Genotype and age shape the risk of persistent high-risk human papillomavirus infections

Background Persistent high-risk human papillomavirus infection detected in cervical cancer screening warrants follow-up, yet genotype-specific persistence times and progression risks remain poorly defined. This knowledge is critical for risk assessment and management of persistent human papillomavirus infections. Objective To evaluate genotype-specific clearance rates and subsequent cervical disease risks for 14 persistent high-risk human papillomavirus genotypes over long-term follow-up, focusing on clearance patterns and implications for follow-up strategies. Study Design We analyzed 35,084 women from the Finnish national cervical cancer screening program (2017–2019, Tampere region). Human papillomavirus–positive samples were genotyped using the Seegene Anyplex II HPV28 Detection assay to identify 14 individual high-risk human papillomavirus genotypes. Persistence was defined as detection of the same genotype 0.5 to 4 years apart. Genotypes were grouped by carcinogenic risk, and multiple-genotype infections were categorized by the most oncogenic type; separate analyses of single-type infections were conducted. Women with mild cytology (Negative for Intraepithelial Lesion or Malignancy or Atypical Squamous Cells of Undetermined Significance) at baseline were followed through 2023 to assess genotype-specific persistence and progression to high-grade lesions or worse. Clearance of infections was evaluated using the Kaplan-Meier estimates and Cox regression. Results Among 2006 high-risk human papillomavirus–positive women with Negative for Intraepithelial Lesion or Malignancy/Atypical Squamous Cells of Undetermined Significance cytology, 884 (44.1%) women had a persistent high-risk human papillomavirus infection. Human papillomavirus 52 showed the highest persistence (52.2%) followed by human papillomavirus 58 (50.5%), human papillomavirus 31 (50.4%), and human papillomavirus 16 (48.9%). Overall, 22.3% (n=197) of persistent infections progressed to precancerous lesions, with the highest proportions of high-grade lesions or worse observed among human papillomavirus 16, 58, and 33 (42.9%, 31.5%, and 31.3%, respectively). Younger women (aged <45 years) exhibited significantly higher progression for Group 1 (human papillomavirus 16, 18, and 45) and Group 2 (human papillomavirus 31, 33, 52, and 58) genotypes compared with older women (36.7 vs 14.3% and 34% vs 10.8%, respectively). Less oncogenic Group 3 genotypes (human papillomavirus 35, 39, 51, 56, 59, 66, and 68) had a significantly lower risk of progression compared with Group 1 regardless of age (hazard ratio, 0.32; 95% confidence interval, 0.20–0.52) in 6-year follow-up. 65.3% of persistent high-risk human papillomavirus infections cleared spontaneously, and Group 3 genotypes were associated with faster clearance compared with Group 1 (hazard ratio, 1.43; 95% confidence interval, 1.11–1.84). Conclusion Persistent infections with human papillomavirus 16, 58, 33, and 52 were associated with the highest risks of progression, whereas Group 3 genotypes frequently persisted without leading to precancerous lesions. Younger women demonstrated an approximately 3-fold higher progression rate compared with older women. These findings suggest that persistence alone may not uniformly reflect oncogenic potential. Incorporating genotype-specific and age-specific risk stratification into screening and follow-up protocols could enhance risk assessment, thereby enabling more precise targeting of resources and minimizing unnecessary interventions.