Human papillomavirus genotype-specific risks for cervical intraepithelial lesions

Mari Nygård, Bo T Hansen, Susanne K Kjaer, Maria Hortlund, Laufey Tryggvadóttir, Christian Munk, Camilla Lagheden, Lara G Sigurdardottir, Suzanne Campbell, Kai-Li Liaw, Joakim Dillner, Mari Nygård, Bo T Hansen, Susanne K Kjaer, Maria Hortlund, Laufey Tryggvadóttir, Christian Munk, Camilla Lagheden, Lara G Sigurdardottir, Suzanne Campbell, Kai-Li Liaw, Joakim Dillner

Abstract

Prevalence of different HPV genotypes is changing after HPV vaccination. The associated risks are needed for optimizing cervical cancer screening.To estimate HPV type-specific prevalence, odds ratio (OR), and positive predictive value (PPV) for cervical cytological abnormalities, we determined 41 different HPV genotypes in cervical samples from a population-based sample of 8351 women aged 18-51 years before HPV vaccination era (V501-033; NCT01077856).Prevalence of HPV16 was 4.9% (95% CI: 4.4-5.5) with the PPV for high-grade cytology 11.2%, and OR 11.9 (95% CI: 8.5-16.5). Carcinogenic HPVs included in the nonavalent vaccine (HPV16,18,31,33,45,52,58) had a population prevalence of 14.4% (95% CI: 13.5-15.4), with PPV of 8.0% (95% CI: 6.8-9.3) and OR 23.7 (95% CI: 16.0-63.5) for high-grade cytology. HPV types currently included in most screening tests, but not vaccinated against (HPV35,39,51,56,59,66,68) had a joint prevalence of 8.5% (95% CI: 7.8-9.2) with PPV of 4.4% (95% CI: 3.3-5.7) and OR of 2.9 (95% CI: 2.0-4.0) for high-grade cytology. The other 27 non-carcinogenic genotypes had a prevalence of 11.8%, PPV of 2.9% (95% CI:2.1-3.9), and OR 1.5 (95% CI: 1.1-2.2.) for high-grade cytology.These results suggest that HPV screening tests in the post-vaccination era might perform better if restricted to the HPV types in the nonavalent vaccine and screening for all 14 HPV types might result in suboptimal balance of harms and benefits.

Keywords: Denmark; Iceland; Norway; Sweden; high-risk HPV; liquid-based cytology; low-risk HPV; population-based prevalence.

Conflict of interest statement

Mari Nygård has received research grants through her affiliating institute from MSD Norway. Bo T. Hansen and Suzanne Campbell report that their affiliating institute received grants from MSD Norway during the conduct of the study. Susanne K. Kjaer reports lecture fees from Sanofi Pasteur, MSD, and Merck & Co., Inc., Kenilworth, NJ, USA, and scientific advisory board fee and unrestricted research grants through her institution from Merck & Co., Inc., Kenilworth, NJ, USA. Maria Hortlund, Camilla Lagheden, and Joakim Dillner report that their affiliating institute received grants from Sanofi Pasteur, MSD, and Merck & Co., Inc., Kenilworth, NJ, USA. Christian Munk reports that he received lecture fees and support for conference participation from Sanofi Pasteur, MSD. Laufey Tryggvadóttir and Lara G. Sigurdardottir report that their affiliating institute received research grants from MSD Denmark ApS. Kai-Li Liaw is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Kenilworth, NJ, USA.

