Human papillomavirus genotype and viral load agreement between paired first-void urine and clinician-collected cervical samples

Severien Van Keer, Wiebren A A Tjalma, Jade Pattyn, Samantha Biesmans, Zoë Pieters, Xaveer Van Ostade, Margareta Ieven, Pierre Van Damme, Alex Vorsters, Severien Van Keer, Wiebren A A Tjalma, Jade Pattyn, Samantha Biesmans, Zoë Pieters, Xaveer Van Ostade, Margareta Ieven, Pierre Van Damme, Alex Vorsters

Abstract

The performance and acceptability of first-void urine as specimen for the detection of HPV DNA in a Belgian referral population was evaluated using an optimized sample collection and processing protocol. One hundred ten first-void urine and cervical samples were collected from 25- to 64-year-old women who were referred for colposcopy (January-November 2016). Paired samples were analyzed by the Riatol qPCR HPV genotyping assay. Acceptability data were gathered through questionnaires (NCT02714127). A higher high-risk HPV DNA prevalence was observed in first-void urine (n = 76/110) compared to cervical samples (n = 73/110), with HPV31 and HPV16/31 being most prevalent correspondingly. For both any and high-risk HPV DNA, good agreement was observed between paired samples (Cohen's Kappa of 0.660 (95% CI: 0.486-0.833) and 0.688 (95% CI: 0.542-0.835), respectively). In addition, significant positive correlations in HPV copies (per microliter of DNA extract) between paired samples were observed for HPV16 (rs = 0.670; FDR (false discovery rate)-adjusted p = 0.006), HPV18 (rs = 0.893; FDR-adjusted p = 0.031), HPV31 (rs = 0.527; FDR-adjusted p = 0.031), HPV53 (rs = 0.691; FDR-adjusted p = 0.017), and HPV68 (rs = 0.569; FDR-adjusted p = 0.031). First-void urine sampling using a first-void urine collection device was preferred over a clinician-collected cervical sample. And mostly, first-void urine sampling at home was favored over collection at the clinic or the general practitioner's office. First-void urine sampling is a highly preferred, non-invasive method that ensures good agreement in HPV DNA (copies) with reference cervical samples. It is particularly interesting as a screening technique to reach non-participants, and its clinical performance should be further evaluated.

Conflict of interest statement

Conflict of interest

P. Van Damme and A. Vorsters are co-founders of Novosanis (Belgium), a spin-off company of the University of Antwerp. All other authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (UZA/University of Antwerp, Belgium (B300201525585)) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Figures

Fig. 1
Fig. 1
Flow diagram for the inclusion of study participants, samples, and medical records. All 127 eligible patients received a questionnaire containing, next to personal, inquiries about the acceptability of first-void urine (FVU) collection. Surveys from 124 out of 127 women who provided a Colli-Pee® (Novosanis, Belgium) collected FVU sample were included to investigate acceptability. aWhen unavailable at D0 (day of study visit/FVU collection), the colposcopy, LBC (liquid based cytology), and histology results from D0 ± 3 months were included for data analysis instead. Thus, two additional colposcopy results were included, as well as one LBC and six histology results. No results were included from D0 ± 3 months if the woman underwent surgical treatment for high-grade cervical abnormalities in this period
Fig. 2
Fig. 2
Prevalence of HPV genotypes according to sample type. The sum of cervical (CS; blue bars) and first-void urine samples (FVU; green bars) observed as positive for HPV are separately displayed on the y-axis for each genotype (x-axis). Ranking of HPV genotypes was performed according to the combined number of CS and FVU samples that tested positive
