Despite its clinical importance, IRIS has not been well studied in children. This is the first report to describe the incidence of and risk factors for IRIS in a cohort of infants and young children less than 24 months of age initiating HAART. Approximately 21% of these children met criteria for IRIS and, similar to findings in cohorts of older children and adults, children with advanced immune suppression were at higher risk for developing the syndrome than those with a less severe disease profile [1
]. We also determined that younger age at HAART initiation was associated with increased risk for IRIS. Intriguingly, our results suggest that children with IRIS may be less likely to suppress HIVafter 6 months of HAART than those without the syndrome.
Diagnosis of IRIS in children is complex due to a lack of standard definitions and diagnostic dilemmas associated with several other infectious and pulmonary conditions in young children, particularly TB [22
]. BCG-related IRIS was the most common diagnosis in our cohort perhaps due in part to the ease of diagnosis: 14.8% of all children starting HAART were diagnosed with a BCG-related complication. This is far higher than the incidence rate of 2% for vaccine site abscesses and 0.7% for lymphadenitis reported in a Thai study of older children [16
] and higher than that reported in another cohort of infants 6–12 weeks of age enrolled in a HAART strategies trial in South Africa in which 8.8% were reported to have developed BCG regional IRIS [14
]. It has been pointed out that BCG vaccination poses a significant risk to HIV-infected infants [17
]. In our cohort, morbidity associated with BCG IRIS was substantial. Three deaths occurred: one in a child with presumed disseminated BCG and TB, and two in children with localized disease (not thought to be related to the children’s deaths). Furthermore, the majority of children required single or repeated abscess aspirations or surgical incision and drainage as well as new medication in addition to their already complex regimens. Recent WHO guidelines discourage BCG for HIV-infected children [25
]. However, as the vaccine is routinely given prior to knowledge of the child’s HIV status, this recommendation has little practical utility. The high rate of BCG-related complications experienced by young HIV-infected children initiating HAART in our study supports recent recommendations for careful monitoring of HIV-infected BCG vaccinated infants particularly during the immediate period following HAART initiation [25
Twelve of the 34 IRIS cases were attributed to TB, including six with BCG comorbidity. TB is notoriously difficult to diagnose in infants and we relied on TB treatment as confirmation of the diagnosis [22
]. For some children, medical records provided further evidence supporting the diagnosis, including tuberculin skin tests, radiographs and bacteriologic cultures. The overwhelming predominance of BCG-related and TB-related causes of IRIS in young children suggests that further investigation of prophylaxis with anti-TB drugs and other approaches to decrease the risk of TB exposure and acquisition are warranted.
The median time to IRIS symptoms was 16 days. This is somewhat shorter than reported from Thailand, but may be explained by our focus on the first 6 months of treatment compared with 48 weeks of observation in the Thai study [6
] or to the younger age of our cohort. We also found that lower CD4 cell%; younger age and lower weight-for-age Z
-score pretreatment were each associated with a significantly higher risk for developing IRIS. Children less than 6 months of age were four-times more likely to be diagnosed with IRIS than older children, whereas CD4 cell% less than 10 was associated with a more than five-fold increase over higher CD4 cell%. Advanced disease has been associated with IRIS in adult and pediatric populations but age has not been previously identified as a risk factor [1
The association between young age and increased risk for IRIS could pose significant challenges in light of new recommendations to initiate HAART in all HIV-infected children less than 1 year of age, regardless of clinical or immunologic status [26
]. It is possible that early initiation of HAART prior to disease progression may decrease the risk for IRIS. This might explain the lower rates of BCG IRIS observed in the treatment strategy trial mentioned earlier [14
]. As all children in our study had evidence of advanced HIV disease to meet enrollment criteria, we could not tease out the relationships between age, disease stage, and the development of IRIS. It will be critically important, therefore, to monitor rates and manifestations of IRIS as more infants initiate HAART early in TB endemic areas with routine newborn BCG vaccination.
After 24 weeks of treatment, mean CD4 cell% and weight-for-age Z
-scores in the IRIS group remained lower than the control group, but mean increases over time for both CD4 cell% and weight were similar between groups [27
]. In contrast, children with IRIS were significantly less likely to achieve viral suppression to less than 400 copies/ml by 24 weeks than controls. We adjusted for markers of disease severity at HAART initiation (CD4 cell%, viral load categories, weight-forage, WHO stage, age, etc.) but these markers did not account for the difference in response rate. However, these parameters only partially capture the full spectrum of the severity of disease and residual confounding may account for the reduced viral suppression. In particular, we were unable to determine the actual viral load value pretreatment when the reported value was more than 750 000 copies/ml and therefore could not adequately adjust for pretreatment viral load. Our finding may represent the longer time needed to achieve complete viral suppression when pretreatment viral load is very high [29
]. Also, as the IRIS-defining conditions that we identified almost all required TB treatment, we are concerned about possible drug-drug interactions. Several studies have identified pharmacokinetic interactions between rifampin and ritonavir as well as ritonavir boosted protease inhibitors that may result in sub-therapeutic antiretroviral drug levels [21
]. In addition, the burdens of acute illness and concomitant medications for treatment of IRIS conditions are likely to result in adherence challenges that may impact HAART efficacy. One study of adherence in young South African children identified ritonavir treatment as a risk factor for incomplete adherence and lower rates of complete viral suppression [36
There are several limitations to this study. IRIS is difficult to diagnose in children secondary to the lack of a standard definition and the well known dilemmas of diagnosing TB and other infectious diseases [22
]. We chose to use the IRIS definition used in a previous studyof children and to rely, to a large extent, on study physician diagnosis [6
]. Although the suspected IRIS cases were determined prospectively during the study, a review of these cases occurred retrospectively by only one independent reviewer. We recognize that classification of some of the cases may not be entirely accurate. Given the difficulties of distinguishing disseminated BCG disease from TB, it is possible that some of the children listed as experiencing both complications were experiencing only disseminated BCG disease. This study was also limited by losses in both groups due to death and withdrawal. Given the lack of clinical detail surrounding deaths (several children died at home) as well as the severity of symptomatic disease pretreatment, it is possible that IRIS may have gone undetected and that the rate and severity of IRIS manifestations may have been underestimated.
In summary, in this cohort of infants and young children initiating HAART, IRIS was a common complication associated with significant morbidity, particularly in the youngest children with advanced HIV disease. Given the continuing large-scale rollout of HAART to infants and children in the developing world, careful monitoring is warranted following the initiation of therapy. Further research is needed to better predict and diagnose IRIS and the underlying infections associated with the syndrome and to determine best practices for prevention and treatment. In areas where BCG vaccination is routine, it will be critically important to continue to examine the consequences of vaccine policy for HIV-infected children.