Long-term use of protease inhibitor-based antiretroviral therapy in children allows CD4 cell counts to recover only if it is started before severe immunosuppression has set in, according to the results of an observational study published in the 15th March edition of Clinical Infectious Diseases.
Although studies have shown that antiretroviral therapy can increase CD4 cell counts in children with HIV, few studies have examined the long-term effects of treatment in these patients. This has made it difficult for doctors to be certain about the best time to start treatment in HIV-positive children.
Now, Spanish researchers have carried out a retrospective review of 113 children who were treated with protease inhibitor-based antiretroviral treatment for at least six years. They have found that the children showed an increase in CD4 cell counts and a decrease in viral loads over the first two years of treatment. In the next four years, viral loads continued to fall, while CD4 cell counts had reached a plateau.
Children starting protease inhibitor treatment with low CD4 percentages were less likely to exhibit immune restoration than those starting with higher CD4 levels. Although the investigators stop short of recommending a CD4 level at which children should start treatment, this finding emphasises the importance of starting powerful combination therapy before the immune system has been damaged beyond repair.
All of the children in the study contracted HIV from their mothers and started highly active antiretroviral therapy (HAART) including a protease inhibitor at around seven years of age. They had all taken HIV therapy containing one or two nucleoside reverse transcriptase inhibitors (NRTIs) before starting HAART, defined in this study as combination antiretroviral therapy containing a protease inhibitor.
During the first two years of protease inhibitor-based treatment, children starting with CD4 percentages below 25% showed a significant increase in CD4 percentage (p
In contrast, viral loads fell in both periods, regardless of the children’s CD4 percentages at the start of protease inhibitor-based treatment.
When they broke down their analysis by CD4 percentage before treatment was started, the investigators found that the mean CD4 level in children starting below 5% failed to reach the 'normal' level of 25% after six years of treatment.
Those starting protease inhibitor treatment with CD4 percentages between 5 and 25% tended to achieve CD4 percentages above 25% after six years of treatment, but they never reached the level of the children starting treatment with CD4 percentages already above 25%.
“Long-term highly active antiretroviral therapy allowed for restoration of CD4 cell counts and control of viral loads in HIV-1-infected children,” they conclude. “However, initiating HAART after severe immunosuppression has occurred is detrimental for the restoration of the CD4 cell count.”
This trend was confirmed in multivariate analyses of the data. Relative to children starting treatment with CD4 percentages above 25%, starting protease inhibitor-based treatment at a CD4 percentage of 5% or lower was associated with a reduced chance of achieving a CD4 percentage above 30% at months 6, 12 and 24 (p
A similar trend was seen for children starting protease inhibitor-based treatment at CD4 percentages between 5 and 25% for the first year (p
“In our study, HIV-1-infected children with CD4 percentages of less than 5% at baseline experienced a slower restoration of CD4 cell percentage than did HIV-1-infected children with baseline CD4 cell percentages of 5 to 15%, and restoration of CD4 cell percentage to a normal level could not be achieved during long-term HAART,” the investigators write.
“These data argue in favour of not delaying initiation of HAART in young children,” they add.
The majority (74%) of the children took two NRTIs alongside their protease inhibitor, the commonest being d4T (stavudine, Zerit) and 3TC (lamivudine, Epivir). The protease inhibitors taken by most children were nelfinavir (Viracept) and ritonavir (Norvir).
Although the retrospective nature of this study demonstrates that HAART in children is effective in a ‘real world’ setting, it limits the study’s findings, since there was no uniform approach to treatment decisions. Treatment changes were made on the opinion of each child’s doctor, without the assistance of resistance testing, with only 50% of the children remaining on their original treatment combination after two years.
Resino S et al. Long-term effects of highly active antiretroviral therapy in pretreated, vertically HIV type 1-infected children: 6 years of follow-up. Clin Infect Dis 42: 862 - 869, 2006.