Immune reconstitution inflammatory syndrome in young children initiating ART
Polly Clayden, HIV i-Base
There has been limited data describing immune reconstitution inflammatory syndrome (IRIS) in infants and children.
In an oral presentation Kelly Smith showed findings from a case note review of children enrolled in NEVEREST 2 (between April 2005 and November 2006), a South African trial in which HIV-positive children <2 years, exposed to nevirapine through PMTCT receive d4T/3TC/LPV/r (or RTV if <6months). Children in this cohort receive BCG vaccination as a matter of routine. Often this occurs prior to HIV diagnosis.
In this study children were monitored for IRIS during the first four months of HAART.
The investigators found 34/162 children initiated on HAART were confirmed to have IRIS. The median time from initiation to first symptom was 16 days (range 7-115 days), with 73.5% of symptoms occurring within 30 days from HAART initiation.
BCG-osis, most commonly BCG injection site inflammation or ipsilateral axillary lymphadenitis with abscess formation, were the most common, 24/34 (70.6%) of all the IRIS events and14.8% of all children initiating HAART.
Other IRIS events included: TB in 11/34 (32%) children, CMV pneumonia, PCP, seborrheic dermatitis, herpes simplex, S peumoniae sepsis and pneumonia.
The investigators reported that children with IRIS were younger, 47% <6months vs 25%; had lower CD4%, 56% CD4% <15% vs 34% and had higher baseline viral load, >750,000 copies/mL 45% vs 21% than children with no IRIS.
These children also had lower average weight for age z-score, mean -3.26 vs -2.09 and 82% vs 49% had < -2 SD below the mean (p=0.0004).
See Table 1 for baseline predictors for development of IRIS.
Table 1: Baseline predictors for development of IRIS
|CD4% <10% vs >/=20%||5.84||1.73-11.74|
|Weight for age </= 2 SD from mean||4.13||1.73-11.74|
After 24 weeks, response to HAART was lower the children with IRIS, with 28% vs 62% <400 copies/mL and 14% vs 44% <50 copies/mL.
Increase in CD4 percentage was similar between groups, but children with IRIS had lower mean CD4% at 24 weeks, 21.5% vs 29.0%, (p=0.001).
Dr Smith concluded that IRIS, particularly BCG-related disease, was common in this cohort of young children initiating HAART. Children with very advanced disease and low weight for age appear to be at particularly high risk.
Additionally, children with IRIS are less likely to achieve complete viral suppression by 24 weeks.
She added, Further research is required to understand the pathogenesis and diagnosis of IRIS and determine best practices for prevention and treatment.
Diagnosing IRIS in children remains difficult and is an inexact science. BCG reactions are the most clear-cut clinical presentations of IRIS (see also study below). CMV pneumonia, PCP, seborrheic dermatitis, herpes simplex, S. pneumoniae sepsis and pneumonia carry an element of subjective assessment.
Was the decision to call a condition IRIS made by clinicians blinded to the CD4 percentage? There is great potential for bias, if the diagnostic criteria for calling a condition IRIS is based in part on the knowledge that the initial CD4 is low. Also, a child developing a new opportunistic infection within a few days or weeks of starting ART, may have been so profoundly immunosuppressed that they remained at much the same risk of OIs as they had prior to initiating ART. Including such children in the data set further perpetuates the notion that IRIS occurs in children with a low CD4 %.
The conclusion that further research is needed to understand the pathogenesis is entirely correct.
Smith K, Kuhn L, Coovadia A et al. Immune reconstitution inflammatory syndrome in HIV-infected infants and young children initiating ART. 15th CROI, February 2008, Boston, MA, USA. Oral abstract 75.