HPV-BASED CERVICAL CANCER SCREENING: FROM ‘ONE-SIZE-FITS-ALL’ TOWARDS RISK-BASED STRATEGIES

Elimination of cervical cancer as a public health problem can be achieved by a combination of HPV vaccination and screening for early detection and treatment of precancerous lesions. Screening by primary HPV testing is currently replacing cytology in many organized screening programs. HPV-based programs will also be adapted multiple times in the future as they need to take into account changes such as the development of more advanced technologies and the decline in HPV infections following HPV vaccination. In this thesis, multiple aspects of HPV-based screening are described, with a focus on optimization of strategies using risk stratification. In particular, this thesis aims to I) evaluate the clinical performance of HPV self-sampling offered in the Netherlands as an alternative primary screening option, II) study risk profiles of unvaccinated women using HPV genotyping and screening history, III) study risk profiles of vaccinated women attending HPV-based screening, and IV) assess the costs of HPV testing following public tendering in Italian regional settings. I) Primary HPV testing on a self-collected sample was found to have similar accuracy but a slightly lower sensitivity as compared to HPV testing on a clinician-collected sample, thus the consensus guidelines for use in cervical screening were met although a re-evaluation of the workflow procedure is warranted to optimize its performance. II) Taking into account HPV genotyping information and screening outcomes from the previous screening round can lead to a more precise risk assessment. We found that 5-year HPV type concordance signals high CIN3+ risk which supports immediate referral for colposcopy without additional cytology triage. We also found that HPV detection and CIN3+ risk were higher among women who had a positive HPV test in the past, warranting a re-evaluation of the 10-year interval implemented in the Dutch program for women with a negative HPV test at age 40 or 50 years. III) With the use of a type-specific data-driven statistical model, we projected the lifetime CIN3+ risks under 5-yearly primary HPV screening and different HPV vaccination scenarios and found that HPV vaccination will lead to a strong decline in the lifetime CIN3+ risk supporting de-intensification of the screening program in vaccinated women. Screening vaccinated women using HPV testing and cytology triage remains feasible, although intervals beyond 5 years should be considered. IV) HPV tests can be purchased at very low prices if procured at high volume. Enhancing transparency by reporting tender-based unit prices can support health authorities in their decision to implement primary HPV screening

Pricing of HPV tests in Italian tender-based settings

Background and aim: Human papillomavirus (HPV) testing has been recommended by the WHO as the first choice method in cervical cancer screening. So far, only a limited number of countries have implemented primary HPV testing, partly because of the assumed high costs of HPV testing. We assessed tender-based prices of HPV testing in Italy, where programmatic HPV-based screening has been implemented at the regional level. Materials and methods: Procurement notices and awards, published between 2014 and December 2021, were retrieved from the European online platform for public procurement. The unit price per HPV test was calculated as the ratio of the contract award price and contract volume. The association between the unit price and contract volume, calendar year, number of offers, region’s per capita gross domestic product and population density was assessed by linear regression. Fractional polynomials were used to describe the association between the unit price and contract volume. Results: We retrieved data from 29 procurement procedures. The median unit price per HPV test was €10.75, ranging from €4.30 to €204.80. The unit price was not higher than €5 for 6 out of 11 contract awards with a volume of at least 100,000 tests. After discarding two low-volume contracts with very high contract prices (€182.40 and €204.80), volume explained 86.5% of the variation in unit price. The unit price was not associated with other variables. Conclusions: The Italian experience showed that the tender-based unit price of an HPV test is very low when procured at high volume, indicating that there is no reason for countries to further delay the implementation of HPV-based screening because of prohibitively high HPV testing costs

Hospitalization rates and outcome of invasive bacterial vaccine-preventable diseases in Tuscany: A historical cohort study of the 2000-2016 period

Background: Invasive bacterial diseases (IBD) are a serious cause of hospitalization, sequelae and mortality. Albeit a low incidence, an increase in cases due to H. influenzae was registered in the past 4 years and, in the Tuscany region, an excess of cases due to N. meningitidis since 2015 is alarming. The purpose of this study is to deepen the knowledge of IBD epidemiology in Tuscany with particular attention to temporal trends. Methods: Tuscan residents hospitalized for IBD from January 1st 2000 to March 18th 2016 were selected from the regional hospital discharge database based on ICD-9-CM codes. Age-specific and standardized hospitalization rates were calculated together with case-fatality rates (CFRs). A time-trend analysis was performed; whereas, prognostic factors of death were investigated through univariable and multivariable analyses. Results: The average standardized hospitalization rates for invasive meningococcal diseases (IMD), invasive pneumococcal diseases and invasive diseases due to H. influenzae from 2000 to 2016 were 0.6, 1.8, and 0.2 per 100,000, respectively. The average CFRs were 10.5%, 14.5% and 11.5% respectively with higher values in the elderly. Older age was significantly associated with higher risk of death from all IBD. A significant reduction in hospitalization rates for IMD was observed after meningococcal C conjugate vaccine introduction. The Annual Percentage Change (APC) was -13.5 (95% confidence interval (CI) -22.3; -3.5) in 2005-2013 but has risen since that period. Furthermore, a significant increasing trend of invasive diseases due to H. influenzae was observed from 2005 onwards in children 1-4 years old (APC 13.3; 95% CI 0; 28.3). Conclusions: This study confirms changes in the epidemiology of invasive diseases due to H. influenzae and IMD. Furthermore, attention is called to the prevention of IBD in the elderly because of the age group's significantly higher rate of hospitalizations and deaths for all types of IBD