Fig. 3
Fig. 3
HPV genotype distribution and agreement of paired cervical (CS) and first-void urine samples (FVU). The number of samples that tested positive in both FVU and CS are indicated by turquoise bars. Discordant samples for each genotype are separately indicated by blue (CS only) and green (FVU only) bars. aThe Cohen’s Kappa (κ) was judged as follows: κ ≤ 0.20, poor; 0.21 ≤ κ ≤ 0.40, fair; 0.41 ≤ κ ≤ 0.60, moderate; 0.61 ≤ κ ≤ 0.80, good; and κ ≥ 0.81, very good agreement [48]. 95% CI 95% confidence interval, NV Due to the zero cell count in the discordant pairs for HPV11, κ was not calculated
Fig. 4
Fig. 4
Distribution of log transformed HPV copies in paired cervical (CS) and first-void urine samples (FVU). The log transformed HPV copies per (A) microliter of DNA extract and (B) per hDNA equivalent in CS (blue bars) and FVU (green bars) are displayed on the y-axis for each genotype (x-axis). Significantly different median log HPV copies between paired samples are indicated by an asterisk (Wilcoxon matched pairs signed rank test), when p-values adjusted for multiple testing using the false discovery rate (FDR) were smaller than 0.05

References

    1. GLOBOCAN (2012) Cervical cancer: estimated incidence, mortality and prevalence worldwide in 2012. . Accessed 1 Sept 2017
    1. Van Damme P, Bonanni P, Bosch FX, Joura E, Kjaer SK, Meijer CJ, Petry KU, Soubeyrand B, Verstraeten T, Stanley M. Use of the nonavalent HPV vaccine in individuals previously fully or partially vaccinated with bivalent or quadrivalent HPV vaccines. Vaccine. 2016;34(6):757–761. doi: 10.1016/j.vaccine.2015.12.063.
    1. Kreimer AR, Struyf F, Del Rosario-Raymundo MR, Hildesheim A, Skinner SR, Wacholder S, Garland SM, Herrero R, David MP, Wheeler CM, Costa Rica Vaccine Trial Study Group A. Gonzalez P, Jimenez S, Lowy DR, Pinto LA, Porras C, Rodriguez AC, Safaeian M, Schiffman M, Schiller JT, Schussler J, Sherman ME, Authors PSG, Bosch FX, Castellsague X, Chatterjee A, Chow SN, Descamps D, Diaz-Mitoma F, Dubin G, Germar MJ, Harper DM, Lewis DJ, Limson G, Naud P, Peters K, Poppe WA, Ramjattan B, Romanowski B, Salmeron J, Schwarz TF, Teixeira JC, Tjalma WA, Collaborators HPPIC-PI. Group GSKVCSS Efficacy of fewer than three doses of an HPV-16/18 AS04-adjuvanted vaccine: combined analysis of data from the Costa Rica vaccine and PATRICIA trials. Lancet Oncol. 2015;16(7):775–786. doi: 10.1016/S1470-2045(15)00047-9.
    1. Arbyn M, Ronco G, Anttila A, Meijer CJLM, Poljak M, Ogilvie G, Koliopoulos G, Naucler P, Sankaranarayanan R, Peto J. Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer. Vaccine. 2012;30:F88–F99. doi: 10.1016/j.vaccine.2012.06.095.
    1. Ronco G, Dillner J, Elfstrom KM, Tunesi S, Snijders PJ, Arbyn M, Kitchener H, Segnan N, Gilham C, Giorgi-Rossi P, Berkhof J, Peto J, Meijer CJ, International HPVswg Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 2014;383(9916):524–532. doi: 10.1016/S0140-6736(13)62218-7.
    1. Van Keer S, Pattyn J, Tjalma WAA, Van Ostade X, Ieven M, Van Damme P, Vorsters A. First-void urine: a potential biomarker source for triage of high-risk human papillomavirus infected women. Eur J Obstet Gynecol Reprod Biol. 2017;216:1–11. doi: 10.1016/j.ejogrb.2017.06.036.
    1. Waller J, Bartoszek M, Marlow L, Wardle J. Barriers to cervical cancer screening attendance in England: a population-based survey. J Med Screen. 2009;16(4):199–204. doi: 10.1258/jms.2009.009073.
    1. Arrossi S, Ramos S, Straw C, Thouyaret L, Orellana L. HPV testing: a mixed-method approach to understand why women prefer self-collection in a middle-income country. BMC Public Health. 2016;16:832. doi: 10.1186/s12889-016-3474-2.
