More evidence that earlier treatment provides greatest benefit for children with HIV

In HIV positive children, starting antiretroviral therapy at younger ages and before severe immune suppression occurs appears to promote better CD4 cell recovery, according to an American study published in the December 20th edition of The Lancet.

Researchers with the Pediatric AIDS Clinical Trials Group (PACTG) analyzed data from 1,012 previously treated HIV-infected children in the PACTG 219 trial, comprising subjects from 72 U.S. clinical centers. Most of the children (93%) were infected perinatally. One-third (33%) were under age 5, 45% were 5-9 years old, and 22% were age 10-17. Half were male and half were female. In terms of race/ethnicity, 17% were white, 47% were black, and 35% were Hispanic. CD4 percentages at the start of the study period were below 15% in 33% of participants, 15-24% in 27%, and >=25% (i.e., normal) in 40%. The children were enrolled before 1996 — when protease inhibitors (PIs) came into widespread use — and followed through 2000. During the follow-up period, 702 children started a PI-based regimen.

The researchers analysed changes in CD4 cell percentage before and after the initiation of highly active antiretroviral therapy (HAART). In young children, the CD4 percentage provides a more stable marker of immune function than absolute CD4 cell count. In the cohort as a whole, the median CD4 percentage increased from 22% in 1996 to 28% in 2000.

Amongst the 577 children who started PI-based therapy and had pre- and post-therapy CD4 percentage measurements available, those with the greatest immune suppression experienced the largest increases in CD4 percentage in the three years after starting HAART (15.7%, 10.6%, 5.1%, and 2.0% for children with pre-therapy CD4 percentages of /=25%, respectively; p

CD4 percentages increased significantly in all age, sex, and race/ethnicity subgroups, but there were some notable differences. Younger children experienced significantly greater CD4 percentage increases compared with older participants (9.2%, 8.0%, and 4.3% for participants aged /=10 years, respectively; p=0.001). There were also significant differences among the three race/ethnicity categories; white children experienced the largest CD4 percentage increases, followed by Hispanics and blacks. There was no significant difference between male and female participants.

Since 1996, the proportion of children with a CD4 percentage less than 5% decreased from 17% to 5%, whilst the proportion with a CD4 percentage of 25% or higher increased from 42% to 60%. Rates of new opportunistic infections, cancers, and death decreased significantly during the study period (from 7.4% to 1.7% for all three indicators combined). However, only a minority of children who started treatment with advanced immune suppression achieved a CD4 percentage above 25% (33%, 26%, and 49% of those with pre-treatment CD4 percentages of

When to start antiretroviral therapy in young children remains controversial. The risk of AIDS-defining illness and death is high in HIV positive children, especially during the first year of life. However, there are concerns about the toxicity and adverse events associated with use of anti-HIV drugs in children, particularly if treatment must continue for life. Current U.S. treatment guidelines recommend antiretroviral therapy for all HIV infected infants, whilst European and World Health Organization guidelines recommend delaying treatment until the CD4 percentage falls below 15% or 20%, unless there are laboratory or clinical indications of disease progression.

The results of this study support early initiation of therapy, both because antiretroviral treatment appears more effective before severe suppression occurs and because therapy appears to work better in younger children. The results are in accordance with those reported by the HIV Paediatric Prognostic Markers Collaborative Study Group in the November 15th edition of the same journal. In a natural history study looking at the relationship between CD4 percentage, viral load, and age in untreated children, the researchers found that among children less than 6 months old, the risk of death increased dramatically when CD4 percentage fell below 10%, and the risk of AIDS-defining illness rose when the CD4 percentage dropped below 15%. Among participants with the same CD4 percentage, those under age 2 fared better than older children. However, the CD4 percentage was not a very good predictor of disease progression in individual children, supporting the recommendation of universal treatment for all HIV-infected infants.

"Although PI-based therapy was associated with substantial improvements in CD4 percentage, initiation before severe immunosuppression and at younger ages may be more effective for recovery or maintenance of normal CD4 percentage," the authors concluded. This research provides additional information to guide decisions about antiretroviral therapy for young children, but studies comparing different treatment strategies are needed.