Persistent high-risk human papillomavirus (HPV) infections as surrogate endpoints of progressive cervical disease. Potential new endpoint for efficacy studies with new-generation (non-HPV16/18) prophylactic HPV vaccines

Recent data indicate that persistent HR-HPV infections represent a significantly increased risk of developing incident high-grade CIN and cervical cancer. Accordingly, 6-month (6M+) or 12-month (12M+) type-specific persistence of HR-HPV have been proposed as powerful surrogates of progressive disease. Because of substantial practical impact in future HPV vaccine trials using non-HPV16/18 vaccines, studies on HR-HPV persistence as a surrogate endpoint of progressive CIN have been subject to a comprehensive meta-analyses recently. The present communication was solicited to bring this important and timely topic to the awareness of the readers, in a format consisting of a review of the recent literature, supplemented with the author’s own experience from different studies. Based on a large number of relevant studies, there remains little doubt that persistence of HR-HPV for 6+ or 12+ months is associated with a significantly increased risk of developing incident high-grade CIN. However, some data also disclosed several important issues that need to be carefully considered and/or adequately resolved before adopting 6M+ or 12M+ HR-HPV persistence as a surrogate of progressive disease. These include i) definitions of HPV persistence, ii) HPV detection techniques and iii) testing intervals and iv) length of follow-up, as well as v) diagnosis of the surrogate endpoints, and vi) other study characteristics, including vii) the type of reference category used in calculating the risk estimates. All these issues are critically discussed in the present communication. Of major impact seems to be the reference category used to calculate these risk estimates, as evident from the NIS-LAMS cohort. Taken together, it is suggested that in all future studies using the 6M+ or 12M+ HR-HPV persistence as a surrogate endpoint of progressive disease, a “gold standard” should be used in calculating the risk estimates. In addition to deciding, 1) whether to use 6M+ or 12M+ persistence criteria, and 2) cytological, histological or combined surrogate endpoints (SIL, CIN1, CIN2, CIN/SIL), one should 3) use exclusively the HPV negative reference group in calculating the risk estimates for viral persistence endpoints. This is supported by the data from the recent meta-analysis as well as from the author’s combined NIS-LAMS cohort, both implicating that the most consistent association to progressive disease is obtained when women with persistent HR-HPV are compared with HPV-negative women. It is the conviction of this author that the two other reference categories (HPV transient and HPV mixed outcome) are far too heterogeneous and subject to potential misclassifications to give consistent and reproducible risk estimates for HR-HPV persistence as a surrogate endpoint of progressive CIN.

Human papillomavirus; High-risk types; Persistent infection; 6-mo and 12-mo persistence; Surrogate endpoint; Pro gres -sive disease; HPV vaccines; Efficacy trials; Study power; NIS cohort; LAMS study

[1] Syrjänen K, Gissmann L, Koss LG. (eds.): “Papillomaviruses and Human Disease”. Heidelberg, Springer Verlag, 1987, 1.

[2] Syrjänen K., Syrjänen S.: “Papillomavirus Infections in Human Pathology”. New York, J. Wiley & Sons, 2000, 1.

[3] zur Hausen H.: “Papillomaviruses in the causation of human cancers- a brief historical account”. Virology, 2009, 384, 260.

[4] Syrjänen S., Syrjänen K.: “The history of papillomavirus research”. Cent. Eur. J. Public Health, 2008, 16 (suppl. ), S7.

[5] Burk R.D., Kelly P., Feldman J., Bromberg J., Vermund S.H., Dehovitz J.A. et al.: “Declining prevalence of cervicovaginal human papillomavirus infection with age is independent of other risk factors”. Sex Transm Dis., 1996, 23, 333.

[6] Kjaer S.K., van den Brule A.J., Bock J.E., Poll P.A., Engholm G., Sherman M.E. et al.: “Determinants for genital human papillomavirus (HPV) infection in 1000 randomly chosen young Danish women with normal Pap smear: are there different risk profiles for oncogenic and nononcogenic HPV types?”. Cancer Epidemiol Biomarkers Prev., 1997, 6, 799.

[7] Melkert P.W., Hopman E., van den Brule A.J., Risse E.K., van Diest P.J., Bleker O.P. et al.:: “Prevalence of HPV in cytomorphologically normal cervical smears, as determined by the polymerase chain reaction, is age-dependent”. Int. J. Cancer, 1993, 53, 919.

