Abstract
Objective
The CCR5Δ32 mutation is associated with slower HIV disease progression in untreated infection. However, it remains controversial as to whether CCR5Δ32 is a relevant prognostic marker in the context of highly active antiretroviral therapy (HAART). Here we investigate associations between CCR5Δ32 and HAART outcomes in a large, population-based cohort of >1000 antiretroviral-naive individuals initiating triple therapy over a median >5 year follow-up.
Methods
CCR5Δ32 genotypes were determined using PCR and DNA sequencing in a cohort of 1188 antiretroviral-naive individuals initiating triple therapy in British Columbia. Associations between CCR5Δ32 and baseline (pre-therapy) sociodemographic and clinical parameters were investigated in a cross-sectional analysis. Cox proportional hazards regression was used to investigate the effect of CCR5Δ32 on clinical outcomes following therapy initiation. The endpoints that were evaluated included time to plasma viral load (pVL) suppression <400 copies HIV RNA/ml, subsequent time to pVL rebound ≥400 copies/ml, time to CD4+ cell decline below baseline, and time to non-accidental death over a median >5 year follow-up.
Results
CCR5Δ32 genotypes were available for 1174 of 1188 individuals (98.8%): 171 (14.6%) CCR5wt/Δ32 and 1003 (85.4%) CCR5wt/wt. At baseline, CCR5wt/Δ32 individuals had higher CD4+ cell counts (P=0.04), lower plasma viral loads (P=0.06) and were slightly older than CCR5wt/wt individuals (P=0.04). In multivariate analyses controlling for baseline parameters and adherence estimates, we observed a significant association between CCR5wt/Δ32 and a shorter time to initial pVL suppression <400 copies/ml (multivariate hazard ratio [HR]: 1.20; 95% confidence interval [CI]: 1.01-1.44). No associations were observed between CCR5Δ32 and other clinical outcomes including subsequent time to pVL rebound or time to CD4+ cell decline below baseline. In univariate analyses, we observed a significant association between CCR5wt/Δ32 genotype and improved survival over the median >5 year period following initiation of HAART (P=0.03). However, this association did not remain significant in multivariate analyses after adjusting for baseline factors including adherence (multivariate HR: 0.64; 95% CI: 0.38-1.07; P=0.09)
Conclusion
Results indicate that, after controlling for adherence, the CCR5Δ32 mutation is likely not a clinically significant predictor of longer-term clinical responses or survival in the context of HAART.