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.

Economic impact of using risk models for eligibility selection to the International lung screening Trial.

OBJECTIVES: Using risk models as eligibility criteria for lung screening can reduce race and sex-based disparities. We used data from the International Lung Screening Trial(ILST; NCT02871856) to compare the economic impact of using the PLCOm2012 risk model or the US Preventative Services' categorical age-smoking history-based criteria (USPSTF-2013). MATERIALS AND METHODS: The cost-effectiveness of using PLCOm2012 versus USPSTF-2013 was evaluated with a decision analytic model based on the ILST and other screening trials. The primary outcomes were costs in 2020 International Dollars ($), quality-adjusted life-years (QALY) and incremental net benefit (INB, in $ per QALY). Secondary outcomes were selection characteristics and cancer detection rates (CDR). RESULTS: Compared with the USPSTF-2013 criteria, the PLCOm2012 risk model resulted in $355 of cost savings per 0.2 QALYs gained (INB=$4294 at a willingness-to-pay threshold of $20 000/QALY (95 %CI: $4205-$4383). Using the risk model was more cost-effective in females at both a 1.5 % and 1.7 % 6-year risk threshold (INB=$6616 and $6112, respectively), compared with males ($5221 and $695). The PLCOm2012 model selected more females, more individuals with fewer years of formal education, and more people with other respiratory illnesses in the ILST. The CDR with the risk model was higher in females compared with the USPSTF-2013 criteria (Risk Ratio = 7.67, 95 % CI: 1.87-31.38). CONCLUSION: The PLCOm2012 model saved costs, increased QALYs and mitigated socioeconomic and sex-based disparities in access to screening.

Updated cost-effectiveness analysis of lung cancer screening for Australia, capturing differences in the health economic impact of NELSON and NLST outcomes.

BACKGROUND: A national, lung cancer screening programme is under consideration in Australia, and we assessed cost-effectiveness using updated data and assumptions. METHODS: We estimated the cost-effectiveness of lung screening by applying screening parameters and outcomes from either the National Lung Screening Trial (NLST) or the NEderlands-Leuvens Longkanker Screenings ONderzoek (NELSON) to Australian data on lung cancer risk, mortality, health-system costs, and smoking trends using a deterministic, multi-cohort model. Incremental cost-effectiveness ratios (ICERs) were calculated for a lifetime horizon. RESULTS: The ICER for lung screening compared to usual care in the NELSON-based scenario was AU$39,250 (95% CI $18,150-108,300) per quality-adjusted life year (QALY); lower than the NLST-based estimate (ICER = $76,300, 95% CI $41,750-236,500). In probabilistic sensitivity analyses, lung screening was cost-effective in 15%/60% of NELSON-like simulations, assuming a willingness-to-pay threshold of $30,000/$50,000 per QALY, respectively, compared to 0.5%/6.7% for the NLST. ICERs were most sensitive to assumptions regarding the screening-related lung cancer mortality benefit and duration of benefit over time. The cost of screening had a larger impact on ICERs than the cost of treatment, even after quadrupling the 2006-2016 healthcare costs of stage IV lung cancer. DISCUSSION: Lung screening could be cost-effective in Australia, contingent on translating trial-like lung cancer mortality benefits to the clinic.

The predicted effect and cost-effectiveness of tailoring colonoscopic surveillance according to mismatch repair gene in patients with Lynch syndrome.

PURPOSE: Lynch syndrome-related colorectal cancer (CRC) risk substantially varies by mismatch repair (MMR) gene. We evaluated the health impact and cost-effectiveness of MMR gene-tailored colonoscopic surveillance. METHODS: We first estimated sex- and MMR gene-specific cumulative lifetime risk of first CRC without colonoscopic surveillance using an optimization algorithm. Next, we harnessed these risk estimates in a microsimulation model, "Policy1-Lynch," and compared 126 colonoscopic surveillance strategies against no surveillance. RESULTS: The most cost-effective strategy was 3-yearly surveillance from age 25 to 70 years (pathogenic variants [path_] in MLH1 [path_MLH1], path_MSH2) with delayed surveillance for path_MSH6 (age 30-70 years) and path_PMS2 (age 35-70 years) heterozygotes (incremental cost-effectiveness ratio = Australian dollars (A) $8,833/life-year saved). This strategy averted 60 CRC deaths (153 colonoscopies per death averted) over the lifetime of 1000 confirmed patients with Lynch syndrome (vs no surveillance). This also reduced colonoscopies by 5% without substantial change in health outcomes (vs nontailored 3-yearly surveillance from 25-70 years). Generally, starting surveillance at age 25 (vs 20) years was more cost-effective with minimal effect on life-years saved and starting 5 to 10 years later for path_MSH6 and path_PMS2 heterozygotes (vs path_MLH1 and path_MSH2) further improved cost-effectiveness. Surveillance end age (70/75/80 years) had a minor effect. Three-yearly surveillance strategies were more cost-effective (vs 1 or 2-yearly) but prevented 3 fewer CRC deaths. CONCLUSION: MMR gene-specific colonoscopic surveillance would be effective and cost-effective.

