Persistent High-Risk HPV Positivity Without Confirmed CIN2+: Diagnostic Uncertainty, Risk Stratification, and Management—A Narrative Review

Primary high-risk human papillomavirus (hrHPV) testing detects cervical precancer earlier than cytology and, by design, generates a large population of virus-positive women in whom high-grade disease is not confirmed. Where the infection persists, the clinician must judge whether a negative or non-diagnostic assessment reflects absence of disease or failure of detection. This review asks what that state represents, which tools reclassify absolute CIN3+ risk, and how surveillance and intervention should be balanced. This narrative review synthesises relevant evidence from published studies and international guidance on persistent hrHPV infection, diagnostic assessment, risk stratification and management, with reporting guided by the Scale for the Assessment of Narrative Review Articles (SANRA). Persistent hrHPV positivity without confirmed CIN2+ is a heterogeneous risk state, not a diagnosis, and covers three clinical situations that should not be conflated. Absolute CIN3+ risk is set principally by genotype and by the duration of type-specific persistence; genotype alone spans an approximately twenty-fold range of immediate risk in hrHPV-positive screening populations. Pooled colposcopic sensitivity for CIN2+ was approximately 75% in heterogeneous referral populations, while one selected retrospective series of cytology-negative hrHPV-positive women reported sensitivity near 50%. Selected referral cohorts have reported CIN2+/HSIL detection yields of approximately 8% to 14% among persistently hrHPV-positive women with normal cytology; these composite, selection-dependent estimates should not be read as the prevalence of occult CIN3+. Extended genotyping and p16/Ki-67 dual-stain cytology carry guideline-adopted management rules, although validation specifically after documented persistence remains limited. Controlled evidence for treating persistent hrHPV without confirmed CIN2+ is sparse and conflicting. Recent randomised trials of vaginal interventions report discordant short-term virological results, and none establishes durable clearance or a reduction in CIN3+ risk. Short-term loss of HPV detectability is not equivalent to prevention of precancer, and management should remain risk-based.