Megan A. Smith

How Does Transitioning to Primary Human Papillomavirus Screening Impact Colposcopy Services? Lessons From an Australian National Program

Objective In 2017, Australian's National Cervical Screening Program changed from 2-yearly cytology to 5-yearly primary human papillomavirus (HPV) testing. The Stakeholder Opinions of Renewal Implementation and Experiences Study (STORIES) aimed to capture stakeholder perspectives during implementation of the renewed National Cervical Screening Program. Materials and Methods Qualitative semistructured interviews were conducted with key National Cervical Screening Program stakeholders 11–20 months following the change, either face-to-face, online, or via phone. Data related to colposcopy services were thematically analyzed using Proctor's conceptual framework for implementation outcomes. Results We identified 4 overarching themes: non-adherence to guidelines, lack of preparedness, unintended consequences, and mitigation strategies. While an initial increase in colposcopy referral was expected following transition, many stakeholders found increased referrals to be inequitably spread across services and exacerbated by confusion about, or overuse of testing for, symptoms. Conclusions The study provides the first assessment of stakeholder perceptions and experiences relating to colposcopy services during a transition from cytology to HPV screening. Significant preparation is required to ensure equitable and timely access to colposcopy when transitioning cervical screening programs, including wide stakeholder communication to build confidence; clear guidelines, especially around symptoms; and adequate resourcing for colposcopy services to meet projected referral rates.

The impact of HPV vaccination beyond cancer prevention: effect on pregnancy outcomes

While the benefits of human papillomavirus (HPV) vaccination relating to cervical cancer prevention have been widely documented, recent published evidence is suggestive of an impact on adverse pregnancy outcomes (APOs) in vaccinated mothers and their infants, including a reduction in rates of preterm births and small for gestational age infants. In this review, we examine this evidence and the possible mechanisms by which HPV vaccination may prevent these APOs. Large-scale studies linking HPV vaccination status with birth registries are needed to confirm these results. Potential confounding factors to consider in future analyses include other risk factors for APOs, and historical changes in both the management of cervical precancerous lesions and prevention of APOs. If confirmed, these additional benefits of HPV vaccination in reducing APO rates will be of global significance, due to the substantial health, social and economic costs associated with APOs, strengthening the case for worldwide HPV immunization.

Eliminating Cervical Cancer: Progress and Challenges for High-income Countries

In 2020, the World Health Organization launched a major initiative to eliminate cervical cancer globally. The initiative is built around the three key pillars of human papillomavirus (HPV) vaccination, cervical screening and treatment, with associated intervention targets for the year 2030. The '90-70-90' targets specify that 90% of adolescent girls receive prophylactic HPV vaccination, 70% of adult women receive a minimum twice-in-a-lifetime cervical HPV test and 90% receive appropriate treatment for preinvasive or invasive disease. Modelling has shown that if these targets are met, the elimination of cervical cancer, defined as fewer than four cases per 100 000 women per annum, will be achieved within a century. Many high-income countries are well positioned to eliminate cervical cancer within the coming decades, but few have achieved '90-70-90' and many challenges must still be addressed to deliver these critical interventions effectively. This review considers the current status of cervical cancer control in relation to each of the three elimination pillars in high-income countries and discusses some of the developments that will assist countries in reaching these ambitious targets by 2030.

Could HPV Testing on Self-collected Samples Be Routinely Used in an Organized Cervical Screening Program? A Modeled Analysis

Abstract Background: Cervical screening on self-collected samples has mainly been considered for targeted use in underscreened women. Updated evidence supports equivalent sensitivity of PCR-based human papillomavirus (HPV) testing on self-collected and clinician-collected samples. Methods: Using a well-established model, we compared the lifetime impact on cancer diagnoses and deaths resulting from cervical screening using self-collected samples only, with and without the existing restriction in Australia to women aged 30+ years and ≥2 years overdue, compared with the mainstream program of 5-yearly HPV screening on clinician-collected samples starting at 25 years of age. We conservatively assumed sensitivity of HPV testing on self-collected relative to clinician-collected samples was 0.98. Outcomes were estimated either in the context of HPV vaccination (“routinely vaccinated cohorts;” uptake as in Australia) or in the absence of HPV vaccination (“unvaccinated cohorts”). Results: In unvaccinated cohorts, the health benefits of increased participation from self-collection outweighed the worst case (2%) loss of relative test sensitivity even if only 15% of women, who would not otherwise attend, used it (“additional uptake”). In routinely vaccinated cohorts, population-wide self-collection could be marginally (0.2%–1.0%) less effective at 15% additional uptake but 6.2% to 12.4% more effective at 50% additional uptake. Most (56.6%–65.0%) of the loss in effectiveness in the restricted self-collection pathway in Australia results from the requirement to be 2 or more years overdue. Conclusions: Even under pessimistic assumptions, any potential loss in test sensitivity from self-collection is likely outweighed by improved program effectiveness resulting from feasible levels of increased uptake. Impact: Consideration could be given to offering self-collection more widely, potentially as an equal choice for women. See related commentary by Lim, p. 245

Estimating the Natural History of Cervical Carcinogenesis Using Simulation Models: A CISNET Comparative Analysis

Abstract Background The natural history of human papillomavirus (HPV)-induced cervical cancer (CC) is not directly observable, yet the age of HPV acquisition and duration of preclinical disease (dwell time) influences the effectiveness of alternative preventive policies. We performed a Cancer Intervention and Surveillance Modeling Network (CISNET) comparative modeling analysis to characterize the age of acquisition of cancer-causing HPV infections and implied dwell times for distinct phases of cervical carcinogenesis. Methods Using four CISNET-cervical models with varying underlying structures but fit to common US epidemiological data, we estimated the age of acquisition of causal HPV infections and dwell times associated with three phases of cancer development: HPV, high-grade precancer, and cancer sojourn time. We stratified these estimates by HPV genotype under both natural history and CC screening scenarios, because screening prevents cancer development that affects the mix of detected cancers. Results The median time from HPV acquisition to cancer detection ranged from 17.5 to 26.0 years across the four models. Three models projected that 50% of unscreened women acquired their causal HPV infection between ages 19 and 23 years, whereas one model projected these infections occurred later (age 34 years). In the context of imperfect compliance with US screening guidelines, the median age of causal infection was 4.4–15.9 years later compared with model projections in the absence of screening. Conclusions These validated CISNET-CC models, which reflect some uncertainty in the development of CC, elucidate important drivers of HPV vaccination and CC screening policies and emphasize the value of comparative modeling when evaluating public health policies.

Elimination of cervical cancer in Tanzania: Modelled analysis of elimination in the context of endemic HIV infection and active HIV control

AbstractThe World Health Organisation (WHO) has launched a strategic initiative for cervical cancer (CC) elimination which involves scaling up three interventions: human papillomavirus (HPV) vaccination, twice‐lifetime HPV‐screening screening and pre‐cancer/cancer treatment by 2030. CC is challenging to control in countries with endemic human immunodeficiency virus (HIV), as women living with HIV (WLHIV) are at elevated risk of HPV infection, persistence and progression. This analysis estimated the impact of the elimination interventions on CC incidence and mortality but additionally considered more intensive screening for WLHIV, using Tanzania as an example. A dynamic HIV/HPV model was used to simulate the elimination strategy for vaccination, screening and pre‐cancer/cancer treatment, with 3‐yearly HPV‐screening in WLHIV starting at age 25 years, in the context of sustained HIV control in Tanzania from 2020 to 2119. Without vaccination or HPV screening, CC incidence rates per 100 000 women are predicted to fall from 58.0 in 2020 to 41.6 (range: 39.1‐44.7) in 2119, due to existing HIV control. HPV vaccination and twice‐lifetime HPV‐screening for the general population and 3‐yearly screening for WLHIV, would reduce CC incidence to 1.3 (range: 1.3‐2.5) by 2119, with elimination (<4/100 000) in 2076 (range: 2076‐2092). CC mortality rates per 100 000 women are predicted to reach 1.1 (range: 1.1‐2.1) with further reductions contingent on increased CC treatment access. Vaccination and 3‐yearly HPV‐screening for WLHIV is predicted to achieve elimination in the subgroup of WLHIV potentially as early as 2061 (range: 2061‐2078), with a 2119 CC incidence rate of 1.7 (range: 1.7‐3.3). Scaling‐up vaccination and HPV‐screening will substantially reduce CC incidence in Tanzania, with elimination predicted within a century. Three‐yearly HPV‐screening and HPV vaccination, at high coverage rates, would facilitate CC elimination among WLHIV, and thus accelerate elimination in the overall population.

“So, if she wasn’t aware of it, then how would everybody else out there be aware of it?”—Key Stakeholder Perspectives on the Initial Implementation of Self-Collection in Australia’s Cervical Screening Program: A Qualitative Study

Background: In December 2017, the Australian National Cervical Screening Program transitioned from 2-yearly cytology-based to 5-yearly human papillomavirus (HPV)-based cervical screening, including a vaginal self-collection option. Until July 2022, this option was restricted to under- or never-screened people aged 30 years and older who refused a speculum exam. We investigated the perspectives and experiences of stakeholders involved in, or affected by, the initial implementation of the restricted self-collection pathway. Methods: Semi-structured interviews were conducted with 49 stakeholders as part of the STakeholder Opinions of Renewal Implementation and Experiences Study. All interviews were audio recorded and transcribed. Data were thematically analysed and coded to the Conceptual Framework for Implementation Outcomes. Results: Stakeholders viewed the introduction of self-collection as an exciting opportunity to provide under-screened people with an alternative to a speculum examination. Adoption in clinical practice, however, was impacted by a lack of clear communication and promotion to providers, and the limited number of laboratories accredited to process self-collected samples. Primary care providers tasked with communicating and offering self-collection described confusion about the availability, participant eligibility, pathology processes, and clinical management processes for self-collection. Regulatory delay in developing an agreed protocol to approve laboratory processing of self-collected swabs, and consequently initially having one laboratory nationally accredited to process samples, led to missed opportunities and misinformation regarding the pathway’s availability. Conclusions: Whilst the introduction of self-collection was welcomed, clear communication from Government regarding setbacks in implementation and how to overcome these in practice were needed. As Australia moves to a policy of providing everyone eligible for screening the choice of self-collection, wider promotion to providers and eligible people, clarity around pathology processes and the scaling up of test availability, as well as timely education and communication of clinical management practice guidelines, are needed to ensure smoother program delivery in the future. Other countries implementing self-collection policies can learn from the implementation challenges faced by Australia.

A model-based analysis of the health impacts of COVID-19 disruptions to primary cervical screening by time since last screen for current and future disruptions

We evaluated how temporary disruptions to primary cervical cancer (CC) screening services may differentially impact women due to heterogeneity in their screening history and test modality. We used three CC models to project the short- and long-term health impacts assuming an underlying primary screening frequency (i.e., 1, 3, 5, or 10 yearly) under three alternative COVID-19-related screening disruption scenarios (i.e., 1-, 2-, or 5-year delay) versus no delay in the context of both cytology-based and human papillomavirus (HPV)-based screening. Models projected a relative increase in symptomatically detected cancer cases during a 1-year delay period that was 38% higher (Policy1-Cervix), 80% higher (Harvard), and 170% higher (MISCAN-Cervix) for underscreened women whose last cytology screen was 5 years prior to the disruption period compared with guidelines-compliant women (i.e., last screen 3 years prior to disruption). Over a woman’s lifetime, temporary COVID-19-related delays had less impact on lifetime risk of developing CC than screening frequency and test modality; however, CC risks increased disproportionately the longer time had elapsed since a woman’s last screen at the time of the disruption. Excess risks for a given delay period were generally lower for HPV-based screeners than for cytology-based screeners. Our independent models predicted that the main drivers of CC risk were screening frequency and screening modality, and the overall impact of disruptions from the pandemic on CC outcomes may be small. However, screening disruptions disproportionately affect underscreened women, underpinning the importance of reaching such women as a critical area of focus, regardless of temporary disruptions.

National experience in the first two years of primary human papillomavirus (HPV) cervical screening in an HPV vaccinated population in Australia: observational study

Abstract Objective To review the first two years of the primary human papillomavirus (HPV) cervical screening programme in an HPV vaccinated population. Design Observational study. Setting Australia. Participants 3 745 318 women with a primary HPV test between 1 December 2017 and 31 December 2019; most women aged <40 years had previously been offered vaccination against HPV16 and HPV18. Interventions Primary HPV screening with referral if HPV16 or HPV18 (HPV16/18) positive and triage with liquid based cytology testing (threshold atypical squamous cells-cannot exclude high grade squamous intraepithelial lesion) for women who were positive for high risk HPV types other than 16/18. A 12 month follow-up HPV test was recommended in triaged women with a negative or low grade cytology result, with referral if they tested positive for any high risk HPV type at follow-up. Main outcome measures Proportion of women who had attended for their first HPV screening test, tested positive, and were referred for colposcopy; and short term risk of detecting cervical intraepithelial neoplasia (CIN) grade 2 or worse, CIN grade 3 or worse, or cancer. Results 54.6% (n=3 507 281) of an estimated 6 428 677 eligible women aged 25-69 had undergone their first HPV test by the end of 2019. Among those attending for routine screening, positivity for HPV16/18 and for HPV types not 16/18 was, respectively, 2.0% and 6.6% in women aged 25-69 (n=3 045 844) and 2.2% and 13.3% in highly vaccinated cohorts of women aged 25-34 (n=768 362). Colposcopy referral (ages 25-69 years) was 3.5%, increasing to an estimated 6.2% after accounting for women who had not yet had a 12 month repeat test. Cervical cancer was detected in 0.98% (456/46 330) of women positive for HPV16/18 at baseline, including 0.32% (89/28 003) of women with HPV16/18 and negative cytology. Women with HPV types not 16/18 and negative or low grade cytology at both baseline and 12 months were at low risk of serious disease (3.4% CIN grade 3 or worse; 0.02% cancer; n=20 019) but estimated to account for 62.0% of referrals for this screening algorithm. Conclusions Colposcopy referral thresholds need to consider underlying cancer risk; on this basis, women with HPV16/18 in the first round of HPV screening were found to be at higher risk regardless of cytology result, even in a previously well screened population. Women with HPV types not 16/18 and negative or low grade cytology showed a low risk of serious abnormalities but constitute most referrals and could be managed safely with two rounds of repeat HPV testing rather than one. HPV16/18 driven referrals were low in HPV vaccinated cohorts.

Cancer Incidence in Migrants in Australia: Patterns of Three Infection-Related Cancers

Abstract Background: Australia provides an ideal population-base for cancer migration studies because of its multicultural society and high-quality cancer registrations. Among migrant groups there is considerable variability in the incidence of infection-related cancers; thus, the patterns of three such cancers were examined among migrant groups relative to Australian-born residents. Methods: Using national incidence data for cancers of the stomach, liver, and cervix diagnosed during 2005 to 2014, incidence rates were compared for selected migrant groups with the Australian-born population using incidence rate ratios (IRR), from a negative binomial regression model. Results: Wide variations in incidence between countries/regions of birth were observed for all three cancers (P < 0.0001). The patterns were similar for cancers of the stomach and liver, in that migrants from countries/regions with higher incidence rates maintained an increased risk in Australia, with the highest being among South American migrants (IRR = 2.35) for stomach cancer and among Vietnamese migrants (5.44) for liver cancer. In contrast, incidence rates of cervical cancer were lower for many migrant groups, with women from Southern Asia (0.39) and North Africa (0.42) having the lowest rates. The rate of cervical cancer was higher in migrants from New Zealand, Philippines, and Polynesia. Conclusions: Several Australian migrant groups were found to experience a disproportionate burden of infection-related cancers; further studies of associated risk factors may inform the design of effective interventions to mediate these disparities. Impact: By identifying these migrant groups, it is hoped that these results will motivate and inform prevention or early detection activities for these migrant groups. See related commentary Dee and Gomez, p. 1251

A modelled analysis of the impact of COVID-19-related disruptions to HPV vaccination

COVID-19 disrupted school attendance in many countries, delaying routine adolescent vaccination against human papillomavirus (HPV) in some settings. We used Policy1-Cervix , a dynamic model simulating HPV transmission, natural history, vaccination, cervical screening, and diagnosis of HPV-related cancers, to estimate the impact on HPV-related cancers from disruptions to HPV vaccination in a high-income setting. A baseline scenario of no disruption to HPV vaccination was modelled, which assumed uptake of the nonavalent vaccine at the age of 12 by 82.4% of females and 75.5% of males, as is the coverage in Australia. Additional lifetime HPV-related cancer cases were calculated for three disruption scenarios affecting one birth cohort (2008; aged 12 in 2020) compared to the baseline scenario: (1) 1-year delay (no doses missed); (2) 1- to 7-year delay (slow catch-up); (3) no catch-up (herd effects only). A fourth scenario assumed no catch-up HPV vaccination for two birth cohorts, that is all individuals born in 2008 and in 2009 missed vaccination (worst-case scenario). Compared to 1532 HPV-related cancer cases estimated for the baseline no disruption scenario, we found a 1-year delay could result in ≤0.3% more HPV-related cancers ( n = 4) but the increase would be greater if catch-up was slower (5%; n = 70), and especially if there was no catch-up (49%; n = 750). Additional cancers for a single missed cohort were most commonly cervical (23% of the additional cases) and anal cancers (16%) in females and oropharyngeal cancers in males (20%). In the worst-case scenario of two birth cohorts missing vaccination, ≤62% more HPV-related cancers would be diagnosed ( n = 1892). In conclusion, providing catch-up of missed HPV vaccines is conducted, short-term delays in vaccinating adolescents are unlikely to have substantial long-term effects on cancer.

Participation in the National Cervical Screening Program Among Women Who Gave Birth in New South Wales, Australia by Place of Maternal Birth: A Data Linkage Analysis

ABSTRACT Objective High participation rates in the National Cervical Screening Program (NCSP) by all groups of women are required to ensure the equitable elimination of cervical cancer in Australia. In this study, we examine screening participation of overseas‐born women compared to Australian‐born women who gave birth. Design Population‐based retrospective cohort study using linked health datasets. Setting and Participants Women who gave birth in New South Wales between January 1, 2000 and June 30, 2017. Main Outcome Measures Participation in the NCSP (≥ 1 cytology test) in the 3‐ and 5‐year periods prior to delivery by place of maternal birth, adjusted for multiple socio‐demographic and health characteristics. Results Among the 1 332 669 mothers who gave birth over the study period, overall cervical screening participation in the 3‐ and 5‐year periods prior to delivery was 67.0% and 75.7%, respectively. Participation was lower for overseas‐born mothers compared to Australian‐born mothers for both the 3‐year (57.8% vs. 71.7%; adjusted odds ratio [aOR]: 0.51, 95% confidence interval [CI]: 0.50–0.51) and 5‐year (64.9% vs. 81.2%; aOR: 0.40, 95% CI: 0.40–0.40) participation periods. All groups of overseas‐born women had substantially lower screening participation compared to Australian‐born women, with the lowest relative 3‐year participation in mothers born in Southern/Central Asia (aOR: 0.30, 95% CI: 0.30–0.31), Oceania (aOR: 0.31, 95% CI: 0.30–0.32), North‐East Asia (aOR: 0.49, 95% CI: 0.48–0.50), and New Zealand (aOR: 0.49, 95% CI: 0.48–0.51). Conclusions Overseas‐born women had around half the cervical screening participation in the period prior to birth compared to Australian‐born women. It is likely that opportunities to screen these under‐screened groups during the antenatal period, typically a time of repeated health services contact, are missed.