Screening test accuracy to improve detection of precancerous lesions of the cervix in women living with HIV: a study protocol

Katayoun Taghavi, Misinzo Moono, Mulindi Mwanahamuntu, Partha Basu, Andreas Limacher, Taniya Tembo, Herbert Kapesa, Kalongo Hamusonde, Serra Asangbeh, Raphael Sznitman, Nicola Low, Albert Manasyan, Julia Bohlius, Katayoun Taghavi, Misinzo Moono, Mulindi Mwanahamuntu, Partha Basu, Andreas Limacher, Taniya Tembo, Herbert Kapesa, Kalongo Hamusonde, Serra Asangbeh, Raphael Sznitman, Nicola Low, Albert Manasyan, Julia Bohlius

Abstract

Introduction: The simplest and cheapest method for cervical cancer screening is visual inspection after application of acetic acid (VIA). However, this method has limitations for correctly identifying precancerous cervical lesions (sensitivity) and women free from these lesions (specificity). We will assess alternative screening methods that could improve sensitivity and specificity in women living with humanimmunodeficiency virus (WLHIV) in Southern Africa.

Methods and analysis: We will conduct a paired, prospective, screening test accuracy study among consecutive, eligible women aged 18-65 years receiving treatment for HIV/AIDS at Kanyama Hospital, Lusaka, Zambia. We will assess a portable magnification device (Gynocular, Gynius Plus AB, Sweden) based on the Swede score assessment of the cervix, test for high-risk subtypes of human papillomavirus (HR-HPV, GeneXpert, Cepheid, USA) and VIA. All study participants will receive all three tests and the reference standard at baseline and at six-month follow-up. The reference standard is histological assessment of two to four biopsies of the transformation zone. The primary histological endpoint is cervical intraepithelial neoplasia grade two and above (CIN2+). Women who are VIA-positive or have histologically confirmed CIN2+ lesions will be treated as per national guidelines. We plan to enrol 450 women. Primary outcome measures for test accuracy include sensitivity and specificity of each stand-alone test. In the secondary analyses, we will evaluate the combination of tests. Pre-planned additional studies include use of cervigrams to test an automated visual assessment tool using image pattern recognition, cost-analysis and associations with trichomoniasis.

Ethics and dissemination: Ethical approval was obtained from the University of Zambia Biomedical Research Ethics Committee, Zambian National Health Regulatory Authority, Zambia Medicines Regulatory Authority, Swissethics and the International Agency for Research on Cancer Ethics Committee. Results of the study will be submitted for publication in a peer-reviewed journal.

Trial registration number: NCT03931083; Pre-results.

Keywords: HIV & AIDS; epidemiology; gynaecology; public health.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
The Gynocular (Gynocular, Gynius Plus AB, Sweden). This photograph was taken at the Centre for Infectious Disease Research in Zambia headquarters on the 27th of April 2020 for the purposes of this manuscript.
Figure 2
Figure 2
Flow of participants through the study*. VIA-positive women and those who have CIN2+ on histopathology will be treated as per national guidelines. Numbers of participants at each step will be reported. Loss to follow-up and missing data will also be reported. *This flow diagram is in accordance with the 2015 ‘Standards for Reporting Diagnostic accuracy studies’. ART, antiretroviral therapy; CD4, cluster of differentiation 4; CIN2+, cervical intraepithelial neoplasia grade two and above; HR-HPV, high-risk human papillomavirus; TZ, transformation zone of the cervix; VIA, visual inspection of the uterine cervix after application of 3%–5% acetic.

