Cancer screening programs in South-east Asia and Western Pacific.

BACKGROUND: The burden of cancer can be altered by screening. The field of cancer screening is constantly evolving; from the initiation of program for new cancer types as well as exploring innovative screening strategies (e.g. new screening tests). The aim of this study was to perform a landscape analysis of existing cancer screening programs in South-East Asia and the Western Pacific. METHODS: We conducted an overview of cancer screening in the region with the goal of summarizing current designs of cancer screening programs. First, a selective narrative literature review was used as an exploration to identify countries with organized screening programs. Second, representatives of each country with an organized program were approached and asked to provide relevant information on the organizations of their national or regional cancer screening program. RESULTS: There was wide variation in the screening strategies offered in the considered region with only eight programs identified as having an organized design. The majority of these programs did not meet all the essential criteria for being organized screening. The greatest variation was observed in the starting and stopping ages. CONCLUSIONS: Essential criteria of organized screening are missed. Improving organization is crucial to ensure that the beneficial effects of screening are achieved in the long-term. It is strongly recommended to consider a regional cancer screening network.

The road to cervical cancer elimination in Malaysia: Evaluation of the impact and cost-effectiveness of human papillomavirus screening with self-collection and digital registry support.

The WHO has launched a global strategy to eliminate cervical cancer through the scale-up of human papillomavirus (HPV) vaccination, cervical screening, and cervical cancer treatment. Malaysia has achieved high-coverage HPV vaccination since 2010, but coverage of the existing cytology-based program remains low. Pilot studies found HPV self-sampling was acceptable and effective, with high follow-up rates when a digital registry was used, and recently the Malaysian Government announced plans for a national HPV-based screening program. We therefore evaluated the impact of primary HPV screening with self-collection in Malaysia in the context of Malaysia's existing vaccination program. We used the "Policy1-Cervix" modeling platform to assess health outcomes, cost-effectiveness, resource use and cervical cancer elimination timing (the year when cervical cancer rates reach four cases per 100 000 women) of implementing primary HPV testing with self-collection, assuming 70% routine-screening coverage could be achieved. Based on available data, we assumed that compliance with follow-up was 90% when a digital registry was used, but that compliance with follow-up would be 50-75% without the use of a digital registry. We found that the current vaccination program would prevent 27 000 to 32 200 cervical cancer cases and 11 700 to 14 000 deaths by 2070. HPV testing with a digital registry was cost-effective (CER = $US 6953-7549 < $US 11 373[<1×GDP per capita]) and could prevent an additional 15 900 to 17 800 cases and 9700 to 10 600 deaths by 2070, expediting national elimination by 11 to 20 years, to 2055 to 2059. If HPV screening were implemented without a digital registry, there would be 1800 to 4900 fewer deaths averted by 2070 and the program would be less cost-effective. These results underline the importance of HPV testing as a key elimination pillar in Malaysia.

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

The 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.

Human papillomavirus vaccination for adults aged 30 to 45 years in the United States: A cost-effectiveness analysis.

BACKGROUND: A nonavalent human papillomavirus (HPV) vaccine has been licensed for use in women and men up to age 45 years in the United States. The cost-effectiveness of HPV vaccination for women and men aged 30 to 45 years in the context of cervical cancer screening practice was evaluated to inform national guidelines. METHODS AND FINDINGS: We utilized 2 independent HPV microsimulation models to evaluate the cost-effectiveness of extending the upper age limit of HPV vaccination in women (from age 26 years) and men (from age 21 years) up to age 30, 35, 40, or 45 years. The models were empirically calibrated to reflect the burden of HPV and related cancers in the US population and used standardized inputs regarding historical and future vaccination uptake, vaccine efficacy, cervical cancer screening, and costs. Disease outcomes included cervical, anal, oropharyngeal, vulvar, vaginal, and penile cancers, as well as genital warts. Both models projected higher costs and greater health benefits as the upper age limit of HPV vaccination increased. Strategies of vaccinating females and males up to ages 30, 35, and 40 years were found to be less cost-effective than vaccinating up to age 45 years, which had an incremental cost-effectiveness ratio (ICER) greater than a commonly accepted upper threshold of $200,000 per quality-adjusted life year (QALY) gained. When including all HPV-related outcomes, the ICER for vaccinating up to age 45 years ranged from $315,700 to $440,600 per QALY gained. Assumptions regarding cervical screening compliance, vaccine costs, and the natural history of noncervical HPV-related cancers had major impacts on the cost-effectiveness of the vaccination strategies. Key limitations of the study were related to uncertainties in the data used to inform the models, including the timing of vaccine impact on noncervical cancers and vaccine efficacy at older ages. CONCLUSIONS: Our results from 2 independent models suggest that HPV vaccination for adult women and men aged 30 to 45 years is unlikely to represent good value for money in the US.

