title: Five-year risks of CIN 3+ and cervical cancer among women who test Pap-negative but are HPV-positive.
abstract: OBJECTIVE
  Current US guidelines for cotesting recommend that the large numbers of women who test Pap-negative, but human papillomavirus (HPV)-positive, return in 1 year, and those who remain HPV-positive or have low-grade squamous intraepithelial lesion (LSIL) or worse Pap results be referred for colposcopy. However, the performance of these guidelines in routine clinical practice has not been evaluated.
  
  
  METHODS
  We estimated cumulative 5-year risks of cervical intraepithelial neoplasia grade 3 or worse (CIN 3+) among 32,374 women aged 30 to 64 years with HPV-positive/Pap-negative cotest results at Kaiser Permanente Northern California during 2003 to 2010.
  
  
  RESULTS
  The 5-year CIN 3+ risk after an HPV-positive/Pap-negative cotest result, which was found in 3.6% of women, was 4.5% (95% confidence interval [CI] = 4.2%-4.8%). The 5-year cancer risk was 0.34% (95% CI = 0.26%-0.45%), and half of the cases were adenocarcinoma. Overall, 48% of the women remained HPV-positive on return (median = 418 days after baseline), a percentage that varied little over ages 30 to 64 years. At the return after a baseline HPV-positive/Pap-negative result, almost every repeat cotest result predicted greater subsequent 5-year CIN 3+ risk than the same cotest result had at baseline (HPV-positive/LSIL, 9.2% vs 6.1%, p = .01; HPV-positive/atypical squamous cells of undetermined significance [ASC-US], 7.9% vs 6.8%, p = .2; HPV-positive/Pap-negative, 7.4% vs 4.5%, p < .0001; HPV-negative/LSIL,1.7% vs 2.0%, p = .8; HPV-negative/ASC-US, 2.9% vs 0.43%, p = .0005; HPV-negative/Pap-negative, 0.93% vs 0.08%, p < .0001).
  
  
  CONCLUSIONS
  Using the principle of "equal management of equal risks," women testing HPV-positive/Pap-negative had a subsequent CIN 3+ risk consistent with risk thresholds for a 1-year return. However, on returning in approximately 1 year, about one-half of women will be referred for colposcopy because of continued HPV positivity or Pap abnormality. Clinicians should keep in mind that cotest results at the return after a baseline HPV-positive/Pap-negative finding are riskier than the same baseline cotest results in the general population, supporting intensified clinical management at return testing.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health/DHHS, Bethesda, MD 20892, USA. katkih@mail.nih.gov
authors.forename: Hormuzd A
authors.initials: HA
authors.lastname: Katki
authors.forename: Mark
authors.initials: M
authors.lastname: Schiffman
authors.forename: Philip E
authors.initials: PE
authors.lastname: Castle
authors.forename: Barbara
authors.initials: B
authors.lastname: Fetterman
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Poitras
authors.forename: Thomas
authors.initials: T
authors.lastname: Lorey
authors.forename: Li C
authors.initials: LC
authors.lastname: Cheung
authors.forename: Tina
authors.initials: T
authors.lastname: Raine-Bennett
authors.forename: Julia C
authors.initials: JC
authors.lastname: Gage
authors.forename: Walter K
authors.initials: WK
authors.lastname: Kinney
mesh_terms: D000328:Adult; D002140:California / Q000453:epidemiology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008403:Mass Screening / Q000379:methods; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000175:diagnosis*; D018570:Risk Assessment; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000453:epidemiology*; D014626:Vaginal Smears / Q000379:methods*; D014773:Virology / Q000379:methods*; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis* / Q000453:epidemiology*