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Background. Although new human papillomavirus (HPV) infections can occur at all ages, the age at which women acquire their \"causal\" HPV infection that develops into cervical cancer is poorly understood and practically unobservable. We aimed to estimate the age distribution at which individuals acquired their causal HPV infection in the absence of HPV vaccination or screening to help guide the optimal use of both. Methods. Using an empirically calibrated mathematical model that simulates the natural history of cervical cancer, we estimated the cumulative number of causal HPV infections by age, stratified by HPV genotype (HPV16 vs. other HPV genotypes), and the direct age-specific reduction in cancer incidence for alternative vaccination initiation scenarios (i.e., age 9–45 years). Results. Our model projected that among all cervical cancers, 50% and 75% of women acquired their causal HPV infection by ages 20.6 (range: 20.1–21.1) and 30.6 (range: 29.6–31.6) years, respectively. HPV16 infections were acquired at an earlier age. Assuming 95% efficacy against HPV16 and HPV18 infections, the direct reduction in lifetime risk of cervical cancer varied from 55% (53%–56%) among women vaccinated at age 9 years to 6% (range: 6–7%) among women vaccinated at age 45 years. Similar patterns were observed for the second-generation vaccine. Conclusions. Although new HPV infections and precancers can occur throughout a woman's lifetime, only a small proportion are acquired in mid-adult women and are vaccine-preventable. Our simulations highlight the potential limitations of using surrogate endpoints for vaccine efficacy studies of mid-adult women to guide policy decisions for implementation.

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. 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. 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.

Background To eliminate cervical cancer as a public health problem, the World Health Organization had recommended routine vaccination of adolescent girls with two doses of the human papillomavirus (HPV) vaccine before sexual initiation. However, many countries have yet to implement HPV vaccination because of financial or logistical barriers to delivering two doses outside the infant immunisation programme. Methods Using three independent HPV transmission models, we estimated the long-term health benefits and cost-effectiveness of one-dose versus two-dose HPV vaccination, in 188 countries, under scenarios in which one dose of the vaccine gives either a shorter duration of full protection (20 or 30 years) or lifelong protection but lower vaccine efficacy (e.g. 80%) compared to two doses. We simulated routine vaccination with the 9-valent HPV vaccine in 10-year-old girls at 80% coverage for the years 2021–2120, with a 1-year catch-up campaign up to age 14 at 80% coverage in the first year of the programme. Results Over the years 2021–2120, one-dose vaccination at 80% coverage was projected to avert 115.2 million (range of medians: 85.1–130.4) and 146.8 million (114.1–161.6) cervical cancers assuming one dose of the vaccine confers 20 and 30 years of protection, respectively. Should one dose of the vaccine provide lifelong protection at 80% vaccine efficacy, 147.8 million (140.6–169.7) cervical cancer cases could be prevented. If protection wanes after 20 years, 65 to 889 additional girls would need to be vaccinated with the second dose to prevent one cervical cancer, depending on the epidemiological profiles of the country. Across all income groups, the threshold cost for the second dose was low: from 1.59 (0.14–3.82) USD in low-income countries to 44.83 (3.75–85.64) USD in high-income countries, assuming one dose confers 30-year protection. Conclusions Results were consistent across the three independent models and suggest that one-dose vaccination has similar health benefits to a two-dose programme while simplifying vaccine delivery, reducing costs, and alleviating vaccine supply constraints. The second dose may become cost-effective if there is a shorter duration of protection from one dose, cheaper vaccine and vaccination delivery strategies, and high burden of cervical cancer.

Radiotherapy is standard of care for cervical cancer, but major global gaps in access exist, particularly in low-income and middle-income countries. We modelled the health and economic benefits of a 20-year radiotherapy scale-up to estimate the long-term demand for treatment in the context of human papillomavirus (HPV) vaccination. We applied the Global Task Force on Radiotherapy for Cancer Control investment framework to model the health and economic benefits of scaling up external-beam radiotherapy and brachytherapy for cervical cancer in upper-middle-income, lower-middle-income, and low-income countries between 2015 and 2035. We estimated the unique costs of external-beam radiotherapy and brachytherapy and included a specific valuation of women's caregiving contributions. Model outcomes life-years gained and the human capital and full income net present value of investment. We estimated the effects of stage at diagnosis, radiotherapy delivery system, and simultaneous HPV vaccination (75% coverage) up to a time horizon set at 2072. For the period from 2015 to 2035, we estimated that 9·4 million women in low-income and middle-income countries required treatment with external-beam radiotherapy, of which 7·0 million also required treatment with brachytherapy. Incremental scale-up of radiotherapy in these countries from 2015 to meet optimal radiotherapy demand by 2035 yielded 11·4 million life-years gained, $59·3 billion in human capital net present value (−$1·5 billion in low-income, $19·9 billion in lower-middle-income, and $40·9 billion in upper-middle-income countries), and $151·5 billion in full income net present value ($1·5 billion in low-income countries, $53·6 billion in lower-middle-income countries, and $96·4 billion in upper-middle-income countries). Benefits increased with advanced stage of cervical cancer and more efficient scale up of radiotherapy. Bivalent HPV vaccination of 12-year-old girls resulted in a 3·9% reduction in incident cases from 2015–2035. By 2072, when the first vaccinated cohort of girls reaches 70 years of age, vaccination yielded a 22·9% reduction in cervical cancer incidence, with 38·4 million requiring external-beam radiotherapy and 28·8 million requiring brachytherapy. Effective cervical cancer control requires a comprehensive strategy. Even with HPV vaccination, radiotherapy treatment scale-up remains essential and produces large health benefits and a strong return on investment to countries at different levels of development. None.