Impact of HPV vaccination and cervical screening on cervical cancer elimination: a comparative modelling analysis in 78 low-income and lower-middle-income countries.

BACKGROUND: The WHO Director-General has issued a call for action to eliminate cervical cancer as a public health problem. To help inform global efforts, we modelled potential human papillomavirus (HPV) vaccination and cervical screening scenarios in low-income and lower-middle-income countries (LMICs) to examine the feasibility and timing of elimination at different thresholds, and to estimate the number of cervical cancer cases averted on the path to elimination. METHODS: The WHO Cervical Cancer Elimination Modelling Consortium (CCEMC), which consists of three independent transmission-dynamic models identified by WHO according to predefined criteria, projected reductions in cervical cancer incidence over time in 78 LMICs for three standardised base-case scenarios: girls-only vaccination; girls-only vaccination and once-lifetime screening; and girls-only vaccination and twice-lifetime screening. Girls were vaccinated at age 9 years (with a catch-up to age 14 years), assuming 90% coverage and 100% lifetime protection against HPV types 16, 18, 31, 33, 45, 52, and 58. Cervical screening involved HPV testing once or twice per lifetime at ages 35 years and 45 years, with uptake increasing from 45% (2023) to 90% (2045 onwards). The elimination thresholds examined were an average age-standardised cervical cancer incidence of four or fewer cases per 100 000 women-years and ten or fewer cases per 100 000 women-years, and an 85% or greater reduction in incidence. Sensitivity analyses were done, varying vaccination and screening strategies and assumptions. We summarised results using the median (range) of model predictions. FINDINGS: Girls-only HPV vaccination was predicted to reduce the median age-standardised cervical cancer incidence in LMICs from 19·8 (range 19·4-19·8) to 2·1 (2·0-2·6) cases per 100 000 women-years over the next century (89·4% [86·2-90·1] reduction), and to avert 61·0 million (60·5-63·0) cases during this period. Adding twice-lifetime screening reduced the incidence to 0·7 (0·6-1·6) cases per 100 000 women-years (96·7% [91·3-96·7] reduction) and averted an extra 12·1 million (9·5-13·7) cases. Girls-only vaccination was predicted to result in elimination in 60% (58-65) of LMICs based on the threshold of four or fewer cases per 100 000 women-years, in 99% (89-100) of LMICs based on the threshold of ten or fewer cases per 100 000 women-years, and in 87% (37-99) of LMICs based on the 85% or greater reduction threshold. When adding twice-lifetime screening, 100% (71-100) of LMICs reached elimination for all three thresholds. In regions in which all countries can achieve cervical cancer elimination with girls-only vaccination, elimination could occur between 2059 and 2102, depending on the threshold and region. Introducing twice-lifetime screening accelerated elimination by 11-31 years. Long-term vaccine protection was required for elimination. INTERPRETATION: Predictions were consistent across our three models and suggest that high HPV vaccination coverage of girls can lead to cervical cancer elimination in most LMICs by the end of the century. Screening with high uptake will expedite reductions and will be necessary to eliminate cervical cancer in countries with the highest burden. FUNDING: WHO, UNDP, UN Population Fund, UNICEF-WHO-World Bank Special Program of Research, Development and Research Training in Human Reproduction, Canadian Institute of Health Research, Fonds de recherche du Québec-Santé, Compute Canada, National Health and Medical Research Council Australia Centre for Research Excellence in Cervical Cancer Control.

Mortality impact of achieving WHO cervical cancer elimination targets: a comparative modelling analysis in 78 low-income and lower-middle-income countries.