References

    1. Bray F, Ferlay J, Soerjomataram I, et al. . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394–424. 10.3322/caac.21492
    1. Ginsburg O, Bray F, Coleman MP, et al. . The global burden of women's cancers: a grand challenge in global health. Lancet 2017;389:847–60. 10.1016/S0140-6736(16)31392-7
    1. Rohner E, Bütikofer L, Schmidlin K, et al. . Cervical cancer risk in women living with HIV across four continents: a multicohort study. Int J Cancer 2020;146:601–9. 10.1002/ijc.32260
    1. Coleman JS, Cespedes MS, Cu-Uvin S, et al. . An insight into cervical cancer screening and treatment capacity in sub Saharan Africa. J Low Genit Tract Dis 2016;20:31–7. 10.1097/LGT.0000000000000165
    1. Simms KT, Steinberg J, Caruana M, et al. . Impact of scaled up human papillomavirus vaccination and cervical screening and the potential for global elimination of cervical cancer in 181 countries, 2020-99: a modelling study. Lancet Oncol 2019;20:394–407. 10.1016/S1470-2045(18)30836-2
    1. Viviano M, DeBeaudrap P, Tebeu P-M, et al. . A review of screening strategies for cervical cancer in human immunodeficiency virus-positive women in sub-Saharan Africa. Int J Womens Health 2017;9:69–79. 10.2147/IJWH.S103868
    1. Bigoni J, Gundar M, Tebeu P-M, et al. . Cervical cancer screening in sub-Saharan Africa: a randomized trial of via versus cytology for triage of HPV-positive women. Int J Cancer 2015;137:127–34. 10.1002/ijc.29353
    1. Chibwesha CJ, Frett B, Katundu K, et al. . Clinical performance validation of 4 point-of-care cervical cancer screening tests in HIV-infected women in Zambia. J Low Genit Tract Dis 2016;20:218–23. 10.1097/LGT.0000000000000206
    1. Huchko MJ, Sneden J, Sawaya G, et al. . Accuracy of visual inspection with acetic acid to detect cervical cancer precursors among HIV-infected women in Kenya. Int J Cancer 2015;136:392–8. 10.1002/ijc.28996
    1. Orang’o O, Liu T, Christoffersen-Deb A, et al. . Use of via, Pap smear, or HR-HPV testing in women living with HIV/AIDS for post-treatment cervical cancer screening: same tests, different priorities. AIDS 2017;31:233–40.
    1. Firnhaber C, Mao L, Levin S, et al. . Evaluation of a cervicography-based program to ensure quality of visual inspection of the cervix in HIV-infected women in Johannesburg, South Africa. J Low Genit Tract Dis 2015;19:7–11. 10.1097/LGT.0000000000000040
    1. World Health Organization (WHO) Draft: global strategy towards the elimination of cervical cancer as a public health problem Geneva, Switzerland, 2019. Available:
    1. Fokom-Domgue J, Combescure C, Fokom-Defo V, et al. . Performance of alternative strategies for primary cervical cancer screening in sub-Saharan Africa: systematic review and meta-analysis of diagnostic test accuracy studies. BMJ 2015;351:h3084. 10.1136/bmj.h3084
    1. Sankaranarayanan R, Anorlu R, Sangwa-Lugoma G, et al. . Infrastructure requirements for human papillomavirus vaccination and cervical cancer screening in sub-Saharan Africa. Vaccine 2013;31 Suppl 5:F47–52. 10.1016/j.vaccine.2012.06.066
    1. Clifford GM, Gonçalves MAG, Franceschi S, et al. . Human papillomavirus types among women infected with HIV: a meta-analysis. AIDS 2006;20:2337–44. 10.1097/01.aids.0000253361.63578.14
    1. Basu P, Banerjee D, Mittal S, et al. . Evaluation of a compact, rechargeable, magnifying device to triage via and HPV positive women in a cervical cancer screening program in rural India. Cancer Causes Control 2016;27:1253–9. 10.1007/s10552-016-0805-7
    1. Ngonzi J, Bajunirwe F, Wistrand C, et al. . Agreement of colposcope and gynocular in assessment of cervical lesions by swede score: a randomized, crossover pilot trial. J Low Genit Tract Dis 2013;17:372–7. 10.1097/LGT.0b013e31827ba7c5
