title: Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial.
abstract: BACKGROUND
  Human papillomavirus (HPV) testing is known to be more sensitive, but less specific than cytology for detecting cervical intraepithelial neoplasia (CIN). We assessed the efficacy of cervical-cancer screening policies that are based on HPV testing.
  
  
  METHODS
  Between March, 2004, and December, 2004, in two separate recruitment phases, women aged 25-60 years were randomly assigned to conventional cytology or to HPV testing in combination with liquid-based cytology (first phase) or alone (second phase). Randomisation was done by computer in two screening centres and by sequential opening of numbered sealed envelopes in the remaining seven centres. During phase one, women who were HPV-positive and aged 35-60 years were referred to colposcopy, whereas women aged 25-34 years were referred to colposcopy only if cytology was also abnormal or HPV testing was persistently positive. During phase two, women in the HPV group were referred for colposcopy if the HPV test was positive. Two rounds of screening occurred in each phase, and all women had cytology testing only at the second round. The primary endpoint was the detection of grade 2 and 3 CIN, and of invasive cervical cancers during the first and second screening rounds. Analysis was done by intention to screen. This trial is registered, number ISRCTN81678807.
  
  
  RESULTS
  In total for both phases, 47,001 women were randomly assigned to the cytology group and 47,369 to HPV testing. 33,851 women from the cytology group and 32,998 from the HPV-testing group had a second round of screening. We also retrieved the histological diagnoses from screening done elsewhere. The detection of invasive cervical cancers was similar for the two groups in the first round of screening (nine in the cytology group vs seven in the HPV group, p=0.62); no cases were detected in the HPV group during round two, compared with nine in the cytology group (p=0.004). Overall, in the two rounds of screening, 18 invasive cancers were detected in the cytology group versus seven in the HPV group (p=0.028). Among women aged 35-60 years, at round one the relative detection (HPV vs cytology) was 2.00 (95% CI 1.44-2.77) for CIN2, 2.08 (1.47-2.95) for CIN3, and 2.03 (1.60-2.57) for CIN2 and 3 together. At round two the relative detection was 0.54 (0.23-1.28) for CIN2, 0.48 (0.21-1.11) for CIN3, and 0.51 (0.28-0.93) for CIN2 and 3 together. Among women aged 25-34 years, there was significant heterogeneity between phases in the relative detection of CIN3. At round one the relative detection was 0.93 (0.52-1.64) in phase one and 3.91 (2.02-7.57) in phase two. At round two the relative detection was 1.34 (0.46-3.84) in phase one and 0.20 (0.04-0.93) in phase two. Pooling both phases, the detection ratio of CIN2 for women aged 25-34 years was 4.09 (2.24-7.48) at round one and 0.64 (0.23-1.27) at round two.
  
  
  CONCLUSIONS
  HPV-based screening is more effective than cytology in preventing invasive cervical cancer, by detecting persistent high-grade lesions earlier and providing a longer low-risk period. However, in younger women, HPV screening leads to over-diagnosis of regressive CIN2.
  
  
  BACKGROUND
  European Union, Italian Ministry of Health, Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia-Romagna, and Public Health Agency of Lazio.
authors.affiliation: Centre for Cancer Prevention, Turin, Italy. guglielmo.ronco@cpo.it
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Ronco
authors.forename: Paolo
authors.initials: P
authors.lastname: Giorgi-Rossi
authors.forename: Francesca
authors.initials: F
authors.lastname: Carozzi
authors.forename: Massimo
authors.initials: M
authors.lastname: Confortini
authors.forename: Paolo
authors.initials: P
authors.lastname: Dalla Palma
authors.forename: Annarosa
authors.initials: A
authors.lastname: Del Mistro
authors.forename: Bruno
authors.initials: B
authors.lastname: Ghiringhello
authors.forename: Salvatore
authors.initials: S
authors.lastname: Girlando
authors.forename: Anna
authors.initials: A
authors.lastname: Gillio-Tos
authors.forename: Laura
authors.initials: L
authors.lastname: De Marco
authors.forename: Carlo
authors.initials: C
authors.lastname: Naldoni
authors.forename: Paola
authors.initials: P
authors.lastname: Pierotti
authors.forename: Raffaella
authors.initials: R
authors.lastname: Rizzolo
authors.forename: Patrizia
authors.initials: P
authors.lastname: Schincaglia
authors.forename: Manuel
authors.initials: M
authors.lastname: Zorzi
authors.forename: Marco
authors.initials: M
authors.lastname: Zappa
authors.forename: Nereo
authors.initials: N
authors.lastname: Segnan
authors.forename: Jack
authors.initials: J
authors.lastname: Cuzick
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D007558:Italy; D008403:Mass Screening / Q000379:methods*; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D030361:Papillomavirus Infections / Q000175:diagnosis*; D012680:Sensitivity and Specificity; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control* / Q000821:virology; D014626:Vaginal Smears; D002578:Uterine Cervical Dysplasia / Q000517:prevention & control* / Q000821:virology