Figures

Figure 1.
Figure 1.
The age-specific prevalence of carcinogenic HPV types and non-carcinogenic HPV types among those with normal cytology. Abbreviation: HPV = human papillomavirus
Figure 2.
Figure 2.
Adjusted odds ratios with 95% CIs for high-grade (A) and low-grade (B) cytology diagnoses among women positive to specified HPV type with HPV infection of the specified type compared with women having normal cytology. Carcinogenic HPV types are marked in red. Abbreviations: CI = confidence interval; HPV = human papillomavirus; OR = odds ratio

References

    1. Zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. 2002;2(5):342–50. doi:10.1038/nrc798.
    1. Kinney WK, Perkins RB, Sawaya GF. Equal management of equal risks: what should be used as the standard for cervical cancer prevention? J Low Genit Tract Dis. 2018;22(3):237–41. doi:10.1097/LGT.0000000000000402.
    1. IARC Working group . IARC handbooks of cancer prevention: cervix cancer screening. Vol. 10. Lyon (France): IARC Press; 2005. Available at
    1. European Commission . European guidelines for quality assurance in cervical cancer screening. In: editors, Anttila A, Arbyn M, De Vuyst H, Dillner J, Dillner L, Franceschi S, Patnick J, Ronco G, Segnan N, Suonio E, et al.Luxembourg: European Union; 2015. Available at
    1. Melnikow J, Henderson JT, Burda BU, Senger CA, Durbin S, Weyrich MS. Screening for cervical cancer with high-risk human papillomavirus testing: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2018;320(7):687–705. doi:10.1001/jama.2018.10400.
    1. Kjaer SK, Nygard M, Dillner J, Brooke Marshall J, Radley D, Li M, Munk C, Hansen BT, Sigurdardottir LG, Hortlund M, et al. A 12-year follow-up on the long-term effectiveness of the quadrivalent human papillomavirus vaccine in 4 Nordic countries. Clin Infect Dis. 2018;66(3):339–45. doi:10.1093/cid/cix797.
    1. Lehtinen M, Lagheden C, Luostarinen T, Eriksson T, Apter D, Harjula K, Kuortti M, Natunen K, Palmroth J, Petäjä T, et al. Ten-year follow-up of human papillomavirus vaccine efficacy against the most stringent cervical neoplasia end-point—registry-based follow-up of three cohorts from randomized trials. BMJ Open. 2017;7(8):e015867. doi:10.1136/bmjopen-2017-015867.
    1. Schiller JT, Castellsague X, Garland SM. A review of clinical trials of human papillomavirus prophylactic vaccines. Vaccine. 2012;30(Suppl 5):F123–138. doi:10.1016/j.vaccine.2012.04.108.
    1. Clifford GM, Gallus S, Herrero R, Muñoz N, Snijders PJ, Vaccarella S, Anh P, Ferreccio C, Hieu NT, Matos E, et al. Worldwide distribution of human papillomavirus types in cytologically normal women in the International agency for research on cancer HPV prevalence surveys: a pooled analysis. Lancet. 2005;366(9490):991–98. doi:10.1016/S0140-6736(05)67069-9.
    1. de Sanjose S, Diaz M, Castellsague X, Clifford G, Bruni L, Muñoz N, Bosch FX. Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. Lancet Infect Dis. 2007;7(7):453–59. doi:10.1016/S1473-3099(07)70158-5.
    1. Bzhalava D, Guan P, Franceschi S, Dillner J, Clifford G. A systematic review of the prevalence of mucosal and cutaneous human papillomavirus types. Virology. 2013;445(1–2):224–31. doi:10.1016/j.virol.2013.07.015.
    1. Karolinska Institutet . International Human Papillomavirus (HPV) Reference Center. [Accessed September16, 2018].
    1. Schiffman M, Wentzensen N. Human papillomavirus infection and the multistage carcinogenesis of cervical cancer. Cancer Epidemiol Biomarkers Prev. 2013;22(4):553–60. doi:10.1158/1055-9965.EPI-12-1406.
