Prognostic Value of Pretreatment Circulating Tumor HPV DNA Load in HPV-Associated Cancers: A Systematic Review and Meta-Analysis

The qualitative detection of circulating tumor human papillomavirus DNA (ctHPV) has shown promise in HPV-associated cancers. We performed a systematic review and meta-analysis to evaluate the association of pretreatment ctHPV levels with survival outcomes and quantitative tumor burden metrics. Databases were searched through 5 January 2026. Studies were eligible if they included patients with HPV-associated cancers and reported quantitative pretreatment ctHPV levels in relation to survival outcomes or tumor burden. Twenty-three studies were included in the quantitative synthesis. Higher pretreatment ctHPV levels were associated with poorer progression-free survival (PFS) (8 studies, n = 883; HR = 1.86, 95% CI 1.19–2.90; p = 0.013). This association was primarily driven by studies in oropharyngeal cancer (OPC; HR = 2.47, 95% CI 1.59–3.84; p = 0.007), whereas no significant association was observed in cervical cancer. In multivariable analyses, elevated ctHPV remained associated with shorter PFS (HR = 1.87, 95% CI 1.66–2.10; p = 0.002). No significant association was observed for overall survival. Pretreatment ctHPV correlated with nodal volume in OPC (r = 0.45), nodal and tumor volume in OPC/anal cancer (r = 0.39), primary tumor volume in OPC (r = 0.22), and tumor diameter in cervical cancer (r = 0.44). Higher pretreatment ctHPV levels are associated with greater tumor burden and poorer PFS in HPV-associated OPC. CtHPV shows potential as a prognostic biomarker, although further prospective studies and assay standardization are needed.