Human Papilloma Virus Genotypes Associated with Non-Cervical HPV Positive Cancer Development in UK and Ireland Cohorts: A Systematic Review

Background Human Papillomavirus (HPV) is an infectious agent notably associated with viral carcinogenesis of the cervix. Since 2019, the UK and Ireland have used the Gardasil-9 HPV vaccine to prevent new cases of HPV-positive cancers. This systematic review aims to assess whether the current HPV vaccination programme provides substantive protection against developing non-cervical HPV-positive cancers. Methods Relevant studies were identified using the OVID-Medline and EMBASE databases. Screening and data extraction were conducted using the systematic review software Covidence. Risk of bias was assessed using the Hoy et al. tool, and statistical analysis was conducted using R statistical software (v 4.3.1). Results Based on pre-defined search parameters, 4,086 papers were identified for screening. Following the title, abstract, and full-text review, data was extracted from 30 eligible studies. A total of 1,411 patients with HPV-positive cancers, with 24 unique HPV genotypes, were considered for analysis in this review. The most prevalent genotype across all patients was HPV16 (94.3%, 1332/1411). Genotypic diversity was notably greater in oropharyngeal and penile cancers compared to other non-cervical HPV-related cancers considered in the present study, with nine unique genotypes reported in these sites alone (p=0.3). Gardasil-9 was found to offer protection against 37.5% (9/24) of the unique HPV genotypes identified. However, if this vaccine had been available, there would have been sufficient genotype-specific protection to prevent 9 out of 10 HPV-positive cancers (96.3%, 1359/1411) retrospectively identified in the current study. It should be noted that significant regional differences in the heterogeneity of reported HPV genotypes (p<0.001) were illustrated, with London-based cohorts having the most HPV-positive cancers associated with unprotected HPV genotypes (4.7%, 31/658). Conclusion This systematic review confirms HPV16 as the dominant genotype in HPV-positive cancers and highlights the genotypic diversity in non-cervical HPV-positive cancers. Moreover, while HPV vaccination using Gardasil-9 provides limited genotype-specific protection, it could have prevented nearly all HPV-positive cancers reported in eligible studies. Regional differences were minimal, but London had the highest proportion of unprotected genotypes. This suggests that while vaccination is highly effective in preventing HPV-related cancers, gaps in protection remain, particularly for less common genotypes.