[8] Syrjänen K.: “Natural history of cervical HPV infections and CIN”. Chapter 6. In: Syrjänen K. and Syrjänen S. “Papillomavirus Infections in Human Pathology”. New York, J. Wiley & Sons, 2000, 142.

[9] Herrero R., Hildesheim A., Bratti C., Sherman M.E., Hutchinson M., Morales J. et al.: “Population-based study of human papillomavirus infection and cervical neoplasia in rural Costa Rica”. J. Natl. Cancer Inst., 2000, 92, 464.

[10] Winer R.L., Lee S.K., Hughes J.P., Adam D.E., Kiviat N.B., Koutsky L.A.: “Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students”. Am. J. Epidemiol., 2003, 157, 218.

[11] Syrjänen S., Shabalova I.P., Petrovichev N., Kozachenko V.P., Zakharova T., Pajanidi A., Podistov J.I., Chemeris G., Sozaeva L.G. et al.: “Acquisition of incident high-risk human papillomavirus (HPV) DNA and PAP smear abnormalities in a cohort of women subjected to HPV screening in the New Independent States (NIS) of the Former Soviet Union”. J. Clin. Microbiol., 2004, 42, 505.

[12] Brummer O., Hollwitz B., Bohmer G., Kuhnle H., Petry K.U.: “Human papillomavirus-type persistence patterns predict the clinical outcome of cervical intraepithelial neoplasia”. Gynecol. Oncol., 2006, 102, 517.

[13] Hildesheim A., Schiffman M.H., Gravitt P.E., Glass A.G., Greer C.E., Zhang T. et al.: “Persistence of type-specific human papillomavirus infection among cytologically normal women”. J. Infect. Dis., 1994, 169, 235.

[14] Syrjänen S., Shabalova I.P., Petrovichev N., Kozachenko V.P., Zakharova T., Pajanidi A. et al.: “Clearance of high-risk human papillomavirus (HPV) DNA and PAP smear abnormalities in a cohort of women subjected to HPV screening in the New Independent States (NIS) of the Former Soviet Union”. Eur. J. Gynecol. Obstet. Reprod. Biol., 2005, 119, 219.

[15] Syrjänen S., Shabalova I.P., Petrovichev N., Kozachenko V.P., Zakharova T., Pajanidi A. et al.: “Age-specific incidence and clearance rates of high-risk Human Papillomavirus (HPV) infections in women subjected to HPV screening in the new independent states”. Int. J. STD & AIDS, 2005, 16, 217.

[16] Dalstein V., Riethmuller D., Pretet J.L., Le Bail C.K., Sautiere J.L., Carbillet J.P. et al.: “Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions: a longitudinal French cohort study”. Int. J. Cancer, 2003, 106, 396

[17] Syrjänen S., Shabalova I.P., Petrovichev N., Kozachenko V.P., Zakharova T., Pajanidi A. et al.: “Factors predicting persistence of high-risk human papillomavirus (HPV) infections in women prospectively followed-up in three New Independent States (NIS) of the Former Soviet Union”. Eur. J. Gynaecol. Oncol., 2005, 26, 491.

[18] Schiffman M., Herrero R., DeSalle R., Hildesheim A., Wacholder S., Cecilia Rodriguez A. et al.: “The carcinogenicity of human papillomavirus types reflects viral evolution”. Virology, 2005, 337, 76.

[19] Schiffman M., Castle P.E., Jeronimo J., Rodriguez A.C., Wacholder S.: “Human papillomavirus and cervical cancer”. Lancet, 2007, 370, 890.

[20] Wang S.S., Zuna R.E., Wentzensen N., Dunn S.T., Sherman M.E., Gold M.A. et al.: “Human papillomavirus cofactors by disease progression and human papillomavirus types in the study to understand cervical cancer early endpoints and determinants”. Cancer Epidemiol. Biomarkers Prev., 2009, 18, 113.

[21] Belinson S., Smith J.S., Myers E., Olshan A., Belinson J., Pretorius R. et al.: “Descriptive evidence that risk profiles for cervicalintraepithelial neoplasia 1, 2, and 3 are unique”. Cancer Epidemiol. Biomarkers Prev., 2008, 17, 2350.

