Risk of breast cancer with CXCR4-using HIV defined by V3 loop sequencing

Objective: Evaluate the risk of female breast cancer associated with HIV-CXCR4 (X4) tropism as determined by various genotypic measures. Methods: A breast cancer case-control study, with pairwise comparisons of tropism determination methods, was conducted. From the Women's Interagency HIV Study repository, one stored plasma specimen was selected from 25 HIV-infected cases near the breast cancer diagnosis date and 75 HIV-infected control women matched for age and calendar date. HIV-gp120 V3 sequences were derived by Sanger population sequencing (PS) and 454-pyro deep sequencing (DS). Sequencingbased HIV-X4 tropism was defined using the geno2pheno algorithm, with both high-stringency DS [false-positive rate (3.5) and 2% X4 cutoff], and lower stringency DS (false-positive rate, 5.75 and 15% X4 cutoff). Concordance of tropism results by PS, DS, and previously performed phenotyping was assessed with kappa (k) statistics. Case-control comparisons used exact P values and conditional logistic regression. Results: In 74 women (19 cases, 55 controls) with complete results, prevalence of HIV-X4 by PS was 5% in cases vs 29% in controls (P = 0.06; odds ratio, 0.14; confidence interval: 0.003 to 1.03). Smaller case-control prevalence differences were found with highstringency DS (21% vs 36%, P = 0.32), lower stringency DS (16% vs 35%, P = 0.18), and phenotyping (11% vs 31%, P = 0.10). HIVX4 tropism concordance was best between PS and lower stringency DS (93%, k = 0.83). Other pairwise concordances were 82%-92% (k = 0.56-0.81). Concordance was similar among cases and controls. Conclusions: HIV-X4 defined by population sequencing (PS) had good agreement with lower stringency DS and was significantly associated with lower odds of breast cancer..