The predicted impact and cost-effectiveness of systematic testing of people with incident colorectal cancer for Lynch syndrome.

OBJECTIVES: To evaluate the health impact and cost-effectiveness of systematic testing for Lynch syndrome (LS) in people with incident colorectal cancer (CRC) in Australia. DESIGN, SETTING, PARTICIPANTS: We investigated the impact of LS testing strategies in a micro-simulation model (Policy1-Lynch), explicitly modelling the cost of testing all patients diagnosed with incident CRC during 2017, with detailed modelling of outcomes for patients identified as LS carriers (probands) and their at-risk relatives throughout their lifetimes. For people with confirmed LS, we modelled ongoing colonoscopic surveillance. MAIN OUTCOME MEASURES: Cost-effectiveness of six universal tumour testing strategies (testing for DNA mismatch repair deficiencies) and of universal germline gene panel testing of patients with incident CRC; impact on cost-effectiveness of restricting testing by age at CRC diagnosis (all ages, under 50/60/70 years) and of colonoscopic surveillance interval (one, two years). RESULTS: The cost-effectiveness ratio of universal tumour testing strategies (annual colonoscopic surveillance, no testing age limit) compared with no testing ranged from $28 915 to $31 904/life-year saved (LYS) (indicative willingness-to-pay threshold: $30 000-$50 000/LYS). These strategies could avert 184-189 CRC deaths with an additional 30 597-31 084 colonoscopies over the lifetimes of 1000 patients with incident CRC with LS and 1420 confirmed LS carrier relatives (164-166 additional colonoscopies/death averted). The most cost-effective strategy was immunohistochemistry and BRAF V600E testing (incremental cost-effectiveness ratio [ICER], $28 915/LYS). Universal germline gene panel testing was not cost-effective compared with universal tumour testing strategies (ICER, $2.4 million/LYS). Immunohistochemistry and BRAF V600E testing was cost-effective at all age limits when paired with 2-yearly colonoscopic surveillance (ICER, $11 525-$32 153/LYS), and required 4778-15 860 additional colonoscopies to avert 46-181 CRC deaths (88-103 additional colonoscopies/death averted). CONCLUSIONS: Universal tumour testing strategies for guiding germline genetic testing of people with incident CRC for LS in Australia are likely to be cost-effective compared with no testing. Universal germline gene panel testing would not currently be cost-effective.

Benefits, harms and cost-effectiveness of cancer screening in Australia: an overview of modelling estimates.

