{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T19:08:39Z","timestamp":1790968119852,"version":"4.1.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T00:00:00Z","timestamp":1668124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Vrije Universiteit"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,2,8]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n Compared with women who are human immunodeficiency virus (HIV) negative, women with human immunodeficiency virus (WWH) have a higher human papillomavirus (HPV) prevalence and increased cervical cancer risk, emphasizing the need for effective cervical cancer screening in this population. The present study aimed to validate methylation markers ASCL1 and LHX8 for primary screening in a South African cohort of WWH.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n In this post hoc analysis within the DIAgnosis in Vaccine And Cervical Cancer Screen (DiaVACCS) study, a South African observational multicenter cohort study, cervical scrape samples from 411 HIV-positive women were analyzed for hypermethylation of ASCL1 and LHX8 genes, HPV DNA, and cytology. Sensitivities, specificities, and positive and negative predictive values of primary methylation-based, HPV-based and cytology-based screening were calculated for the detection of cervical intraepithelial neoplasia of grade 3 or higher.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Single markers ASCL1 and LHX8 resulted in a good performance for the detection of cervical intraepithelial neoplasia of grade 3 or higher, with sensitivities of 85.9% (95% confidence interval [CI], 78.2%\u201393.6%) and 89.7% (83.0%\u201396.5%), respectively, and specificities of 72.9% (67.3%\u201378.5%) and 75.0% (69.5%\u201380.5%). Combining markers ASCL1 and LHX8 resulted in a lower sensitivity compared with HPV testing (84.6% vs 93.6%, respectively; ratio, 0.90 [95% CI, .82\u2013.99]) and a higher specificity (86.7% vs 78.3%; ratio 1.11 [1.02\u20131.20]) and reduced the referral rate from 46.8% to 33.4%. ASCL1\/LHX8 methylation had a significantly higher sensitivity than cytology (threshold, high-grade intraepithelial squamous lesion or worse), (84.6% vs 74.0%, respectively; ratio, 1.16 [95% CI, 1.01\u20131.32]) and similar specificity (86.7% vs 91.0%; ratio, 0.95 [.90\u20131.003]).<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Our results validate the accuracy of ASCL1\/LHX8 methylation analysis for primary screening in WWH, which offers a full-molecular alternative to cytology- or HPV-based screening, without the need for additional triage testing.<\/jats:p>\n <\/jats:sec>","DOI":"10.1093\/cid\/ciac801","type":"journal-article","created":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T07:29:16Z","timestamp":1668151756000},"page":"416-423","source":"Crossref","is-referenced-by-count":13,"title":["Validation of ASCL1<\/i> and LHX8<\/i> Methylation Analysis as Primary Cervical Cancer Screening Strategy in South African Women with Human Immunodeficiency Virus"],"prefix":"10.1093","volume":"76","author":[{"given":"Frederique J","family":"Vink","sequence":"first","affiliation":[{"name":"Department of Pathology, Amsterdam UMC, location Vrije Universiteit Amsterdam , Amsterdam , the Netherlands"},{"name":"Imaging and Biomarkers, Cancer Center Amsterdam , Amsterdam , the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris J L M","family":"Meijer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam UMC, location Vrije Universiteit Amsterdam , Amsterdam , the Netherlands"},{"name":"Imaging and Biomarkers, Cancer Center Amsterdam , Amsterdam , the Netherlands"},{"name":"Self-screen , Amsterdam , the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit I","family":"Lissenberg-Witte","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Data Science, Amsterdam UMC, location Vrije Universiteit Amsterdam , Amsterdam , the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Visser","sequence":"additional","affiliation":[{"name":"Gynaecologic Oncology Unit, Department of Obstetrics & Gynaecology, University of Pretoria Faculty of Health Sciences , Pretoria , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Duin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam UMC, location Vrije Universiteit Amsterdam , Amsterdam , the Netherlands"},{"name":"Imaging and Biomarkers, Cancer Center Amsterdam , Amsterdam , the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon C","family":"Snyman","sequence":"additional","affiliation":[{"name":"Gynaecologic Oncology Unit, Department of Obstetrics & Gynaecology, University of Pretoria Faculty of Health Sciences , Pretoria , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin L","family":"Richter","sequence":"additional","affiliation":[{"name":"Department of Medical Virology, University of Pretoria Faculty of Health Sciences , Pretoria , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick H","family":"van der Merwe","sequence":"additional","affiliation":[{"name":"Gynaecologic Oncology Unit, Department of Obstetrics & Gynaecology, Stellenbosch University Faculty of Health Sciences , Stellenbosch , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthys H","family":"Botha","sequence":"additional","affiliation":[{"name":"Gynaecologic Oncology Unit, Department of Obstetrics & Gynaecology, Stellenbosch University Faculty of Health Sciences , Stellenbosch , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renske D M","family":"Steenbergen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam UMC, location Vrije Universiteit Amsterdam , Amsterdam , the Netherlands"},{"name":"Imaging and Biomarkers, Cancer Center Amsterdam , Amsterdam , the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greta","family":"Dreyer","sequence":"additional","affiliation":[{"name":"Gynaecologic Oncology Unit, Department of Obstetrics & Gynaecology, University of Pretoria Faculty of Health Sciences , Pretoria , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,11,11]]},"reference":[{"key":"2023020817081394800_ciac801-B1","doi-asserted-by":"crossref","first-page":"e25110","DOI":"10.1002\/jia2.25110","article-title":"Evidence of synergistic relationships between HIV and human papillomavirus (HPV): systematic reviews and meta-analyses of longitudinal studies of HPV acquisition and clearance by HIV status, and of HIV acquisition by HPV status","volume":"21","author":"Looker","year":"2018","journal-title":"J Int AIDS Soc"},{"key":"2023020817081394800_ciac801-B2","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1177\/0956462413491735","article-title":"Incidence and progression of cervical lesions in women with HIV: a systematic global review","volume":"25","author":"Denslow","year":"2014","journal-title":"Int J STD AIDS"},{"key":"2023020817081394800_ciac801-B3","doi-asserted-by":"crossref","first-page":"e161","DOI":"10.1016\/S2214-109X(20)30459-9","article-title":"Estimates of the global burden of cervical cancer associated with HIV","volume":"9","author":"Stelzle","year":"2021","journal-title":"Lancet Glob Health"},{"key":"2023020817081394800_ciac801-B4","doi-asserted-by":"crossref","first-page":"670032","DOI":"10.3389\/fpubh.2021.670032","article-title":"A framework for cervical cancer elimination in low-and-middle-income countries: a scoping review and roadmap for interventions and research priorities","volume":"9","author":"Shin","year":"2021","journal-title":"Front Public Health"},{"key":"2023020817081394800_ciac801-B5","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"2023020817081394800_ciac801-B6","volume-title":"WHO guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention. 2nd ed","author":"World Health Organization","year":"2021"},{"key":"2023020817081394800_ciac801-B7","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.1003528","article-title":"Diagnostic accuracy of cervical cancer screening and screening-triage strategies among women living with HIV-1 in Burkina Faso and South Africa: a cohort study","volume":"18","author":"Kelly","year":"2021","journal-title":"PLoS Med"},{"key":"2023020817081394800_ciac801-B8","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.ijid.2020.02.051","article-title":"Human papillomavirus prevalence and risk factors among HIV-negative and HIV-positive women residing in rural Eastern Cape, South Africa","volume":"95","author":"Taku","year":"2020","journal-title":"Int J Infect Dis"},{"key":"2023020817081394800_ciac801-B9","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/nrc3728","article-title":"Clinical implications of (epi)genetic changes in HPV-induced cervical precancerous lesions","volume":"14","author":"Steenbergen","year":"2014","journal-title":"Nat Rev Cancer"},{"key":"2023020817081394800_ciac801-B10","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1038\/s41416-019-0593-4","article-title":"Performance of DNA methylation assays for detection of high-grade cervical intraepithelial neoplasia (CIN2+): a systematic review and meta-analysis","volume":"121","author":"Kelly","year":"2019","journal-title":"Br J Cancer"},{"key":"2023020817081394800_ciac801-B11","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1111\/1471-0528.16395","article-title":"The