Increasingly, countries have introduced female vaccination against human papillomavirus (HPV), causally linked to several cancers and genital warts, but few have recommended vaccination of boys. Declining vaccine prices and strong evidence of vaccine impact on reducing HPV-related conditions in both women and men prompt countries to reevaluate whether HPV vaccination of boys is warranted. A previously-published dynamic model of HPV transmission was empirically calibrated to Norway. Reductions in the incidence of HPV, including both direct and indirect benefits, were applied to a natural history model of cervical cancer, and to incidence-based models for other non-cervical HPV-related diseases. We calculated the health outcomes and costs of the different HPV-related conditions under a gender-neutral vaccination program compared to a female-only program. Vaccine price had a decisive impact on results. For example, assuming 71% coverage, high vaccine efficacy and a reasonable vaccine tender price of $75 per dose, we found vaccinating both girls and boys fell below a commonly cited cost-effectiveness threshold in Norway ($83,000/quality-adjusted life year (QALY) gained) when including vaccine benefit for all HPV-related diseases. However, at the current market price, including boys would not be considered 'good value for money.' For settings with a lower cost-effectiveness threshold ($30,000/QALY), it would not be considered cost-effective to expand the current program to include boys, unless the vaccine price was less than $36/dose. Increasing vaccination coverage to 90% among girls was more effective and less costly than the benefits achieved by vaccinating both genders with 71% coverage. At the anticipated tender price, expanding the HPV vaccination program to boys may be cost-effective and may warrant a change in the current female-only vaccination policy in Norway. However, increasing coverage in girls is uniformly more effective and cost-effective than expanding vaccination coverage to boys and should be considered a priority.

Sweden revised their cervical cancer screening program in 2017 to include cytology-based screening for women aged 23-29 years and primary human papillomavirus (HPV) testing for women aged 30-64 years; however, alternative strategies may be preferred. To inform cervical cancer prevention policies for unvaccinated women, we evaluated the cost-effectiveness of alternative screening strategies, including the current Swedish guidelines. We adapted a mathematical simulation model of HPV and cervical cancer to the Swedish context using primary epidemiologic data. We compared the cost-effectiveness of alternative screening strategies that varied by the age to start screening, the age to switch from cytology to HPV testing, HPV strategies not preceded by cytology, screening frequency, and management of HPV-positive/cytology-negative women. We found that the current Swedish guidelines were more costly and less effective than alternative primary HPV-based strategies. All cost-efficient strategies involved primary HPV testing not preceded by cytology for younger women. Given a cost-effectiveness threshold of [euro]85,619 per quality-adjusted life year gained, the optimal strategy involved 5-yearly primary HPV-based screening for women aged 23-50 years and 10-yearly HPV-based screening for women older than age 50 years. Primary screening based on HPV alone may be considered for unvaccinated women for those countries with similar HPV burdens.

Background Public health efforts to prevent human papillomavirus (HPV)-related cancers include HPV vaccination and cervical cancer screening. We quantified the annual healthcare cost of six HPV-related cancers in order to provide inputs in cost-effectiveness analyses and quantify the potential economic savings from prevention of HPV-related cancers in Norway. Methods Using individual patient-level data from three unlinked population-based registries, we estimated the mean healthcare costs 1) annually across all phases of disease, 2) during the first 3 years of care following diagnosis, and 3) for the last 12 months of life for patients diagnosed with an HPV-related cancer. We included episodes of care related to primary care physicians, specialist care (private specialists and hospital-based care and prescriptions), and prescription drugs redeemed at pharmacies outside hospitals between 2012 and 2014. We valued costs (2014 €1.00 = NOK 8.357) based on diagnosis-related groups (DRG), patient copayments, reimbursement fees and pharmacy retail prices. Results In 2014, the total healthcare cost of HPV-related cancers amounted to €39.8 million, of which specialist care accounted for more than 99% of the total cost. The annual maximum economic burden potentially averted due to HPV vaccination will be lower for vulvar, penile and vaginal cancer (i.e., €984,620, €762,964 and €374,857, respectively) than for cervical, anal and oropharyngeal cancers (i.e., €17.2 million, €6.7 million and €4.6 million, respectively). Over the first three years of treatment following cancer diagnosis, patients diagnosed with oropharyngeal cancer incurred the highest total cost per patient (i.e. €49,774), while penile cancer had the lowest total cost per patient (i.e. €18,350). In general, costs were highest the first year following diagnosis and then declined; however, costs increased rapidly again towards end of life for patients who did not survive. Conclusion HPV-related cancers constitute a considerable economic burden to the Norwegian healthcare system. As the proportion of HPV-vaccinated individuals increase and secondary prevention approaches advance, this study highlights the potential economic burden avoided by preventing these cancers.

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.

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. 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. 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. 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. 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.

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. 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. 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. 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. 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.