INTRODUCTION: There are three government-funded population-based screening programs in Australia - the national breast cancer screening program (BreastScreen Australia), the National Cervical Screening Program (NCSP), and the National Bowel Cancer Screening Program (NBCSP). Options for early detection of other cancers (e.g. hepatocellular carcinoma and melanoma) are under investigation. This study provides an overview of the health benefits, harms and cost-effectiveness of population-level breast, cervical and colorectal cancer screening, targeted-risk screening for lung cancer and Lynch syndrome, and prostate specific antigen (PSA) testing in Australia. METHODS: The study reviewed and, where possible, updated the estimated health benefits, harms and cost-effectiveness of screening approaches from modelling studies for four cancer types, PSA testing and Lynch syndrome testing in Australia. Costs are presented in 2018 Australian dollars. RESULTS: The renewed NCSP (for women not HPV-vaccinated) and the NBCSP were estimated to be cost-effective versus no screening; the cost-effectiveness ratio (CER) was $16 632 per life-year saved (LYS) for the NCSP, and $3380/LYS for the NBCSP. BreastScreen Australia was predicted to have a CER of $40 279/LYS-$65 065/LYS. In 2017, the NCSP transitioned to 5-yearly primary HPV testing with partial genotyping for HPV types 16 and 18 for women aged 25-74 years. Alongside vaccination, this change is predicted to prevent a further 587 cervical cancer deaths in 2018-2035, and have a favourable benefit-to-harm balance versus prior practice (biennial cytology testing for women aged 18-69 years). On average, the NBCSP (biennial screening using an immunochemical faecal occult blood test for people aged 50-74 years) is estimated to prevent 2519 colorectal cancer deaths and result in 350 colonoscopy-related adverse events annually. The inaccuracy of PSA testing as a screening tool impedes the capacity to conduct meaningful cost-effectiveness analyses at a population level, based on current evidence. Three annual low-dose computed tomography screens for lung cancer using the US National Lung Screening Trial selection criteria would not be cost-effective in Australia. A comprehensive cost-effectiveness evaluation of systematic proband testing, cascade testing and subsequent surveillance for Lynch syndrome in Australia is currently underway. CONCLUSIONS: Current evidence supports a favourable cost-effectiveness and benefit-to-harm balance for the NCSP and NBCSP. An updated cost-effectiveness and benefits-to-harms analysis for BreastScreen Australia is required. Carefully founded quantitative estimates of health benefits, harms and cost-effectiveness provide an important aid to policy decision making, and form the basis for developing decision aids to guide individual screening decisions. Opportunities exist for lung cancer screening, systematic Lynch syndrome testing and informed decision making about PSA testing. However, more evidence is required on risk assessment, targeting of screening tests, optimal referral pathways, managing potential harms and delivering services in a cost-effective framework.

Benefits, Harms, and Cost-Effectiveness of Potential Age Extensions to the National Bowel Cancer Screening Program in Australia.

BACKGROUND: The Australian National Bowel Cancer Screening Program (NBCSP) is rolling out 2-yearly immunochemical fecal occult blood test screening in people aged 50 to 74 years. This study aimed to evaluate the benefits, harms, and cost-effectiveness of extending the NBCSP to younger and/or older ages. METHODS: A comprehensive validated microsimulation model, Policy1-Bowel, was used to simulate the fully rolled-out NBCSP and alternative strategies assuming screening starts at 40 or 45 years and/or ceases at 79 or 84 years given three scenarios: (i) perfect adherence (100%), (ii) high adherence (60%), and (ii) low adherence (40%, as currently achieved). RESULTS: The current NBCSP will reduce colorectal cancer incidence (mortality) by 23% to 51% (36% to 74%) compared with no screening (range reflects participation); extending screening to younger or older ages would result in additional reductions of 2 to 6 (2 to 9) or 1 to 3 (3 to 7) percentage points, respectively. With an indicative willingness-to-pay threshold of A$50,000/life-year saved (LYS), only screening from 50 to 74 years [incremental cost-effective ratio (ICER): A$2,984-5,981/LYS) or from 45 to 74 years (ICER: A$17,053-29,512/LYS) remained cost-effective in all participation scenarios. The number-needed-to-colonoscope to prevent a death over the lifetime of a cohort in the current NBCSP is 35 to 49. Starting screening at 45 years would increase colonoscopy demand for program-related colonoscopies by 3% to 14% and be associated with 55 to 170 additional colonoscopies per additional death prevented. CONCLUSIONS: Starting screening at 45 years could be cost-effective, but it would increase colonoscopy demand and would be associated with a less favorable incremental benefits-to-harms trade-off than screening from 50 to 74 years. IMPACT: The study underpins recently updated Australian colorectal cancer management guidelines that recommend that the NBCSP continues to offer bowel screening from 50 to 74 years.

Estimating the Cost-Effectiveness of Lung Cancer Screening with Low-Dose Computed Tomography for High-Risk Smokers in Australia.

