Background:  Immune reconstitution inflammatory syndrome (IRIS) in association with cryptococcosis has been reported following administration of ART. There is little information regarding timing of cryptococcal IRIS.

Methods:  A retrospective cohort study was conducted among HIV-infected patients who had initiated ART after the first episode of culture-proved cryptococcal meningitis. Cryptococcal IRIS was defined as culture-negative meningitis after immunological response to ART. Kaplan-Meier survival analysis was used to determine the timing of cryptococcal IRIS occurrence.

Results:  There were 52 patients with a mean age of 34.4 years of whom 60% were males. Median (IQR) CD4 cell count was 26 cells/mm³ (9 to 46) when the patients presented with the first episode of culture-proved cryptococcal menigitis. All patients received secondary prophylaxis after treatment of cryptococcal menigitis. Median (IQR) time of ART initiation after diagnosis of cryptococcal menigitis was 2.6 (1.6 to 5.0) months. The majority of patients (96%) received non-nucleoside reverse transcriptase inhibitor (NNRTI) -based regimens. At 6 months of ART, median (IQR) CD4 cell count was 121 cells/mm³ (80 to 178) and 88% achieved undetecteable HIV RNA. During a median (IQR) follow-up period of 15.7 months (8.6 to 30.3), 10 patients (19%) developed cryptococcal IRIS at a timing of 3.0 to 27.3 months after initiation of ART. No patient with cryptococcal IRIS died. From Kaplan-Meier analysis, the median time to develop cryptococcal IRIS was 9.9 months (95% confidence interval, 3.9 to 17.9). The cumulative 25% and 75% occurrence of cryptococcal IRIS was at 8.6 and 21.0 months, respectively. From univariate and multivariate analysis, there were no factors to predict the timing of cryptococcal IRIS.

Conclusions:  Cryptococcal IRIS occurs at a rate of 19% and at a median time of 10 months after initiation of ART in advanced HIV-infected patients with cryptococcal meningitis. Immune reconsitution cryptococcosis within the first three months of ART is uncommon and this syndrome may occur as late as 27 months after ART. During the first 3 years of ART, immune reconsitution cryptococcosis should be recognized in patients presented with culture-negative cryptococcosis and occurrence of this syndrome should not indicate ART failure.