    1. Arbyn M, Verdoodt F, Snijders PJ, Verhoef VM, Suonio E, Dillner L, Minozzi S, Bellisario C, Banzi R, Zhao FH, Hillemanns P, Anttila A. Accuracy of human papillomavirus testing on self-collected versus clinician-collected samples: a meta-analysis. Lancet Oncol. 2014;15(2):172–183. doi: 10.1016/S1470-2045(13)70570-9.
    1. von Karsa L, Arbyn M, De Vuyst H, Dillner J, Dillner L, Franceschi S, Patnick J, Ronco G, Segnan N, Suonio E, Törnberg S, Anttila A. 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. Tamalet C, Le Retraite L, Leandri FX, Heid P, Sancho Garnier H, Piana L. Vaginal self-sampling is an adequate means of screening HR-HPV types in women not participating in regular cervical cancer screening. Clin Microbiol Infect: Off Publ Eur Soc Clin Microbiol Infect Dis. 2013;19(1):E44–E50. doi: 10.1111/1469-0691.12063.
    1. Racey CS, Withrow DR, Gesink D. Self-collected HPV testing improves participation in cervical cancer screening: a systematic review and meta-analysis. Can J Publ Health Rev Can Sante Publique. 2013;104(2):e159–e166.
    1. Verdoodt F, Jentschke M, Hillemanns P, Racey CS, Snijders PJ, Arbyn M. Reaching women who do not participate in the regular cervical cancer screening programme by offering self-sampling kits: a systematic review and meta-analysis of randomised trials. Eur J Cancer. 2015;51(16):2375–2385. doi: 10.1016/j.ejca.2015.07.006.
    1. Ducancelle A, Reiser J, Pivert A, Le Guillou-Guillemette H, Le Duc-Banaszuk AS, Lunel-Fabiani F. Home-based urinary HPV DNA testing in women who do not attend cervical cancer screening clinics. J Infect. 2015;71(3):377–384. doi: 10.1016/j.jinf.2015.05.001.
    1. Sellors JW, Lorincz AT, Mahony JB, Mielzynska I, Lytwyn A, Roth P, Howard M, Chong S, Daya D, Chapman W, Chernesky M. Comparison of self-collected vaginal, vulvar and urine samples with physician-collected cervical samples for human papillomavirus testing to detect high-grade squamous intraepithelial lesions. CMAJ. 2000;163(5):513–518.
    1. Senkomago V, Des Marais AC, Rahangdale L, Vibat CR, Erlander MG, Smith JS. Comparison of urine specimen collection times and testing fractions for the detection of high-risk human papillomavirus and high-grade cervical precancer. J Clin Virol. 2016;74:26–31. doi: 10.1016/j.jcv.2015.11.005.
    1. Leeman A, Del Pino M, Molijn A, Rodriguez A, Torne A, de Koning M, Ordi J, van Kemenade F, Jenkins D, Quint W (2017) HPV testing in first-void urine provides sensitivity for CIN2+ detection comparable to a physician-taken smear or brush-based self-sample: cross-sectional data from a triage population. BJOG: Int J Obstet Gynaecol 124(9):1356–1363. 10.1111/1471-0528.14682
    1. Burroni E, Bonanni P, Sani C, Lastrucci V, Carozzi F, Hpv ScreeVacc Working G, Iossa A, Andersson KL, Brandigi L, Di Pierro C, Confortini M, Levi M, Boccalini S, Indiani L, Sala A, Tanini T, Bechini A, Azzari C. Human papillomavirus prevalence in paired urine and cervical samples in women invited for cervical cancer screening. J Med Virol. 2015;87(3):508–515. doi: 10.1002/jmv.24085.
    1. Combita AL, Gheit T, Gonzalez P, Puerto D, Murillo RH, Montoya L, Vorsters A, Van Keer S, Van Damme P, Tommasino M, Hernandez-Suarez G, Sanchez L, Herrero R, Wiesner C. Comparison between urine and cervical samples for HPV DNA detection and typing in young women in Colombia. Cancer Prev Res (Phila) 2016;9(9):766–771. doi: 10.1158/1940-6207.CAPR-16-0038.