INTRODUCTION: Health economic evaluations of lung cancer screening with low-dose computed tomography (LDCT) that are underpinned by clinical outcomes are relatively few. METHODS: We assessed the cost-effectiveness of LDCT lung screening in Australia by applying Australian cost and survival data to the outcomes observed in the U.S. National Lung Screening Trial (NLST), in which a 20% lung cancer mortality benefit was demonstrated for three rounds of annual screening among high-risk smokers age 55 to 74 years. Screening-related costs were estimated from Medicare Benefits Schedule reimbursement rates (2015), lung cancer diagnosis and treatment costs from a 2012 Australian hospital-based study, lung cancer survival rates from the New South Wales Cancer Registry (2005-2009), and other-cause mortality from Australian life tables weighted by smoking status. The health utility outcomes, screening participation rates, and lung cancer rates were those observed in the NLST. Incremental cost effectiveness ratios (ICER) were calculated for a 10-year time horizon. RESULTS: The cost-effectiveness of LDCT lung screening was estimated at AU$138,000 (80% confidence interval: AU$84,700-AU$353,000)/life-year gained and AU$233,000 (80% confidence interval: AU$128,000-AU$1,110,000)/quality-adjusted life year (QALY) gained. The ICER was more favorable when LDCT screening impact on all-cause mortality was considered, even when the costs of incidental findings were also estimated in sensitivity analyses: AU$157,000/QALY gained. This can be compared to an indicative willingness-to-pay threshold in Australia of AU$30,000 to AU$50,000/QALY. CONCLUSIONS: LDCT lung screening using NLST selection and implementation criteria is unlikely to be cost-effective in Australia. Future economic evaluations should consider alternative screening eligibility criteria, intervals, nodule management, the impact and cost of new therapies, investigations of incidental findings, and incorporation of smoking cessation interventions.

Evaluation of the benefits, harms and cost-effectiveness of potential alternatives to iFOBT testing for colorectal cancer screening in Australia.

The Australian National Bowel Cancer Screening Program (NBCSP) will fully roll-out 2-yearly screening using the immunochemical Faecal Occult Blood Testing (iFOBT) in people aged 50 to 74 years by 2020. In this study, we aimed to estimate the comparative health benefits, harms, and cost-effectiveness of screening with iFOBT, versus other potential alternative or adjunctive technologies. A comprehensive validated microsimulation model, Policy1-Bowel, was used to simulate a total of 13 screening approaches involving use of iFOBT, colonoscopy, sigmoidoscopy, computed tomographic colonography (CTC), faecal DNA (fDNA) and plasma DNA (pDNA), in people aged 50 to 74 years. All strategies were evaluated in three scenarios: (i) perfect adherence, (ii) high (but imperfect) adherence, and (iii) low adherence. When assuming perfect adherence, the most effective strategies involved using iFOBT (annually, or biennially with/without adjunct sigmoidoscopy either at 50, or at 54, 64 and 74 years for individuals with negative iFOBT), or colonoscopy (10-yearly, or once-off at 50 years combined with biennial iFOBT). Colorectal cancer incidence (mortality) reductions for these strategies were 51-67(74-80)% in comparison with no screening; 2-yearly iFOBT screening (i.e. the NBCSP) would be associated with reductions of 51(74)%. Only 2-yearly iFOBT screening was found to be cost-effective in all scenarios in context of an indicative willingness-to-pay threshold of A$50,000/life-year saved (LYS); this strategy was associated with an incremental cost-effectiveness ratio of A$2,984/LYS-A$5,981/LYS (depending on adherence). The fully rolled-out NBCSP is highly cost-effective, and is also one of the most effective approaches for bowel cancer screening in Australia.

Protocol for Compass: a randomised controlled trial of primary HPV testing versus cytology screening for cervical cancer in HPV-unvaccinated and vaccinated women aged 25-69 years living in Australia.

INTRODUCTION: Australia's National Cervical Screening Program (NCSP) currently recommends 2-year cytology in women aged 18-69 years. Following a review of the NCSP prompted by the implementation of human papillomavirus (HPV) vaccination, the programme will transition in 2017 to 5-year primary HPV screening with partial genotyping for HPV16/18 in women aged 25-74 years. Compass is a sentinel experience for the renewed NCSP and the first prospectively randomised trial of primary HPV screening compared with cytology to be conducted in a population with high uptake of HPV vaccination. This protocol describes the main Compass trial, which commenced after a pilot study of ~5000 women completed recruitment. METHODS AND ANALYSIS: Women aged 25-69 years will be randomised at a 1:2 allocation to (1) 2.5-year image-read, liquid-based cytology (LBC) screening with HPV triage of low-grade smears (active control Arm A) or (2) 5-year HPV screening with partial genotyping and referral of HPV16/18-positive women to colposcopy (intervention Arm B). Women in Arm B positive for other oncogenic HPV (not 16/18) will undergo secondary randomisation at a 1:1 allocation to either LBC or dual-stained (p16INK4a and Ki-67) cytology testing (dual-stained cytology). The primary outcome is cumulative CIN3+ (CIN3, adenocarcinoma in situ and invasive cervical cancer) following a 5-year HPV exit testing round in both arms, in women randomised to the HPV arm versus women randomised to the LBC arm, based on an intention-to-treat analysis. The primary outcome will first be tested for non-inferiority and if declared, the primary outcome will be tested for superiority. A total of 36 300 women in birth cohorts not offered vaccination and 84 700 women in cohorts offered vaccination will be recruited, bringing the final sample size to 121 000. The trial is powered for the secondary outcome of cumulative CIN3+ in screen-negative women, adjusted for censoring after CIN2+ treatment and hysterectomy. ETHICS AND DISSEMINATION: Approved by the Bellberry Ethics Committee (2014-11-592). Findings will be reported in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: NCT02328872; Pre-results.

