Timing of Cryptococcal Immune Reconstitution Inflammatory Syndrome After Antiretroviral Therapy in Patients With AIDS and Cryptococcal Meningitis (2007)

To the Editor: Cryptococcosis is the most common lethal fungal infection in patients with AIDS. The introduction of combined antiretroviral therapy (ART) has markedly decreased the overall mortality for these advanced HIV-infected patients.1 After initiation of ART, some patients experience immune reconstitution inflammatory syndrome (IRIS), a well-recognized complication of ART in patients with extremely low initial CD4 cell counts.2 This syndrome has been described in multiple opportunistic pathogens, commonly with Mycobacterium avium complex, Mycobacterium tuberculosis, Cryptococcus neoformans, cytomegalovirus, and hepatitis virus.3-8 Various studies reported that 8% to 50% of patients with cryptococcal infection who responded to ART developed cryptococcal IRIS despite the use of fluconazole therapy.8-10 Lortholarya et al9 have demonstrated that independent risk factors for the occurrence of cryptococcal IRIS are HIV infection that was revealed by cryptococcosis, low CD4 cell count, fungemia at baseline, and initiation of treatment within 2 months of cryptococcosis. In noncryptococcal IRIS, most patients present in the first 8 weeks after the start of ART.3,11,12 There is little information regarding timing of cryptococcal IRIS, however. Previous small studies have described that cryptococcal IRIS can occur from as short as <2 weeks to 22 months after initiation of ART.8,13 To clarify the timing of cryptococcal IRIS after ART in patients with AIDS, a retrospective cohort study was conducted among HIV-infected patients who initiated ART after the first episode of culture-proven cryptococcal meningitis. Cryptococcal IRIS was defined as culture-negative cryptococcosis after immunologic response to ART according to the criteria previously described.2 Kaplan-Meier survival analysis was used to determine the timing of cryptococcal IRIS occurrence after ART. Cox proportional hazard modeling was used to determine the predicting factor of cryptococcal IRIS. There were 52 patients with a mean (SD) age of 34.4 (6.9) years, and 60% were male. The median (range) CD4 count was 26 (1-93) cells/mm3 when the patients presented with the first episode of culture-proven cryptococcal meningitis. All patients received secondary prophylaxis after treatment of cryptococcal meningitis. The median (range) time of ART initiation after diagnosis of cryptococcal meningitis was 2.6 (0.8-10.6) months. Most patients (96%) received nonnucleoside reverse transcriptase inhibitor-based regimens. At 6 and 12 months of ART, the median (range) CD4 counts were 121 (59-203) cells/mm3 and 237 (87-302) cells/mm3, respectively. In intent-to-treat analysis, 88% and 78% of patients achieved undetectable HIV RNA (<50 copies/mL) in the corresponding periods. During a median (range) follow-up period of 15.7 (7.9-54.0) months, 10 patients (19%) developed cryptococcal IRIS at a timing of 3.0 to 27.3 months after initiation of ART. All patients presented with aseptic meningitis: high opening pressure, positive cryptococcal antigen in cerebrospinal fluid (CSF), and culture-negative. ART was continued in all patients, and no patient with cryptococcal IRIS died. From Kaplan-Meier analysis, the median survival (free from cryptococcal IRIS) duration was >54 months. The 75% survival (free from cryptococcal IRIS) duration was 21.5 months (Fig. 1). Among patients with cryptococcal IRIS, the median time to develop this syndrome was 9.9 (95% confidence interval: 3.9 to 17.9) months. The cumulative 25% and 75% occurrences of cryptococcal IRIS were at 8.6 and 21.0 months, respectively. From Cox proportional hazard modeling, including various factors (baseline CD4 cell count, baseline HIV RNA level, fungemia at baseline, cryptococcal antigen titer, type of ART regimen, initiation of ART within 2 months of cryptococcosis, and CD4 cell count and HIV RNA level change at 6 and 12 months after ART), there were no factors to predict the occurrence or timing of cryptococcal IRIS.FIGURE 1: Kaplan-Meier survival curve demonstrating timing of cryptococcal IRIS after initiation of ART.The results from the present study have demonstrated that the timing of cryptococcal IRIS seems to be quite variable. Interestingly, this syndrome is uncommon within the first 3 months of ART and may occur as late as 27 months after initiation of ART. IRIS presenting during the first 3 months of ART reflects an immune response against an active infection by opportunistic pathogens, whereas late IRIS may result from an immune response against the antigens of nonviable pathogens.2 This may explain why secondary prophylaxis of cryptococcosis cannot prevent cryptococcal IRIS. Unfortunately, there was no predicting factor for the occurrence or timing of cryptococcal IRIS in the present study. Risk factors for the occurrence of cryptococcal IRIS reported in the literature include low CD4 cell count, fungemia at baseline, and initiation of treatment within 2 months of cryptococcosis.2,9 These factors are not significant predictors for the occurrence or timing of cryptococcal IRIS in our Cox proportional hazard models, however. A recent study reported that the model to predict IRIS may not be accurate, or at least not applicable, for Asian populations.14 Until we have more accurate predicting factors, this finding demonstrates the difficulty of diagnosing cryptococcal IRIS, particularly if it occurs late after ART and physicians are not aware of this syndrome. Of note, no patient developed cryptococcal IRIS after 27 months of ART. During the first 3 years of ART, immune reconstitution cryptococcosis should be recognized in patients presenting with culture-negative cryptococcosis, and occurrence of this syndrome should not indicate ART failure. ACKNOWLEDGMENT This study was presented at the 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, February 25-28, 2007 (abstract P 842). Somnuek Sungkanuparph, MD* Ubonvan Jongwutiwes, MD† Sasisopin Kiertiburanakul, MD* *Department of Medicine Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok Bangkok, Thailand †Department of Medicine Faculty of Medicine Siriraj Hospital Mahidol University Bangkok Bangkok, Thailand