    1. Franceschi S, Chantal Umulisa M, Tshomo U, Gheit T, Baussano I, Tenet V, Tshokey T, Gatera M, Ngabo F, Van Damme P, Snijders PJ, Tommasino M, Vorsters A, Clifford GM. Urine testing to monitor the impact of HPV vaccination in Bhutan and Rwanda. Int J Cancer. 2016;139(3):518–526. doi: 10.1002/ijc.30092.
    1. Vorsters A, Micalessi I, Bilcke J, Ieven M, Bogers J, Van Damme P. Detection of human papillomavirus DNA in urine. A review of the literature. Eur J Clin Microbiol Infect Dis. 2012;31(5):627–640. doi: 10.1007/s10096-011-1358-z.
    1. Vorsters A, Van Keer S, Biesmans S, Hens A, De Coster I, Goossens H, Ieven M, Van Damme P (2016) Long-term follow-up of HPV infection using urine and cervical quantitative HPV DNA testing. Int J Mol Sci 17(5). 10.3390/ijms17050750
    1. Ducancelle A, Legrand MC, Pivert A, Veillon P, Le Guillou-Guillemette H, De Brux MA, Beby-Defaux A, Agius G, Hantz S, Alain S, Catala L, Descamps P, Postec E, Caly H, Charles-Petillon F, Labrousse F, Lunel F, Payan C. Interest of human papillomavirus DNA quantification and genotyping in paired cervical and urine samples to detect cervical lesions. Arch Gynecol Obstet. 2014;290(2):299–308.
    1. Payan C, Ducancelle A, Aboubaker MH, Caer J, Tapia M, Chauvin A, Peyronnet D, Le Hen E, Arab Z, Legrand MC, Tran A, Postec E, Tourmen F, Avenel M, Malbois C, De Brux MA, Descamps P, Lunel F. Human papillomavirus quantification in urine and cervical samples by using the Mx4000 and LightCycler general real-time PCR systems. J Clin Microbiol. 2007;45(3):897–901. doi: 10.1128/JCM.02022-06.
    1. Pathak N, Dodds J, Zamora J, Khan K. Accuracy of urinary human papillomavirus testing for presence of cervical HPV: systematic review and meta-analysis. BMJ. 2014;349:g5264. doi: 10.1136/bmj.g5264.
    1. Enerly E, Olofsson C, Nygard M. Monitoring human papillomavirus prevalence in urine samples: a review. Clin Epidemiol. 2013;5:67–79. doi: 10.2147/CLEP.S39799.
    1. Hagihara M, Yamagishi Y, Izumi K, Miyazaki N, Suzuki T, Kato H, Nishiyama N, Koizumi Y, Suematsu H, Mikamo H. Comparison of initial stream urine samples and cervical samples for detection of human papillomavirus. J Infect Chemother: Off J Jpn Soc Chemother. 2016;22(8):559–562. doi: 10.1016/j.jiac.2016.05.009.
    1. Sahasrabuddhe VV, Gravitt PE, Dunn ST, Brown D, Allen RA, Eby YJ, Smith K, Zuna RE, Zhang RR, Gold MA, Schiffman M, Walker JL, Castle PE, Wentzensen N. Comparison of human papillomavirus detections in urine, vulvar, and cervical samples from women attending a colposcopy clinic. J Clin Microbiol. 2014;52(1):187–192. doi: 10.1128/JCM.01623-13.
    1. Vorsters A, Van Damme P, Clifford G. Urine testing for HPV: rationale for using first void. BMJ. 2014;349:g6252. doi: 10.1136/bmj.g6252.
    1. Smith JS, Smith JB, Faherty BR, Isaacson SC, Des Marais AC, Fakner A, Rahangdale L, Vaughan LM (2017) Effect of urine preservative on HPV testing results among urine samples. In: HPV2017, Cape Town, South Africa
    1. Vorsters A, Van den Bergh J, Micalessi I, Biesmans S, Bogers J, Hens A, De Coster I, Ieven M, Van Damme P. Optimization of HPV DNA detection in urine by improving collection, storage, and extraction. Eur J Clin Microbiol Infect Dis. 2014;33(11):2005–2014. doi: 10.1007/s10096-014-2147-2.
