To evaluate the association of DNA methylation of the human gene EPB41L3 with high-grade cervical intraepithelial neoplasia (CIN2+) and HIV-related factors among women living with HIV-1 (WLHIV) in Burkina Faso (BF) and South Africa (SA).
Case-control study of WLHIV aged 25-50 with histology-determined CIN2+ (cases, N=152) or without lesions (≤CIN1, controls, N=210). Methylation levels of EPB41L3 were measured by pyrosequencing of exfoliated cervical specimens. Among 185 controls that were followed over a median 16 months (endline), methylation levels were measured among 26 incident CIN2/3 and 159 controls that remained ≤CIN1 at endline. Methylation levels were dichotomized using the 66.7 percentile among controls in each country for high/low cut-off.
The median methylation levels for EBP41L3 were significantly higher among women with prevalent CIN2/3 compared to those with ≤CIN1 in both countries (Cuzick p for trend by CIN grade <0.001). Women with CD4+ count ≤200 cells/mm3 were more likely to have higher levels of EPB41L3 methylation compared to women with CD4+ >350 cells/mm3 at baseline (BF: adjusted Odds Ratio [aOR]=7.45, 95%CI 1.53-36.22; SA: aOR=2.74, 95%CI 1.16-6.47; adjusted for HR-HPV and CIN status). Among 36 women with prevalent CIN2+ at baseline who had not gone for treatment by endline visit in SA, women with persistent CIN3, or CIN2 which progressed to CIN3 had higher baseline EPB41L3 median methylation levels compared to women who spontaneously regressed to ≤CIN1 (Mann-Whitney p=0.016).
Methylation of human gene EPB41L3 DNA is elevated in prevalent CIN2/3, and incident and persistent CIN3 cases, and independently associated with lower CD4 count. DNA methylation based assays could be useful in settings with limited resources for management, by identifying women most likely to have CIN3 that will persist or progress.