Background: Among perinatally-infected children, the effects of certain alleles of the CCR5 and CCR2 genes on the rate of disease progression remain unclear. We addressed the effects of the CCR5-Δ32 and CCR2-64I alleles in an international meta-analysis.

Methods: Genotype data were contributed from 10 studies from the U.S. and Europe with 1,317 HIV-1 infected children with a total of 7,263 person-yrs of follow-up. Time-to-event analyses with Kaplan-Meier plots and Cox models were performed, stratified by study and racial group. Endpoints included progression to clinical AIDS, death, and death after the diagnosis of clinical AIDS. Time-dependence of the genetic effects was specifically investigated using separation of follow-up into distinct time periods.

Results: There was large heterogeneity in the observed rates of disease progression between different cohorts. For progression to clinical AIDS, both CCR5 -Δ32 and CCR2-64I showed overall non-significant trends for protection (hazard ratios 0.84, 95% CI, 0.58–1.23; and 0.87, 95% CI, 0.67–1.14, respectively). However, analyses of survival showed statistically significant time-dependence. No deaths occurred among CCR5-Δ32 carriers in the first 3 years of life, while there was no protective effect (hazard ratio 0.95 [95% CI, 0.43–2.10]) in later years (p = 0.01 for the time-dependent model). For CCR2-64I, the hazard ratio for death was 0.69 (95% CI, 0.39–1.21) in the first 6 years of life and 2.56 (95% CI, 1.26–5.20) in subsequent years (p < 0.01 for the time-dependent model). The CCR5-Δ32 and CCR2-64I polymorphisms offered no clear protection after clinical AIDS had developed.

Conclusions: The CCR5-Δ32 and CCR2-64I alelles are associated with decreased risk of death among perinatally-infected children, but the protective effect is present only early in the course of HIV-1 infection and is lost afterwards.