[22] Castle P.E., Schiffman M., Herrero R., Hildesheim A., Rodriguez A.C., Bratti M.C. et al.: “A prospective study of age trends in cervical human papillomavirus acquisition and persistence in Guanacaste, Costa Rica”. J. Infect. Dis., 2005, 191, 1808.

[23] Syrjänen K.J., Kulmala S.-M., Shabalova I.P., Petrovichev N., Kozachenko V.P., Zakharova T. et al.: “Epidemiological, clinical and viral determinants of the increased prevalence of high-risk human papillomavirus (HPV) infections in elderly women”. Eur. J. Gynecol. Oncol., 2008, 29, 114.

[24] Harper D.M., Franco E.L., Wheeler C.M., Moscicki A.B., Romanowski B., Roteli-Martins C.M. et al.: “Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial”. Lancet, 2006, 367, 1247.

[25] Plummer M., Schiffman M., Castle P.E., Maucort-Boulch D., Wheeler C.M.: “A 2-year prospective study of human papillomavirus persistence among women with a cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion”. J. Infect. Dis., 2007, 195, 1582.

[26] Kjaer S.K., van den Brule A.J., Paull G., Svare E.I., Sherman M.E., Thomsen B.L. et al.: “Type specific persistence of high risk human papillomavirus (HPV) as indicator of high grade cervical squamous intraepithelial lesions in young women: population based prospective follow up study”. BMJ, 2002, 325, 572.

[27] Kjaer S., Hogdall E., Frederiksen K., Munk C., Van den B.A., Svare E. et al.: “The absolute risk of cervical abnormalities in high-risk human papillomavirus-positive, cytologically normal women over a 10-year period”. Cancer Res., 2006, 66, 10630.

[28] Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR et al.: “The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice”. J. Natl. Cancer Inst., 2005, 97, 1072.

[29] Winer R.L., Kiviat N.B., Hughes J.P., Adam D.E., Lee S.K., Kuypers J.M. et al.: “Development and duration of human papillomavirus lesions, after initial infection”. J. Infect. Dis., 2005, 191, 731.

[30] Castle P.E., Solomon D., Schiffman M., Wheeler C.M.: “Human papillomavirus type 16 infections and 2-year absolute risk of cervical precancer in women with equivocal or mild cytologic abnormalities”. J. Natl. Cancer Inst., 2005, 97, 1066.

[31] Harper D.M., Franco E.L., Wheeler C. et al.: “Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomisedcontrolled trial”. Lancet, 2004, 364, 1757.

[32] Mao C., Koutsky L.A., Ault K.A. et al.: “Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial”. Obstet. Gynecol., 2006, 107, 18.

[33] Kulasingam S.L., Hughes J.P., Kiviat N.B. et al.: “Evaluation of human papillomavirus testing in primary screening for cervical abnormalities: comparison of sensitivity, specificity, and frequency of referral”. JAMA, 2002, 288, 1749.

[34] Perrons C., Brink N., Jalal H. et al.: “The impact of high risk human papillomavirus testing in an inner London colposcopy clinic”. J. Med. Virol., 2005, 76, 576.

[35] Koshiol J., Lindsay L., Pimenta J.M., Poole C., Jenkins D., Smith J.S.: “Persistent human papillomavirus infection and cervical neoplasia: a systematic review and meta-analysis”. Am. J. Epidemiol., 2008, 168, 123.

[36] Schiffman M., Kjaer S.K.: “Chapter 2: Natural history of anogenital human papillomavirus infection and neoplasia”. J. Natl. Cancer Inst. Monogr., 2003, 31, 14.

[37] Woodman C.B., Collins S.: “A critique of cohort studies examining the role of human papillomavirus infection in cervical neoplasia”. BJOG, 2002, 109, 1311.

[38] Giuliano A.R., Harris R., Sedjo R.L., Baldwin S., Roe D., Papenfuss M.R. et al.: “Incidence, prevalence, and clearance of type-specific human papillomavirus infections: The Young Women’s Health Study”. J. Infect. Dis., 2002, 186, 462.

[39] Molano M., Van den Brule A., Plummer M., Weiderpass E., Posso H., Arslan A. et al.: “Determinants of clearance of human papillomavirus infections in Colombian women with normal cytology: a population-based, 5-year follow-up study”. Am. J. Epidemiol., 2003, 158, 486.

