Background: Although the microbiome and lifestyle factors are associated with HPV clearance, few studies have systematically explored the relevant factors. This formal follow-up prospective study aims to predict HPV clearance based on vaginal microbiota and lifestyle clinical factors. Participants and Methods: Participants were recruited through a digital eHealth platform. Participants were unvaccinated for HPV and were assessed at baseline and a follow-up consultation between August 2021 and January 2022. Both clinical factors and cervicovaginal mucus (CVM) samples were collected from each participant. CVM samples were used to detect HPV and characterize vaginal microbiome by metagenomics. Lifestyle clinical factors were grouped into low-, middle-, and high-risk to operate the stratified analysis as well as survival analysis for HPV clearance. Results: We recruited 141 HPV-positive women at baseline. For the first follow-up, there were 116 HPV persistent infection and 25 HPV clearance participants. Among 28 clinical factors, six factors were identified as significantly associated: age, age of first sexual intercourse, diet balance, marital status, abortion and physical activity under the stratified analysis. Those with a middle-risk diet balance had an odds ratio (OR) (3.91, 95% CI: 1.02-28.03). Those with extremely high-risk diet balance also had a high OR (11.26, 95% CI: 1.35-122.14), but with a faster and higher proportion of HPV clearance. Conversely, clinical factors with low risk and correspondingly faster HPV clearance were physical activity, sleep quality, depression, and anxiety. Although HPV clearance was unrelated to each microbiome specie, HPV clearance was related to the lower overall diversity of species in the vaginal microbiome and the larger abundance of lactobacillus inners. Conclusions: This study systematically depicts HPV clearance influenced by clinical factors and its relationship with the vaginal microbial ecosystem. HPV clearance can be improved by modulation of lifestyle habits and marital relationship. The findings from this prospective study have implications for the future design of guidelines to control cervical cancer or other HPV-related cancer, and therefore might be beneficial to women infected with HPV. Keywords: HPV clearance, Clinical lifestyle factors, Vaginal microbiome, eHealth Platform

The authors have declared no competing interest.

This study did not receive any funding

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Ethics committee/IRB of Beijing Genomics Institution (BGI-IRB 21078) gave ethical approval for this work.

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