    1. Kjaer SK, Frederiksen K, Munk C, Iftner T. Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence. J Natl Cancer Inst. 2010;102(19):1478–88. doi:10.1093/jnci/djq356.
    1. Dillner J, Rebolj M, Birembaut P, Petry KU, Szarewski A, Munk C, de Sanjose S, Naucler P, Lloveras B, Kjaer S, et al. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ. 2008;337:a1754. doi:10.1136/bmj.a1754.
    1. IARC Working Group . IARC Monographs - 100B: human Papillomaviruses. Lyon (France): WHO Press: International agency for research on cancer; 2012. .
    1. Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Benbrahim-Tallaa L, Guha N, Freeman C, Galichet L, et al. A review of human carcinogens–Part B: biological agents. Lancet Oncol. 2009;10(4):321–22. doi:10.1016/S1470-2045(09)70096-8.
    1. Pedersen K, Burger EA, Nygard M, Kristiansen IS, Kim JJ. Adapting cervical cancer screening for women vaccinated against human papillomavirus infections: the value of stratifying guidelines. Eur J Cancer. 2018;91:68–75. doi:10.1016/j.ejca.2017.12.018.
    1. Petry KU, Bollaerts K, Bonanni P, Stanley M, Drury R, Joura E, Kjaer SK, Meijer CJLM, Riethmuller D, Soubeyrand B, et al. Estimation of the individual residual risk of cervical cancer after vaccination with the nonavalent HPV vaccine. Hum Vaccin Immunother. 2018;14(7):1800–06. doi:10.1080/21645515.2018.1450125.
    1. Nygard M, Hansen BT, Dillner J, Munk C, Oddsson K, Tryggvadottir L, Hortlund M, Liaw K-L, Dasbach EJ, Kjær SK, et al. Targeting human papillomavirus to reduce the burden of cervical, vulvar and vaginal cancer and pre-invasive neoplasia: establishing the baseline for surveillance. PLoS One. 2014;9(2):e88323. doi:10.1371/journal.pone.0088323.
    1. Baandrup L, Blomberg M, Dehlendorff C, Sand C, Andersen KK, Kjaer SK. Significant decrease in the incidence of genital warts in young danish women after implementation of a national human papillomavirus vaccination program. Sex Transm Dis. 2013;40(2):130–35. doi:10.1097/OLQ.0b013e31827bd66b.
    1. Baldur-Felskov B, Dehlendorff C, Munk C, Kjaer SK. Early impact of human papillomavirus vaccination on cervical neoplasia–nationwide follow-up of young Danish women. J Natl Cancer Inst. 2014;106(3):djt460. doi:10.1093/jnci/djt460.
    1. Leval A, Herweijer E, Ploner A, Eloranta S, Fridman Simard J, Dillner J, Young C, Netterlid E, Sparén P, Arnheim-Dahlström L, et al. Quadrivalent human papillomavirus vaccine effectiveness: a Swedish national cohort study. J Natl Cancer Inst. 2013;105(7):469–74. doi:10.1093/jnci/djt032.
    1. Feiring B, Laake I, Bakken IJ, Greve-Isdahl M, Wyller VB, Håberg SE, Magnus P, Trogstad L. HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-based study from Norway. Vaccine. 2017;35(33):4203–12. doi:10.1016/j.vaccine.2017.06.031.
    1. Vaccarella S, Franceschi S, Engholm G, Lonnberg S, Khan S, Bray F. 50 years of screening in the Nordic countries: quantifying the effects on cervical cancer incidence. Br J Cancer. 2014;111(5):965–69. doi:10.1038/bjc.2014.362.
    1. Elfstrom KM, Sparen P, Olausson P, Almstedt P, Strander B, Dillner J. Registry-based assessment of the status of cervical screening in Sweden. Journal of Medical Screening. 2016;23(4):217–26. doi:10.1177/0969141316632023.
    1. Solomon D, Nayar R. The Bethesda System for reporting cervical cytology. Second. New-York, USA: Springer-Verlag New-York, Inc.; 2004.
