Effects of CCR5-δ32 and CCR2-641 alleles on disease progression of perinatally HIV-1-infected children: An international meta-analysis

Objective: 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 CCR5-A32 and CCR2-641 in an international meta-analysis. Methods: Genotype data were contributed from 10 studies with 1317 HIV-1-infected children (7263 person-years of follow-up). Time-to-event analyses were performed stratified by study and racial group. Endpoints included progression to clinical AIDS, death, and death after the diagnosis of clinical AIDS. The time-dependence of the genetic effects was specifically investigated. Results: There was large heterogeneity in the observed rates of disease progression between different cohorts. For progression to clinical AIDS, both CCR5-A32 and CCR2-641 showed overall non-significant trends for protection [hazard ratios 0.84, 95% confidence interval (Cl) 0.58-1.23; and 0.87, 95% Cl 0.67-1.14, respectively]. However, analyses of survival showed statistically significant time-dependence. No deaths occurred among CCR5-A32 carriers in the first 3 years of life, whereas there was no protective effect (hazard ratio 0.95; 95% Cl 0.43-2.10) in later years (P = 0.01 for the time-dependent model). For CCR2-641, the hazard ratio for death was 0.69 (95% Cl 0.39-1.21) in the first 6 years of life and 2.56 (95% Cl 1.26-5.20) subsequent years (P < 0.01 for the time-dependent model). CCR5-Δ32 and CCR2-641 offered no clear protection after clinical AIDS had developed. Conclusion: The CCR5-A32 and CCR2-641 alelles are associated with a decreased risk of death among perinatally infected children, but only for the first years of life.