BACKGROUND: WHO is developing a global strategy towards eliminating cervical cancer as a public health problem, which proposes an elimination threshold of four cases per 100 000 women and includes 2030 triple-intervention coverage targets for scale-up of human papillomavirus (HPV) vaccination to 90%, twice-lifetime cervical screening to 70%, and treatment of pre-invasive lesions and invasive cancer to 90%. We assessed the impact of achieving the 90-70-90 triple-intervention targets on cervical cancer mortality and deaths averted over the next century. We also assessed the potential for the elimination initiative to support target 3.4 of the UN Sustainable Development Goals (SDGs)-a one-third reduction in premature mortality from non-communicable diseases by 2030. METHODS: The WHO Cervical Cancer Elimination Modelling Consortium (CCEMC) involves three independent, dynamic models of HPV infection, cervical carcinogenesis, screening, and precancer and invasive cancer treatment. Reductions in age-standardised rates of cervical cancer mortality in 78 low-income and lower-middle-income countries (LMICs) were estimated for three core scenarios: girls-only vaccination at age 9 years with catch-up for girls aged 10-14 years; girls-only vaccination plus once-lifetime screening and cancer treatment scale-up; and girls-only vaccination plus twice-lifetime screening and cancer treatment scale-up. Vaccination was assumed to provide 100% lifetime protection against infections with HPV types 16, 18, 31, 33, 45, 52, and 58, and to scale up to 90% coverage in 2020. Cervical screening involved HPV testing at age 35 years, or at ages 35 years and 45 years, with scale-up to 45% coverage by 2023, 70% by 2030, and 90% by 2045, and we assumed that 50% of women with invasive cervical cancer would receive appropriate surgery, radiotherapy, and chemotherapy by 2023, which would increase to 90% by 2030. We summarised results using the median (range) of model predictions. FINDINGS: In 2020, the estimated cervical cancer mortality rate across all 78 LMICs was 13·2 (range 12·9-14·1) per 100 000 women. Compared to the status quo, by 2030, vaccination alone would have minimal impact on cervical cancer mortality, leading to a 0·1% (0·1-0·5) reduction, but additionally scaling up twice-lifetime screening and cancer treatment would reduce mortality by 34·2% (23·3-37·8), averting 300 000 (300 000-400 000) deaths by 2030 (with similar results for once-lifetime screening). By 2070, scaling up vaccination alone would reduce mortality by 61·7% (61·4-66·1), averting 4·8 million (4·1-4·8) deaths. By 2070, additionally scaling up screening and cancer treatment would reduce mortality by 88·9% (84·0-89·3), averting 13·3 million (13·1-13·6) deaths (with once-lifetime screening), or by 92·3% (88·4-93·0), averting 14·6 million (14·1-14·6) deaths (with twice-lifetime screening). By 2120, vaccination alone would reduce mortality by 89·5% (86·6-89·9), averting 45·8 million (44·7-46·4) deaths. By 2120, additionally scaling up screening and cancer treatment would reduce mortality by 97·9% (95·0-98·0), averting 60·8 million (60·2-61·2) deaths (with once-lifetime screening), or by 98·6% (96·5-98·6), averting 62·6 million (62·1-62·8) deaths (with twice-lifetime screening). With the WHO triple-intervention strategy, over the next 10 years, about half (48% [45-55]) of deaths averted would be in sub-Saharan Africa and almost a third (32% [29-34]) would be in South Asia; over the next 100 years, almost 90% of deaths averted would be in these regions. For premature deaths (age 30-69 years), the WHO triple-intervention strategy would result in rate reductions of 33·9% (24·4-37·9) by 2030, 96·2% (94·3-96·8) by 2070, and 98·6% (96·9-98·8) by 2120. INTERPRETATION: These findings emphasise the importance of acting immediately on three fronts to scale up vaccination, screening, and treatment for pre-invasive and invasive cervical cancer. In the next 10 years, a one-third reduction in the rate of premature mortality from cervical cancer in LMICs is possible, contributing to the realisation of the 2030 UN SDGs. Over the next century, successful implementation of the WHO elimination strategy would reduce cervical cancer mortality by almost 99% and save more than 62 million women's lives. FUNDING: WHO, UNDP, UN Population Fund, UNICEF-WHO-World Bank Special Program of Research, Development and Research Training in Human Reproduction, Germany Federal Ministry of Health, National Health and Medical Research Council Australia, Centre for Research Excellence in Cervical Cancer Control, Canadian Institute of Health Research, Compute Canada, and Fonds de recherche du Québec-Santé.

Historical and projected hysterectomy rates in the USA: Implications for future observed cervical cancer rates and evaluating prevention interventions.

BACKGROUND: SEER-reported cervical cancer incidence rates reflect the total female population including women no longer at risk due to hysterectomy. Hysterectomy rates have been declining in the United States as alternative treatments have become available, which could result in an apparent increase in SEER-reported cervical cancer rates. We aimed to obtain nationally representative historical data on hysterectomy rates in USA, use trends analysis to project rates back to 1935 and forward to 2035, and then predict the impact of changing hysterectomy rates on SEER-reported cervical cancer rates. METHODS: We performed a systematic search of Medline, Embase, Premedline, Cochrane Central databases and extracted nationally-representative hysterectomy incidence data from 1965 to 2009, including data on the number of cervix-preserving (subtotal) procedures. We then projected rates back to 1935, and forward to 2035 based on trends from joinpoint regression. These rates were then used to estimate hysterectomy prevalence out to 2035, and then to predict the impact of changing hysterectomy rates on SEER-reported cervical cancer rates to 2035. We examined alternative assumptions regarding projected hysterectomy incidence rates out to 2035, including a scenario in which rates decline no further from 2009 rates, and a scenario where rates decline at twice the baseline rate. RESULTS: Estimated age-standardized hysterectomy incidence increased from 2.4 to 10.6 per 1000 women between 1935 and 1975. Thereafter, rates are predicted to fall to 3.9 per 1000 by 2035. Subtotal hysterectomy procedures declined from being the predominant method in 1935 to less than 12% of procedures from 1970 onwards. Consequently, holding all else constant, an increase in SEER-reported age-standardized cervical cancer incidence rates (ages 0-85+) of 9% is expected from 2009 to 2035. The predictions were minimally impacted by alternative scenarios for future hysterectomy rates. CONCLUSIONS: Declining hysterectomy rates have implications for the interpretation of SEER-reported cervical cancer rates. A background increase in cervical cancer rates due to decreasing population hysterectomy exposure may partially offset expected decreases from recent cervical screening changes recommended by the US Preventive Services Task Force. Evaluations of new cervical cancer prevention opportunities should consider the background impact of historical and projected hysterectomy rates.

