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      Risk of Newly Detected Infections and Cervical Abnormalities in Women Seropositive for Naturally Acquired Human Papillomavirus Type 16/18 Antibodies: Analysis of the Control Arm of PATRICIA

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      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 1 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 30 , 31 , 30 , 30
      The Journal of Infectious Diseases
      Oxford University Press
      HPV, naturally acquired antibodies, infection, cervical abnormality, risk reduction

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          Abstract

          Background.  We examined risk of newly detected human papillomavirus (HPV) infection and cervical abnormalities in relation to HPV type 16/18 antibody levels at enrollment in PATRICIA (Papilloma Trial Against Cancer in Young Adults; NCT00122681).

          Methods.  Using Poisson regression, we compared risk of newly detected infection and cervical abnormalities associated with HPV-16/18 between seronegative vs seropositive women (15–25 years) in the control arm (DNA negative at baseline for the corresponding HPV type [HPV-16: n = 8193; HPV-18: n = 8463]).

          Results.  High titers of naturally acquired HPV-16 antibodies and/or linear trend for increasing antibody levels were significantly associated with lower risk of incident and persistent infection, atypical squamous cells of undetermined significance or greater (ASCUS+), and cervical intraepithelial neoplasia grades 1/2 or greater (CIN1+, CIN2+). For HPV-18, although seropositivity was associated with lower risk of ASCUS+ and CIN1+, no association between naturally acquired antibodies and infection was demonstrated. Naturally acquired HPV-16 antibody levels of 371 (95% confidence interval [CI], 242–794), 204 (95% CI, 129–480), and 480 (95% CI, 250–5756) EU/mL were associated with 90% reduction of incident infection, 6-month persistent infection, and ASCUS+, respectively.

          Conclusions.  Naturally acquired antibodies to HPV-16, and to a lesser extent HPV-18, are associated with some reduced risk of subsequent infection and cervical abnormalities associated with the same HPV type.

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          Most cited references31

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          Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women

          The Lancet, 374(9686), 301-314
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            Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial

            The Lancet, 369(9580), 2161-2170
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              Cross-protective efficacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial.

