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

Abstract

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. 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. 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. 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). 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.