Risk of cervical intraepithelial neoplasia grade 3 or worse in HPV-positive women with normal cytology and five-year type concordance: A randomized comparison

Background: In human papillomavirus (HPV)-based cervical screening programs, management of HPV-positive women with normal cytology is debated. Longitudinal information on HPV type persistence may be employed for risk stratification. Methods: We assessed the risk of cervical intraepithelial neoplasia grade 3 or worse (CIN3þ) after repeatedly testing positive for the same HPV type(s) in the randomized population-based screening study Amsterdam (POBASCAM). We compared 18-month CIN3þ risks in HPV-positive women (intervention, n ¼ 1,066) to those in HPV-positive/cytology-negative women who tested HPV-positive in the next screening round (control, n ¼ 111) five years later, stratified for HPV type concordance. Results: The 18-month CIN3þ risk was 15% in HPV-positive women in the intervention group, 40% in the control group after two-round type concordance (relative risk 2.6, 95% confidence interval 1.9–3.4), and 20% in the control group after a type switch (1.3, 0.5–3.2). The relative increase in CIN3þ risk after two-round type concordance was similar in <35-year-old (3.0, 2.0–4.4) and older women (2.2, 1.4–3.5), and was high in high-risk HPV-positive women who were HPV16/18/31/33/45-negative in both rounds (9.9, 4.4–21.9). Conclusions: Five-year HPV type concordance signals high CIN3þ risk and warrants referral for colposcopy without additional cytology triage. Impact: HPV screening programs become highly efficient when HPV-positive women with negative triage testing at baseline are offered repeat HPV genotyping after five years

Risk of cervical precancer among HPV-negative women in the Netherlands and its association with previous HPV and cytology results: A follow-up analysis of a randomized screening study

Background AU Human: Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly papillomavirus (HPV)-based screening programs still : use one-size-fits-all protocols but efficiency and efficacy of programs may be improved by stratifying women based on previous screening results. Methods and findings We studied the association between cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) and previous screening results in the Population-Based Screening Study Amsterdam (POBASCAM) trial, performed in the Netherlands in the setting of regular screening, where women aged from 29 to 61 years old were invited to cytology and HPV co-testing at enrolment in year 1999/2002 and at the next round in 2003/2007. We selected 18,448 women (9,293 from the intervention group and 9,155 from the control group) who tested HPV–negative in 2003/2007 and did not have cervical intraepithelial neoplasia grade 2 or worse (CIN2+) or hysterectomy after enrolment. Follow-up was collected until 14 years after the 2003/2007 screen, covering 4 rounds of screening. Risk of CIN3+ and CIN2+ among women with an HPV–negative test, irrespective of previous round results and stratified according to previous round HPV and cytology results, were calculated by the Kaplan–Meier method. During 14 years of follow-up, 62 CIN3+ cases (24 in the intervention group and 38 in the control group) were detected. HPV–negative women had a 14-year CIN3+ risk of 0.48% (95% confidence interval 0.37 to 0.62) and CIN2+ risk of 1.17% (0.99 to 1.38). The CIN3+ risk among HPV–negative women was increased in women with a previous positive HPV test (2.36%, 1.20 to 4.63; p < 0.001) or co-test (1.68%, 0.87 to 3.20; p < 0.001) and, equivalently, decreased in women with a previous negative HPV test (0.43%, 0.33 to 0.57) or a negative co-test (0.43%, 0.33 to 0.57). The CIN3+ risk was not influenced by the previous cytology result. The CIN3+ risk among HPV–negative women was increased after both a previous HPV16–positive test (3.90%, 1.47 to 10.12; p < 0.001) and a previous HPV16–negative/HPVother–positive test (1.91%, 0.76 to 4.74; p = 0.002). For endpoint CIN2+ (147 cases), findings were similar except that the CIN2+ risk was increased after previous abnormal cytology (4.06%, 2.30 to 7.12; p < 0.001). The presented risk estimates were calculated by tracking histological results through the Dutch nationwide pathology archive (PALGA) and were not adjusted for non-compliance with the colposcopy referral advice. Conclusions HPV–negative women had an increased long-term risk of CIN3+ when the HPV test in the previous screening round was positive. This supports the implementation of risk-based intervals that depend on HPV results in the current and previous screening round

Women with a positive high-risk human papillomavirus (HPV) test remain at increased risk of HPV infection and cervical precancer ≥15 years later

