The role of HPV vaccination on HPV infection and recurrence of HPV-related disease after local surgical treatment: a systematic review and meta-analysis.

Abstract

Objective: The efficacy of prophylactic human papillomavirus (HPV) vaccines after surgical treatment for pre-invasive genital disease remains unclear. Our aim was to explore the efficacy of HPV vaccination on HPV infection risk and risk of recurrent HPV-related disease in individuals undergoing local surgical treatment for cervical or other HPV-related disease. Methods: Design: Systematic review and meta-analysis Data sources: PubMed/Medline, Scopus, Cochrane, Web of Science and ClinicalTrials.gov were screened from inception until March 2021. Inclusion criteria: Studies reporting on HPV infection risk and recurrence of HPV-related disease after local surgical treatment of pre-invasive genital disease in vaccinated individuals. Outcome measures: Primary: Recurrence risk for cervical intraepithelial neoplasia grade 2 or higher (CIN2+)(follow-up as reported by individual studies); Secondary: risk of HPV infection, other HPV-related lesions. Data extraction and risk of bias assessment: Independent and in duplicate data extraction and quality assessment using ROBINS-I and RoB-2 tools was performed for observational studies and randomised controlled trials (RCTs). Grading of Recommendations Assessment, Development and Evaluation (GRADE) was implemented for the primary outcome. Data synthesis: Observational studies and RCTs were analysed separately from post-hoc analyses of RCTs. Pooled risk ratios (RR) and 95% confidence intervals (95% CI) were calculated using a random-effects (RE) meta-analysis model. The restricted maximum likelihood was used as an estimator for heterogeneity, and the Hartung-Knapp-Sidik-Jonkman method was used to derive confidence intervals. Results: Twenty-two articles met the inclusion criteria of the review; eighteen studies also reported data from a non-vaccinated group and were included in the meta-analyses (12 observational; 2 RCTs and 4 post-hoc analyses of RCTs). The risk of CIN2+ recurrence was reduced in vaccinated when compared to non-vaccinated individuals (11 studies; 19,909 participants; RR 0.43, 95%CI 0.30 to0.60; I2=58%, τ2=0.14)(median follow-up 36 months, interquartile range 24-43.5). The effect estimate was even stronger when CIN2+ recurrence risk was assessed for HPV16/18-related disease (6 studies; 1879 participants; RR 0.26, 95%CI 0.16 to 0.43; I2=0%, τ2=0). However, the confidence in the meta-analysis for CIN2+ overall and HPV16/18-related CIN2+ as assessed by GRADE ranged from very low to moderate due to the potential presence of publication bias as well as bias and inconsistency in the included studies. The recurrence risk for CIN3 was also reduced among vaccinated patients but there was large uncertainty (3 studies; 17,757 participants; RR 0.28, 95%CI 0.01 to6.37; I2=71%, τ2=1.23). There was no strong evidence to support benefit for VIN/VaIN/AIN /genital warts recurrence, persistent and incident HPV infections, although the number of studies and participants in each outcome was low. Conclusion: HPV vaccination may reduce risk of CIN recurrence and in particular HPV16/18-related CIN in women treated with local excision. However, the GRADE assessment for quality of evidence ranged from very low to moderate; as such, the data remains inconclusive. Large-scale high-quality RCTs are required to establish level of effectiveness and cost of risk-reducing HPV vaccination in women undergoing treatment for HPV-related disease. Systematic review registration: PROSPERO (CRD42021237350).