About 33% of children infected with HIV have impaired growth.  The extent of such impairment may be regarded as a clinical criterion predicting progression to AIDS.  The addition of protease inhibitors (PIs) has been demonstrated to frequently reduce plasma HIV RNA levels, to increase CD4 lymphocyte numbers, and to improve the general condition of children and adults with HIV retrovirus type I infections. 

Steiner et al present data on the long-term (72 week) impact of PI treatment on growth of infected children.  Data are reported on 44 children between the ages of 0-17 years with confirmed infection.  They were observed for 72 weeks prior to starting PI treatment.  Nitonavir or nelfinavir were added to the previous treatment of two nucleoside analogue reverse transcriptase inhibitors.  Growth, HIV-1 RNA plasma levels, and CD4 lymphocyte counts were determined at 0, 24, 48, and 72 weeks of treatment.  Heights were reported in SD scores as determined from normal aged and gender individuals.  Data from 44 children were analyzed in 3 age groups [6 children <3 years of age (group I), 23 children 3-10 years of age (group II), and 15 children >10 years of age (group III)]. All had completed 72 weeks of PI treatment. Multiple regression analyses were used to determine the relationship between parameters of growth and variables such as CD4 cell count and CDC HIV-1 categories.  Children in group I were more frequently in the severe CDC clinical category “C” and had higher plasma HIV-1 RNA levels at baseline than those in groups II and III.

By 24 weeks of treatment, there was a significant decrease in mean plasma HIV-1 levels in children of group I vs. those in groups II and III.  Twenty-seven of the 44 children showed a sustained reduction of HIV 1 RNA levels.  In the 72 weeks before the initiation of PI therapy the differences between Δ-Z scores at 24 week intervals indicated progressive growth retardation which was reversed with a significant increase in growth during the 72 weeks after the PIs were added.  This increase was biphasic with a greater increase between weeks 0-24, and a second increase between 48-72 weeks.  The greatest increase in growth was in the 6 children in group I, all of whom had significant growth retardation at baseline and in the 4 significantly retarded children in group II.  The 19 other children in group II and all 15 in group III had growth rates maintained within 1 SDS of the mean.  Growth while receiving PIs was negatively correlated with growth during the preceding period, and positively correlated with an increase in CD4 cells.  No correlation was seen between the decrease in plasma HIV-1 levels.  Thus, age categories and CDC clinical categories were significantly associated with catch-up growth, but multiple regression analysis revealed that only growth during the preceding period and the age category were significantly associated with growth during PI therapy.

The authors note that previous studies have shown that stunting has been correlated with higher plasma HIV-1 RNA levels.  Of note, the older children in the cohort were not as severely stunted as the younger children, and did not have as significant a growth response to PI therapy.  The authors speculate that these findings may be the result of the older children having a slower progression of HIV infection than the younger children, since they survived infancy in the era prior to aggressive therapy.  In addition, the authors point out that others have attributed stunting in HIV infected children to sub-clinical hypothyroidism, low IGF-1, or proteolysis of IGF BP3.  The authors did not measure these hormone levels.

Editor’s Comment: The data reported in this paper by Steiner, et al are important from two aspects.  First, treatment with a protease inhibitor can improve growth rates in young HIV infected children.  Secondly, those with the greatest catch-up growth are those who are the most stunted initially.  Such information is similar to that which has been shown for treatment of nearly every chronic disease of childhood.  Unfortunately the authors did not determine biochemical markers of growth, including IGF-1 and IGF BP3.  They suggest this be done in future studies.  These data might have been useful in helping decide which children could benefit the most from such therapy.  The data presented, however, are clinically useful.

William L. Clarke, MD