[40] Moscicki A.B., Ellenberg J.H., Crowley-Nowick P., Darragh T.M., Xu J., Fahrat S.: “Risk of high-grade squamous intraepithelial lesion in HIV-infected adolescents”. J. Infect. Dis., 2004, 190, 1413.

[41] Ahdieh L., Klein R.S., Burk R., Cu-Uvin S., Schuman P., Duerr A. et al.: “Prevalence, incidence, and type-specific persistence of human papillomavirus in human immunodeficiency virus (HIV)-positive and HIV-negative women”. J. Infect. Dis., 2001, 184, 682.

[42] Paraskevaidis E., Kaponis A., Malamou-Mitsi V., Davidson E.J., Hirsch P.M., Koliopoulos G. et al.: “The natural history of HPV infection of the uterine cervix. Long-term observational and histological data”. Anticancer Res., 2002, 22, 1177.

[43] Syrjänen K., Shabalova I., Naud P., Kozachenko V., Derchain S., Zakharchenko S., Roteli-Martins C. et al.: “Persistent high-risk human papillomavirus (HPV) infections and other endpoint markers of progressive cervical disease among women prospectively followed-up in the NIS and LAMS cohorts”. Int. J. Gynecol. Cancer, 2009, 19, 934.

[44] Syrjänen K., Shabalova I., Naud P., Sarian L., Derchain S., Kozachenko V. et al.: “Risk estimates for persistent high-risk human papillomavirus (HPV) infections as surrogate endpoints of progressive cervical disease critically depend on reference category. Analysis of the combined prospective cohort of the NIS and LAMS studies”. Int. J. STD & AIDS, 2010, in press.

[45] Liaw K.L., Glass A.G., Manos M.M., Greer C.E., Scott D.R., Sherman M. et al.: “Detection of human papillomavirus DNA in cytologically normal women and subsequent cervical squamous intraepithelial lesions”. J. Natl. Cancer Inst., 1999, 91, 954.

[46] Cuzick J., Szarewski A., Cubie H., Hulman G., Kitchener H., Luesley D. et al.: “Management of women who test positive for high-risk types of human papillomavirus: the HART study”. Lancet, 2003, 362, 1871.

[47] Bais A.G., Rebolj M., Snijders P.J., de Schipper F.A., van der Meulen D.A., Verheijen R.H. et al.: “Triage using HPV testing in persistent borderline and mildly dyskaryotic smears: proposal for new guidelines”. Int. J. Cancer, 2005, 116, 122.

[48] Moberg M., Gustavsson I., Gyllensten U.: “Type-specific associations of human papillomavirus load with risk of developing cervical carcinoma in situ”. Int. J. Cancer, 2004, 112, 854.

[49] Schlecht N.F., Kulaga S., Robitaille J., Ferreira S., Santos M., Miyamura R.A. et al.: “Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia”. JAMA, 2001, 286, 3106.

[50] Wallin K.L., Wiklund F., Angstrom T., Bergman F., Stendahl U., Wadell G. et al.: “Type-specific persistence of human papillomavirus DNA before the development of invasive cervical cancer”. N. Engl. J. Med., 1999, 341, 1633.

[51] Koutsky L.A., Holmes K.K., Critchlow C.W., Stevens C.E., Paavonen J., Beckmann A.M. et al.: “A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection”. N. Engl. J. Med., 1992, 327, 1272.

[52] Dannecker C., Siebert U., Thaler C.J., Kiermeir D., Hepp H., Hillemanns P.: “Primary cervical cancer screening by self-sampling of human papillomavirus DNA in internal medicine outpatient clinics”. Ann. Oncol., 2004, 15, 863.

[53] Elfgren K., Kalantari M., Moberger B., Hagmar B., Dillner J.: “A population-based five-year follow-up study of cervical human papillomavirus infection”. Am. J. Obstet. Gynecol., 2000, 183, 561.

[54] Ylitalo N., Josefsson A., Melbye M., Sörensen P., Frisch M., Andersen P.K. et al.: “A prospective study showing long-term infection with human papillomavirus 16 before the development of cervical carcinoma in situ”. Cancer Res., 2000, 60,6027.

[55] Cuschieri K.S., Cubie H.A., Whitley M.W., Gilkison G., Arends M.J, Graham C. et al.: “Persistent high risk HPV infection associated with development of cervical neoplasia in a prospective population study”. J. Clin. Pathol., 2005, 58, 946.

[56] Bory J.P., Cucherousset J., Lorenzato M., Gabriel R., Quereux C., Birembaut P. et al.: “Recurrent human papillomavirus infection detected with the hybrid capture II assay selects women with normal cervical smears at risk for developing high gradecervical lesions: a longitudinal study of 3,091 women”. Int. J. Cancer, 2002, 102, 519.

[57] Harris T.G., Kulasingam S.L., Kiviat N.B., Mao C., Agoff S.N., Feng Q. et al.: “Cigarette smoking, oncogenic human papillomavirus, Ki-67 antigen, and cervical intraepithelial neoplasia”. Am. J. Epidemiol., 2004, 159, 834.

[58] ter Harmsel B., Smedts F., Kuijpers J., van Muyden R., Oosterhuis W., Quint W.: “Relationship between human papillomavirus type 16 in the cervix and intraepithelial neoplasia”. Obstet. Gynecol., 1999, 93, 46.

[59] Moscicki A.B., Shiboski S., Broering J., Powell K., Clayton L., Jay N. et al.: “The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women”. J. Pediatr., 1998, 132, 277.

[60] Saito J., Sumiyoshi M., Nakatani H., Ikeda M., Hoshiar H., Noda K.: “Dysplasia and HPV infection initially detected by DNA analysis in cytomorphologically normal cervical smears”. Int. J. Gynaecol. Obstet., 1995, 51, 43.

[61] Peto J., Gilham C., Deacon J., Taylor C., Evans C., Binns W. et al.: “Cervical HPV infection and neoplasia in a large population-based prospective study: the Manchester cohort”. Br. J. Cancer, 2004, 91, 942.

[62] Beskow A.H., Josefsson A.M., Gyllensten U.B.: “HLA class II alleles associated with infection by HPV16 in cervical cancer in situ”. Int. J. Cancer, 2001, 93, 817.

[63] Syrjänen K., Shabalova I., Naud P., Sarian L., Derchain S., Kozachenko V. et al.: “Cofactors of high-risk human papillomavirus (HPV) infections display unique profiles in incident CIN1, CIN2 and CIN3. Analysis of the combined prospective cohort of the NIS* and LAMS studies”. Int. J. STD & AIDS 2010, in press.

[64] Syrjänen S., Shabalova I.P., Petrovichev N., Kozachenko V.P., Zakharova T., Pajanidi A. et al.: “Human Papillomavirus testing and conventional PAP smear cytology as optional screening tools of women at different risk for cervical cancer in countries of former Soviet Union”. J. Lower Genital Tract. Dis., 2002, 6, 97.

[65] Syrjänen K., Naud P., Derchain S.M., Roteli-Martins C., Longatto-Filho A., Tatti S. et al.: “Comparing PAP smear cytology, aided visual inspection, screening colposcopy, cervicography and HPV testing as optional screening tools in Latin America. Study design and baseline data of the LAMS Study”. Anticancer Res., 2005, 25, 3469.

[66] Longatto-Filho A., Maeda M.Y.S., Eržen M., Branca M., Roteli-Martins C., Naud P. et al.: “Conventional PAP smear and liquid-based cytology as screening tools in low-resource settings of Latin America. Experience of the Latin American Screening Study”. Acta Cytol., 2005, 49, 500.

[67] Sarian L., Derchain S.M., Naud P., Roteli-Martins C., Longatto-Filho A., Tatti S. et al.: “Evaluation of visual inspection with acetic acid (VIA), Lugol’s iodine (VILI) cervical cytology and HPVtesting as cervical screening tools in Latin America. This report refers to partial results from the LAMS (Latin American Screening) study”. J. Med. Screen, 2005, 12, 142.

[68] Longatto-Filho A., Eržen M., Branca M., Roteli-Martins C., Naud P., Derchain S. et al.: “Human papillomavirus (HPV) testing as an optional screening tool in low-resource settings of Latin America. Experience from the LAMS Study”. Int. J. Gynecol. Cancer, 2006, 16, 955.

[69] Hammes L.S., Naud P., Passos E., Rivoire W., Matos J., Brouwers K., Syrjänen K.J.: “Value of the International Federation of Colposcopy and Cervical Pathology (IFCPC) terminology in predicting cervical pathology”. J. Lower Genital Tract. Dis., 2007, 11, 158-165.

