Background:  Little is known about immune reconstitution inflammatory syndrome (IRIS) in infants and children, especially in areas with high tuberculosis (TB) prevalence and routine newborn Bacille-Calmette-Guerin (BCG) vaccination.

Methods:  HAART-naive HIV-infected children <24 months of age who were exposed to nevirapine for prevention of mother-to-child transmission (PMTCT) and met criteria for HAART were enrolled in NEVEREST II, an antiretroviral strategy trial, in Johannesburg, South Africa, April 2005 to November 2006. Children were monitored for IRIS during the first 4 months of HAART. Study clinicians identified children with suspected IRIS. All cases were reviewed by the study team and cases consistent with published descriptions of IRIS, new diagnosis of mycobacterial disease or other opportunistic infection, or severe exacerbation of a preexisting infection following HAART initiation, were included as IRIS cases. Suspected cases that were not confirmed and all those without IRIS symptoms were classified as controls. Baseline and post-treatment characteristics of the 2 groups were compared using 2-sided t-tests.

Results:  At mean age of 10 months, 170 children initiated stavudine (d4T) + lamivudine (3TC) + lopinavir (LPV)/ritonavir (RTV) or RTV (for children <6 months of age). Of these, 148 completed ≥4 months’ follow-up (16 died, 3 were lost to follow-up, 2 transferred, 1 was withdrawn); 25 of the 148 (17%) were confirmed to have IRIS. No deaths were attributed to IRIS but cause of death was available for only 5 of the 16 children who died. Median time from HAART initiation to first IRIS symptoms was 15 days. Of 25 children, 20 developed BCG-osis, most commonly BCG injection site inflammation or ipsilateral axillary lymphadenitis with abscess formation. Other IRIS events included TB (n = 7), cytomegalovirus (CMV) pneumonia (n = 1), Pneumocystis carinii pneumonia (PCP) (n = 1), and severe dermatitis (n = 1); 5 IRIS cases had 2 or more distinct clinical diagnoses. Children with IRIS were younger, mean age 7.2 months vs 10.7 months, p = 0.006, with lower mean CD4% (13.9 vs. 20.1, p = 0.002), and CD4⁺ count (675 vs 1174 cells/mm³, p = 0.003) compared with controls. Mean decrease in viral load after 24 weeks of HAART was greater for controls (3.14 log₁₀) than for IRIS cases (2.10 log₁₀), p = 0.001. Increase in CD4 percentage was similar between groups, but children with IRIS had lower mean CD4 percentage at 24 weeks (21.5% vs 29.0%, p = 0.001).

Conclusions:  IRIS, particularly BCG-related disease, was common in this cohort of young children initiating HAART. Children starting ART at a young age with low CD4 may be particularly vulnerable. The effect of IRIS on HAART treatment outcomes requires further study.