceral 14 (5) 21 (4,89) 6 (43; 18 71) MAC 10 (4) 8 (2,40) 1 (10; 0.3 45) PCP 72 (28) 25 (8,54) 3 (4; 0.9 12) PML 3 (1) 11 (7,102) 0 (0) Tuberculosis 25 (10) 53 (20,136) 4 (16; 5 36) Pulmonary 17 (7) 53 (12,128) 3 (18; 4 43) Disseminated 8 (3) 76 (41,168) 1 (13; 0.3 53) Toxoplasmosis, CNS 7 (3) 13 (6,30) 0 (0) Other b 3 (1) 7 (5,19) 0 (0) Abbreviations: CI, confidence interval; CMV, cytomegalovirus; CNS, central nervous system; IQR, interquartile range; IRIS, immune reconstitution inflammatory syndrome; KS, Kaposi sarcoma; MAC, Mycobacterium avium complex; MC, mucocutaneous; PCP, Pneumocystis pneumonia; PML, progressive multifocal leukoencephalopathy. a Data are no. (%) of patients. b Other diagnoses included 1 case each of visceral herpes simplex virus, disseminated histoplasmosis, and isosporiasis. agreement regarding whether or not a patient had IRIS as per study criteria in 41/50 (82%) of cases. The remaining 9 cases required a third reviewer to make a final IRIS determination. IRIS was confirmed in 21 of the 50 reviewed cases of OI worsening or recurrence; 11% (95% CI, 7% 16%) of the entire cohort of 196 patients. For the 29 cases not classified as IRIS, reviewers determined that 11 (38%) had a different infection or disease (including 1 unmasking IRIS), 9 (31%) were of unknown etiology or lacked sufficient information to confirm IRIS, 8 (28%) had progression of their prior OI without an atypical or exaggerated inflammatory syndrome, and 1 (3%) was due to medication toxicity. Clinical Characteristics and Comparison of Paradoxical IRIS Cases Paradoxical IRIS occurred in the first year of ART among patients with KS (12/41 [29%]; 95% CI, 16% 46%), tuberculosis (4/ 25 [16%]; 95% CI, 5% 36%), disseminated Cryptococcus (1/ 7 [14%]; 95% CI, 0.4% 58%), disseminated MAC (1/10 [10%]; HIV/AIDS d CID d 3

Table 3. Clinical Summary of 21 Immune Reconstitution Inflammatory Syndrome Cases Categorized by Type of Opportunistic Infection OI Days from OI to ART Other pre-art OIs (no.) OI Tx or Px at ART start ART regimen Days on ART before IRIS IRIS hospital Days of IRIS symptoms Provider IRIS IRIS Tx IRIS OI Tx IRIS M&M KS MC 150 None (0) None BPI 20 No 41 Yes None None None KS MC 6 PCP (1) None NNRTI 359 No 49 Yes None dox None KS MC 137 None (0) None PI 15 Yes 342 No None dox None KS MC 504 None (0) None PI 153 No 151 No None None None KS MC 27 PCP, CMV None BPI 89 No 329 No None None None Visc, HSV Visc (3) KS MC 1240 Candida None NNRTI 62 No 24 No None dox None Esoph (1) KS MC: 144 0.5 0. 76 17 117 33 0 50 0 median or % KS Visc 35 None (0) None PI 1 NNRTI 112 Yes 118 No None dox Death KS Visc 485 Crypto (1) None NNRTI 23 No 152 Yes None dox Death KS Visc 11 None (0) dox BPI 109 Yes 17 Yes None None Death KS Visc 12 None (0) None NNRTI 13 No 505 No None dox Chronic LE edema KS Visc 13 Crypto (1) None NNRTI 29 No 1286 No None dox Chronic LE edema KS Visc 1210 Candida Esoph (1) KS Visc: median or % Tuberculosis, dissem Tuberculosis, pulm Tuberculosis, pulm Tuberculosis, pulm Tuberculosis: median or % dox PI 217 No 259 No None dox Chronic LE edema 24 0.5 33. 69 33 206 33 0 83 100 488 KS MC (1) None BPI 8 No 43 Yes NSAID None None 38 None (0) RIPE PI 7 Yes 126 Yes None RIPE None 18 None (0) RIPE NNRTI 31 Yes 96 No Ster RIPE None 65 PCP (1) RIPE NNRTI 22 No 220 Yes NSAID None Chronic dyspnea 52 0.5 75. 15 50 111 75 75 50 25 PCP 170 None (0) None NNRTI 301 Yes 67 No Ster TS None PCP 49 None (0) None PI 71 No 69 No None None None PCP 36 None (0) None BPI 5 Yes 30 Yes Ster pent IV None PCP: median or % 49 0 0. 