HPV-based cervical cancer screening, including self-sampling, versus screening with cytology in Argentina
Authors: Marc Arbyn, Silvia de Sanjose, Elisabete Weiderpass
Journal: The Lancet Global Health (2019)

Screening for high-risk human papillomavirus (HPV) is more sensitive in the detection of precancerous cervical lesions than screening with cytology; randomised trials have shown that it is more effective in preventing cervical cancer.1Arbyn M Ronco G Anttila A et al.Evidence regarding HPV testing in secondary prevention of cervical cancer.Vaccine. 2012; 30: F88-F99Crossref PubMed Scopus (597) Google Scholar, 2Ronco G Dillner J Elfstrom KM et al.Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials.Lancet. 2014; 383: 524-532Summary Full Text Full Text PDF PubMed Scopus (1093) Google Scholar In this issue of The Lancet Global Health, Silvina Arrossi and colleagues3Arrossi S Paolino M Laudi R et al.Programmatic human papillomavirus testing in cervical cancer prevention in the Jujuy Demonstration Project in Argentina: a population-based, before-and-after retrospective cohort study.Lancet Global Health. 2019; 7: e772-e783Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar report a comparison of the detection rate of cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) using cytology-based screening with HPV-based screening (on clinician-collected and self-collected cervical samples) in the Jujuy demonstration project—a population-based, cervical cancer screening programme launched in 2012 in northern Argentina. Our own calculations show that the detection rate ratio (DRR) approximately doubled with clinician-collected HPV screening (DRR 1·85, 95% CI 1·59–2·14; appendix).3Arrossi S Paolino M Laudi R et al.Programmatic human papillomavirus testing in cervical cancer prevention in the Jujuy Demonstration Project in Argentina: a population-based, before-and-after retrospective cohort study.Lancet Global Health. 2019; 7: e772-e783Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar The programme was well planned and findings were monitored through a comprehensive screening registry capturing participation of women, their screen test results, and subsequent histologically confirmed lesions among women with positive results. The HPV test used in Jujuy was the Hybrid Capture 2 (HC2) assay (Qiagen, Germantown, MD, USA). The observed DRRs for CIN3+ and cancer were also higher in the clinician-collected HPV-screened cohort (DRR 2·00, 95% CI 1·69–2·36 for CIN3+ and 1·73, 1·07–2·80 for cancer). These ratios are higher than the meta-analytically pooled relative sensitivity estimates derived from cross-sectional screening studies or detection ratios observed in the first screening rounds of randomised trials comparing cytology with HPV screening.1Arbyn M Ronco G Anttila A et al.Evidence regarding HPV testing in secondary prevention of cervical cancer.Vaccine. 2012; 30: F88-F99Crossref PubMed Scopus (597) Google Scholar At least a part of the higher detection rate for HPV testing might be due to incomplete follow-up data in the cytology cohort. Nevertheless, relative sensitivity estimates for CIN2+ approaching or exceeding two are not exceptional in settings where the quality of cytology-based screening is not optimal.1Arbyn M Ronco G Anttila A et al.Evidence regarding HPV testing in secondary prevention of cervical cancer.Vaccine. 2012; 30: F88-F99Crossref PubMed Scopus (597) Google Scholar Another advantage of HPV screening is its ability to use self-collected vaginal samples, which offers opportunities to reach under-screened women. HPV testing using self-samples has similar accuracy for CIN2+ or CIN3+ as clinician-collected cervical samples, if clinically validated PCR-based assays are used.4Arbyn M Castle P Offering self-sampling kits for HPV testing to reach women who do not attend in the regular cervical cancer screening program.Cancer Epidemiol Biomarkers Prev. 2015; 24: 769-772Crossref PubMed Scopus (92) Google Scholar, 5Arbyn M Smith SB Temin S et al.Detecting cervical precancer and reaching underscreened women by using HPV testing on self samples: updated meta-analyses.BMJ. 2018; 363: k4823Crossref PubMed Scopus (298) Google Scholar By contrast, signal-amplification-based HPV assays are less sensitive on self-collected samples, probably due to the lower viral load of high-risk HPV in a vaginal sample than in cellular material scraped from the surface of the cervix.6Belinson JL Hu S Niyazi M et al.Prevalence of type-specific human papillomavirus in endocervical, upper and lower vaginal, perineal and vaginal self-collected specimens: Implications for vaginal self-collection.Int J Cancer. 2010; 127: 1151-1157Crossref PubMed Scopus (66) Google Scholar Therefore, amplification of viral target DNA by a validated PCR is needed to reach sufficient analytical and clinical sensitivity. In Jujuy, HC2 (a signal-amplification-based assay) was used on self-collected samples. As expected, and shown by our own calculations (appendix) the detection of CIN2+ generated through HC2 testing on self-samples was significantly lower than in the cohort where HC2 was applied on a cervical sample taken by a health worker (DRR 0·49, 95% CI 0·31–0·65) and similar to the cohort with cytology-based screening (DRR 0·90, 0·63–1·29). The detection ratio (self-collected vs clinician-collected sampling) observed in Jujuy is lower than the pooled relative sensitivity of HC2 for CIN2+ reported in recent meta-analyses of 0·85 (95% CI 0·81–0·89).5Arbyn M Smith SB Temin S et al.Detecting cervical precancer and reaching underscreened women by using HPV testing on self samples: updated meta-analyses.BMJ. 2018; 363: k4823Crossref PubMed Scopus (298) Google Scholar, 7Arbyn M Verdoodt F Snijders PJF et al.Accuracy of human papillomavirus testing on self-collected versus clinician-collected samples: a meta-analysis.Lancet Oncol. 