title: Risk estimates for persistent high-risk human papillomavirus infections as surrogate endpoints of progressive cervical disease critically depend on reference category: analysis of the combined prospective cohort of the New Independent States of the Former Soviet Union and Latin American Screening studies.
abstract: To make feasible future clinical trials with new-generation human papillomavirus (HPV) vaccines, novel virological surrogate endpoints of progressive disease have been proposed, including high-risk HPV (HR-HPV) persistence for six months (6M+) or 12 months (12M+). The risk estimates (relative risks [RRs]) of these 'virological endpoints' are influenced by several variables, not yet validated adequately. We compared the impact of three referent groups: (i) HPV-negative, (ii) HPV-transient, (iii) HPV-mixed outcome on the risk estimates for 6M+ or 12M+ HR-HPV persistence as predictors of progressive disease. Generalized estimating equation models were used to estimate the strength of 6M+ and 12M+ HR-HPV persistence with disease progression to squamous intraepithelial lesions (SILs), cervical intraepithelial neoplasia (CIN) grade 1+, CIN2+, CIN/SIL endpoints, comparing three optional reference categories (i)-(iii) in a prospective sub-cohort of 1865 women from the combined New Independent States of the Former Soviet Union (NIS) and Latin American Screening (LAMS) studies cohort (n = 15,301). The RRs of these viral endpoints as predictors of progressive disease are affected by the length of viral persistence (6M+ or 12M+) and the surrogate endpoint (SIL, CIN1, CIN2, CIN/SIL). Most dramatic is the effect of the referent group used in risk estimates, with the HPV-negative referent group giving the highest and most consistent RRs for both 6M+ and 12M+ viral persistence, irrespective of which surrogate is used. In addition to deciding on whether to use 6M+ or 12M+ persistence criteria, and cytological, histological or combined surrogate endpoints, one should adopt the HPV-negative referent group as the gold standard in all future studies using viral persistence as the surrogate endpoint of progressive disease.
authors.affiliation: Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Syrjänen
authors.forename: I
authors.initials: I
authors.lastname: Shabalova
authors.forename: P
authors.initials: P
authors.lastname: Naud
authors.forename: V
authors.initials: V
authors.lastname: Kozachenko
authors.forename: S
authors.initials: S
authors.lastname: Derchain
authors.forename: S
authors.initials: S
authors.lastname: Zakharchenko
authors.forename: C
authors.initials: C
authors.lastname: Roteli-Martins
authors.forename: R
authors.initials: R
authors.lastname: Nerovjna
authors.forename: A
authors.initials: A
authors.lastname: Longatto-Filho
authors.forename: L
authors.initials: L
authors.lastname: Kljukina
authors.forename: S
authors.initials: S
authors.lastname: Tatti
authors.forename: M
authors.initials: M
authors.lastname: Branovskaja
authors.forename: L S
authors.initials: LS
authors.lastname: Hammes
authors.forename: M
authors.initials: M
authors.lastname: Branca
authors.forename: V
authors.initials: V
authors.lastname: Grunjberga
authors.forename: M
authors.initials: M
authors.lastname: Eržen
authors.forename: A
authors.initials: A
authors.lastname: Juschenko
authors.forename: S
authors.initials: S
authors.lastname: Costa
authors.forename: L
authors.initials: L
authors.lastname: Sarian
authors.forename: J
authors.initials: J
authors.lastname: Podistov
authors.forename: S
authors.initials: S
authors.lastname: Syrjänen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D003627:Data Interpretation, Statistical; D018450:Disease Progression; D005061:Europe, Eastern; D005260:Female; D006801:Humans; D007843:Latin America; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000453:epidemiology* / Q000517:prevention & control; D053918:Papillomavirus Vaccines / Q000008:administration & dosage; D011446:Prospective Studies; D018570:Risk Assessment; D002577:Uterine Cervical Diseases / Q000453:epidemiology* / Q000821:virology*; D055815:Young Adult
chemical_list: D053918:Papillomavirus Vaccines