A British-Irish study has found no association between pre-highly active antiretroviral therapy (HAART) viral load, and CD4 T-cell and viral load responses in treatment-naïve children on HAART. The study, from the Collaborative HIV Paediatric Study (CHIPS) cohort, also found that CD4 T-cell recovery is faster in infants under two years of age, even in those who were severely immunocompromised prior to HAART. The results are published in the 24th September issue of the journal AIDS, now available online.
CHIPS is a multicentre cohort of HIV infected children in the UK and Ireland, representing about 75% of all HIV-infected children reported to the National Study of HIV in Pregnancy and Childhood and in follow-up. Of 698 children enrolled in the up to June 1st 2003, 462 had ever taken a HAART regimen. Of the 324 who were antiretroviral naîve, 265 had both CD4 and viral load information available prior to initiating HAART, and this was the population examined in this study. Previous studies examining response to HAART have included pre-treated children or only focused on CD4 T-cell response. By including both CD4 T-cell and virological data, and focussing on treatment naïve children, this study is most relevant for children presenting for the first time, in both well-resourced, and resource-limited countries.
Seventy-seven (29%) children were under two years of age, and 36 (17%) were under a year old when they began HAART. Just over half (138) of the cohort began HAART with a CD4 T-cell percentage of 15% or lower. The most popular regimen (48%) was non-nucleoside (NNRTI)-containing, followed by protease inhibitor (PI)-containing HAART (41%). Other regimens included triple nucleoside therapy with abacavir and two other nucleosides (11%), a boosted PI regimen (3%), a PI- and NNRTI-containing regimen (1%); 11% began with a four drug regimen, of which the most common was AZT (zidovudine)/3TC (lamivudine)/abacavir/nevirapine (Viramune).
Six-month CD4 T-cell response
After six months, 86% of children had higher CD4 T-cell percentages than at baseline. Younger age [odds ratio (OR), 0.84 per year, p
Six-month viral load reponse
The median reduction in viral load was 2.7 log10, with 60% achieving a viral load below 400 copies/ml after six months. There was a trend (p = 0.03) towards older children having a higher chance of achieving a viral load below 400 copies/ml after removing non-significant variables, and children starting with a four-drug regimen had a slightly higher chance of a viral load below 400 copies/ml. However, after adjusting for the number of drugs in the regimen, there was no evidence to suggest a difference between regimens.
Longer term follow-up
Twelve and 24 month follow-up information is available for 76% and 60% of the 265-strong cohort, respectively. Generally, overall response reflected short-term results, with slower increases in CD4 percentage in older children and those with higher pre-HAART CD4 percentages (both p
When to start: infants
Notably, infants took a median time of less than twelve months to achieve a CD4 percentage of 30% or above (considered near-normal levels) when they initiated HAART with CD4 percentages at or below 25%, irrespective of their pre-HAART CD4 T-cell percentage or viral load. In fact, both short-term and longer-term increases in CD4 T-cell percentage were greater and faster in the youngest children. “This raises the possibility that early HAART for a limited period could appreciably preserve immune function and alter the natural history of the disease,” note the investigators. Current guidelines are unclear whether to treat all infants, or only symptomatic infants, although the recent Paediatric European Network for Treatment of AIDS (PENTA) guidelines do suggest that all infants should receive HAART regardless of clinical status.
When to start: children
Although a previous three year study by Soh and others, (see 'More evidence that earlier treatment provides greatest benefit for children with HIV' in aidsmap resources), concluded that children starting HAART with a low CD4 percentage were at a disadvantage, the investigators suggest that restoring CD4 levels to near normal values may be possible in the long term, “given the greater thymic reserve and activity of the paediatric immune system.” Using estimated survivor functions from Cox regression analysis on 215 children with CD4 percentage less than or equal to 25% when starting HAART, they estimate that all children starting HAART with a CD4 percentage of 15% would reach 30% within two-and-a-half years. They also note that 20 children had discordant responses; CD4 percentage increases of over 10% without ever achieving a viral load below 400 copies/ml (n = 10) or with at most two measurements below 400 copies/ml before rebounding (n = 10). The investigators argue that “in contrast to adults, children can restore immune function well without complete virological suppression, most likely due to the presence of a functioning thymus.”
The authors conclude that “there are substantial and opposed effects of age on immunological and virological response, and a lack of association between response and pre-HAART HIV-1 RNA.” They strongly suggest that more trials be done in order to examine the long-term impact of HAART on infants and children, the role of early limited HAART in infants in altering longer-term CD4 levels, and most importantly, “an assessment of overall survival expectations for children initiating HAART at different ages.”
Reference
Walker SA et al. Response to highly active antiretroviral therapy varies with age: the UK and Ireland Collaborative HIV Paediatric Study. AIDS 18: 1915-1924, 2004.