Impact of scaled up human papillomavirus vaccination and cervical screening and the potential for global elimination of cervical cancer in 181 countries, 2020-99: a modelling study.

BACKGROUND: Cervical screening and human papillomavirus (HPV) vaccination have been implemented in most high-income countries; however, coverage is low in low-income and middle-income countries (LMICs). In 2018, the Director-General of WHO announced a call to action for the elimination of cervical cancer as a public health problem. WHO has called for global action to scale-up vaccination, screening, and treatment of precancer, early detection and prompt treatment of early invasive cancers, and palliative care. An elimination threshold in terms of cervical cancer incidence has not yet been defined, but an absolute rate of cervical cancer incidence could be chosen for such a threshold. In this study, we aimed to quantify the potential cumulative effect of scaled up global vaccination and screening coverage on the number of cervical cancer cases averted over the 50 years from 2020 to 2069, and to predict outcomes beyond 2070 to identify the earliest years by which cervical cancer rates could drop below two absolute levels that could be considered as possible elimination thresholds-the rare cancer threshold (six new cases per 100 000 women per year, which has been observed in only a few countries), and a lower threshold of four new cases per 100 000 women per year. METHODS: In this statistical trends analysis and modelling study, we did a statistical analysis of existing trends in cervical cancer worldwide using high-quality cancer registry data included in the Cancer Incidence in Five Continents series published by the International Agency for Research on Cancer. We then used a comprehensive and extensively validated simulation platform, Policy1-Cervix, to do a dynamic multicohort modelled analysis of the impact of potential scale-up scenarios for cervical cancer prevention, in order to predict the future incidence rates and burden of cervical cancer. Data are presented globally, by Human Development Index (HDI) category, and at the individual country level. FINDINGS: In the absence of further intervention, there would be 44·4 million cervical cancer cases diagnosed globally over the period 2020-69, with almost two-thirds of cases occurring in low-HDI or medium-HDI countries. Rapid vaccination scale-up to 80-100% coverage globally by 2020 with a broad-spectrum HPV vaccine could avert 6·7-7·7 million cases in this period, but more than half of these cases will be averted after 2060. Implementation of HPV-based screening twice per lifetime at age 35 years and 45 years in all LMICs with 70% coverage globally will bring forward the effects of prevention and avert a total of 12·5-13·4 million cases in the next 50 years. Rapid scale-up of combined high-coverage screening and vaccination from 2020 onwards would result in average annual cervical cancer incidence declining to less than six new cases per 100 000 individuals by 2045-49 for very-high-HDI countries, 2055-59 for high-HDI countries, 2065-69 for medium-HDI countries, and 2085-89 for low-HDI countries, and to less than four cases per 100 000 by 2055-59 for very-high-HDI countries, 2065-69 for high-HDI countries, 2070-79 for medium-HDI countries, and 2090-2100 or beyond for low-HDI countries. However, rates of less than four new cases per 100 000 would not be achieved in all individual low-HDI countries by the end of the century. If delivery of vaccination and screening is more gradually scaled up over the period 2020-50 (eg, 20-45% vaccination coverage and 25-70% once-per-lifetime screening coverage by 2030, increasing to 40-90% vaccination coverage and 90% once-per-lifetime screening coverage by 2050, when considered as average coverage rates across HDI categories), end of the century incidence rates will be reduced by a lesser amount. In this scenario, average cervical cancer incidence rates will decline to 0·8 cases per 100 000 for very-high-HDI countries, 1·3 per 100 000 for high-HDI countries, 4·4 per 100 000 for medium-HDI countries, and 14 per 100 000 for low-HDI countries, by the end of the century. INTERPRETATION: More than 44 million women will be diagnosed with cervical cancer in the next 50 years if primary and secondary prevention programmes are not implemented in LMICs. If high coverage vaccination can be implemented quickly, a substantial effect on the burden of disease will be seen after three to four decades, but nearer-term impact will require delivery of cervical screening to older cohorts who will not benefit from HPV vaccination. Widespread coverage of both HPV vaccination and cervical screening from 2020 onwards has the potential to avert up to 12·5-13·4 million cervical cancer cases by 2069, and could achieve average cervical cancer incidence of around four per 100 000 women per year or less, for all country HDI categories, by the end of the century. A draft global strategy to accelerate cervical cancer elimination, with goals and targets for the period 2020-30, will be considered at the World Health Assembly in 2020. The findings presented here have helped inform initial discussions of elimination targets, and ongoing comparative modelling with other groups is supporting the development of the final goals and targets for cervical cancer elimination. FUNDING: National Health and Medical Research Council (NHMRC) Australia, part-funded via the NHMRC Centre of Excellence for Cervical Cancer Control (C4; APP1135172).

