The Influence of Human Papillomavirus Genotypes, the Vaginal Ecosystem, Co-Occurring Sexually Transmitted Infections, Host Immunogenetic, and Social Factors on the Development of Cervical Neoplasia. Doctoral Thesis

Abstract

Cervical cancer remains a significant public health challenge, particularly in regions where prevention programmes have not achieved optimal effectiveness. While persistent high-risk human papillomavirus infection is a necessary cause of cervical neoplasia, disease progression is influenced by a complex interplay of viral, host, microbial, and behavioural factors. This study aimed to identify associations between various social factors, the vaginal ecosystem, vaginal infections, including sexually transmitted infections and high-risk human papillomavirus, human leucocyte antigen (HLA) class II alleles, and different degrees of cervical precancerous changes. The study group included 112 consecutive new patients referred to Riga East University Hospital for colposcopy examination due to abnormal cervical cytology smear results. The control group consisted of 120 women who underwent a gynaecological examination for other reasons (routine examination, follow-up of other gynaecological pathology). All patients included in the study were interviewed, and a custom-designed questionnaire was filled out. After that, women had gynaecological examination, pH measurement of vaginal discharge; samples were taken for wet-mount microscopy, testing of HPV DNA, mRNA, vaginal infections, and HLA class II genes. As a next step, a colposcopy was performed, and biopsies were taken if indicated. The study revealed that smoking is a significant independent risk factor for CIN2+, whereas higher educational attainment has a protective effect. Disturbances of vaginal ecosystem, including elevated pH and abnormal microflora, were more common among women with cervical neoplasia. Specifically, bacterial vaginosis was linked to low-grade lesions. At the same time, aerobic vaginitis – exceptionally moderate to severe cases – demonstrated a strong, independent association with high-grade cervical lesions (CIN2+), highlighting the critical role of vaginal inflammation in cervical carcinogenesis. Detection of HR-HPV DNA and E6/E7 mRNA emerged as the most important predictors of high-grade cervical lesions. Although no significant associations were found between sexually transmitted infections and CIN, Mycoplasma hominis ranked as the third most important independent risk factor for CIN2+. Genetic analysis identified significant associations between specific HLA class II alleles (HLA-DRB1*11:01, DRB1*15:01, DQA1*01:03, DQA1*04:01, DQB1*03:01, and DQB1*04:01) and an increased risk of CIN2+, while other alleles (DRB1*14:01, DRB1*16:01, and DQA1*03:01) appeared to confer a protective effect. The findings underscore the limitations of universal, one-size-fits-all screening strategies and highlight the urgent need for personalised, risk-based cervical cancer prevention models that integrate viral, microbial, genetic, and epidemiological risk factors. Such individualised approaches could improve screening precision, resource allocation, and ultimately contribute to the elimination of cervical cancer as a public health concern. The Doctoral Thesis was developed at the Department of Obstetrics and Gynaecology of Rīga Stradiņš University and the Outpatient Department of Riga East University Hospital. Defence of the Doctoral Thesis will take place at the public session of the Promotion Council of Clinical Medicine on 23 of September 2026 at 13.00 in the Hippocrates Lecture Theatre, 16 Dzirciema iela, Rīga Stradiņš University. The Doctoral Thesis was developed with the support of the project “Research of clinical and molecular characteristics of cervical cancer research to improve the early diagnostics and treatment strategy” No.: RSU ZP 04/2013. 3.2. Clinical Medicine; Sub-Sector – Obstetrics and Gynaecology. Keywords: cervical intraepithelial neoplasia; high-risk human papillomavirus; personalised screening.