71 66 67 33 66 66 0 Crypto 31 None (0) Fluc BPI 73 No 319 Yes None Fluc None MAC 31 PCP (1) None PI 289 No 105 Yes None ClarEth None Abbreviations: ART, antiretroviral therapy; BPI, boosted protease inhibitor; ClarEth, clarithromycin and ethambutol; CMV, cytomegalovirus; Crypto, Cryptococcus; dissem, disseminated; dox, liposomal doxorubicin; Esoph, esophagitis; Fluc, fluconazole; HSV, herpes simplex virus; IRIS, immunce reconstitution inflammatory syndrome; KS, Kaposisarcoma; LE, lower extremity; M&M, morbidity and mortality; MAC, Mycobacterium avium complex; MC, mucocutaneous; NNRTI, nonnucleoside reverse transcriptase inhibitor; NSAID, nonsteroidal anti-inflammatory drug; OI, opportunistic infection; PCP, Pneumocystis pneumonia; pent IV, pentamidine intravenous; PI, protease inhibitor; pulm, pulmonary; Px, prophylaxis; RIPE, rifampin isoniazid pyrazinamide ethambutol; Ster, corticosteroids; TS, trimethoprim-sulfamethoxazole; Tx, treatment; Visc, visceral. 95 % CI, 0.3% 45%), and PCP (3/72 [4%]; 95% CI, 0.9% 12%) (Table 2). Individual IRIS cases are presented and summarized in Table 3. As observed in Figure 2, two-thirds (14/21) of IRIS cases occurred during the first 3 months of ART. Median time from OI diagnosis to initiation of ART was longer for mucocutaneous KS-IRIS cases than for other types of IRIS (144 vs 36 days, P 5.47); however, this difference was not significant. Patients with Tuberculosis-IRIS developed IRIS symptoms after a shorter median time on ART compared with other types of IRIS (15 vs 73 days, P 5.07), and Tuberculosis-IRIS cases were also more often treated with either nonsteroidal anti-inflammatory drugs or corticosteroids compared to other IRIS 4 d CID d HIV/AIDS

Figure 2. Proportion of patients developing immune reconstitution inflammatory syndrome over the first year of antiretroviral therapy, categorized by type of opportunistic infection. Abbreviations: ART, antiretroviral therapy; IRIS, Immune Reconstitution Inflammatory Syndrome; KS, Kaposi sarcoma; MC, mucocutaneous; PCP, Pneumocystis pneumonia; Visc, visceral. cases (3/4 [75%] vs 2/17 [12%], P 5.01). Fewer patients with mucocutaneous KS-IRIS required hospitalization compared to those with other types of IRIS (1/6 [17%] vs 6/15 [40%], P 5.31). Among those with visceral KS-IRIS, the median duration of IRIS symptoms (206 vs 96 days, P 5.21), and the proportion of cases with IRIS-related morbidity or mortality (6/6 [100%] vs 1/15 [7%], P,.01) were higher compared with all other types of IRIS. P,.01]) and those with multiple or widespread OIs (odds ratio [OR] 2.7 [95% CI 1.1 6.7, P 5.05]). Risk of IRIS was significantly lower for patients with PCP (OR 0.3 [95% CI 0.1 0.99, P 5.04]) and Candida esophagitis (0/21 [0%] vs 57/175 [33%], P,.01) when compared with all other OIs. In adjusted analysis, we observed a significantly higher risk of IRIS only for patients with KS compared with all other OIs (OR 7.5 [95% CI 2.6 21.5, P,.01]). Predictors of Paradoxical IRIS Baseline characteristics of study patients and bivariate associations among those with and without paradoxical IRIS are shown in Table 4. In unadjusted analyses, there was no difference in risk of IRIS according to age, sex, race, HIV transmission risk factor, year or type of ART initiated, median time from OI diagnosis to ART initiation, median nadir CD4 1 cell count, or median baseline HIV RNA level. Risk of IRIS was significantly increased for patients with KS (OR 6.7 [95% CI 2.6 17.4, CD4 1 and CD8 1 Cell Count Changes on ART Median CD4 1 and CD8 1 cell count increases and plots of CD4 1 cell count measurements in the first 6 months of ART are presented in Table 5 and Figure 3. We found higher median increases in CD4 1 (1158 vs 153 cells/ll, P 5.04) and CD8 1 (1693 ves 1265 cells/ll, P 5.04) cell counts for patients with mucocutaneous KS who developed KS-IRIS compared with those who did not. No significant differences were found for patients with visceral KS; lower median CD4 1 (115 vs 139 cells/ll, HIV/AIDS d CID d 5

