The Role of Multiple High-risk Human Papillomavirus Infection on the Persistence Recurrence of High-grade Cervical Lesions After Standard Treatment: A Systematic Review and a Meta-analysis

Introduction: The role of multiple high-risk human papillomavirus (HR-HPV) infections on the occurrence of persistence/recurrence of high-grade squamous intraepithelial lesion (HSIL) after conization/surgery for cervical intraepithelial neoplasia was evaluated.

Material And Methods: A systematic search of Pubmed/Medine, Scopus, Cochrane databases from inception to June 30, 2023 was performed. Three reviewers independently screened the abstracts of the selected studies and extracted data from full-text articles. The data were subsequently tabulated and compared for consistency. The bias associated with each included study was evaluated according to the OSQE method. PROSPERO registration number CRD42023433022.

Results: Out of 1606 records screened, 22 full text articles met the inclusion criteria. A total of 8321 subjects treated (loop electrosurgical excision, laser or surgery) because of HSIL were followed-up and included in the meta-analysis. The pooled prevalence of overall persistence and/or recurrence was 17.6 (95% CI: 12.3-23.5) in multiple and 14.3 (95% CI: 10.1-19.2) in single HR-HPV infections detected shortly before or at surgery. The pooled rate of multiple HR-HPV infections was 25% (95% CI: 20.4-30). The odds ratio of histologically confirmed HSIL persistence and/or recurrence was significantly higher (OR: 1.38, 95% CI:1.08-1.75, p = 0.01, heterogeneity = 39%) among multiple than single HR-HPV infections. Increased risk of HSIL persistence/recurrence was more marked among studies with multiple HR-HPVs prevalence ≥25% (12 studies, N = 3476) (OR: 1.47, 95% CI: 1.18-1.84, heterogeneity = 0%) and in those evaluating true histologically confirmed recurrence after at least 6 months of negative follow-up (9 studies, N = 5073) (OR: 1.67, 95% CI: 1.17-2.37, heterogeneity = 37%). Multiple HR-HPVs infection detected during follow-up visits had no effect on the risk of recurrence although the number of included studies was small (4 studies, N = 1248) (OR: 0.98, 95% CI: 0.68-1.39, heterogeneity = 0%). The risk of bias was rated as high in 10 and low-moderate in 12 studies, respectively. In subgroup analysis, the risk of bias of the included studies (low/moderate vs. high), had a small, although not significant effect on the odds ratios of persistence/recurrence of HSIL (OR: 1.57, 95% CI: 1.23-2 for low-moderate risk of bias and OR: 1.06, 95% CI: 0.65-1.75 for high risk of bias; p-value for subgroup differences = 0.17).

Conclusions: Multiple HR-HPVs infections at the time of standard treatment of HSIL entail a small but significant increased risk of persistence/recurrence of HSIL and should be taken into account in the follow-up plan.