HPV infection, cervical carcinogenesis and the reproductive impact of local treatment for cervical preinvasive and early invasive disease

Background The human papillomavirus (HPV) infects the majority of sexually-active women, yet it is unclear how this highly-prevalent virus causes cervical intraepithelial neoplasia (CIN) and cervical cancer in only a minority of women. Cervical screening programmes exist to detect and treat high-grade CIN to the reduce risk of invasive cancer development, although may be associated with adverse reproductive and obstetric outcomes. Aims Firstly, this thesis aimed to test the hypothesis that the vaginal microbiome and innate immune factors (antimicrobial peptides and cytokines) are altered in CIN compared to healthy controls, and that the microbiome composition plays a role in disease outcomes. Secondly, it aimed to summarise, critically appraise and meta-analyse the current literature on adverse reproductive outcomes after treatment for CIN, and to test the hypothesis that treatment impacts on microbiome structure and innate mucosal immunity. Results 16s rRNA sequencing was used to characterise the vaginal microbiome of women with CIN and revealed increasing diversity with decreasing Lactobacillus spp. levels with increased disease severity compared to healthy controls, which in a longitudinal study of women with untreated CIN2 was associated with slower regression and greater rates of persistence. Levels of proinflammatory cytokines and antimicrobial peptides quantified using enzyme-linked immunosorbent assay were higher in high-grade CIN compared to controls. Meta-analysis demonstrated that treatment did not affect fertility, but was associated with higher rates of second-trimester miscarriage. There was heterogeneity in the literature regarding the link between treatment and preterm birth which was shown to be partly explained by choice of control group. There was a positive correlation between preterm birth risk and amount of tissue excised. The altered vaginal microbiome and proinflammatory environment persisted after successful excision, and levels of antimicrobial peptides were lower than in untreated controls. Discussion These results suggest the vaginal microbiome and innate immune factors are altered in CIN and may play a role in disease outcomes. Whilst the degree of cervical structural deficit impacts on risk of adverse reproductive outcomes an altered microbiome structure and innate mucosal immune factors likely also play a role.Open Acces