Evaluation of Persistent Infection by Oncogenic Human Papillomavirus (HPV) in Patients Treated for Cervical Carcinoma and Its Relation to Prognostic Factors

Evaluation of Persistent Infection by Oncogenic Human Papillomavirus (HPV) in Patients Treated for Cervical Carcinoma and Its Relation to Prognostic Factors

Cervical cancer is strongly associated with HPV infection, yet current post-treatment follow-up relies on cytology and imaging, which have limited accuracy, particularly after radiotherapy. Emerging evidence suggests that HPV clearance is linked to better outcomes and that HPV testing may outperform cytology in detecting recurrence.

This study aims to evaluate a panel of prognostic biomarkers to identify patients at higher risk of recurrence. These include cervical and circulating HPV-DNA (presence, genotype, and load), vaginal microbiota, host DNA methylation, SOD2 expression, and immune profile.

By enabling earlier and more accurate detection of recurrence, these biomarkers may improve patient outcomes, reduce reliance on costly imaging, and support earlier discharge for low-risk patients.

The association between HPV infection and cervical carcinoma is established in medicine. Tests that assess the presence of HPV in the cervix are already used in primary screening and post-treatment follow-up of cervical precursor lesions (CINs), allowing earlier discharge from tertiary centers, reducing costs and the number of outpatients returns.

Post-treatment follow-up of cervical carcinoma is performed with cervical-vaginal cytology and imaging tests. However, there are already studies demonstrating that both the sensitivity and specificity of cytology are low, leading to false-positive diagnoses or late diagnoses of recurrences, since the treatment with radiotherapy, the treatment of choice for locally advanced cervical carcinoma, can lead to cytological alterations not always related to carcinogenesis.

For cervical carcinoma, there are few studies on the role of the persistence of viral infection in the therapeutic response and recurrence of the disease, most of which are retrospective and with few patients. Despite this, the results show that viral clearance is associated with better outcomes. In addition, when studying the comparison between HPV testing and cervical-vaginal cytology in predicting recurrences at 3 years, HPV testing was shown to be superior in both sensitivity and specificity. Since cervical carcinoma is the third most common in Brazilian women and currently follow-up is conducted with low-accuracy tests, it is of paramount importance that new methodologies be studied, aiming at more accurate and earlier diagnoses of recurrences.

In this context, this project aims to evaluate different prognostic biomarkers that could indicate the group of patients at higher risk of recurrence.

The biomarkers analyzed will be presence, genotyping and load of cervical HPV-DNA, presence of circulating HPV-DNA, vaginal microbiota profile, host DNA methylation, SOD2 expression in tumor tissue and the patient's immunological profile.

The results of this study will identify early cases with a higher chance of recurrence for early treatment, aiming to increase the cure of this population. In addition, such biomarkers can replace high-cost imaging tests currently used and encourage early discharge in the group with clearance of HPV infection.

Inclusion Criteria:

• Diagnosis of HPV-associated squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma
• Treatment-naïve
• FIGO 2018 stage IB3 to IVA
• Candidates for curative-intent pelvic radiotherapy with concurrent chemoradiation

Exclusion Criteria:

• Tumors with rare histology, such as small cell tumors, sarcomas, and lymphomas
• FIGO 2018 stages IA, IB1, IB2, and IVB
• Planned initial treatment is surgical or palliative
• Uncertain primary tumor site (cervix vs. endometrium)
• Pregnant or in the postpartum period
• Immunosuppression (e.g., HIV infection with active disease, autoimmune diseases, transplant recipients)