    1. Nessa A, Roy JS, Chowdhury MA, et al. . Evaluation of the accuracy in detecting cervical lesions by nurses versus doctors using a stationary colposcope and Gynocular in a low-resource setting. BMJ Open 2014;4:e005313. 10.1136/bmjopen-2014-005313
    1. Nessa A, Wistrand C, Begum SA, et al. . Evaluation of stationary colposcope and the Gynocular, by the swede score systematic colposcopic system in via positive women: a crossover randomized trial. Int J Gynecol Cancer 2014;24:339–45. 10.1097/IGC.0000000000000042
    1. Kallner HK, Persson M, Thuresson M, et al. . Diagnostic colposcopic accuracy by the GYNOCULAR and a stationary COLPOSCOPE. Int J Technol Assess Health Care 2015;31:181–7. 10.1017/S0266462315000252
    1. Strander B, Ellström-Andersson A, Franzén S, et al. . The performance of a new scoring system for colposcopy in detecting high-grade dysplasia in the uterine cervix. Acta Obstet Gynecol Scand 2005;84:1013–7. 10.1111/j.0001-6349.2005.00895.x
    1. Hu L, Bell D, Antani S, et al. . An observational study of deep learning and automated evaluation of cervical images for cancer screening. J Natl Cancer Inst 2019;111:343–4. 10.1097/OGX.0000000000000687
    1. Crucitti T, Jespers V, Mulenga C, et al. . Non-Sexual transmission of Trichomonas vaginalis in adolescent girls attending school in Ndola, Zambia. PLoS One 2011;6:e16310. 10.1371/journal.pone.0016310
    1. Torondel B, Sinha S, Mohanty JR, et al. . Association between unhygienic menstrual management practices and prevalence of lower reproductive tract infections: a hospital-based cross-sectional study in Odisha, India. BMC Infect Dis 2018;18:473. 10.1186/s12879-018-3384-2
    1. Sellors JW, Sankaranarayanan R. Colposcopy and treatment of cervical intraepithelial neoplasia: a beginners’ manual. Lyon: IARC Press, 2003.
    1. Ranga R, Rai S, Kumari A, et al. . A comparison of the strength of association of Reid colposcopic index and swede score with cervical histology. J Low Genit Tract Dis 2017;21:55–8. 10.1097/LGT.0000000000000278
    1. Bateman AC, Katundu K, Mwanahamuntu MH, et al. . The burden of cervical pre-cancer and cancer in HIV positive women in Zambia: a modeling study. BMC Cancer 2015;15:541. 10.1186/s12885-015-1558-5
    1. Parham GP, Sahasrabuddhe VV, Mwanahamuntu MH, et al. . Prevalence and predictors of squamous intraepithelial lesions of the cervix in HIV-infected women in Lusaka, Zambia. Gynecol Oncol 2006;103:1017–22. 10.1016/j.ygyno.2006.06.015
    1. World Health Organization Department of HIV/AIDS, guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV, 2015. Available:
    1. Hall MT, Smith MA, Simms KT, et al. . The past, present and future impact of HIV prevention and control on HPV and cervical disease in Tanzania: a modelling study. PLoS One 2020;15:e0231388. 10.1371/journal.pone.0231388
    1. Wilson EB. Probable inference, the law of succession, and statistical inference. J Am Stat Assoc 1927;22:209–12. 10.1080/01621459.1927.10502953
    1. World Health Organisation WHO comprehensive cervical cancer control, 2014. Available:
    1. World Health Organisation Who prequalification of in vitro diagnostics public report PQDx 0268-070-00 who PQ public report December 2017/version 3.0, 2017. Available:
    1. Chung MH, McKenzie KP, De VH, et al. . Comparing Pap smear, via, and HPV cervical cancer screening methods among HIV-positive women by immune status and antiretroviral therapy. Aids 2013;27:2909–19.
    1. Firnhaber C, Mayisela N, Mao L, et al. . Validation of cervical cancer screening methods in HIV positive women from Johannesburg South Africa. PLoS One 2013;8:e53494–9. 10.1371/journal.pone.0053494
