# Analysis of Molecular Markers of HPV Infection Persistence: A Narrative Review

## TL;DR

This paper reviews how different molecular tests detect persistent HPV infections, which are a major cause of cervical cancer, and how these tests can improve screening and risk assessment.

## Contribution

The paper provides a narrative synthesis of three complementary molecular approaches to define HPV persistence and their implications for cervical cancer screening.

## Key findings

- HPV DNA testing identifies persistent infection with high sensitivity but limited specificity.
- E6/E7 mRNA testing detects active oncogenic infection and improves specificity for clinically relevant lesions.
- DNA methylation biomarkers reflect epigenetic changes linked to long-term infection and cancer progression.

## Abstract

Persistent infection with high-risk human papillomavirus is the key driver of cervical cancer development. Molecular diagnostics have evolved through three complementary approaches that reflect different biological stages of HPV persistence. The earliest approach, HPV DNA testing, identifies repeated detection of the same viral genotype over time and provides high sensitivity for identifying infection but limited specificity for predicting disease progression. The second approach, HPV E6/E7 mRNA testing, detects expression of viral oncogenes responsible for cell cycle dysregulation, representing active oncogenic infection and offering improved specificity for clinically relevant lesions. The most recent approach involves DNA methylation biomarkers, which measure epigenetic alterations in viral and host genes associated with long-term infection, viral integration, and progression to high-grade cervical lesions or cancer. Together, these molecular markers represent a continuum from viral presence to oncogenic activity and stable cellular transformation, providing complementary tools for improved risk stratification and more precise cervical cancer screening and triage strategies.

Background: Persistent infection with high-risk human papillomavirus (hr-HPV) is the necessary agent of cervical cancer, yet its molecular definition remains heterogeneous. Multiple molecular approaches have been developed to characterize HPV persistence, including repeated detection of viral DNA, assessment of viral oncogene expression, and analysis of HPV-related DNA methylation. These approaches originate from different scientific traditions and reflect distinct conceptualizations of persistence. Objective: To synthesize and compare molecular methods used to detect persistent HPV infection through a narrative review and to clarify how different biomarkers conceptualize HPV persistence and disease progression. Methods: We conducted a narrative review in accordance with the RAMESES guidelines. Medline, Scopus, and the Cochrane Library were searched for original studies published between 2016 and 2025 investigating molecular markers of HPV persistence. An interpretive synthesis was performed to identify research traditions, underlying assumptions, and clinical implications. Results: Three major molecular narratives were identified. Persistent DNA positivity defines persistence as repeated detection of the same HR-HPV genotype over time and reflects an epidemiological–virological perspective with high sensitivity but limited specificity. Persistent oncogene expression, assessed by E6/E7 mRNA detection, conceptualizes persistence as active viral oncogenic activity and shows improved specificity for clinically relevant lesions. Persistent epigenetic imprint, measured by DNA methylation of viral and host genes, captures cumulative biological effects of long-term infection and is strongly associated with high-grade lesions and cervical cancer. These narratives represent complementary stages along a continuum of molecular persistence. Conclusions: Molecular markers of HPV persistence reflect the evolving understanding of cervical carcinogenesis, progressing from repeated viral DNA detection to oncogenic activity and stable epigenetic alterations. These complementary biomarkers represent different biological stages of persistent infection and may improve risk stratification in HPV-based screening and triage strategies.