In developed countries, with broadly accepted efforts to prevent mother to child transmission (MTCT) of the virus, the incidence of HIV-infected newborns has become rare. But in the rest of the world, and despite the initial deployment of some simplified protocols to prevent MTCT, several hundred thousand HIV-infected infants continue to be born each year. It has been recognised that the greatest risk of mortality for an infant infected at birth is during the first year of life, as viral load soars during primary infection and the immature immune system is still developing.
For those who survive the first year of life and have access to good clinical management, the chance of survival during subsequent years improves. Because of concerns about treatment toxicity and difficulties of adherence, there has been some controversy about when to start therapy and whether all newborns should routinely be given antiretroviral drugs or if treatment should be reserved for infants with clinical or laboratory signs of disease progression.
But there has been little careful study of how the risk of HIV disease progression changes during early childhood, and the question of when and if to treat children has remained open.
A study by the HIV Paediatric Prognostic Markers Collaborative Study Group published in The Lancet addresses this question more carefully and with greater resolution than ever before by examining the relationship between CD4 percentage, viral load and age with progression to AIDS and with death. The investigators conducted a meta-analysis of nearly 4000 cases of children infected at birth as collected in 17 international studies and cohorts, beginning in the mid-1980s and continuing until HAART had become an accepted intervention.
To assess the natural history of untreated HIV, children who had received antiretroviral therapy (except AZT monotherapy) were excluded from the analysis. The Group reports that while CD4 percentage and viral load were useful as prognostic markers in older children, those markers gave little guidance about which younger children and infants were likely to survive without treatment. This finding supports the position of providing universal antiretroviral therapy for all infected newborns, as recommended in U.S. Public Heath Service guidelines. The authors suggest that in settings where routine HIV detection cannot be done or where these guidelines cannot otherwise be embraced, close attention should be given to detecting and responding to the first clinical signs of AIDS.
In all cases, CD4 percentage was a stronger predictor of disease progression than viral load. In children under 6 months, when the CD4 percentage fell below 15 (roughly corresponding to an absolute CD4 cell count of 200) the probability of developing AIDS within 12 months was 40% compared to less that 10% in children older than two years. As an infant’s CD4 percentage fell towards 5, the probability of developing AIDS within a year approached 70%. These dramatically high progression rates clearly argue for intervention. Although CD4 percentage and viral load cannot be relied upon to distinguish which infant is not at risk of AIDS or death, the authors note their potential usefulness in treating an increasing population of older children, many of them migrants, who are first diagnosed in Europe and the U.S.
But, if treatment is indicated for all during the first year of life, does this mean that children are committed to a lifetime of therapy that can never cease? This question was brought to the foreground by the authors of an accompanying commentary in The Lancet that discussed when and if it may be safe to discontinue therapy for children who survive the critical first few years of HIV infection and what guidance CD4 percentage and viral load can offer for making that decision.
Since the data about the predictive value of the blood markers comes from children who had survived their first year, it is unclear if CD4 percentage and viral load would remain predictive in children who escaped early AIDS due to therapy or if those children would still be particularly susceptible to disease progression once treatment was halted. It may be that untreated surviving children have a protective genetic factor in play. A question also arises about the meaning that CD4 data derived from this untreated population will have for children who face restarting treatment, especially if resistance mutations have developed during their course of therapy as an infant.
To help balance these questions about the risks and benefits of early therapy, much more data must be obtained about the long-term developmental effects that chronic antiretroviral use during childhood may have and on the impact that drug resistance will have in children. Yet while several questions and concerns remain, the case for treating infants whenever practical now seems beyond dispute.
Reference
HIV Paediatric Prognostic Markers Collaborative Study Group. Short-term risk of disease progression in HIV-1 infected children receiving no antiretroviral therapy or zidovudine monotherapy: a meta-analysis. The Lancet: 362: 1605-12, 2003.
Abrams EJ and Kuhn L. Should treatment be started among all HIV-infected children and then stopped? The Lancet: 362: 1595, 2003.