Benefits and potential harms of human papillomavirus (HPV)‐based cervical cancer screening: A real‐world comparison of HPV testing versus cytology

Abstract

Introduction Human papillomavirus (HPV) testing as the primary cervical cancer screening method is implemented in several countries. We report data from the first round of a large Danish pilot implementation of HPV‐based screening. Our aim was to compare colposcopy referrals, detection of high‐grade cervical intraepithelial neoplasia (CIN) and cervical cancer, and positive predictive value (PPV) of colposcopy referral in HPV vs cytology‐based screening. Material and methods From May 2017 to October 2018, women aged 30‐59 years attending cervical cancer screening in the uptake area of the Department of Pathology, Vejle Hospital, Region of Southern Denmark were screened by primary HPV testing (n = 16 067) or primary cytology (n = 23 981) depending on municipality of residence. In the HPV group, women with HPV16/18, or other high‐risk HPV types and abnormal cytology, were referred to immediate colposcopy. Women with other high‐risk HPV types and normal cytology were invited for repeat screening with HPV test and cytology after 12 months. From a nationwide pathology register, we obtained information on screening results and subsequent histological diagnoses during up to 2.9 years after the first screen. PPVs included diagnoses within 1 year after referral. Results In the HPV group, 3.7% were referred to immediate colposcopy and 2.8% were referred at the 12‐month repeat screening. The total referral to colposcopy was higher in the HPV (6.6%) than cytology group (2.1%) (age‐adjusted relative referral = 3.05, 95% confidence interval [CI] 2.75‐3.38). The detection of CIN3+ was higher in the HPV (1.5%) than the cytology group (0.8%) (age‐adjusted relative detection = 1.88, 95% CI 1.56‐2.28). The probability of CIN3+ among women referred to colposcopy (= PPV) was lower in the HPV (21.1%; 95% CI 18.7%‐23.7%) than the cytology group (34.6%; 95% CI 30.7%‐38.9%). In the HPV group, the PPV was lower among women referred at repeat screening (12.1%) than among women referred immediately (27.8%). Conclusions Compared with cytology‐based screening, HPV‐based screening provided a 90% increased CIN3+ detection at the cost of a threefold increase in colposcopy referrals, when considering complete data from the prevalence round. Our findings support implementation of HPV‐based screening in Denmark, but modifications of screening algorithms may be warranted to decrease unnecessary colposcopy referrals.

Human papillomavirus (HPV) testing for cervical cancer screening in a middle-income country: comment on a large real-world implementation study in China

“…To our knowledge, the study by Zhao et al is the largest to date on the performance of HPV testing versus cytology for cervical cancer screening in a middleincome country. In line with findings from high-income settings [5,7,8], the authors found that HPV testing detected more cases of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) than cytology-based screening, underlining the superior sensitivity of HPV testing. However, in contrast to results in high-income settings [7,8], the referral rate to immediate colposcopy was lower for HPV than cytology-based screening.…”

“…In line with findings from high-income settings [5,7,8], the authors found that HPV testing detected more cases of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) than cytology-based screening, underlining the superior sensitivity of HPV testing. However, in contrast to results in high-income settings [7,8], the referral rate to immediate colposcopy was lower for HPV than cytology-based screening. As noted by the authors [10], this likely reflects that in the Chinese cytology-based screening program, all women with atypical squamous cells of undetermined significance or worse were referred directly to colposcopy, because not all laboratories could perform HPV triage testing for mild abnormalities, and compliance with repeat cytology could not be ensured [10].…”

“…These findings have been corroborated by real-world implementation studies in high-income countries, e.g., the Netherlands [7] and Denmark [8]. A challenge with HPV testing, however, is that most HPV infections are transient, and therefore, triage testing of HPV positive women is recommended to prevent over-referral and over-treatment [4,7,8]. of BMC Medicine, Zhao et al report results from a large implementation study of HPV-based cervical cancer screening in China [10].…”

“…Randomized trials in high-income [5] and middle-income [6] countries have demonstrated that HPV testing is more sensitive and prevents more cervical cancers than cytology. These findings have been corroborated by real-world implementation studies in high-income countries, e.g., the Netherlands [7] and Denmark [8]. A challenge with HPV testing, however, is that most HPV infections are transient, and therefore, triage testing of HPV positive women is recommended to prevent over-referral and over-treatment [4,7,8].…”

Targeted Next Generation Sequencing for Human Papillomavirus Genotyping in Cervical Liquid-Based Cytology Samples

“…Since an increase of colposcopy referrals have been observed with the shift to HPV detection in cervical cancer screening [13,48], an introduction of all possibly carcinogenic HPV types into cervical cancer screening could potentially result in an additional increase of colposcopy referrals. The reason for this is that most HPV infections clear spontaneously without the need of any treatment.…”