Little is known about the long-term association between high-risk human papillomavirus (hrHPV) test results in women participating in a hrHPV-based cervical cancer screening program. To address this question, we collected data of 2217 women who participated in the POBASCAM hrHPV-based screening trial (enrolment 1999/2002) and also attended the Dutch hrHPV-based screening program between January 2017 and March 2018. Among 143 women who tested hrHPV-positive in 1999/2002, 45 (31.5%) had ≥ CIN2 or hysterectomy before 2017 and 17 (11.9%) tested hrHPV-positive at the 2017/2018 screen. In comparison, among 2074 women who tested hrHPV-negative in 1999/2002, 10 (0.5%) had ≥ CIN2 or hysterectomy before 2017 and 119 (5.7%) tested hrHPV-positive at the 2017/2018 screen. It follows that in the group of women who were not treated for ≥ CIN2 or had a hysterectomy in between the two screens 15 years apart (N = 2162), women who were hrHPV-positive in 1999/2002 had a higher risk of being hrHPV-positive in 2017/2018 than those who were hrHPV-negative in 1999/2002 (OR 3.4, 95% CI 1.8-6.1). A similar association was found at the genotype level for genotype-concordant results (5.1, 1.0-11.3) and for genotype non-concordant results (3.7, 1.6-6.7). Women who were hrHPV-positive in 2017/2018 had a higher risk of CIN3 after a hrHPV-positive result in 1999/2002 than after a hrHPV-negative result (5.8, 1.0-27.8). In conclusion, a positive hrHPV result in screening gives a long-term increased risk of a hrHPV-positive result, also for different genotypes, and a long-term increased risk of CIN3. This supports the concept of risk-stratification in hrHPV-based cervical cancer screening where previous hrHPV results are included in screening recommendations

Estimating the direct effect of human papillomavirus vaccination on the lifetime risk of screen-detected cervical precancer.

Birth cohorts vaccinated against human papillomavirus (HPV) are now entering cervical cancer screening. Assessment of (pre)cancer (CIN3+) risk is needed to assess the residual screening need in vaccinated women. We estimated the lifetime (screen-detected) CIN3+ risk under five-yearly primary HPV screening between age 30 and 60, using HPV genotyping and histology data of 21,287 women participating in a screening trial with two HPV-based screening rounds, 5 years apart. The maximum follow-up after an HPV-positive test was 9 years. We re-estimated the CIN3+ risk after projecting direct vaccine efficacy for the bivalent and the nonavalent HPV vaccines, assuming life-long protection. The lifetime CIN3+ risk was 4.1% (95% confidence interval 3.5-4.9) and declined by 53.5% and 70.5% after bivalent vaccination without and with cross-protection, respectively, translating into a residual lifetime CIN3+ risk of 1.9% (1.4-2.4) and 1.2% (0.9-1.5). The CIN3+ risk declined by 88.5% after nonavalent vaccination, translating into a residual lifetime CIN3+ risk of 0.5% (0.2-0.7). The latter risk increased to 1.6% when vaccine protection only lasted until the first screening round at age 30. Among HPV-positive women with abnormal adjunct cytology, the nine-year CIN3+ risk was 16.9% (8.7-32.4) after nonavalent vaccination. In conclusion, HPV vaccination will lead to a strong decline in the lifetime CIN3+ risk and the remaining absolute CIN3+ risk will be very low. Primary HPV testing combined with adjunct cytology at five-year intervals still seems feasible even after nonavalent vaccination, although unlikely to be cost-effective. Our results support a de-intensification of screening programs in settings with high vaccination coverage

Clinical performance of high-risk HPV testing on self-samples versus clinician samples in routine primary HPV screening in the Netherlands: An observational study

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Sociodemographic Characteristics and Screening Outcomes of Women Preferring Self-Sampling in the Dutch Cervical Cancer Screening Programme: A Population-Based Study

BACKGROUND: In the Netherlands, lower high-risk human papillomavirus (hrHPV) positivity but higher cervical intraepithelial neoplasia (CIN) 2+ detection were found in self-collected compared with clinician-collected samples. To investigate the possible reason for these differences, we compared sociodemographic and screening characteristics of women and related these to screening outcomes. METHODS: We extracted data from PALGA on all primary hrHPV screens and associated follow-up tests for 857,866 screened women, invited in 2017 and 2018. We linked these data with sociodemographic data from Statistics Netherlands. Logistic regression was performed for hrHPV positivity and CIN 2+/3+ detection. RESULTS: Out of the 857,866 women, 6.8% chose to use a self-sampling device. A higher proportion of self-sampling users was ages 30 to 35 years, was not previously screened, was living in a one-person household, or was the breadwinner in the household. After adjustment for these factors self-sampling had lower hrHPV positivity (aOR, 0.65; 95% CI, 0.63-0.68)) as compared with clinician-collected sampling, as well as lower odds of CIN 2+ (aOR, 0.76; 95% CI, 0.70-0.82) and CIN 3+ (aOR, 0.86; 95% CI, 0.78-0.95) detection. CONCLUSIONS: It is likely that the observed differences between the two sampling methods are not only related to sociodemographic differences, but related to differences in screening test accuracy and/or background risk. IMPACT: Self-sampling can be used for targeting underscreened women, as a more convenient screening tool. Further investigation is required to evaluate how to implement self-sampling, when it is used as a primary instrument in routine screening. See related commentary by Arbyn et al., p. 159