use of host cell DNA methylation analysis in the detection and management of women with advanced cervical intraepithelial neoplasia: a review","volume":"128","author":"Kremer","year":"2021","journal-title":"BJOG"},{"key":"2023020817081394800_ciac801-B12","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1159\/000450595","article-title":"Virtues and weaknesses of DNA methylation as a test for cervical cancer prevention","volume":"60","author":"Lorincz","year":"2016","journal-title":"Acta Cytol"},{"key":"2023020817081394800_ciac801-B13","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.3892\/etm.2021.10916","article-title":"Epigenetic approaches for cervical neoplasia screening (review)","volume":"22","author":"Albulescu","year":"2021","journal-title":"Exp Ther Med"},{"key":"2023020817081394800_ciac801-B14","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1097\/QAI.0000000000000744","article-title":"Methylation levels of CADM1, MAL, and MIR124-2 in cervical scrapes for triage of HIV-infected, high-risk HPV-positive women in Kenya","volume":"70","author":"De Vuyst","year":"2015","journal-title":"J Acquir Immune Defic Syndr"},{"key":"2023020817081394800_ciac801-B15","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1200\/JCO.21.02433","article-title":"Clinical regression of high-grade cervical intraepithelial neoplasia is associated with absence of FAM19A4\/miR124-2 DNA methylation (CONCERVE study)","volume":"40","author":"Kremer","year":"2022","journal-title":"J Clin Oncol"},{"key":"2023020817081394800_ciac801-B16","doi-asserted-by":"crossref","first-page":"3456","DOI":"10.1158\/1078-0432.CCR-17-3615","article-title":"Identification and validation of a 3-gene methylation classifier for HPV-based cervical screening on self-samples","volume":"24","author":"Verlaat","year":"2018","journal-title":"Clin Cancer Res"},{"key":"2023020817081394800_ciac801-B17","doi-asserted-by":"crossref","first-page":"e25165","DOI":"10.1002\/jia2.25165","article-title":"Detection of hypermethylated genes as markers for cervical screening in women living with HIV","volume":"21","author":"Kremer","year":"2018","journal-title":"J Int AIDS Soc"},{"key":"2023020817081394800_ciac801-B18","doi-asserted-by":"crossref","first-page":"478","DOI":"10.7196\/SAMJ.2022.v112i7.16478","article-title":"Phase I of the DiaVACCS screening trial: study design, methods, population demographics and baseline results","volume":"112","author":"Dreyer","year":"2022","journal-title":"S Afr Med J"},{"key":"2023020817081394800_ciac801-B19","author":"South Africa National Department of Health"},{"key":"2023020817081394800_ciac801-B20","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1001\/jama.287.16.2114","article-title":"The 2001 Bethesda system: terminology for reporting results of cervical cytology","volume":"287","author":"Solomon","year":"2002","journal-title":"JAMA"},{"key":"2023020817081394800_ciac801-B21","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/978-3-319-46334-6_5","volume-title":"Blaustein's pathology of the female genital tract","author":"Wright","year":"2019","edition":"7th ed"},{"key":"2023020817081394800_ciac801-B22","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"2023020817081394800_ciac801-B23","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1002\/ijc.28138","article-title":"CADM1 and MAL promoter methylation levels in hrHPV-positive cervical scrapes increase proportional to degree and duration of underlying cervical disease","volume":"133","author":"Bierkens","year":"2013","journal-title":"Int J Cancer"},{"key":"2023020817081394800_ciac801-B24","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1136\/jclinpath-2014-202616","article-title":"CADM1, MAL and miR124-2 methylation analysis in cervical scrapes to detect cervical and endometrial cancer","volume":"67","author":"De Strooper","year":"2014","journal-title":"J Clin Pathol"},{"key":"2023020817081394800_ciac801-B25","doi-asserted-by":"crossref","first-page":"3813","DOI":"10.1158\/1078-0432.CCR-16-2641","article-title":"Genome-wide DNA methylation profiling reveals methylation markers associated with 3q gain for detection of cervical precancer and cancer","volume":"23","author":"Verlaat","year":"2017","journal-title":"Clin Cancer Res"},{"key":"2023020817081394800_ciac801-B26","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1002\/ijc.32614","article-title":"Fam19a4\/miR124-2 methylation in invasive cervical cancer: a retrospective cross-sectional worldwide