Natural history, dynamics, and ecology of human papillomaviruses in genital infections of young women: protocol of the PAPCLEAR cohort study

Carmen Lía Murall, Massilva Rahmoun, Christian Selinger, Monique Baldellou, Claire Bernat, Marine Bonneau, Vanina Boué, Mathilde Buisson, Guillaume Christophe, Giuseppe D'Auria, Florence De Taroni, Vincent Foulongne, Rémy Froissart, Christelle Graf, Sophie Grasset, Soraya Groc, Christophe Hirtz, Audrey Jaussent, Julie Lajoie, Frédérique Lorcy, Eric Picot, Marie-Christine Picot, Jacques Ravel, Jacques Reynes, Thérèse Rousset, Aziza Seddiki, Martine Teirlinck, Vincent Tribout, Édouard Tuaillon, Tim Waterboer, Nathalie Jacobs, Ignacio G Bravo, Michel Segondy, Nathalie Boulle, Samuel Alizon, Carmen Lía Murall, Massilva Rahmoun, Christian Selinger, Monique Baldellou, Claire Bernat, Marine Bonneau, Vanina Boué, Mathilde Buisson, Guillaume Christophe, Giuseppe D'Auria, Florence De Taroni, Vincent Foulongne, Rémy Froissart, Christelle Graf, Sophie Grasset, Soraya Groc, Christophe Hirtz, Audrey Jaussent, Julie Lajoie, Frédérique Lorcy, Eric Picot, Marie-Christine Picot, Jacques Ravel, Jacques Reynes, Thérèse Rousset, Aziza Seddiki, Martine Teirlinck, Vincent Tribout, Édouard Tuaillon, Tim Waterboer, Nathalie Jacobs, Ignacio G Bravo, Michel Segondy, Nathalie Boulle, Samuel Alizon

Abstract

Introduction: Human papillomaviruses (HPVs) are responsible for one-third of all cancers caused by infections. Most HPV studies focus on chronic infections and cancers, and we know little about the early stages of the infection. Our main objective is to better understand the course and natural history of cervical HPV infections in healthy, unvaccinated and vaccinated, young women, by characterising the dynamics of various infection-related populations (virus, epithelial cells, vaginal microbiota and immune effectors). Another objective is to analyse HPV diversity within hosts, and in the study population, in relation to co-factors (lifestyle characteristics, vaccination status, vaginal microbiota, human genetics).

Methods and analysis: The PAPCLEAR study is a single center longitudinal study following 150 women, aged 18-25 years, for up to 2 years. Visits occur every 2 or 4 months (depending on HPV status) during which several variables are measured, such as behaviours (via questionnaires), vaginal pH, HPV presence and viral load (via qPCR), local concentrations of cytokines (via MesoScale Discovery technology) and immune cells (via flow cytometry). Additional analyses are outsourced, such as titration of circulating anti-HPV antibodies, vaginal microbiota sequencing (16S and ITS1 loci) and human genotyping. To increase the statistical power of the epidemiological arm of the study, an additional 150 women are screened cross-sectionally. Finally, to maximise the resolution of the time series, participants are asked to perform weekly self-samples at home. Statistical analyses will involve classical tools in epidemiology, genomics and virus kinetics, and will be performed or coordinated by the Centre National de la Recherche Scientifique (CNRS) in Montpellier.

Ethics and dissemination: This study has been approved by the Comité de Protection des Personnes Sud Méditerranée I (reference number 2016-A00712-49); by the Comité Consultatif sur le Traitement de l'Information en matière de Recherche dans le domaine de la Santé (reference number 16.504); by the Commission Nationale Informatique et Libertés (reference number MMS/ABD/AR1612278, decision number DR-2016-488) and by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (reference 20160072000007). Results will be published in preprint servers, peer-reviewed journals and disseminated through conferences.

Trial registration number: NCT02946346; Pre-results.

Keywords: HPV; acute infection; immunity; microbiota; persistence; viral kinetics; virus load.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
General structure of the PAPCLEAR study. For the longitudinal study, participants have an inclusion visit (V1), a results visit (V2) and then return visits (Vi with i>2). For the cross-sectional study, participants only have V1 and V2. HPV, human papillomavirus; STI, sexually transmitted infection.
Figure 2
Figure 2
Fitting viral kinetics models to within-host times series. Dashed lines indicate a model fitted using virus load (in black) or immune cells (in red) time series. In panel A, the follow-up is bi-monthly with two missing visits and several delayed visits, whereas in panel B the follow-up is every 4 months without any missing or delayed visits. In spite of missing data this, the situation shown in panel A is clearly the best for inferring parameter values and for fitting the underlying dynamics.

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