              We evaluated the efficacy of the human papillomavirus HPV-16/18 AS04-adjuvanted vaccine against non-vaccine oncogenic HPV types in the end-of-study analysis after 4 years of follow-up in PATRICIA (PApilloma TRIal against Cancer In young Adults). Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to HPV-16/18 vaccine or a control hepatitis A vaccine, via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The study was double-blind. The primary endpoint of PATRICIA has been reported previously; the present analysis evaluates cross-protective vaccine efficacy against non-vaccine oncogenic HPV types in the end-of-study analysis. Analyses were done for three cohorts: the according-to-protocol cohort for efficacy (ATP-E; vaccine n=8067, control n=8047), total vaccinated HPV-naive cohort (TVC-naive; no evidence of infection with 14 oncogenic HPV types at baseline, approximating young adolescents before sexual debut; vaccine n=5824, control n=5820), and the total vaccinated cohort (TVC; all women who received at least one vaccine dose, approximating catch-up populations that include sexually active women; vaccine n=9319, control=9325). Vaccine efficacy was evaluated against 6-month persistent infection, cervical intraepithelial neoplasia grade 2 or greater (CIN2+) associated with 12 non-vaccine HPV types (individually or as composite endpoints), and CIN3+ associated with the composite of 12 non-vaccine HPV types. This study is registered with ClinicalTrials.gov, number NCT00122681. Consistent vaccine efficacy against persistent infection and CIN2+ (with or without HPV-16/18 co-infection) was seen across cohorts for HPV-33, HPV-31, HPV-45, and HPV-51. In the most conservative analysis of vaccine efficacy against CIN2+, where all cases co-infected with HPV-16/18 were removed, vaccine efficacy was noted for HPV-33 in all cohorts, and for HPV-31 in the ATP-E and TVC-naive. Vaccine efficacy against CIN2+ associated with the composite of 12 non-vaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), with or without HPV-16/18 co-infection, was 46·8% (95% CI 30·7-59·4) in the ATP-E, 56·2% (37·2-69·9) in the TVC-naive, and 34·2% (20·4-45·8) in the TVC. Corresponding values for CIN3+ were 73·8% (48·3-87·9), 91·4% (65·0-99·0), and 47·5% (22·8-64·8). Data from the end-of-study analysis of PATRICIA show cross-protective efficacy of the HPV-16/18 vaccine against four oncogenic non-vaccine HPV types-HPV-33, HPV-31, HPV-45, and HPV-51-in different trial cohorts representing diverse groups of women. GlaxoSmithKline Biologicals. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                J Infect Dis
                J. Infect. Dis
                jid
                jinfdis
                The Journal of Infectious Diseases
                Oxford University Press
                0022-1899
                1537-6613
                15 August 2014
                08 March 2014
                08 March 2014
                : 210
                : 4
                : 517-534
                Affiliations
                [1 ]Unit of Infections and Cancer, Cancer Epidemiology Research Program, Institut Català d'Oncologia, IDIBELL, CIBER-ESP, L'Hospitalet de Llobregat , Catalonia, Spain
                [2 ]Department of Gynecology and Obstetrics, Federal University of Rio Grande do Sul, Hospital de Clínicas de Porto Alegre , Brazil
                [3 ]Department of Obstetrics and Gynecology, College of Medicine and the Hospital , National Taiwan University , Taipei, Taiwan
                [4 ]Department of Pathology and Department of Obstetrics and Gynecology, University of New Mexico Health Sciences Center , Albuquerque
                [5 ]Department of Obstetrics and Gynaecology, University of the Philippines College of Medicine, Philippine General Hospital, Manila, The Philippines
                [6 ]University of Tampere, School of Public Health , Tampere
                [7 ]Department of Obstetrics and Gynaecology, University of Helsinki , Finland
                [8 ]Department of Obstetrics and Gynaecology, Faculty of Medicine, Chulalongkorn University , Bangkok, Thailand
                [9 ]Department of Microbiology and Infectious Diseases, The Royal Women's Hospital
                [10 ]Department of Microbiology, The Royal Children's Hospital , Parkville/Murdoch Childrens Research Institute
                [11 ]Department of Obstetrics and Gynaecology, University of Melbourne , Parkville, Victoria, Australia
                [12 ]Unidad de Investigación Epidemiológica y en Servicios de Salud, Instituto Mexicano del Seguro Social , Morelos, Mexico
                [13 ]Family Federation of Finland, Sexual Health Clinic , Helsinki, Finland
                [14 ]Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, St Mary's Hospital , Manchester, United Kingdom
                [15 ]Departamento de Tocoginecologia da Unicamp, University of Campinas , Sao Paulo, Brazil
                [16 ]Vaccines Trials Group, Telethon Institute for Child Health Research , Perth, Western Australia
                [17 ]Sydney University Discipline of Paediatrics and Child Health , Children's Hospital Westmead , Sydney, New South Wales, Australia
                [18 ]College of Medicine, University of the Philippines, Philippine General Hospital, Makati Medical Centre , Makati City, The Philippines
                [19 ]Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London , United Kingdom
                [20 ]Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, Canada
                [21 ]Department of Medical Microbiology, University of Manitoba , Winnipeg, Canada
                [22 ]Central Laboratory and Vaccination Centre, Stiftung Juliusspital, Academic Teaching Hospital of the University of Wuerzburg , Germany
                [23 ]Department of Gynaecology, University Hospital KU Leuven Gasthuisberg , Belgium
                [24 ]Network on Cooperative Cancer Research, RTICC , Catalonia, Spain
                [25 ]Department of Gynecology and Obstetrics, Federal University of Paraná, Infectious Diseases in Gynecology and Obstetrics Sector , Curitiba, Brazil
                [26 ]Facharzt für Frauenheilkunde und Geburtshilfe, Hamburg, Germany
                [27 ]Multidisciplinary Breast Clinic–Gynecologic Oncology, Antwerp University Hospital , University of Antwerp , Belgium
                [28 ]Division of Cancer Epidemiology and Genetics, Infections and Immunoepidemiology Branch, National Cancer Institute , Rockville, Maryland
                [29 ]4Clinics, Paris, France
                [30 ]GlaxoSmithKline Vaccines, Wavre, Belgium
                [31 ]GlaxoSmithKline Vaccines, King of Prussia, Pennsylvania
                Author notes
                [a]

                Deceased.

                Presented in part at: European Research Organization on Genital Infection and Neoplasia Prague, 8–11 July 2012. 2012;SS13–3:89; IGCS (2010) International Gynecologic Cancer Society, 13th Biennial Meeting Prague, 23–26 October 2010; Int J Gynecol Cancer 2010;20 (Suppl 2):44.

                Correspondence: Xavier Castellsagué, MD, MPH, PhD, Unit of Infections and Cancer, Cancer Epidemiology Research Program, Institut Català d'Oncologia, Avda Gran via 199–203, 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain ( xcastellsague@ 123456iconcologia.net ).
                Article
                jiu139
                10.1093/infdis/jiu139
                4111909
                24610876
                6bf12913-e52b-454b-8426-60874084d66a
                © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com .

                History
                : 16 October 2013
                : 31 January 2014
                Categories
                Major Articles and Brief Reports
                Viruses
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                Infectious disease & Microbiology
                hpv,naturally acquired antibodies,infection,cervical abnormality,risk reduction

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