Cognitive function and neurodevelopmental outcomes in HIV-infected Children older than 1 year of age randomized to early versus deferred antiretroviral therapy: the PREDICT neurodevelopmental study

Abstract

Background: We previously reported similar AIDS-free survival at 3 years in children who were >1 year old initiating antiretroviral therapy (ART) and randomized to early versus deferred ART in the Pediatric Randomized to Early versus Deferred Initiation in Cambodia and Thailand (PREDICT) study. We now report neurodevelopmental outcomes.

Methods: Two hundred eighty-four HIV-infected Thai and Cambodian children aged 1-12 years with CD4 counts between 15% and 24% and no AIDS-defining illness were randomized to initiate ART at enrollment ("early," n = 139) or when CD4 count became <15% or a Centers for Disease Control (CDC) category C event developed ("deferred," n = 145). All underwent age-appropriate neurodevelopment testing including Beery Visual Motor Integration, Purdue Pegboard, Color Trails and Child Behavioral Checklist. Thai children (n = 170) also completed Wechsler Intelligence Scale (intelligence quotient) and Stanford Binet Memory test. We compared week 144 measures by randomized group and to HIV-uninfected children (n = 319).

Results: At week 144, the median age was 9 years and 69 (48%) of the deferred arm children had initiated ART. The early arm had a higher CD4 (33% versus 24%, P < 0.001) and a greater percentage of children with viral suppression (91% versus 40%, P < 0.001). Neurodevelopmental scores did not differ by arm, and there were no differences in changes between arms across repeated assessments in time-varying multivariate models. HIV-infected children performed worse than uninfected children on intelligence quotient, Beery Visual Motor Integration, Binet memory and Child Behavioral Checklist.

Conclusions: In HIV-infected children surviving beyond 1 year of age without ART, neurodevelopmental outcomes were similar with ART initiation at CD4 15%-24% versus <15%, but both groups performed worse than HIV-uninfected children. The window of opportunity for a positive effect of ART initiation on neurodevelopment may remain in infancy.

Figure 1

Study design, patient disposition and numbers completing each neurodevelopmental test Footnote: The number of children who underwent each test in each of the 4 study groups is shown. For the HIV-infected children in the early and deferred ART study arms, the mean (standard deviation) of the number of tests performed during the study period is also shown. The cognitive and behavior assessments include 1) The intelligence tests: Wechsler Intelligence Scale for Children (WISC)-III (age 6 to 17 years) or the Wechsler Preschool and Primary Scale of Intelligence (WPPSI)-III (age 2 to 7.25 years); 2) The Stanford Binet II memory test (Beads/Sentences for age 3.5 to 17 years; Digits/Objects for age 6 to 17 years); 3) Beery Visual Motor Integration Test (VMI) (age 2 to 17 years); 4) Purdue Pegboard (age 5 to 17 years); 5) Children’s Color Trails (age 8 to 17 years); 6) The Child Behavior Checklist (age 2-17 years).

Figure 2

Intelligence quotient (IQ) comparison between the HIV-infected children (early vs. deferred antiretroviral therapy arms) at week 144 of PREDICT and the HIV-uninfected (HIV-exposed and –unexposed) control group children. Footnote: Mean (standard deviation) scores are shown. P values for the comparison between PREDICT children and the uninfected HIV-exposed and HIV-unexposed controls have been adjusted for parent as caregiver, educational level of caregiver and income. The intelligence quotient (IQ) tests included Wechsler Intelligence Scale for Children (WISC)-III (age 6 to 17 years) or the Wechsler Preschool and Primary Scale of Intelligence (WPPSI)-III (age 2 to 7.25 years). The number of children in each group: HIV-infected/early antiretroviral therapy arm (n=79), HIV-infected/deferred antiretroviral therapy arm (n=82), HIV-uninfected/exposed (n=93) and HIV-uninfected/unexposed (n=103). P value represents significant differences between each of the HIV-uninfected groups relative to the combined early and deferred groups.