Immune reconstitution in children treated with HAART is independent of age
Polly Clayden, HIV i-Base
A Dutch study reported by van Rossum and colleagues examined the extent of immune reconstitution in a group of HIV-infected children after initiation of HAART .
Previously age was believed to be the best predictor of the initial increase in naive CD4 cells, but it was not clear quite how much the immune system was able to recover, as long-term data on children treated with HAART were not available. This study evaluated immune reconstitution in a group of children treated with one protease inhibitor (PI) and two nucleoside reverse transcriptase inhibitors (RTIs) over a period of 96 weeks. Changes in the number of CD4 and CD8 cells and their naive and memory subsets were analysed and compared to normal paediatric age specific reference values.
71 children were enrolled (age range 1 month to 18 years) in two prospective, open label, uncontrolled studies to evaluate their response to PI-containing HAART regimens of either IDV/ZDV/3TC or NFV/d4T/3TC. Entry criteria included antiretroviral naive or previous RTI treated and HIV-1 RNA values above 5000 copies/ml or CD4 counts less than the lower limit of age specific normal reference values. Blood samples were taken 2-0 weeks before HAART was initiated and throughout the 96-week study period (at weeks 1, 2, 4, 8,12, 24, 36, 48 and 96). Lymphocytes were phenotyped as CD4 and CD8 T-cells, with naive and memory subsets. Relative CD4 cells were calculated in relation to the median age-specific reference values. Virologic responders were defined as those who either reached undetectable viral load (<400 or <500 copies/ml) or achieved and maintained (throughout the study period) a >1.5 log drop by week 12.
Analysis revealed that both the absolute CD4 count and the CD4 percentages increased significantly (p<0.001) from a median of 471x10x6 cells and 17%, to 939 x 10×6 cells and 32% respectively after 48 weeks. In all age groups the increase of total CD4 cells was caused by an increase of naive CD4 cells. A tendency towards an inverse correlation between the increase of absolute naive CD4 cells and the age range of children was observed at 4, 24 and 48 weeks (r=-0.31, p=0.03; r=0.34, p=0.02; r=-0.47, p=0.01; and r=0.33, p=0.04 respectively). When CD4 cell restoration was evaluated as a percentage of normal values however, an inverse correlation between the increase of naive CD4 cells and age was only observed after 48 weeks (r=-0.41, p=0.02). Although younger children produce more CD4 cells in absolute numbers, they require relatively more CD4 cells to catch up and normalise their CD4 counts. It was concluded therefore that older children are able to normalise their CD4 counts equally well as younger ones.
The investigators also found that, although strongly immunosupressed HIV-infected adults experience poor immune reconstitution, children with lower baseline CD4 counts showed a greater increase of CD4 counts and recovery to normal values after the initiation of HAART. They were also surprised to find that children defined as virologic non-responders still benefited from HAART and showed no difference in immune reconstitution at any time-point than those defined as virologic responders.
Overall they concluded that, their results indicate that immune reconstitution in HIV-infected children is independent of their age, suggesting that children’s thymic function enables all age groups to restore their different CD4 production demands. They observed a more rapid and complete immune reconstitution than would be expected in adults, even in children with advanced HIV-infection. And they also added that ‘Remarkably, HAART had a beneficial effect on immune reconstitution regardless of virological success’.
Dr Ronald de Groot, the principle paediatrician from this group in Rotterdam will also be speaking at our paediatric meeting on October 27th
- Van Rossum et al, Immune reconstitution in HIV-1 infected children treated with highly active antiretroviral therapy is independent of their age and pre-treatment immunestatus. Abstract 569. 40th ICAAC, Toronto, Canada, September 17-20, 2000.