Immune reconstitution in children treated with HAART is independent of age and pre-treatment immune status

Research published in the 23 November 2001 edition of AIDS describes the ability of HIV-1 infected children treated with protease inhibitor (PI) containing highly active antiretroviral therapy (HAART) to normalise their CD4+ T cell counts regardless of their age or their immune status prior to initiation of therapy [1].

This Dutch study was first presented at the 2000 ICAAC meeting and then covered in the following HTB conference report [2,3].

Seventy-one children between the ages of one month and 18 years were followed for 96 weeks in two open label uncontrolled studies to evaluate their response to PI containing HAART regimens (either IDV/ZDV/3TC or NFV/d4T/3TC). The investigators found that both the absolute CD4+ count and the CD4+ percentages increased significantly, and in all age groups the increase of total CD4+ T cells was caused by an increase of naïve CD4+ T cells. In addition they reported a tendency towards an inverse correlation between the increase of absolute naïve CD4+ T cells and the children’s age but this was only observed when evaluated as a percentage after 48 weeks. Although younger children produce more CD4+ T cells in absolute numbers, they require relatively more CD4+ T cells to catch up and normalise their CD4+ counts. It was concluded therefore that older children are able to normalise their CD4+ count equally well as younger ones.

Overall the investigators concluded that their results indicate that normalisation of the CD4 cell counts in children treated with HAART is independent of age, suggesting that children’s thymic function enables all age groups to restore their different CD4 T cell production demands. They also noted that: “In general, it appears that children restore their CD4 T cell counts better and more rapidly than adults, even in a late stage of HIV-1 infection.”

Comment

In this study multiple dose pharmacokinetics of either indinavir or nelfinavir were determined four weeks after HAART was initiated. A dosage adjustment of indinavir or nelfinavir was made when necessary to adjust the area under the curve (AUC) to adult values.

The Dutch have led the way amongst European paediatric investigators in emphasising the importance of TDM with individual dose adjustments. This is a highly labour intensive approach, but may be justified by their generally excellent immunological and virological responses over two years. It’s worth saying that similar results are being achieved with PI-sparing regimens without intensive TDM even in highly symptomatic infants (to be presented – hopefully – in Barcelona).

The observation that children of all ages respond to HAART by increasing CD4 naïve cells is not new: similar results have been reported from many studies including from the PENTA 5 study group. [Gibb DM, Newberry A, Klein N et al. Immune repopulation after HAART in previously untreated HIV-1-infected children. Paediatric European Network for Treatment of AIDS (PENTA) Steering Committee. Lancet 2000 Apr 15;355(9212):1331-2.]