Growth and Mortality Outcomes for Different Antiretroviral Therapy Initiation Criteria in Children Ages 1-5 Years: A Causal Modeling Analysis

Abstract

Background: There is limited evidence regarding the optimal timing of initiating antiretroviral therapy (ART) in children. We conducted a causal modeling analysis in children ages 1-5 years from the International Epidemiologic Databases to Evaluate AIDS West/Southern-Africa collaboration to determine growth and mortality differences related to different CD4-based treatment initiation criteria, age groups, and regions.

Methods: ART-naïve children of ages 12-59 months at enrollment with at least one visit before ART initiation and one follow-up visit were included. We estimated 3-year growth and cumulative mortality from the start of follow-up for different CD4 criteria using g-computation.

Results: About one quarter of the 5,826 included children was from West Africa (24.6%).The median (first; third quartile) CD4% at the first visit was 16% (11%; 23%), the median weight-for-age z-scores and height-for-age z-scores were -1.5 (-2.7; -0.6) and -2.5 (-3.5; -1.5), respectively. Estimated cumulative mortality was higher overall, and growth was slower, when initiating ART at lower CD4 thresholds. After 3 years of follow-up, the estimated mortality difference between starting ART routinely irrespective of CD4 count and starting ART if either CD4 count <750 cells/mm³ or CD4% <25% was 0.2% (95% CI = -0.2%; 0.3%), and the difference in the mean height-for-age z-scores of those who survived was -0.02 (95% CI = -0.04; 0.01). Younger children ages 1-2 and children in West Africa had worse outcomes.

Conclusions: Our results demonstrate that earlier treatment initiation yields overall better growth and mortality outcomes, although we could not show any differences in outcomes between immediate ART and delaying until CD4 count/% falls below 750/25%.

Figure 1

Flowchart: Selection of patients.

Figure 2

Estimated probability of falling below a CD4 count of 750 cells/mm³ or a CD4 percentage of 25%. (A) via the Kaplan-Meier estimator: this figure is based on 613 children (514 from Southern Africa, 99 from West Africa) presenting with a CD4 count of 750 cells/mm³ or above and a CD4% of 25% or above. Only pre-ART follow-up is considered and lost or dead children were censored at the time of the respective event. (B) ART initiation, death, and loss to follow-up (LTFU) were treated as competing risks. The probability of falling below the threshold was estimated via the cumulative incidence of falling below the threshold before any other event occurred divided by one minus the probability that any other event occurred before the threshold was reached. 95% confidence intervals were obtained via bootstrapping and are visualised via the shaded area.

Figure 3

Estimated cumulative mortality by intervention strategy (top left) and differences between these intervention strategies (top right). For the intervention ‘immediate ART’ cumulative mortality differences are displayed for both comparing the two different age groups and regions (bottom panel). Results are based on g-computation and 95% bootstrap confidence intervals are represented by the shaded area.

Figure 4

Estimated mean height-for-age z-score by intervention strategy (for survivors at the respective time point, top left) and differences between these intervention strategies (top right). For the intervention ‘immediate ART’ the mean height-for-age z-score for both age groups as well as the difference between them are displayed (bottom panel). Results are based on g-computation and 95% bootstrap confidence intervals are represented by the shaded area.