Randomized Implementation of Primary HPV Testing in the Organized Screening for Cervical Cancer in Stockholm

Evaluation of primary HPV-based cervical screening among older women: Long-term follow-up of a randomized healthcare policy trial in Sweden

Background Evidence on invasive cervical cancer prevention among older women is limited, especially with the introduction of human papillomavirus (HPV)-based screening and longer interval. We conducted a long-term follow-up of the first phase of a randomized healthcare policy trial in cervical screening, targeting women aged 56 to 61 years old, to investigate the effectiveness of primary HPV-based screening in preventing invasive cervical cancer (ICC) and the safety of extending screening interval. Methods and findings The randomized healthcare policy trial of primary HPV-based cervical screening targeted women residing in Stockholm-Gotland region during 2012 to 2016, aged 30 to 64 years. The trial aimed to investigate the detection rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) within 24 months and long-term protection against invasive cervical cancer, comparing primary HPV-based screening to primary cytology-based screening. The initial phase of the trial, which was the focus of this study, targeted women aged 56 to 61 years old in 2012 to 2014 who were randomized to primary cytology arm (n = 7,401) or primary HPV arm (n = 7,318). We used national registries to identify the subsequent cervical tests and all histopathological diagnoses including ICC before December 31, 2022. We calculated cumulative incidence, incidence rate (IR) and IR ratio (IRR) of ICC, by baseline test result. Furthermore, we calculated longitudinal sensitivity and specificity for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) by receipt of primary cytology or primary HPV test for the recommended screening intervals in this age group. We found that the IR of ICC among women in the primary HPV arm was 7.2/100,000 person-years (py) and 3.0 for women who tested HPV negative, compared to 18.4/100,000 py among women in the primary cytology arm and 18.8 for women who tested cytology negative. We further found that the overall point estimate for the risk of ICC over 10 years of follow-up among women in the primary HPV arm was 0.39 compared to women in the primary cytology arm, but this was not statistically significant (IRR: 0.39; 95% confidence interval, CI [0.14, 1.09]; p = 0.0726). However, among women with a negative test result at baseline, women in the primary HPV arm had an 84% lower risk of ICC compared to women in the primary cytology arm (IRR: 0.16; 95% CI [0.04, 0.72]; p = 0.0163). Moreover, primary HPV testing had a higher sensitivity for detecting CIN2+ within a 7-year interval than primary cytology testing within a 5-year interval (89.6% versus 50.9%, p < 0.0001). We were limited by a partial imbalance of invitations during the follow-up between the 2 arms which may have led to an underestimation of the effectiveness of primary HPV-based screening. Conclusions In this study, we observed that women over 55 years of age who received a primary negative HPV test result had substantially lower risk of CIN2+, and ICC, compared to women who received a primary negative cytology result. This should apply even if the screening interval were prolonged to 7 years. Trial Registration NCT01511328.

Impact of cervical screening by human papillomavirus genotype: Population-based estimations

Background Cervical screening programs use testing for human papillomavirus (HPV) genotypes. Different HPV types differ greatly in prevalence and oncogenicity. We estimated the impact of cervical screening and follow-up for each HPV type. Methods and findings For each type of HPV, we calculated the number of women needed to screen (NNS) and number of women needing follow-up (NNF) to detect or prevent one cervical cancer case, using the following individual level input data (i) screening and cancer data for all women aged 25 to 80 years, resident in Sweden during 2004 to 2011 (N = 3,568,938); (ii) HPV type-specific prevalences and screening histories among women with cervical cancer in Sweden in 2002 to 2011(N = 4,254); (iii) HPV 16/18/other HPV prevalences in the population-based HPV screening program (N = 656,607); and (iv) exact HPV genotyping in a population-based cohort (n = 12,527). Historical screening attendance was associated with a 72% reduction of cervical cancer incidence caused by HPV16 (71.6%, 95% confidence interval (CI) [69.1%, 73.9%]) and a 54% reduction of cancer caused by HPV18 (53.8%, 95% CI [40.6%, 63.1%]). One case of HPV16-caused cervical cancer could be prevented for every 5,527 women attending screening (number needed to screen, NNS). Prevention of one case of HPV16-caused cervical cancer required follow-up of 147 HPV16–positive women (number needed to follow-up, NNF). The NNS and NNF were up to 40 to 500 times higher for HPV types commonly screened for with lower oncogenic potential (HPV35,39,51,56,59,66,68). For women below 30 years of age, NNS and NNF for HPV16 were 4,747 and 289, respectively, but >220,000 and >16,000 for HPV35,39,51,56,59,66,68. All estimates were either age-standarized or age-stratified. The primary limitation of our study is that NNS is dependent on the HPV prevalence that can differ between populations and over time. However, it can readily be recalculated in other settings and monitored when HPV type-specific prevalence changes. Other limitations include that in some age groups, there was little data and extrapolations had to be made. Finally, there were very few cervical cancer cases associated with certain HPV types in young age group. Conclusions In this study, we observed that the impact of cervical cancer screening varies depending on the HPV type screened for. Estimating and monitoring the impact of screening by HPV type can facilitate the design of effective and efficient HPV-based cervical screening programs. Trial registration ClinicalTrials.gov with numbers NCT00479375, NCT01511328.

