Objective Thirteen human papillomavirus (HPV) genotypes are associated with the highest risk of cervical disease/cancer; however, the risk of disease progression and cancer is genotype dependent. The objective of this systematic review was to examine evidence for high-grade cervical intraepithelial neoplasia (≥CIN 3) risk discrimination using HPV genotyping. Materials and Methods A systematic review of English and non-English articles through MEDLINE, Cochrane, clinicaltrials.gov, and abstracts presented at relevant professional society conferences were searched from 2000 to 2019. Search terms included: cervical cancer screening, HPV genotyping, CIN, HPV persistence, humans, and colposcopy; prospective, controlled trials, observational studies, and retrospective studies of residual specimens; evidence included HPV genotyping (beyond genotypes 16/18/45) results. Data were obtained independently by authors using predefined fields. Risk of bias was evaluated with a modified Newcastle-Ottawa Scale. The Grading of Recommendations, Assessment, Development and Evaluation methodology facilitated overall quality of evidence evaluation for risk estimation. The study protocol was registered with the PROSPERO International Prospective Register of Systematic Reviews (CRD42018091093). The primary outcome was CIN 3 or worse risk both at baseline and at different follow-up periods. Results Of 236 identified sources, 60 full texts were retrieved and 16 articles/sources were included. Risk of bias was deemed low; the overall quality of evidence for CIN 3 or worse risk with negative for intraepithelial lesions or malignancies or low-grade squamous intraepithelial cytology was assessed as moderate; that with atypical squamous cells-undetermined significance and “all cytology” was assessed as high. Clinical and methodological heterogeneity precluded meta-analysis. Human papillomavirus genotyping discriminated risk of CIN 3 or worse to a clinically significant degree, regardless of cytology result. Conclusions The evidence supports a clinical utility for HPV genotyping in risk discrimination during cervical cancer screening.

Whereas HPV16 and HPV18 have been the focus in current risk‐based cervical cancer screening algorithms using HPV genotype information, mounting evidence suggests that oncogenic HPV types such as HPV31, 33, 52 and 58 pose a ≥CIN3 risk equivalent to or greater than that of HPV18, and the combined risk of HPV31 and HPV33 rivals even HPV16 in women above 30 years of age. Here, we evaluate the baseline risk of CIN2 and CIN3 by genotype in a colposcopy referral population from Denmark and Italy. In total, 655 women were enrolled upon a referral to colposcopy after a positive screening sample. All samples were HPV analyzed using Onclarity HPV assay with extended genotyping and combined with the histology outcomes, a Bayesian probability modeling was used to determine the risk per genotype assessed. The combined data for this referral population showed that the ≥CIN2 risk of HPV16 was 69.1%, HPV31 at 63.3%, HPV33/58 at 52.7%, HPV18 at 46.6% and HPV52 at 40.8%. For ≥CIN3, the risks were 44.3%, 38.5%, 36.8%, 30.9% and 16.8% for HPV16, HPV31, HPV18, HPV33/58 and HPV52, respectively, indicating that the baseline risk of disease arising from HPV16 is, not surprisingly, the highest among the oncogenic HPV genotypes. We find that the HPV genotype‐specific ≥CIN2 and ≥CIN3 risk‐patterns are so distinct that, for example, 35/39/68 and 56/59/66 should be considered only for low intensive follow‐up, thereby proposing active use of this information in triage strategies for screening HPV‐positive women.

Human papillomavirus (HPV) is the etiological agent for the development of cervical cancer and its precursor lesions (1): a persistent infection with high-risk (HR) HPV types has been established as a necessary step in the progression from precancerous to neoplastic disease (2). It is widely recognized that different HR HPV genotypes have different oncogenic potential, with genotype 16 being the most oncogenic of the cancer-causing HPV genotypes (3, 4).For decades, the test of choice for the detection of cervical intraepithelial neoplasia (CIN) was the Pap smear (5). However, the Pap test has severe limitations: a relatively low sensitivity for detection of disease (range, 51 to 74%, depending on the study), limited reproducibility, interobserver variability, and finally the occurrence of equivocal results (6). The advent of HPV testing has introduced an epochal change in cervical cancer screening: in recent years, we observed a gradual shift in the use of HPV test from a "triage test," in case of equivocal cytology, or as an adjunct test to cytology in women older than 30 years, to a primary screening test. This introduction of molecular HPV testing is slowly changing the premise of cervical screening, promising better performance than cytology-based screening but also posing new challenges (7). Over the last 7 years, HPV testing has gained a foothold in a number of national screening programs, most notably in triage of equivocal cytology or as an adjunct test to cytology in women older than 30 years, as well as more recently as a primary screening modality. Four European randomized control trials (RCTs), as recently summarized by Ronco and colleagues, clearly demonstrate the benefit of HPV testing over the use of the Pap smear (8). In this scenario, the performance of the HPV testing system of choice is crucial: the key is for an HPV assay to have an optimal balance between sensitivity and specificity for detection of CIN grade 2 or 3 (CIN2ϩ) lesions in order to identify virtually all women with immediate precursors or in rare cases cervical cancer, and at the same time not to result in too many screening false-positive samples (9, 10). The advantage of HPV testing relies on its high sensitivity, Ն95% for CIN2ϩ lesions, which translates into a high negative predictive value (NPV) allowing for extended screening intervals without increased risk of cervical cancer: HPV-negative women have a reduced risk for CIN2/3 lesions and cancer in the subsequent screening round as demonstrated by the European RCTs (8).Several in-house HPV DNA detection methods have been successfully used in research laboratories worldwide for more than 2 decades, and some have been employed for diagnostic purposes in countries where "nonapproved" tests for routine clinical testing are allowed (11). Recently, new tests using microarrays or real-time PCRs have been developed: the majority of them have been designed to

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