2014; 15: 172-183Summary Full Text Full Text PDF PubMed Scopus (420) Google Scholar This finding might be explained by the poor adherence to further follow-up among women with a HPV-positive self-collected sample, who needed to contact a health-care worker themselves to have a Papanicolaou (Pap) smear taken. Only individuals with a positive Pap smear were referred for diagnostic tests by colposcopy and biopsy. Results from systematic reviews and the Jujuy project underscore the need for research to find accurate HPV assays that are validated for screening, are as accurate on self-collected samples as on clinician-collected samples, and are affordable and available for resource-limited settings. Identifying the right combination of a point-of-care screening and a triage test—both applicable on self-collected samples and fulfilling these conditions—is a challenge for future screening strategies that envisage having an impact on elimination of cervical cancer.8WHOWHO Director-General calls for all countries to take action to help end the suffering caused by cervical cancer.www.who.int/reproductivehealth/call-to-action-elimination-cervical-cancer/en/Date: 2018Date accessed: July 9, 2019Google Scholar Validation protocols for new HPV assays such as VALGENT9Arbyn M Depuydt C Benoy I et al.VALGENT: a protocol for clinical validation of human papillomavirus assays.J Clin Virol. 2016; 76: S14-S21Crossref PubMed Scopus (97) Google Scholar and VALHUDES10Arbyn M Peeters E Benoy I et al.VALHUDES: a protocol for VALidation of HUman papillomavirus assays and collection DEvices for HPV testing on Self-samples and urine samples.J Clin Virol. 2018; 117: 52-56Crossref Scopus (46) Google Scholar provide a forum for the evaluation of such tests. Extending these evaluation platforms to settings with additional potential modifiers of test performance is needed to fully understand the effect of new screening strategies. Around 5 years after initiation of the Jujuy screening programme, about half of the target population was reached. By adding self-collected sampling, the coverage could be increased further. The achievement of screening quality indicators could be assessed and the early effect of newly-introduced methods (in terms of detection of pre-cancerous lesions) could be estimated from the screening registry.3Arrossi S Paolino M Laudi R et al.Programmatic human papillomavirus testing in cervical cancer prevention in the Jujuy Demonstration Project in Argentina: a population-based, before-and-after retrospective cohort study.Lancet Global Health. 2019; 7: e772-e783Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar In this project, Arrossi and colleagues showed the feasibility of setting up a successful, organised, population-based regional cervical cancer screening programme, which could be rolled out at larger scale and might be an inspiration for implementing screening programmes elsewhere in resource-limited countries. Access to effective procedures to treat the lesions detected during screening was not described in the Article by Arrossi and colleagues, but are an additional crucial condition that must be met for a successful screening programme. MA's team was supported by the US Centers for Disease Control and Prevention through its cooperative agreement with the National Network of Public Health Institutes; by the High Authority for Health (Paris, France), the COHEAHR Network (grant no. 603019), funded by the 7th Framework Programme of DG Research and Innovation, European Commission (Brussels, Belgium), by the German Guideline Program in Oncology (Hannover, Germany), and by the Belgian Cancer Foundation. The Sciensano institute has received funding through VALGENT and VALHUDES. In previous employment, SdS was PI in a research project with institutional support from Merck. SdS's research is partly funded by the Bill & Melinda Gates Foundation. EW declares no competing interests. The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated or of the Bill & Melinda Gates Foundation. Download .pdf (.33 MB) Help with pdf files Supplementary appendix Programmatic human papillomavirus testing in cervical cancer prevention in the Jujuy Demonstration Project in Argentina: a population-based, before-and-after retrospective cohort studyHPV testing in middle-income settings increases detection of CIN2+ lesions and allows for improvement of programmatic indicators. Evidence suggests that the introduction of HPV testing will accelerate the reduction of cervical cancer burden. Full-Text PDF Open AccessAccess to treatment in the Jujuy Demonstration ProjectIn their Comment (June, 2019)1 on our Article2 presenting results from the Jujuy Demonstration Project, Marc Arbyn and colleagues point out that access to treatment was not described. This observation is of high importance because it implies that to attain the high level of treatment obtained in the Jujuy project, specific activities must have been done to increase access to treatment for women. In effect, social and health system barriers are a main cause of the shortage of treatment for women with preneoplastic disease or cervical cancer in a variety of settings, which is one of the reasons why screening programmes from low-resource settings have failed. Full-Text PDF Open Access