    1. Schmitt M, Depuydt C, Benoy I, Bogers J, Antoine J, Arbyn M, Pawlita M, Group VS Multiple human papillomavirus infections with high viral loads are associated with cervical lesions but do not differentiate grades of cervical abnormalities. J Clin Microbiol. 2013;51(5):1458–1464. doi: 10.1128/JCM.00087-13.
    1. Wu Z, Qin Y, Yu L, Lin C, Wang H, Cui J, Liu B, Liao Y, Warren D, Zhang X, Chen W. Association between human papillomavirus (HPV) 16, HPV18, and other HR-HPV viral load and the histological classification of cervical lesions: results from a large-scale cross-sectional study. J Med Virol. 2017;89(3):535–541. doi: 10.1002/jmv.24645.
    1. Carcopino X, Henry M, Mancini J, Giusiano S, Boubli L, Olive D, Tamalet C. Significance of HPV 16 and 18 viral load quantitation in women referred for colposcopy. J Med Virol. 2012;84(2):306–313. doi: 10.1002/jmv.23190.
    1. Marongiu L, Godi A, Parry JV, Beddows S. Human papillomavirus 16, 18, 31 and 45 viral load, integration and methylation status stratified by cervical disease stage. BMC Cancer. 2014;14:384. doi: 10.1186/1471-2407-14-384.
    1. Depuydt CE, Jonckheere J, Berth M, Salembier GM, Vereecken AJ, Bogers JJ. Serial type-specific human papillomavirus (HPV) load measurement allows differentiation between regressing cervical lesions and serial virion productive transient infections. Cancer Med. 2015;4(8):1294–1302. doi: 10.1002/cam4.473.
    1. Depuydt CE, Criel AM, Benoy IH, Arbyn M, Vereecken AJ, Bogers JJ. Changes in type-specific human papillomavirus load predict progression to cervical cancer. J Cell Mol Med. 2012;16(12):3096–3104. doi: 10.1111/j.1582-4934.2012.01631.x.
    1. Bissett SL, Howell-Jones R, Swift C, De Silva N, Biscornet L, Parry JV, Saunders NA, Nathan M, Soldan K, Szarewski A, Cuzick J, Beddows S. Human papillomavirus genotype detection and viral load in paired genital and urine samples from both females and males. J Med Virol. 2011;83(10):1744–1751. doi: 10.1002/jmv.22167.
    1. Sehgal A, Gupta S, Parashari A, Sodhani P, Singh V (2009) Urine HPV-DNA detection for cervical cancer screening: prospects and prejudices. J Inst Obstet Gynaecol 29(7):583–589. 10.1080/01443610903061736
    1. IARC (2016) Agents classified by the IARC Monographs. vol 1–120. . Accessed 27 Oct. 2017
    1. Depuydt CE, Thys S, Beert J, Jonckheere J, Salembier G, Bogers JJ. Linear viral load increase of a single HPV-type in women with multiple HPV infections predicts progression to cervical cancer. Int J Cancer. 2016;139(9):2021–2032. doi: 10.1002/ijc.30238.
    1. Micalessi IM, Boulet GAV, Bogers JJ, Benoy IH, Depuydt CE. High-throughput detection, genotyping and quantification of the human papillomavirus using real-time PCR. Clin Chem Lab Med. 2012;50(4):655–661. doi: 10.1515/cclm.2011.835.
    1. Depuydt CE, Benoy IH, Beert JF, Criel AM, Bogers JJ, Arbyn M. Clinical validation of a type-specific real-time quantitative human papillomavirus PCR against the performance of hybrid capture 2 for the purpose of cervical cancer screening. J Clin Microbiol. 2012;50(12):4073–4077. doi: 10.1128/JCM.01231-12.
    1. Pattyn J, Dekoeijer, Van Keer S, Biesmans S, Ieven M, Beyers K, Vankerckhoven V, Van Damme P, Vorsters A (2017) HPV DNA detection in urine: effect of a first-void urine collection device and timing of collection. In: HPV2017, Cape Town, South Africa
    1. Greenland S. Small-sample bias and corrections for conditional maximum-likelihood odds-ratio estimators. Biostatistics. 2000;1(1):113–122. doi: 10.1093/biostatistics/1.1.113.
