Annemarie van Rossum
This Dutch study gives a very clear report of the extent to which HAART is capable of reconstituting the immune system of children, regardless of their age or the stage of their HIV.
In this Dutch study we examined the extent of immune reconstitution in a group of HIV-infected children after initiation of HAART . We found that children with HIV-1 infection have a greater capacity to reconstitute their naive CD4+ T-cells when compared to HIV-infected adults treated with similar antiretroviral therapy.
This is not an unexpected finding, since naive T-cell recovery is believed to be thymus-dependent and thymic function diminishes with age. Previously, age was reported to be the best predictor of the rise in CD4+ T-cell numbers and naive T-cell numbers after initiation of antiretroviral therapy in HIV-1 infected children. CD4+ T-cell numbers in HIV-infected children on HAART recover more rapidly than CD4+ T-cells in HIV-infected adults. However, it is still unclear to what extent the immune system of HIV-infected children is capable of normalising, since data on long-term immune reconstitution in HIV-infected children on HAART is not available.
In a considerable number of HIV-infected adults treated with HAART, CD4+ T-cell numbers stabilised or even slightly decreased after 1.5 years of therapy, sometimes without having reached normal levels.
In this study we evaluated immune reconstitution in a group of children treated with one protease inhibitor and two nucleoside reverse transcriptase inhibitors 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 - 18 years) in two prospective, open label, uncontrolled studies to evaluate their response to PI-containing HAART regimens of either indinavir/AZT/3TC or nelfinavir/d4T/3TC. Entry criteria included antiretroviral naive or nucleoside-experienced children, with viral load values above 5000 copies/mL or CD4 counts below the lower limit of age specific normal reference values. Blood samples were taken weeks -2 and 0 before HAART was started 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 471 cells/mm3 and 17%, to 939 cells/mm3 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 as 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 we concluded that, these 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. We observed a more rapid and complete immune reconstitution than would be expected in adults, even in children with advanced HIV-infection. Remarkably, HAART had a beneficial effect on immune reconstitution regardless of virological success.
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. 40th ICAAC, Toronto, Canada, September 17-20, 2000. Abstract 569.
Annemarie van Rossum is paediatrician in training, Department of Paediatrics, University Hospital Rotterdam/Sophia Children's Hospital. She is currently working on a PhD thesis on the treatment of HIV-1 infected children enrolled in a Dutch multicentre trial. Her interests are clinical, pharmacological, immunological and virological aspects of HIV infection in children.