study","volume":"147","author":"Vink","year":"2020","journal-title":"Int J Cancer"},{"key":"2023020817081394800_ciac801-B27","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S1470-2045(14)70019-1","article-title":"Triage by methylation-marker testing versus cytology in women who test HPV-positive on self-collected cervicovaginal specimens (PROHTECT-3): a randomised controlled non-inferiority trial","volume":"15","author":"Verhoef","year":"2014","journal-title":"Lancet Oncol"},{"key":"2023020817081394800_ciac801-B28","doi-asserted-by":"crossref","first-page":"114219","DOI":"10.1016\/j.jviromet.2021.114219","article-title":"Performance of a six-methylation-marker assay on self-collected cervical samples\u2014a feasibility study","volume":"295","author":"Klischke","year":"2021","journal-title":"J Virol Methods"},{"key":"2023020817081394800_ciac801-B29","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1038\/bjc.2014.392","article-title":"DNA methylation analysis in self-sampled brush material as a triage test in hrHPV-positive women","volume":"111","author":"Boers","year":"2014","journal-title":"Br J Cancer"},{"key":"2023020817081394800_ciac801-B30","first-page":"8","article-title":"Guidelines for cervical cancer screening in South Africa","volume":"9","author":"Botha","year":"2017","journal-title":"S Afr J Gynaecol Oncol"},{"key":"2023020817081394800_ciac801-B31","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1097\/QCO.0000000000000805","article-title":"Progress and challenges in human papillomavirus and cervical cancer in southern Africa","volume":"35","author":"Ramogola-Masire","year":"2022","journal-title":"Curr Opin Infect Dis"},{"key":"2023020817081394800_ciac801-B32","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0229086","article-title":"High-risk human papillomavirus prevalence in self-collected cervicovaginal specimens from human immunodeficiency virus (HIV)-negative women and women living with HIV living in Botswana","volume":"15","author":"Castle","year":"2020","journal-title":"PLoS One"},{"key":"2023020817081394800_ciac801-B33","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1097\/QAD.0000000000001932","article-title":"Associations of human gene EPB41L3 DNA methylation and cervical intraepithelial neoplasia in women living with HIV-1 in Africa","volume":"32","author":"Kelly","year":"2018","journal-title":"AIDS"},{"key":"2023020817081394800_ciac801-B34","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1097\/QAD.0000000000002325","article-title":"The use of molecular markers for cervical screening of women living with HIV in South Africa","volume":"33","author":"Kremer","year":"2019","journal-title":"AIDS"},{"key":"2023020817081394800_ciac801-B35","doi-asserted-by":"crossref","first-page":"560296","DOI":"10.3389\/fonc.2021.560296","article-title":"Promoter hypermethylation analysis of host genes in cervical cancer patients with and without human immunodeficiency virus in Botswana","volume":"11","author":"Tawe","year":"2021","journal-title":"Front Oncol"},{"key":"2023020817081394800_ciac801-B36","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1097\/QAD.0000000000001583","article-title":"Selection of women at risk for cervical cancer in an HIV-infected South African population","volume":"31","author":"Van Zummeren","year":"2017","journal-title":"AIDS"},{"key":"2023020817081394800_ciac801-B37","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1080\/15592294.2021.1992911","article-title":"Direct bisulphite conversion of cervical samples for DNA methylation analysis","volume":"17","author":"Verhoef","year":"2022","journal-title":"Epigenetics"}],"container-title":["Clinical Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/cid\/advance-article-pdf\/doi\/10.1093\/cid\/ciac801\/46954870\/ciac801.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/76\/3\/416\/49125135\/ciac801.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/76\/3\/416\/49125135\/ciac801.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T17:44:56Z","timestamp":1675878296000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cid\/article\/76\/3\/416\/6822465"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,11]]},"references-count":37,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,11,11]]},"published-print":{"date-parts":[[2023,2,8]]}},"URL":"https:\/\/doi.org\/10.1093\/cid\/ciac801","relation":{},"ISSN":["1058-4838","1537-6591"],"issn-type":[{"value":"1058-4838","type":"print"},{"value":"1537-6591","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,2,1]]},"published":{"date-parts":[[2022,11,11]]}}}