Table 4. Characteristics of Study Patients and Bivariate Comparison of Factors Associated With the Occurrence of Paradoxical Immune Reconstitution Inflammatory Syndrome During the First Year of Antiretroviral Therapy a Characteristic Overall (n 5 196) IRIS (n 5 21) No IRIS (n 5 175) OR (95% CI) P value Age, median years (IQR) 49 (43,53) 50 (45,54) 48 (43,53) NA.42 Male sex 170 (88) 18 (86) 152 (88) 0.9 (0.3 3.3) 1.0 White race 123 (63) 14 (67) 109 (62) 1.2 (0.5 3.2).81 IDU 62 (32) 5 (24) 57 (33) 0.7 (0.2 1.9).47 Year of ART initiation, median (IQR) 2001 (1998, 2004) 2001 (1998, 2003) 2001 (1998, 2004)..98 1996 1999 80 (41) 9 (43) 71 (41) 1.0. Ref 2000 2003 60 (31) 7 (33) 53 (30) 1.0 (0.4 3.0).94 2004 2008 56 (28) 5 (24) 51 (29) 0.8 (0.3 2.5).66 Type of ART Boosted PI 55 (28) 6 (29) 49 (28) 1.0 Ref PI 55 (28) 6 (29) 49 (28) 1.0 (0.3 3.3) 1.0 PI and NNRTI 24 (12) 1 (5) 23 (13) 0.4 (0.04 3.1).35 NNRTI 62 (32) 8 (38) 54 (31) 1.21 (0.4 3.7).74 Time from OI diagnosis to ART, median 2.2 (1.0,7.0) 1.3 (0.9,5.7) 2.3 (1.1,7.0) NA.41 months (IQR) b #3 months 122 (62) 13 (62) 109 (62) 0.98 (0.4 2.5) 1.0 Type of OI: versus all others KS 41 (21) 12 (57) 29 (17) 6.7 (2.6 17.4),.01 PCP 68 (35) 3 (14) 65 (37) 0.28 (0.1 0.99).04 Candida esophagitis 57 (29) 0 (0) 57 (33) NA,.01 OI treatment at ART initiation 61 (31) 5 (24) 56 (32) 0.7 (0.2 1.9).62 Disseminated or multiple OIs c 70 (36) 12 (57) 58 (33) 2.7(1.1 6.7).05 Nadir CD4 1 count, median cells/ll (IQR) 32 (9,90) 34 (5,74) 31 (10,95)..43 Nadir CD4 1 count, #100 cells/ll 146 (78) 18 (86) 128 (78) 1.8 (0.5 6.5).42 Pre-ART HIV RNA, median log 10 copies/ml (IQR) 5.2 (4.7,5.7) 5.5 (4.7,5.7) 5.2 (4.7,5.7)..58 Pre-ART HIV RNA.5.0 log 10 copies/ml 120 (61) 14 (67) 106 (61) 0.8 (0.3 2.0).64 Abbreviations: ART, potent antiretroviral therapy; CI, confidence interval; CMV, cytomegalovirus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; IDU, intravenous drug user; IQR, interquartile range; IRIS, immune reconstitution inflammatory syndrome; KS, Kaposi sarcoma; NA, not applicable; NNRTI, nonnucleoside reverse transcriptase inhibitor; OI, opportunistic infection; OR, odds ratio; PCP, Pneumocystis pneumonia; PI, protease inhibitor; Ref, reference. a Data are no. (%) of patients, unless otherwise specified. b If more than 1 prior OI diagnosis, then diagnosis with paradoxical IRIS or closest to ART initiation selected for this analysis. c Disseminated or multiple OIs defined as patients with visceral CMV, visceral KS, disseminated tuberculosis, visceral HSV, or $2 OIs prior to initiation of ART. P 5.25) and CD8 1 (147 vs 1229 cells/ll, P 5.42) cell count increases occurred in those with KS-IRIS compared to those without. Similar to patients with mucocutaneous KS-IRIS, patients with Tuberculosis-IRIS also experienced greater median increases in CD4 1 cell count (1261 vs 1113, P 5.04), but no difference in CD8 1 cell count increase (1221 vs 1281, P 5.72). Among patients with PCP, there was no association between increases in either CD4 1 cell count (188 vs 1133, P 5 1.0) or CD8 1 cell count (1372 vs 1431, P 5.98) and the development of IRIS. DISCUSSION We found a cumulative incidence of paradoxical IRIS within the first year of ART of 11% (95% CI, 7% 16%), similar to that reported in prospective studies [11, 13, 14, 17, 18]. Distinct from previous studies, we examined the risk of IRIS across many AIDS-defining OIs, including common conditions such as Candida esophagitis, PCP, and KS. The incidence of IRIS for individual OIs varied greatly and often differed from that reported in previous investigations. We observed no cases of IRIS due to CMV disease or Candida esophagitis, whereas 29% of patients with KS developed IRIS in the first year of ART, in contrast to previous studies that reported a combined incidence of immune recovery CMV uveitis of 37.7% and only 6.4% for KS-IRIS [15]. These conflicting findings likely reflect lack of a standard definition of IRIS, temporal and regional differences in OI and HIV treatments, and OI severity, as well as variability in study size, demographics, and follow-up. We observed a remarkably high rate of IRIS in patients with KS (29%; 95% CI 16% 46%), similar to that reported in a study from sub Saharan Africa [16]. The higher cumulative incidence of IRIS in patients with visceral KS compared 6 d CID d HIV/AIDS

Table 5. Nadir CD4 1 Cell Count and Increases in CD4 1 or CD8 1 Cell Counts During the First 6 Months of Antiretroviral Therapy for Patients With and Without Immune Reconstitution Inflammatory Syndrome Categorized by Type of Opportunistic Infection with patients with mucocutaneous KS (6/14 [43%; 95% CI 18% 71%] vs 6/27 [22%; 95% CI 9% 42%], respectively) is consistent with the hypothesis that higher OI disease burden increases the risk of IRIS [7, 10, 18, 22, 23]. An explanation for the high incidence of KS-IRIS might be that worsening or spreading KS lesions are easier to detect clinically and that our case definition was more sensitive than those used in previous studies. It is also possible that some cases identified as KS-IRIS represented KS disease progression. This highlights the need for a standardized definition of IRIS and KS-IRIS in particular. KS-IRIS was associated with significant morbidity in patients with visceral disease. Three out of 6 patients with visceral KS-IRIS died within 6 months and the other 3 had persistent lymphedema. Several earlier studies have also reported substantial morbidity and mortality associated with KS-IRIS, including IRIS n No IRIS n P value Mucocutaneous KS a Nadir CD4 1 count 39 (17,72) 6 51 (7,98) 19.90 CD4 1 increase 1158 (122,254) 6 153 (32,124) 19.04 $1100, n (%) 5/6 (83). 5/19 (26)..02 CD8 1 increase 1693 (367,1443) 6 1265 (178,502) 21.04 Visceral KS a Nadir CD4 1 7 (3,40) 6 62 (4170) 7.27 CD4 1 increase 115 (7,72) 6 139 (29,124) 7.25 $1100, n (%) 0/6 (0). 2/7 (29)..46 CD8 1 increase 147 (22, 160) 6 1229 (25,628) 8.42 Tuberculosis a Nadir CD4 1 78 (27,117) 4 53 (20,186) 21.74 CD4 1 increase 1261 (161,328) 4 1113 (71,174) 19.04 $1100, n (%) 4/4 (100). 11/19 (58)..26 CD8 1 increase 1221 (139,1033) 4 1281 (196,584) 19.72 PCP a Nadir CD4 1 74 (6,82) 3 24 (8,47) 67.42 CD4 1 increase 188 (50,518) 3 1133 (64,236) 65 1.0 $1100, n (%) 1/3 (33). 40/65 (62)..56 CD8 1 increase 1372 (126,1066) 3 1431 (204,931) 67.98 Cryptococcus a Nadir CD4 1 34 (34,34) 1 5 (3,10) 6.48 CD4 1 increase 1233 (233, 233) 1 120 (9,49) 6.25 $1100, n (%) 1/1 (100). 0/6 (0)..14 CD8 1 increase 11063 (1063,1063) 1 1503 (127,673) 6.48 MAC a Nadir CD4 1 1 (1,1) 1 21 (4,43) 8.28 CD4 1 increase 136 (36,36) 1 147 (15,190) 8 1.0 $1100, n (%) 0/1 (0). 3/8 (38). 1.0 CD8 1 increase 1359 (359,359) 1 1367 (198,413) 8 1.0 Abbreviations: IRIS, Immune reconstitution inflammatory syndrome; KS, Kaposi sarcoma; MAC, Mycobacterium avium complex; PCP, Pneumocystis pneumonia. a Data are median cells/ll (IQR), unless otherwise specified. persistent mucocutaneous lesions, lymphedema, and death [24 28]. Recent research presentations suggest that IRIS related to KS may be particularly aggressive and respond poorly to standard therapy. The traditional approach to severe IRIS often includes administration of systemic corticosteroids, which may be contraindicated in KS-IRIS given the finding that corticosteroids are associated with progression of the tumor [29 31]. Additional studies are needed to characterize the frequency, natural history, and prognosis of KS-associated IRIS. Among patients in our study with OIs other than visceral KS, there were no IRIS-related deaths and only a single patient developed long-term sequelae (tuberculosis-iris leading to chronic dyspnea). Prospective observational cohorts examining tuberculosis and MAC IRIS in various settings have also reported no excess mortality and minimal morbidity due to IRIS HIV/AIDS d CID d 7

Figure 3. CD4 1 cell counts in the first 6 months of antiretroviral therapy (ART) for individual immune reconstitution inflammatory syndrome (IRIS) cases categorized by type of AIDS-defining opportunistic infection. Note: I, marks timing of the IRIS event; I*, IRIS event occurred after the first 6 months of ART. Abbreviations: KS, Kaposi sarcoma; MAC, Mycobacterium avium complex; PCP, Pneumocystis pneumonia. [8, 9, 13, 32]. Unfortunately, our sample size did not allow us to assess whether these observations were due to HIV disease severity or treatment differences. We observed a remarkably low frequency of IRIS in patients with Candida esophagitis (0%). Despite reports of increased Candida delayed-type hypersensitivity responses and in vitro lymphocyte proliferation early in ART [33, 34], IRIS due to Candida esophagitis has not been reported in the literature. In contrast, IRIS has been observed in patients with Candida meningitis [12, 35], angular cheilitis [36] and in HIV-uninfected 8 d CID d HIV/AIDS

leukemic children with hepatosplenic candidiasis [37]. It is possible that the absence of observed cases of Candida esophagitis IRIS is due to the ease with which the infection is treated and the rapid clearance of antigens that serve as a target for the recovering immune system. We also observed a low incidence of PCP-related IRIS (4%; 95% CI, 0.9% 12%), similar to that reported for the AIDS Clinical Trials Group (ACTG) 5164 trial (2% [4/171]) [17]. Two possible explanations for this finding are that patients with PCP remain on secondary prophylaxis, leading to declining numbers of organisms in the early phase of ART, and that patients with moderate-to-severe PCP are treated with corticosteroids in addition to antibiotics to prevent paradoxical worsening of the infection early in treatment. Investigators for ACTG 5164 concluded that receipt of corticosteroids during acute OI treatment did not decrease IRIS incidence, but may have led to a delay in IRIS presentation. Our findings also suggest that corticosteroid use at the time of ART initiation does not fully explain this low rate. Nearly all of the patients we studied (67/72 [93%]) initiated ART several days to weeks after completion of their PCP treatment course when they were no longer on corticosteroids (median time from PCP diagnosis and treatment to ART initiation was 66 days [range, 14 1040]). Our finding of an earlier presentation of IRIS in the setting of tuberculosis compared with other OIs is consistent with previous studies of tuberculosis in which the majority of IRIS events occurred within the first 3 months of ART [8, 11, 13]. In contrast, KS-IRIS and PCP-IRIS events were dispersed throughout the first year, as seen in Figure 2. In some cases, KS-IRIS might be delayed relative to Tuberculosis-IRIS due to an immunomodulary effect of chemotherapy used to treat the KS. However, 1 study of KS patients treated with ART and liposomal anthracycline chemotherapy did not find a significant drop in CD4 1 cell counts in the year following chemotherapy [38], suggesting that if chemotherapy attenuated the immune response, it did so independent of T-cell number. Finally, even among a highly immune-suppressed group of patients, CD4 1 cell reconstitution for those with and without IRIS differed depending on the type of OI. Patients with tuberculosis, Cryptococcus, and mucocutaneous KS-IRIS experienced greater increases in CD4 1 cell counts during the first 6 months of ART compared with those without IRIS. Other studies of IRIS in patients with tuberculosis and Cryptococcus also noted greater CD4 1 cell count increases in patients who developed IRIS [8, 23, 39]; however, ours is the first to report this finding in patients with mucocutaneous KS-IRIS. Notably, peak elevation in CD4 1 cell count often occurs long after the IRIS event (see Figure 3A and 3C), and therefore, may not be helpful in the diagnosis of the majority of IRIS cases. Total peripheral blood CD4 1 or CD8 1 cell counts, as measured in our study, are nonspecific immunologic markers that may not reflect pathogenspecific immune activity or regional immune responses. Strengths of our study include a standardized approach to evaluating IRIS and use of a validated clinical definition along with independent event adjudication. Several limitations deserve mention: (1) retrospective review by clinicians not involved in the care and diagnosis of IRIS in these patients could have led to misclassification, as reviewers may have had insufficient information to make appropriate clinical judgments; (2) determination of IRIS was particularly challenging in cases of KS recrudescence; (3) the small number of IRIS cases in our analysis limited examination of complex associations; and (4) limiting our analysis to patients with paradoxical IRIS after certain AIDS-defining diagnoses underestimated the true incidence of all types of IRIS, including unmasking versions of this syndrome. In conclusion, we demonstrated that the risk of developing IRIS varies widely and is dependent on the underlying OI. Patients with profound immune deficiency and AIDS-defining Candida esophagitis or PCP are unlikely to develop IRIS in settings where patients are promptly treated or receive steroids to prevent paradoxical worsening (PCP), whereas over 10% of those with KS, tuberculosis, or Cryptococcus experienced this syndrome. We found that paradoxical visceral KS-IRIS occurred frequently, despite only modest increases in CD4 1 cell counts, and was associated with high morbidity and mortality. Our study suggests that additional research is needed to understand and prevent KS-IRIS, particularly in countries with a high burden of this malignancy. Notes Acknowledgments. We would like to acknowledge Margaret Griffith, Thomas Davis, Christine Bagley, and LaurieSmithfortheirsignificant contributions to this study. Financial support. This work was supported by the University of Washington AIDS and STD Research Training Grant (National Institutes of Health T32 AI07140-31). Potential conflicts of interests. 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