Pathways to a cancer-free future: A protocol for modelled evaluations to maximize the future impact of interventions on cervical cancer in Australia.

OBJECTIVE: Australia's HPV vaccination and HPV-based cervical screening programs are changing the landscape in cervical cancer prevention. We aim to identify areas which can make the biggest further impact on cervical cancer burden. This protocol describes the first stage of a program of work called Pathways-Cervix that aims to generate evidence from modelled evaluations of interventions across the cervical cancer spectrum. METHODS: Based on evidence from literature reviews and guidance from a multi-disciplinary Scientific Advisory Committee (SAC), the most relevant evaluations for prevention, diagnosis and treatment were identified. RESULTS: Priority evaluations agreed by the SAC included: increasing/decreasing and retaining vaccination uptake at the current level; vaccinating older women; increasing screening participation; methods for triaging HPV-positive women; improving the diagnosis of cervical intraepithelial neoplasia (CIN) and cancer; treating cervical abnormalities and cancer; and vaccinating women treated for CIN2/3 to prevent recurrence. Evaluations will be performed using a simulation model, Policy1-Cervix previously used to perform policy evaluations in Australia. Exploratory modelling of interventions using idealised scenarios will initially be conducted in single birth cohorts. If these have a significant impact on findings then evaluations with more realistic assumptions will be conducted. Promising strategies will be investigated further by multi-cohort simulations predicting health outcomes, resource use and cost outcomes. CONCLUSIONS: Pathways-Cervix will assess the relative benefits of strategies and treatment options in a systematic and health economic framework, producing a list of 'best buys' for future decision-making in cervical cancer control.

How will transitioning from cytology to HPV testing change the balance between the benefits and harms of cervical cancer screening? Estimates of the impact on cervical cancer, treatment rates and adverse obstetric outcomes in Australia, a high vaccination coverage country.

Primary HPV screening enables earlier diagnosis of cervical lesions compared to cytology, however, its effect on the risk of treatment and adverse obstetric outcomes has not been extensively investigated. We estimated the cumulative lifetime risk (CLR) of cervical cancer and excisional treatment, and change in adverse obstetric outcomes in HPV unvaccinated women and cohorts offered vaccination (>70% coverage in 12-13 years) for the Australian cervical screening program. Two-yearly cytology screening (ages 18-69 years) was compared to 5-yearly primary HPV screening with partial genotyping for HPV16/18 (ages 25-74 years). A dynamic model of HPV transmission, vaccination, cervical screening and treatment for precancerous lesions was coupled with an individual-based simulation of obstetric complications. For cytology screening, the CLR of cervical cancer diagnosis, death and treatment was estimated to be 0.649%, 0.198% and 13.4% without vaccination and 0.182%, 0.056% and 6.8%, in vaccinated women, respectively. For HPV screening, relative reductions of 33% and 22% in cancer risk for unvaccinated and vaccinated women are predicted, respectively, compared to cytology. Without the implementation of vaccination, a 4% increase in treatment risk for HPV versus cytology screening would have been expected, implying a possible increase in pre-term delivery (PTD) and low birth weight (LBW) events of 19 to 35 and 14 to 37, respectively, per 100,000 unvaccinated women. However, in vaccinated women, treatment risk will decrease by 13%, potentially leading to 4 to 41 fewer PTD events and from 2 more to 52 fewer LBW events per 100,000 vaccinated women. In unvaccinated women in cohorts offered vaccination as 12-13 year olds, no change to lifetime treatment risk is expected with HPV screening. In unvaccinated women in cohorts offered vaccination as 12-13 year olds, no change to lifetime treatment risk is expected with HPV screening. HPV screening starting at age 25 in populations with high vaccination coverage, is therefore expected to both improve the benefits (further decrease risk of cervical cancer) and reduce the harms (reduce treatments and possible obstetric complications) associated with cervical cancer screening.

Will cervical screening remain cost-effective in women offered the next generation nonavalent HPV vaccine? Results for four developed countries.

A next generation nonavalent human papillomavirus (HPV) vaccine ("HPV9 vaccine") is being introduced in several countries. The aims of this study were to evaluate whether cervical screening will remain cost-effective in cohorts offered nonavalent vaccines and if so, to characterize the optimal number of screening tests. We used a dynamic model of HPV vaccination and cervical screening to evaluate the cost-effectiveness of strategies involving varying numbers of primary HPV tests per lifetime for cohorts offered the nonavalent vaccine as 12 year-olds. For each of four countries-the USA, New Zealand (NZ), Australia and England-we considered local factors including vaccine uptake rates (USA/NZ uptake ∼50%; Australia/England uptake >70%), attributable fractions of HPV9-included types, demographic factors, costs and indicative willingness-to-pay (WTP) thresholds. Extensive probabilistic sensitivity analysis was performed. We found that, in the USA, four screens per lifetime was the most likely scenario, with 34% probability of being optimal at WTP US$50,000/LYS, increasing to 84% probability at US$100,000/LYS. In New Zealand, five screens per lifetime was the most likely scenario, with 100% probability of being optimal at NZ$42,000/LYS, given the assumptions used. In Australia, two screens per lifetime was the most likely scenario, with 62% probability of being optimal at AU$50,000/LYS. In England, four screens per lifetime was the most likely scenario, with 32% probability of being optimal at GB£20,000/LYS, increasing to 96% probability at GB£30,000/LYS. We conclude that some cervical screening will remain cost-effective, even in countries with high vaccination coverage. However, the optimal number of screens may vary between countries.

A modelled evaluation of the impact of COVID-19 on breast, bowel, and cervical cancer screening programmes in Australia.

Australia introduced COVID-19 infection prevention and control measures in early 2020. To help prepare health services, the Australian Government Department of Health commissioned a modelled evaluation of the impact of disruptions to population breast, bowel, and cervical cancer screening programmes on cancer outcomes and cancer services. We used the Policy1 modelling platforms to predict outcomes for potential disruptions to cancer screening participation, covering periods of 3, 6, 9, and 12 mo. We estimated missed screens, clinical outcomes (cancer incidence, tumour staging), and various diagnostic service impacts. We found that a 12-mo screening disruption would reduce breast cancer diagnoses (9.3% population-level reduction over 2020-2021) and colorectal cancer (up to 12.1% reduction over 2020-21), and increase cervical cancer diagnoses (up to 3.6% over 2020-2022), with upstaging expected for these cancer types (2, 1.4, and 6.8% for breast, cervical, and colorectal cancers, respectively). Findings for 6-12-mo disruption scenarios illustrate that maintaining screening participation is critical to preventing an increase in the burden of cancer at a population level. We provide programme-specific insights into which outcomes are expected to change, when changes are likely to become apparent, and likely downstream impacts. This evaluation provided evidence to guide decision-making for screening programmes and emphasises the ongoing benefits of maintaining screening in the face of potential future disruptions.

Benefits and harms of cervical screening, triage and treatment strategies in women living with HIV.

To support a strategy to eliminate cervical cancer as a public health problem, the World Health Organisation (WHO) reviewed its guidelines for screening and treatment of cervical pre-cancerous lesions in 2021. Women living with HIV have 6-times the risk of cervical cancer compared to women in the general population, and we harnessed a model platform ('Policy1-Cervix-HIV') to evaluate the benefits and harms of a range of screening strategies for women living with HIV in Tanzania, a country with endemic HIV. Assuming 70% coverage, we found that 3-yearly primary HPV screening without triage would reduce age-standardised cervical cancer mortality rates by 72%, with a number needed to treat (NNT) of 38.7, to prevent a cervical cancer death. Triaging HPV positive women before treatment resulted in minimal loss of effectiveness and had more favorable NNTs (19.7-33.0). Screening using visual inspection with acetic acid (VIA) or cytology was less effective than primary HPV and, in the case of VIA, generated a far higher NNT of 107.5. These findings support the WHO 2021 recommendation that women living with HIV are screened with primary HPV testing in a screen-triage-and-treat approach starting at 25 years, with regular screening every 3-5 years.

Benefits, harms and cost-effectiveness of cervical screening, triage and treatment strategies for women in the general population.

In 2020, the World Health Organization (WHO) launched a strategy to eliminate cervical cancer as a public health problem. To support the strategy, the WHO published updated cervical screening guidelines in 2021. To inform this update, we used an established modeling platform, Policy1-Cervix, to evaluate the impact of seven primary screening scenarios across 78 low- and lower-middle-income countries (LMICs) for the general population of women. Assuming 70% coverage, we found that primary human papillomavirus (HPV) screening approaches were the most effective and cost-effective, reducing cervical cancer age-standardized mortality rates by 63-67% when offered every 5 years. Strategies involving triaging women before treatment (with 16/18 genotyping, cytology, visual inspection with acetic acid (VIA) or colposcopy) had close-to-similar effectiveness to HPV screening without triage and fewer pre-cancer treatments. Screening with VIA or cytology every 3 years was less effective and less cost-effective than HPV screening every 5 years. Furthermore, VIA generated more than double the number of pre-cancer treatments compared to HPV. In conclusion, primary HPV screening is the most effective, cost-effective and efficient cervical screening option in LMICs. These findings have directly informed WHO's updated cervical screening guidelines for the general population of women, which recommend primary HPV screening in a screen-and-treat or screen-triage-and-treat approach, starting from age 30 years with screening every 5 years or 10 years.

Towards the elimination of cervical cancer in low-income and lower-middle-income countries: modelled evaluation of the effectiveness and cost-effectiveness of point-of-care HPV self-collected screening and treatment in Papua New Guinea.

INTRODUCTION: WHO has launched updated cervical screening guidelines, including provisions for primary HPV screen-and-treat. Papua New Guinea (PNG) has a high burden of cervical cancer, but no national cervical screening programme. We recently completed the first field trials of a screen-and-treat algorithm using point-of-care self-collected HPV and same-day treatment (hereafter self-collected HPV S&T) and showed this had superior clinical performance and acceptability to visual inspection of the cervix with acetic acid (VIA). We, therefore, evaluated the effectiveness, cost-effectiveness and resource implications of a national cervical screening programme using self-collected HPV S&T compared with VIA in PNG. METHODS: An extensively validated platform ('Policy1-Cervix') was calibrated to PNG. A total of 38 strategies were selected for investigation, and these incorporated variations in age ranges and screening frequencies and allowed for the identification of the optimal strategy across a wide range of possibilities. A selection of strategies that were identified as being the most effective and cost-effective were then selected for further investigation for longer-term outcomes and budget impact estimation. In the base case, we assumed primary HPV testing has a sensitivity to cervical intraepithelial neoplasia 2 (CIN2+) + of 91.8% and primary VIA of 51.5% based on our earlier field evaluation combined with evidence from the literature. We conservatively assumed HPV sampling and testing would cost US$18. Costs were estimated from a service provider perspective based on data from local field trials and local consultation. RESULTS: Self-collected HPV S&T was more effective and more cost-effective than VIA. Either twice or thrice lifetime self-collected HPV S&T would be cost-effective at 0.5× gross domestic product (GDP) per capita (incremental cost-effectiveness ratio: US$460-US$656/life-years saved; 1GDPper-capita: US$2829 or PGK9446 (year 2019)) and could prevent 33 000-42 000 cases and 23 000-29 000 deaths in PNG over the next 50 years, if scale-up reached 70% coverage from 2023. CONCLUSION: Self-collected HPV S&T was effective and cost-effective in the high-burden, low-resource setting of PNG, and, if scaled-up rapidly, could prevent over 20 000 deaths over the next 50 years. VIA screening was not effective or cost-effective. These findings support, at a country level, WHO updated cervical screening guidelines and indicate that similar approaches could be appropriate for other low-resource settings.

Point-of-care HPV DNA testing of self-collected specimens and same-day thermal ablation for the early detection and treatment of cervical pre-cancer in women in Papua New Guinea: a prospective, single-arm intervention trial (HPV-STAT).

BACKGROUND: WHO recommends human papillomavirus (HPV) testing and same-day treatment for cervical screening in low-income and middle-income countries (LMICs); however, few published data exist on the validity of the strategy. We aimed to evaluate the clinical performance, treatment completion rates, adverse events profile, and acceptability of a fully integrated strategy, comprising point-of-care HPV DNA testing of self-collected specimens and same-day thermal ablation, for screening of cervical cancer in women in Papua New Guinea. METHODS: HPV-STAT was a large-scale, prospective, single-arm intervention trial conducted at two clinical sites in Papua New Guinea. Cervical screening clinics with an on-site consultant gynaecologist were selected in consultation with national and provincial health authorities, church health services, and local stakeholders. Eligible participants were women aged 30-59 years attending cervical screening services at the two clinics, who were willing to comply with study procedures and able to provide written informed consent. Women self-collected vaginal specimens for point-of-care GeneXpert testing (Cepheid, Sunnyvale, CA, USA) for oncogenic HPV types. Women testing positive for HPV underwent pelvic examination followed by same-day thermal ablation or referral for gynaecology review. All HPV-positive women and a 15% random sample of HPV-negative women provided a clinician-collected cervical specimen for liquid-based cytology. The primary outcome was clinical performance (ie, sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]) of the strategy for the detection of high-grade squamous intraepithelial lesion (HSIL) or worse. This trial is registered with ISRCTN, ISRCTN13476702. FINDINGS: Between June 5, 2018, and Jan 6, 2020, we recruited 4285 women, 3638 (84·9%) of whom tested negative for HPV and 647 (15·1%) tested positive for one or more oncogenic HPV type. Sensitivity of the algorithm to detect HSIL or worse was 85·4% (95% CI 81·0-89·6), with specificity 89·6% (88·6-90·6), PPV 35·2% (31·6-39·0), and NPV 98·9% (98·6-99·2). Among HPV-positive women, 602 (93·0%) received same-day thermal ablation and 42 (6·5%) were referred for gynaecology review, 37 (88·1%) of whom attended. Acceptability was high among both HPV-positive and HPV-negative women. Among the 329 HPV-positive women who attended a 3-month follow-up visit, 51 (15·5%) reported mild adverse symptoms that resolved in all cases by the follow-up visit. There were no serious adverse events. INTERPRETATION: We conducted the first real-world evaluation of a fully integrated point-of-care HPV self-collect, test, and treat strategy for same-day cervical screening in a LMIC and found it to be effective, acceptable, and safe when implemented at scale in primary health-care facilities in Papua New Guinea. Our findings support the introduction and scale-up of HPV screening and treatment for the control and elimination of cervical cancer in LMICs, as recommended by WHO. FUNDING: Australian National Health and Medical Research Council.