    1. Klaus B, Strimmer K (2015) fdrtool: estimation of (local) false discovery rates and higher criticism. R package version 1.2.15.
    1. Team RC (2017) R: A Language and Environment for Statistical Computing.
    1. Altman DG (1991) Practical statistics for medical research. Chapman and Hall/CRC
    1. Stanczuk G, Baxter G, Currie H, Lawrence J, Cuschieri K, Wilson A, Arbyn M. Clinical validation of hrHPV testing on vaginal and urine self-samples in primary cervical screening (cross-sectional results from the papillomavirus Dumfries and Galloway-PaVDaG study) BMJ Open. 2016;6(4):e010660. doi: 10.1136/bmjopen-2015-010660.
    1. Tshomo U, Franceschi S, Tshokey T, Tobgay T, Baussano I, Tenet V, Snijders PJ, Gheit T, Tommasino M, Vorsters A, Clifford GM. Evaluation of the performance of human papillomavirus testing in paired urine and clinician-collected cervical samples among women aged over 30 years in Bhutan. Virol J. 2017;14(1):74. doi: 10.1186/s12985-017-0744-2.
    1. Cuzick J, Cadman L, Ahmad AS, Ho L, Terry G, Kleeman M, Lyons D, Austin J, Stoler MH, Vibat CRT, Dockter J, Robbins D, Billings PR, Erlander MG. Performance and diagnostic accuracy of a urine-based human papillomavirus assay in a referral population. Cancer Epidemiol Biomark Prev: Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2017;26(7):1053–1059. doi: 10.1158/1055-9965.EPI-16-0960.
    1. D’Hauwers KW, Tjalma WA. Screening for human papillomavirus: is urine useful? Indian J Cancer. 2009;46(3):190–193. doi: 10.4103/0019-509X.52952.
    1. ICO (2017) Human papillomavirus and related disease report. . Accessed 1 Sept 2017
    1. Tjalma WA, Trinh XB, Rosenlund M, Makar AP, Kridelka F, Rosillon D, Van Dam PA, Collas De Souza S, Holl K, Simon P, Jenkins D. A cross-sectional, multicentre, epidemiological study on human papillomavirus (HPV) type distribution in adult women diagnosed with invasive cervical cancer in Belgium. Facts Views Vis Obgyn. 2015;7(2):101–108.
    1. Tjalma WA, Fiander A, Reich O, Powell N, Nowakowski AM, Kirschner B, Koiss R, O’Leary J, Joura EA, Rosenlund M, Colau B, Schledermann D, Kukk K, Damaskou V, Repanti M, Vladareanu R, Kolomiets L, Savicheva A, Shipitsyna E, Ordi J, Molijn A, Quint W, Raillard A, Rosillon D, De Souza SC, Jenkins D, Holl K. Differences in human papillomavirus type distribution in high-grade cervical intraepithelial neoplasia and invasive cervical cancer in Europe. Int J Cancer. 2013;132(4):854–867. doi: 10.1002/ijc.27713.
    1. Chamot E, Mulambia C, Kapambwe S, Shrestha S, Parham GP, Macwan’gi M, Mwanahamuntu MH. Preference for human papillomavirus-based cervical cancer screening: results of a choice-based conjoint study in Zambia. J Low Genit Tract Dis. 2015;19(2):119–123. doi: 10.1097/LGT.0000000000000081.
    1. Vorsters A, Van Keer S, Van Damme P. The use of urine in the follow-up of HPV vaccine trials. Hum Vacc Immunother. 2015;11(2):350–352. doi: 10.4161/21645515.2014.995058.
    1. Cuschieri K, Nandwani R, McGough P, Cook F, Hogg L, Robertson C, Cubie H. Urine testing as a surveillance tool to monitor the impact of HPV immunization programs. J Med Virol. 2011;83(11):1983–1987. doi: 10.1002/jmv.22183.

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