Colposcopic and histopathologic evaluation of women with HPV persistence exiting an organized screening program

Human papillomavirus-based screening has a higher sensitivity for precursors of cervical cancer compared with cytology-based screening. However, more evidence is needed on optimal management of human papillomavirus-positive women. The objective of the study was to compare the risk of histopathologically confirmed cervical intraepithelial lesions grade 2 or worse after 1 and 3 years of human papillomavirus persistence, respectively, and evaluate the clinical management of human papillomavirus-positive women in the 56-60 year age group. This was a randomized health care policy offering human papillomavirus screening to 50% of resident women aged 56-60 years in the Stockholm/Gotland region of Sweden during January 2012 through May 2014. Women who were human papillomavirus positive/cytology negative at baseline were referred for a repeat test after 1 or 3 years. In case of human papillomavirus persistence, women were referred for colposcopy, including biopsies and endocervical sampling. The human papillomavirus prevalence was 5.5% (405 women of 7325 attending). Among the 405 human papillomavirus-positive women, 313 were reflex test cytology negative at baseline and were referred for a repeat human papillomavirus test, 176 women after 1 year and 137 women after 3 years. After 1 year, 91 of 176 (52%) were persistently human papillomavirus positive and after 3 years 55 of 137 (40%) (P = .042). In repeat cytology, 10 of the 91 (12%) were positive after 1 year and 15 of 55 (33%) after 3 years (P = .005). The attendance rates for colposcopy were similar: 82 of 91 (90%) in the 1 year group and 45 of 55 (82%) in the 3 year group. All women attending colposcopy were postmenopausal, and endocervical sampling and punch biopsies were performed to facilitate colposcopic management, with a positive predictive value of 43-50% and 28-31%, respectively. Histopathologically confirmed cervical intraepithelial lesions grade 2 or worse was found in 19 of 82 women (23%) and 9 of 45 women (20%) in the 1 year and 3 year groups, respectively, and registry linkage follow-up found no cancers in either group. Human papillomavirus genotyping was predictive of cervical intraepithelial lesions grade 2 or worse, and human papillomavirus 16 was the most common genotype at human papillomavirus persistence, occurring in 18% of the cases in the 1 year group and 20% in the 3 year group. It was safe to postpone repeat human papillomavirus tests for 3 years in postmenopausal women attending the organized cervical screening program. There was a high risk for cervical intraepithelial lesions grade 2 or worse at follow-up and noteworthy yields from human papillomavirus genotyping as well as endocervical sampling and random biopsies in the absence of visible colposcopic lesions.

Human papillomavirus-based cervical screening and long-term cervical cancer risk: a randomised health-care policy trial in Sweden

Human papillomavirus (HPV)-based cervical screening is a globally recommended public health policy. Randomised clinical trials find superior performance of primary HPV-based screening compared with cytology for preventing cervical cancer. However, additional evidence from real-world public health policies is needed. In preplanned secondary analysis of a randomised health-care policy trial in Sweden we aimed to evaluate which policy provided better protection against invasive cervical cancer, after two full rounds of screening. The organised cervical screening programme in the capital region of Sweden invited all women aged 30-64 years and eligible for screening to a randomised health-care policy trial of HPV-based versus cytology-based screening. During 2014-16, 395 725 eligible women were randomly assigned (non-concealed) to either policy and the invasive cervical cancer incidences over 8 years of follow-up were compared. Intention-to-screen analyses included all invited women and per-protocol analyses the women that attended baseline screening according to protocol. This trial is registered with ClinicalTrials.gov, NCT01511328. Women invited to HPV-based cervical screening had a 17% lower invasive cervical cancer risk compared with women invited to cytology (hazard ratio [HR] 0·83, 95% CI 0·70-0·98). Women participating in HPV-based screening had a 28% lower invasive cervical cancer risk compared with women participating with cytology (HR 0·72, 95% CI 0·54-0·95). Adverse events were a higher number of referrals to colposcopy with biopsy in the HPV policy (15 832 [7·5%] of 212 199 in intention to screen analyses and 9968 [9·0%] of 110 176 per protocol at baseline) than in the cytology policy (12 650 [6·9%] of 183 120 in intention to screen analyses, and 7179 [7·9%] of 90 821 per protocol at baseline). Women who were HPV-negative at baseline had invasive cervical cancer risks of 1·3 (95% CI 0·6-2·4) per 100 000 person-years, whereas the risk for women with normal cytology was 9·1 (6·7-11·8) per 100 000 person-years. HPV-positive women with negative cytology triage had invasive cervical cancer risks of 79·2 per 100 000 person-years and HPV 16 or HPV 18-positive women with negative cytology triage had risks of 318·2 per 100 000 person-years. This randomised policy trial found HPV-based screening to be superior for preventing invasive cervical cancer in the real-world setting. A single baseline HPV-negative test was associated with a very low invasive cervical cancer risk after 8 years. However, HPV positivity with negative cytology triage was associated with high invasive cervical cancer risks. Region Stockholm, Swedish Cancer Society, and European Union Horizon 2020.

Björn Strander

Jiangrong Wang

Joakim Dillner

Karin Sundström

K. Miriam Elfström

Pär Sparén

Qingyun Yao