    1. Kremer WW, van Zummeren M, Breytenbach E, et al. . The use of molecular markers for cervical screening of women living with HIV in South Africa. AIDS 2019;33:2035–42. 10.1097/QAD.0000000000002325
    1. Jin G, LanLan Z, Li C, et al. . Pregnancy outcome following loop electrosurgical excision procedure (LEEP) a systematic review and meta-analysis. Arch Gynecol Obstet 2014;289:85–99. 10.1007/s00404-013-2955-0
    1. Wentzensen N, Walker JL, Gold MA, et al. . Multiple biopsies and detection of cervical cancer precursors at colposcopy. J Clin Oncol 2015;33:83–9. 10.1200/JCO.2014.55.9948
    1. Wentzensen N, Walker J, Smith K, et al. . A prospective study of risk-based colposcopy demonstrates improved detection of cervical precancers. Am J Obstet Gynecol 2018;218:604.e1–604.e8. 10.1016/j.ajog.2018.02.009
    1. Gage JC, Hanson VW, Abbey K, et al. . Number of cervical biopsies and sensitivity of colposcopy. Obstet Gynecol 2006;108:264–72. 10.1097/01.AOG.0000220505.18525.85
    1. van der Marel J, van Baars R, Rodriguez A, et al. . The increased detection of cervical intraepithelial neoplasia when using a second biopsy at colposcopy. Gynecol Oncol 2014;135:201–7. 10.1016/j.ygyno.2014.08.040
    1. Hu S-Y, Zhang W-H, Li S-M, et al. . Pooled analysis on the necessity of random 4-quadrant cervical biopsies and endocervical curettage in women with positive screening but negative colposcopy. Medicine 2017;96:e6689. 10.1097/MD.0000000000006689
    1. Zhao Y, Song Y, Zhao F, et al. . [Value of 4-quadrant biopsies under colposcopy for detecting precancerous lesions in cervical cancer screening]. Zhonghua Zhong Liu Za Zhi 2015;37:875–9.
    1. Baasland I, Hagen B, Vogt C, et al. . Colposcopy and additive diagnostic value of biopsies from colposcopy‐negative areas to detect cervical dysplasia. Acta Obstet Gynecol Scand 2016;95:1258–63. 10.1111/aogs.13009
    1. Huh WK, Sideri M, Stoler M, et al. . Relevance of random biopsy at the transformation zone when colposcopy is negative. Obstet Gynecol 2014;124:670–8. 10.1097/AOG.0000000000000458
    1. Pretorius RG, Belinson JL, Azizi F, et al. . Utility of random cervical biopsy and endocervical curettage in a low-risk population. J Low Genit Tract Dis 2012;16:333–8. 10.1097/LGT.0b013e3182480c18
    1. Pretorius RG, Zhang W-H, Belinson JL, et al. . Colposcopically directed biopsy, random cervical biopsy, and endocervical curettage in the diagnosis of cervical intraepithelial neoplasia II or worse. Am J Obstet Gynecol 2004;191:430–4. 10.1016/j.ajog.2004.02.065
    1. Bateman AC, Parham GP, Sahasrabuddhe VV, et al. . Clinical performance of digital cervicography and cytology for cervical cancer screening in HIV-infected women in Lusaka, Zambia. J Acquir Immune Defic Syndr 2014;67:212–5. 10.1097/QAI.0000000000000270
    1. Ghosh I, Mittal S, Banerjee D, et al. . Study of accuracy of colposcopy in via and HPV detection-based cervical cancer screening program. Aust N Z J Obstet Gynaecol 2014;54:570–5. 10.1111/ajo.12282
    1. Tebeu P-M, Fokom-Domgue J, Crofts V, et al. . Effectiveness of a two-stage strategy with HPV testing followed by visual inspection with acetic acid for cervical cancer screening in a low-income setting. Int J Cancer 2015;136:E743–50. 10.1002/ijc.29250
    1. Wang M, Hu S, Zhao S, et al. . Accuracy of triage strategies for human papillomavirus DNA-positive women in low-resource settings: a cross-sectional study in China. Chin J Cancer Res 2017;29:496–509. 10.21147/j.issn.1000-9604.2017.06.04
    1. Sangrajrang S, Laowahutanont P, Wongsena M, et al. . Comparative accuracy of Pap smear and HPV screening in Ubon Ratchathani in Thailand. Papillomavirus Res 2017;3:30–5. 10.1016/j.pvr.2016.12.004

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe