title: Post hoc analysis of the PATRICIA randomized trial of the efficacy of human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against incident and persistent infection with nonvaccine oncogenic HPV types using an alternative multiplex type-specific PCR assay for HPV DNA.
abstract: The efficacy of the human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against cervical infections with HPV in the Papilloma Trial against Cancer in Young Adults (PATRICIA) was evaluated using a combination of the broad-spectrum L1-based SPF10 PCR-DNA enzyme immunoassay (DEIA)/line probe assay (LiPA25) system with type-specific PCRs for HPV-16 and -18. Broad-spectrum PCR assays may underestimate the presence of HPV genotypes present at relatively low concentrations in multiple infections, due to competition between genotypes. Therefore, samples were retrospectively reanalyzed using a testing algorithm incorporating the SPF10 PCR-DEIA/LiPA25 plus a novel E6-based multiplex type-specific PCR and reverse hybridization assay (MPTS12 RHA), which permits detection of a panel of nine oncogenic HPV genotypes (types 16, 18, 31, 33, 35, 45, 52, 58, and 59). For the vaccine against HPV types 16 and 18, there was no major impact on estimates of vaccine efficacy (VE) for incident or 6-month or 12-month persistent infections when the MPTS12 RHA was included in the testing algorithm versus estimates with the protocol-specified algorithm. However, the alternative testing algorithm showed greater sensitivity than the protocol-specified algorithm for detection of some nonvaccine oncogenic HPV types. More cases were gained in the control group than in the vaccine group, leading to higher point estimates of VE for 6-month and 12-month persistent infections for the nonvaccine oncogenic types included in the MPTS12 RHA assay (types 31, 33, 35, 45, 52, 58, and 59). This post hoc analysis indicates that the per-protocol testing algorithm used in PATRICIA underestimated the VE against some nonvaccine oncogenic HPV types and that the choice of the HPV DNA testing methodology is important for the evaluation of VE in clinical trials. (This study has been registered at ClinicalTrials.gov under registration no. NCT00122681.).
authors.affiliation: GlaxoSmithKline Vaccines, Rixensart, Belgium frank.struyf@gsk.com.
authors.forename: Frank
authors.initials: F
authors.lastname: Struyf
authors.affiliation: GlaxoSmithKline Vaccines, Rixensart, Belgium.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Colau
authors.affiliation: Departments of Pathology and Obstetrics and Gynecology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
authors.forename: Cosette M
authors.initials: CM
authors.lastname: Wheeler
authors.affiliation: University Federal of Rio Grande do Sul, Hospital de Clínica de Porto Alegre, Porto Alegre, Brazil.
authors.forename: Paulo
authors.initials: P
authors.lastname: Naud
authors.affiliation: Microbiology and Infectious Diseases Department, Royal Women's and Royal Children's Hospitals, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Garland
authors.affiliation: DDL Diagnostic Laboratory, Rijswijk, the Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Quint
authors.affiliation: Department of Obstetrics and Gynecology, College of Medicine and the Hospital, National Taiwan University, Taipei, Taiwan.
authors.forename: Song-Nan
authors.initials: SN
authors.lastname: Chow
authors.affiliation: Unidad de Investigación Epidemiológica y en Servicios de Salud, Instituto Mexicano del Seguro Social, Morelos, Mexico.
authors.forename: Jorge
authors.initials: J
authors.lastname: Salmerón
authors.affiliation: University of Tampere, School of Public Health, Tampere, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Lehtinen
authors.affiliation: Department of Obstetrics and Gynecology, San Pablo Colleges Medical Center, San Pablo City, Laguna, Philippines.
authors.forename: M Rowena
authors.initials: MR
authors.lastname: Del Rosario-Raymundo
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki, Helsinki, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Paavonen
authors.affiliation: Departamento de Tocoginecologia da Unicamp, University of Campinas, Campinas, Brazil.
authors.forename: Júlio C
authors.initials: JC
authors.lastname: Teixeira
authors.affiliation: University of the Philippines College of Medicine, Philippine General Hospital, Manila, Philippines.
authors.forename: Maria Julieta
authors.initials: MJ
authors.lastname: Germar
authors.affiliation: Facharzt für Frauenheilkunde und Geburtshilfe, Hamburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Peters
authors.affiliation: Vaccine Trials Group, Telethon Institute for Child Health Research, Sydney, New South Wales, Australia Sydney University Discipline of Paediatrics and Child Health, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
authors.forename: S Rachel
authors.initials: SR
authors.lastname: Skinner
authors.affiliation: University of the Philippines, College of Medicine, Philippine General Hospital, Makati Medical Centre, Makati City, Philippines.
authors.forename: Genara
authors.initials: G
authors.lastname: Limson
authors.affiliation: Institut Català d'Oncologia, IDIBELL, CIBER-ESP, L'Hospitalet de Llobregat, Catalonia, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Castellsagué
authors.affiliation: Department of Gynaecology, University Hospital KU Leuven Gasthuisberg, Leuven, Belgium.
authors.forename: Willy A J
authors.initials: WA
authors.lastname: Poppe
authors.affiliation: First Line Medical Services Ltd., St John's, Newfoundland and Labrador, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Ramjattan
authors.affiliation: Heartland Research Associates, LLC, Wichita, Kansas, USA.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Klein
authors.affiliation: Central Laboratory and Vaccination Centre, Stiftung Juliusspital, Academic Teaching Hospital of the University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Tino F
authors.initials: TF
authors.lastname: Schwarz
authors.affiliation: Department of Pediatrics, University of South Dakota, Sanford School of Medicine and Sanford Children's Specialty Clinic, Sioux Falls, South Dakota, USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Multidisciplinary Breast Clinic, Gynecological Oncology Unit, Department of Obstetrics and Gynecology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
authors.forename: Wiebren A A
authors.initials: WA
authors.lastname: Tjalma
authors.affiliation: Advanced Medical Research Institute of Canada, Sudbury, Ontario, Canada.
authors.forename: Francisco
authors.initials: F
authors.lastname: Diaz-Mitoma
authors.affiliation: Clinical Research Centre, University of Surrey, Surrey, United Kingdon.
authors.forename: David J M
authors.initials: DJ
authors.lastname: Lewis
authors.affiliation: Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Harper
authors.affiliation: DDL Diagnostic Laboratory, Rijswijk, the Netherlands.
authors.forename: Anco
authors.initials: A
authors.lastname: Molijn
authors.affiliation: DDL Diagnostic Laboratory, Rijswijk, the Netherlands.
authors.forename: Leen-Jan
authors.initials: LJ
authors.lastname: van Doorn
authors.affiliation: GlaxoSmithKline Vaccines, Rixensart, Belgium.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: David
authors.affiliation: GlaxoSmithKline Vaccines, King of Prussia, Pennsylvania, USA.
authors.forename: Gary
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authors.lastname: Dubin
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000293:Adolescent; D000328:Adult; D000536:Aluminum Hydroxide / Q000008:administration & dosage*; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives*; D027383:Papillomaviridae / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000517:prevention & control / Q000821:virology*; D053918:Papillomavirus Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D016133:Polymerase Chain Reaction; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C532963:ASO4 mixture; D000276:Adjuvants, Immunologic; D004279:DNA, Viral; D008050:Lipid A; D053918:Papillomavirus Vaccines; C510352:human papillomavirus vaccine, L1 type 16, 18; D000536:Aluminum Hydroxide