The epidemiology of Human Papillomavirus (HPV) infection and epigenetic factors associated with the development of cervical cancer precursor lesions in women living with HIV in Africa.

Background: The relationships between human papillomavirus (HPV) and HIV, in an African context are limited. Given the large number of women living with HIV (WLHIV) accessing antiretroviral therapy (ART), it is important to establish associations of HIV-related factors with high-risk (HR)-HPV and cervical intraepithelial neoplasia (CIN). Design: Prospective cohort of WLHIV attending HIV treatment centres in Ouagadougou, Burkina Faso (BF) and Johannesburg, South Africa (SA). Methods: At baseline and endline (median 16 months), cervical samples and biopsies were analyzed for HPV genotyping (InnoLiPA) and by histology. HPV serology targeting 15 HPV types (12 HR) was by multiplexed pseudovirion-based serological assay. Methylation of a human gene EPB41L3 and HPV16 was measured by pyrosequencing. Logistic regression was used to estimate associations of HIV-related factors with HR-HPV and CIN2+ outcomes. Results: Among 1238 enrolled WLHIV (BF=615; SA=623) HR-HPV prevalence was 59.1% in BF and 79.1% in SA. CIN2+ prevalence was 5.8% in BF and 22.5% in SA. Prolonged ART use (>2 years) was associated with lower HR-HPV prevalence in BF and lower CIN2+ prevalence compared to short-duration ART users and ART-naïve participants in SA. Among 963 (77.8%) women seen at endline, HR-HPV persistence was 41.1% in BF and 30.2% in SA; CIN2+ incidence over 16-months was 1.2% in BF and 5.8% in SA. HR-HPV persistence was lower among those with prolonged ART compared to ART-naïve and short-duration ART users. CIN2+ incidence was reduced among women on ART in SA. HPV seroprevalence and seropersistence were high (93% and 95%, respectively). Seroconversion was 23.1%, and was higher among recent ART users (≤2 years) and among those with type-specific DNA persistence compared to those who cleared infection. v The human gene EPB41L3 showed elevated methylation in CIN2+ compared to ≤CIN1 (Mann Whitney U p=<0.001) at baseline. Higher methylation levels were found among recent ART users (≤2 years) and women with CD4 ≤200 cells/mm3. Conclusion: WLHIV in BF and SA have high rates of HR-HPV and CIN2+, and WLHIV in SA have higher CIN2+, linked with poorer control of HIV and higher frequency of cofactors for HR-HPV and CIN2+. Prolonged and effective ART is important in controlling HR-HPV and the development of CIN2+. WLHIV are infected with multiple HR-HPV types and there is limited evidence that HPV antibodies protect against same-type reinfection. WLHIV may benefit from vaccination using a multivalent vaccine. DNA methylation of a tumour suppressor gene EPB41L3 is elevated among women with CIN2+ and shows promise as a biomarker test for CIN2+ prediction among WLHIV.