    1. Soderlund-Strand A, Eklund C, Kemetli L, Grillner L, Törnberg S, Dillner J, Dillner L. Genotyping of human papillomavirus in triaging of low-grade cervical cytology. Am J Obstet Gynecol. 2011;205(2):145e1–16. doi:10.1016/j.ajog.2011.03.056.
    1. Eliasen M, Kaer SK, Munk C, Nygård M, Sparén P, Tryggvadottir L, Liaw K-L, Grønbæk M. The relationship between age at drinking onset and subsequent binge drinking among women. Eur J Public Health. 2009;19(4):378–2. doi:10.1093/eurpub/ckp023.
    1. Hansen BT, Kjaer SK, Munk C, Tryggvadottir L, Sparén P, Hagerup-Jenssen M, Liaw K-L, Nygård M. Early smoking initiation, sexual behavior and reproductive health - a large population-based study of Nordic women. Prev Med. 2010;51(1):68–72. doi:10.1016/j.ypmed.2010.03.014.
    1. Jensen KE, Munk C, Sparen P, Tryggvadottir L, Liaw KL, Dasbach E, NYGÅRD M, KJAER SK. Women’s sexual behavior. Population-based study among 65,000 women from four Nordic countries before introduction of human papillomavirus vaccination. Acta Obstet Gynecol Scand. 2011;90(5):459–67. doi:10.1111/j.1600-0412.2010.01066.x.
    1. Olesen TB, Jensen KE, Nygard M, Tryggvadottir L, Sparén P, Hansen BT, Liaw K-L, Kjaer SK. Young age at first intercourse and risk-taking behaviours–a study of nearly 65 000 women in four Nordic countries. Eur J Public Health. 2012;22(2):220–24. doi:10.1093/eurpub/ckr055.
    1. R Core Team . R: A language and environment for statistical computing. Vienna (Austria): R Foundation for Statistical Computing; 2012.
    1. Lumley T. Complex surveys: a guide to analysis using R. Hoboken (NJ): Wiley & Sons; 2010. Available at
    1. Korn EL, Graubard BI. Confidence intervals for proportions with small expected number of positive counts estimated from survey data. Surv Methodol. 1998;24:193–201.
    1. Lewandowski GS, Vaccarello L, Copeland LJ. Surgical issues in the management of carcinoma of the cervix in pregnancy. Surg Clin North Am. 1995;75(1):89–100. doi:10.1016/S0039-6109(16)46536-9.
    1. Orumaa M, Kjaer SK, Dehlendorff C, Munk C, Olsen AO, Hansen BT, Campbell S, Nygård M. The impact of HPV multi-cohort vaccination: real-world evidence of faster control of HPV-related morbidity. Vaccine. 2020;38(6):1345–51. doi:10.1016/j.vaccine.2019.12.016.
    1. Bonde J, Rebolj M, Ejegod DM, Preisler S, Lynge E, Rygaard C. HPV prevalence and genotype distribution in a population-based split-sample study of well-screened women using CLART HPV2 human papillomavirus genotype microarray system. BMC Infect Dis. 2014;14(1):413. doi:10.1186/1471-2334-14-413.
    1. Bruni L, Diaz M, Castellsague X, Ferrer E, Bosch FX, de Sanjose S. Cervical human papillomavirus prevalence in 5 continents: meta-analysis of 1 million women with normal cytological findings. J Infect Dis. 2010;202(12):1789–99. doi:10.1086/657321.
    1. von Karsa L, Arbyn M, De Vuyst H, Dillner J, Dillner L, Franceschi S, Patnick J, Ronco G, Segnan N, Suonio E, et al. European guidelines for quality assurance in cervical cancer screening. Summary of the supplements on HPV screening and vaccination. Papillomavirus Res. 2015;1:22–31. doi:10.1016/j.pvr.2015.06.006.
    1. Hashim D, Engesaeter B, Baadstrand Skare G, Castle PE, Bjørge T, Tropé A, Nygård M. Real-world data on cervical cancer risk stratification by cytology and HPV genotype to inform the management of HPV-positive women in routine cervical screening. Br J Cancer. 2020;122(11):1715–23. doi:10.1038/s41416-020-0790-1.
    1. Lee EH, Um TH, Chi HS, Hong YJ, Cha YJ. Prevalence and distribution of human papillomavirus infection in Korean women as determined by restriction fragment mass polymorphism assay. J Korean Med Sci. 2012;27(9):1091–97. doi:10.3346/jkms.2012.27.9.1091.