[70] Diggle P.J., Liang K.-Y., Zeger S.L.: “Analysis of Longitudinal Data”, 1st edition, Oxford, Oxford University Press, 1994.

[71] Hardin J., Hilbe J.M.: “Generalized estimating equations”. Boca Raton, FL, Chapman & Hall/CRC, 2003.

[72] Syrjänen K., Väyrynen M., Saarikoski S., Mäntyjärvi R., Parkkinen S., Hippeläinen M., Castren O.: “Natural history of cervical Human papillomavirus (HPV) infections based on prospective follow-up”. Brit. J. Obstet. Gynaecol., 1985, 92, 1086.

[73] Syrjänen K., Mäntyjärvi R., Saarikoski S., Väyrynen M., Syrjänen S., Parkkinen S. et al.: “Factors associated with progression of cervical Human papillomavirus (HPV) infections into carcinoma in situ during a long-term prospective follow-up”. Brit. J. Obstet. Gynaecol., 1988, 95, 1096.

[74] Kataja V., Syrjänen S., Yliskoski M., Hippeläinen M., Väyrynen M., Saarikoski S. et al.: “Risk factors associated with cervical human papillomavirus (HPV) infections: A case-control study”. Am. J. Epidemiol., 1993, 138, 735.

[75] Syrjänen K.J.: “Spontaneous evolution of intraepithelial lesions according to the grade and type of the implicated HPV”. Eur. J. Obstet. Gynecol. Reprod. Biol., 1996, 65, 45.

[76] Syrjänen K.J.: “Biological behaviour of cervical intraepithelial neoplasia”. In: Franco E., Monsonego J. (eds.): “New Developments in Cervical Cancer Screening and Prevention”. Oxford, Blackwell Science, 1997, 93.

[77] Syrjänen K.J.: “Natural history of HPV infections: Recent developments”. In: Monsonego J. (ed.). 5th International Multidisciplinary Congress EUROGIN 2003. Monduzi Editore, Milano 2003, 1.

[78] Costa S., Simone P.D., Venturoli S., Cricca M., Zerbini M.L., Musiani M. et al.: “Factors predicting Human papillomavirus (HPV) clearance in cervical intraepithelial neoplasia (CIN) lesions treated by conization”. Gynecol. Oncol., 2003, 90, 358.

[79] Louvanto K., Rintala M.A., Syrjänen K.J., Grénman S.E., Syrjänen S.M.: “Genotype-specific persistence of genital high- and low-risk human papillomavirus (HPV) infections in women followed-up for 6 years in the Finnish Family HPV Study”. J. Infect. Dis., 2010, 202, 436.

[80] De Villiers E.M., Fauquet C., Broker T.R., Bernard H.U., zur Hausen H.: “Classification of papillomaviruses”. Virology, 2004, 324, 17.

[81] Wang S.S., Zuna R.E., Wentzensen N., Dunn S.T., Sherman M.E., Gold M.A. et al.: “Human papillomavirus cofactors by disease progression and human papillomavirus types in the study to understand cervical cancer early endpoints and determinants”. Cancer Epidemiol. Biomarkers Prev., 2009, 18, 113.

[82] Belinson S., Smith J.S., Myers E., Olshan A., Belinson J., Pretorius R. et al.: “Descriptive evidence that risk profiles for cervicalintraepithelial neoplasia 1, 2, and 3 are unique”. Cancer Epidemiol. Biomarkers Prev., 2008, 17, 2350.

[83] Moscicki A.B., Ma Y., Wibbelsman C., Powers A., Darragh T.M., Farhat S. et al.: “Risks for Cervical Intraepithelial Neoplasia 3 Among Adolescents and Young Women With Abnormal Cytology”. Obstet. Gynecol., 2008, 112, 1335.

[84] Östor A.G.: “Natural history of cervical intraepithelial neoplasia a critical review”. Int. J. Gynecol. Pathol., 1993, 12, 186.

[85] Louvanto K., Syrjänen K.J., Rintala M.A., Grénman S.E., Syrjänen S.M.: “Human papillomavirus (HPV) and other predictors ofincident CIN among young mothers prospectively followed-up for 6 years in the Finnish Family HPV Study”. BMC Infect. Dis. Submitted.