Abstract
Triage tests enhance the efficiency cervical cancer screening based on human papillomavirus (HPV), but the best approach for maximizing programmatic effectiveness is still uncertain, particularly in a real-world scenario. To compare the clinical performance of 6 triage strategies based on liquid-based cytology (LBC) and HPV-16 and HPV-18 genotyping individually or in combination as sequential triage tests to detect cervical intraepithelial neoplasia (CIN) grade 2 or higher among women with high-risk HPV. This diagnostic study of routine cervical cancer screening was conducted at 100 primary health centers in Tlaxcala, Mexico. Women aged 30 to 64 years were recruited from August 1, 2013, to February 24, 2016, as part of the Forwarding Research for Improved Detection and Access for Cervical Cancer Screening and Triage study. Six triage scenarios for referral to colposcopy were examined: (1) LBC testing that found atypical squamous cells of undetermined significance (ASC-US) or worse, (2) positive results in HPV-16 genotyping, (3) positive results in HPV-18 genotyping, (4) positive results in HPV-16/HPV-18 genotyping, (5) positive results in HPV-16 genotyping or, if genotyping results were negative, reflex LBC testing that found ASC-US or worse, and (6) positive results in HPV-16/HPV-18 genotyping or, if genotyping results were negative, reflex LBC testing that found ASC-US or worse. Data were analyzed from October 2017 to August 2018. Liquid-based cytological testing with simultaneous HPV-16 and HPV-18 genotyping. Women whose HPV genotyping results were positive for HPV-16 or HPV-18 or whose LBC results found ASC-US or worse and a random set of negative and normal results were referred to colposcopy with histologic analysis used for disease confirmation. Clinical performance of each test strategy for detection of CIN grade 2 or higher. Secondary outcomes included resource utilization of each triage scenario, measured by the number of tests performed, the referral rate for colposcopy, and the numbers of colposcopies per CIN grade 2 or higher detected. A total of 36 212 women (median [interquartile range] age, 40 [35-47] years) were screened, and 4051 women (11.2%) had high-risk HPV. Of these women, 1109 (24.6%) were found to have HPV-16, HPV-18, or ASC-US or worse. Further histologic testing detected CIN grade 2 or higher in 110 of 788 women (14.0%) who underwent follow-up colposcopy. Sensitivity and specificity for 3 main triage strategies were 42.9% and 74.0% for LBC; 58.3% and 54.4% for HPV-16/HPV-18 genotyping; and 86.6% and 34.0% for HPV-16/HPV-18 genotyping with reflex LBC. The referral rate to colposcopy was 29% for HPV-16/HPV-18 with reflex LBC, which was 2-fold higher than the referral rate of 12% for LBC. Triage of women with high-risk HPV with HPV-16/HPV-18 genotyping with reflex LBC was significantly associated with improvement in detection of CIN grade 2 or higher compared with LBC alone. The benefit of disease prevented may outweigh the cost of increasing requirements for colposcopy services in settings with limited adherence to follow-up after a positive screening result.
Highlights
It has been estimated that 311 365 deaths worldwide were due to cervical cancer in 2018, with 90% occurring in developing countries.[1]
Key Points Question What combination of human papillomavirus 16 (HPV-16) and Human papillomavirus (HPV)-18 genotyping with liquid-based cytological (LBC) testing is associated with the best performance for triaging women with HPV to detect cervical intraepithelial neoplasia ? Findings This diagnostic study included 36 212 participants in the Forwarding Research for Improved Detection and Access for Cervical Cancer Screening and Triage study and found that a combined triage strategy of HPV-16/ HPV-18 genotyping with reflex liquid-based cytology (LBC) was associated with an increase in the relative sensitivity to detect cervical intraepithelial neoplasia grade 2 or higher compared with LBC testing alone
Triage of women with high-risk HPV with HPV-16/HPV-18 genotyping with reflex LBC was significantly associated with improvement in detection of cervical intraepithelial neoplasia (CIN) grade 2 or higher compared with LBC alone
Summary
It has been estimated that 311 365 deaths worldwide were due to cervical cancer in 2018, with 90% occurring in developing countries.[1]. A question that remains is the nature of the best combination of triage tests for cervical cancer screening using primary HPV testing.[10,11] Recently, HPV-16/HPV-18 genotyping or cytological examination have been recommended to triage for immediate colposcopy in some national screening guidelines from highincome countries, offering greater sensitivity than cytological examination alone and better specificity than referring all women with HPV for colposcopy.[12,13,14] the suitability of these strategies in the routine health care practice in other resource-constrained settings has not been explored, to our knowledge. Country-based type-specific HPV prevalence and genotype distribution in cervical precancerous lesions,[15] as well as the health care infrastructure relevant to LMICs, could influence the performance of these triage strategies.[4]
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