    1. Chan PK, Ho WC, Yu MY, Pong WM, Chan AC, Chan AK, Cheung T-H, Wong MCS, To K-F, Ng H-K, et al. Distribution of human papillomavirus types in cervical cancers in Hong Kong: current situation and changes over the last decades. Int J Cancer. 2009;125(7):1671–77. doi:10.1002/ijc.24495.
    1. Malagon T, Drolet M, Boily MC, Franco EL, Jit M, Brisson J, Brisson M. Cross-protective efficacy of two human papillomavirus vaccines: a systematic review and meta-analysis. Lancet Infect Dis. 2012;12(10):781–89. doi:10.1016/S1473-3099(12)70187-1.
    1. Hansen BT, Kjaer SK, Arnheim-Dahlstrom L, Liaw KL, Juul KE, Thomsen LT, Frederiksen K, Elfström KM, Munk C, Nygård M, et al. Age at first intercourse, number of partners and sexually transmitted infection prevalence among Danish, Norwegian and Swedish women: estimates and trends from nationally representative cross-sectional surveys of more than 100 000 women. Acta Obstet Gynecol Scand. 2020;99(2):175–85. doi:10.1111/aogs.13732.
    1. Chow EP, Danielewski JA, Fehler G, Tabrizi SN, Law MG, Bradshaw CS, Garland SM, Chen MY, Fairley CK. Human papillomavirus in young women with chlamydia trachomatis infection 7 years after the Australian human papillomavirus vaccination programme: a cross-sectional study. Lancet Infect Dis. 2015;15(11):1314–23. doi:10.1016/S1473-3099(15)00055-9.
    1. Landy R, Windridge P, Gillman MS, Sasieni PD. What cervical screening is appropriate for women who have been vaccinated against high risk HPV? A simulation study. Int J Cancer. 2017;142(4):709–18. doi:10.1002/ijc.31094.
    1. Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci (Lond). 2006;110(5):525–41. doi:10.1042/CS20050369.
    1. Egawa N, Egawa K, Griffin H, Doorbar J. Human papillomaviruses; epithelial tropisms, and the development of neoplasia. Viruses. 2015;7(7):3863–90. doi:10.3390/v7072802.
    1. Carreon JD, Sherman ME, Guillen D, Solomon D, Herrero R, Jerónimo J, Wacholder S, Rodríguez AC, Morales J, Hutchinson M, et al. CIN2 is a much less reproducible and less valid diagnosis than CIN3: results from a histological review of population-based cervical samples. Int J Gynecol Pathol. 2007;26(4):441–46. doi:10.1097/pgp.0b013e31805152ab.
    1. Ismail SM, Colclough AB, Dinnen JS, Eakins D, Evans DM, Gradwell E, O’Sullivan JP, Summerell JM, Newcombe RG. Observer variation in histopathological diagnosis and grading of cervical intraepithelial neoplasia. BMJ. 1989;298(6675):707–10. doi:10.1136/bmj.298.6675.707.
    1. Robertson AJ, Anderson JM, Beck JS, Burnett RA, Howatson SR, Lee FD, Lessells AM, McLaren KM, Moss SM, Simpson JG, et al. Observer variability in histopathological reporting of cervical biopsy specimens. J Clin Pathol. 1989;42(3):231–38. doi:10.1136/jcp.42.3.231.
    1. Stoler MH, Schiffman M. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. Jama. 2001;285(11):1500–05. doi:10.1001/jama.285.11.1500.
    1. Skare G, Lönnberg S, Bjorge T, Trope A. Masseundersøkelsen mot livmorhalskreft. Årsrapport 2015: Kreftregisteret. Institutt for populasjonsbasert kreftforskning. Oslo, Norway: Kreftregisteret; 2016.
    1. Dillner J, Nygard M, Munk C, Hortlund M, Hansen BT, Lagheden C, Liaw K-L, Kjaer SK. Decline of HPV infections in Scandinavian cervical screening populations after introduction of HPV vaccination programs. Vaccine. 2018;36(26):3820–29. doi:10.1016/j.vaccine.2018.05.019.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa