A three-year study on genotype-specific natural course of human papillomavirus infection in women

Cilji: S triletnim spremljanjem kohorte 4510 žensk v starostni skupini 20?64 let smo želeli opisati genotipsko specifičen naravni potek okužb s klinično najpomembnejšimi genotipi HPV s kombiniranim pristopom spremljanja DNK HPV v brisih materničnega vratu in genotipsko specifičnih protiteles proti HPV v serumskih vzorcihopredeliti podtipske različice HPV vzorcih, pri katerih je bila v obeh vzorčenjih potrjena okužba s HPV16opisati prevalenco okužb s HPVdoločiti stopnjo serokonverzije in izgube protiteles proti HPVter določiti kumulativno incidenco okužb s HPV v triletnem obdobju. Metode: Za dokazovanje okužbe s HPV smo v obeh presejalnih krogih študije uporabili test Abbott RealTime High Risk HPV, čemur je sledila trostopenjska strategija genotipizacije z uporabo testov: Linear Array HPV Genotyping Test, INNO-LIPA HPV Genotyping Extra assay in GP5+/GP6+ PCR. Z neposrednim določanjem nukleotidnega zaporedja genomskega področja LCR smo opredelili podtipske različice HPV v vzorcih, pri katerih je bila v obeh vzorčenjih potrjena okužba s HPV16. Protitelesa proti izbranim genotipom HPV smo določili z uporabo serološkega testa, ki temelji na tehnologiji Luminex. Rezultati: Med opazovanimi genotipi HPV smo v obeh presejalnih krogih potrdili najvišjo prevalenco okužb s HPV16 (3,6 % in 2,6 %). V vseh razpoložljivih parnih vzorcih, pri katerih je bila v obeh vzorčenjih potrjena okužba s HPV16, smo dokazali identične podtipske različice. Med opazovanimi genotipi je bila najvišja seroprevalenca okužb s HPV16 (25,7 % in 24,6 %). Protitelesa proti HPV56 so bila v triletnem obdobju najbolj stabilna (85,7 %), povprečna stopnja stabilnosti protiteles za vse opazovane genotipe je znašala 65,1 %. Seropozitivne ženske, ki v prvem presejalnem krogu niso imele okužbe s HPV16, so imele znatno zmanjšano tveganje za novo okužbo s HPV16 po treh letih. Triletna kumulativna incidenca okužb s HPV je bila najvišja pri HPV35 (10,0 %). Zaključki: Opisali smo genotipsko specifičen naravni potek okužb s HPV in določili kumulativno incidenco okužb s HPV za največji izbor genotipov HPV doslej. Zdi se, da naravno pridobljena serumska protitelesa proti HPV16 nudijo zaščito pred ponovno okužbo. Naše ugotovitve predstavljajo predstavljajo izhodiščne podatke za razumevanje epidemiologije okužb s HPV.Objectives: With a three-year follow-up of a cohort of 4,510 Slovenian women, we aimed to describe a genotype-specific natural course of infections with clinically most relevant HPV genotypes using a combined approach of monitoring HPV DNA in cervical smear specimens and dynamics of genotype-specific serum anti-HPV antibodies. We aimed to assess subtype variants in paired HPV16-DNA-positive samplesto describe HPV DNA prevalence and seroprevalenceseroconversion and seroreversion rates of anti-HPV antibodiesand to determine the cumulative incidence of HPV infections. Methods: The RealTime High Risk HPV test was used as a primary test for HPV DNA detection at baseline and at follow-up, followed by a three-step genotyping strategy with the Linear Array HPV Genotyping Test, INNO-LIPA HPV Genotyping Extra assay, and an in-house GP5+/GP6+ PCR. In paired HPV16-positive samples, the LCR region was sequenced to establish possible subtype variants. Seropositivity for selected HPV genotypes was determined using a multiplex heparin-pseudovirion Luminex immunoassay. Results: The most prevalent HPV genotype at both time-points was HPV16 (3.6% and 2.6%) and we confirmed identical subtype variants in all available paired HPV16-DNA-positive samples. Seroprevalence of HPV16 infection was highest among the observed genotypes (25.7% and 24.6%). Anti-HPV56 antibodies were most stable at follow up (85.7%). The average seropositivity rate at follow-up for baseline seropositive women was 65.1%. Baseline HPV16 DNA-negative and seropositive women in our study had significantly reduced odds of acquisition of HPV16 infection at follow-up. The three-year cumulative HPV incidence was highest in HPV35 (10.0%). Conclusions: We described a genotype-specific natural course of HPV infections and determined the cumulative incidence of HPV infections for the largest selection of HPV genotypes so far. Naturally acquired serum antibodies against HPV16 seem to confer protection against an incident infection. Findings from our established Slovenian cohort represent baseline data for understanding the epidemiology of HPV infections