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

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.

Health economic evaluation of primary human papillomavirus screening in urban populations in China.

BACKGROUND: On Nov 17, 2020, WHO launched a global initiative to accelerate the elimination of cervical cancer through the implementation of HPV vaccination, cervical cancer screening and treatment for precancer and cancer. China has the largest burden of cervical cancer in the world, but only has a national cervical cancer screening program in rural areas since 2009. Here, we aimed to evaluate the effectiveness and cost-effectiveness of cervical cancer screening in urban China, using Shenzhen City as an example. METHODS: We use an extensively validated platform ('Policy1-Cervix'), calibrated to data from Shenzhen city and Guandong Province. We evaluated a range of strategies that have previously been implemented as pilot studies in China, or recommended as guidelines within China and globally, spanning primary HPV, cytology and co-testing strategies. We additionally considered alternate triaging methods, age ranges and screening intervals, resulting in 19 algorithms in total. RESULTS: Of the 19 strategies considered, the most effective approach involved primary HPV testing. At 3- to 10-yearly intervals, primary HPV testing reduced the age-standardized cancer mortality rate by 37-71 %. The most cost-effective strategy was 5-yearly primary HPV testing with partial genotyping triage for ages 25-65, discharging to 10-yearly screening for low-risk women (ICER = US$7191/QALYS using 2018 costs; willingness-to-pay threshold<1xGDP [US$9771]). This strategy gave an incidence and mortality reduction of 56 % and 63 %, respectively. This remained the most cost-effective strategy under most conditions in sensitivity analysis. CONCLUSION: Primary HPV testing would be cost-effective in Shenzhen and could more than halve cervical cancer incidence rates to 6 per 100,000 over the long term. In order to achieve rates below 4 per 100,000, the elimination threshold set by the World Health Organization, vaccination will likely also be necessary.

Impact of HPV vaccine hesitancy on cervical cancer in Japan: a modelling study.

BACKGROUND: Funding for human papillomavirus (HPV) vaccination in Japan began in 2010 for girls aged 12-16 years, with three-dose coverage initially reaching more than 70%. On June 14, 2013, 2 months after formal inclusion in Japan's national immunisation programme, proactive recommendations for the HPV vaccine were suspended following reports of adverse events since found to be unrelated to vaccination, but which were extensively covered in the media. Vaccine coverage subsequently dropped to less than 1% and has remained this low to date. We aimed to quantify the impact of this vaccine hesitancy crisis, and the potential health gains if coverage can be restored. METHODS: In this modelling study, we used the Policy1-Cervix modelling platform. We adapted the model for Japan with use of data on HPV prevalence, screening practices and coverage, and cervical cancer incidence and mortality. We evaluated the expected number of cervical cancer cases and deaths over the lifetime of cohorts born from 1994 to 2007 in the context of the vaccine hesitancy crisis. We assessed a range of recovery scenarios from 2020 onwards, including a scenario in which routine coverage is restored to 70%, with 50% catch-up coverage for the missed cohorts (aged 13-20 years in 2020). To estimate the impact of the vaccine crisis to date, we also modelled a counterfactual scenario in which 70% coverage had been maintained in 12-year-olds from 2013 onwards. FINDINGS: The vaccine crisis from 2013 to 2019 is predicted to result in an additional 24 600-27 300 cases and 5000-5700 deaths over the lifetime of cohorts born between 1994 and 2007, compared with if coverage had remained at around 70% since 2013. However, restoration of coverage in 2020, including catch-up vaccination for missed cohorts, could prevent 14 800-16 200 of these cases and 3000-3400 of these deaths. If coverage is not restored in 2020, an additional 3400-3800 cases and 700-800 deaths will occur over the lifetime of individuals who are 12 years old in 2020 alone. If the crisis continues, 9300-10 800 preventable deaths due to cervical cancer will occur in the next 50 years (2020-69). INTERPRETATION: The HPV vaccine crisis to date is estimated to result in around 5000 deaths from cervical cancer in Japan. Many of these deaths could still be prevented if vaccination coverage with extended catch-up can be rapidly restored. FUNDING: National Health and Medical Research Council Australia Centre of Research Excellence in Cervical Cancer Control, Japan Society for the Promotion of Science.