Primary HPV testing versus cytology-based cervical screening in women in Australia vaccinated for HPV and unvaccinated: effectiveness and economic assessment for the National Cervical Screening Program.

BACKGROUND: Australia's National Cervical Screening Program currently recommends cytological screening every 2 years for women aged 18-69 years. Human papillomavirus (HPV) vaccination was implemented in 2007 with high population coverage, and falls in high-grade lesions in young women have been reported extensively. This decline prompted a major review of the National Cervical Screening Program and new clinical management guidelines, for which we undertook this analysis. METHODS: We did effectiveness modelling and an economic assessment of potential new screening strategies, using a model of HPV transmission, vaccination, natural history, and cervical screening. First, we evaluated 132 screening strategies, including those based on cytology and primary HPV testing. Second, after a recommendation was made to adopt primary HPV screening with partial genotyping and direct referral to colposcopy of women positive for HPV16/18, we evaluated the final effect of HPV screening after incorporating new clinical guidelines for women positive for HPV. Both evaluations considered both unvaccinated and vaccinated cohorts. FINDINGS: Strategies entailing HPV testing every 5 years and either partial genotyping for HPV16/18 or cytological co-testing were the most effective. One of the most effective and cost-effective strategies comprised primary HPV screening with referral of women positive for oncogenic HPV16/18 direct to colposcopy, with reflex cytological triage for women with other oncogenic types and direct referral for those in this group with high-grade cytological findings. After incorporating detailed clinical guidelines recommendations, this strategy is predicted to reduce cervical cancer incidence and mortality by 31% and 36%, respectively, in unvaccinated cohorts, and by 24% and 29%, respectively, in cohorts offered vaccination. Furthermore, this strategy is predicted to reduce costs by up to 19% for unvaccinated cohorts and 26% for cohorts offered vaccination, compared with the current programme. INTERPRETATION: Primary HPV screening every 5 years with partial genotyping is predicted to be substantially more effective and potentially cost-saving compared with the current cytology-based screening programme undertaken every 2 years. These findings underpin the decision to transition to primary HPV screening with partial genotyping in the Australian National Cervical Screening Program, which will occur in May, 2017. FUNDING: Department of Health, Australia.

Long-term evaluation of benefits, harms, and cost-effectiveness of the National Bowel Cancer Screening Program in Australia: a modelling study.

BACKGROUND: No assessment of the National Bowel Screening Program (NBCSP) in Australia, which considers all downstream benefits, costs, and harms, has been done. We aimed to use a comprehensive natural history model and the most recent information about cancer treatment costs to estimate long-term benefits, costs, and harms of the NBCSP (2 yearly immunochemical faecal occult blood testing screening at age 50-74 years) and evaluate the incremental effect of improved screening participation under different scenarios. METHODS: In this modelling study, a microsimulation model, Policy1-Bowel, which simulates the development of colorectal cancer via both the conventional adenoma-carcinoma and serrated pathways was used to simulate the NBCSP in 2006-40, taking into account the gradual rollout of NBCSP in 2006-20. The base-case scenario assumed 40% screening participation (currently observed behaviour) and two alternative scenarios assuming 50% and 60% participation by 2020 were modelled. Aggregate year-by-year screening, diagnosis, treatment and surveillance-related costs, resource utilisation (number of screening tests and colonoscopies), and health outcomes (incident colorectal cancer cases and colorectal cancer deaths) were estimated, as was the cost-effectiveness of the NBCSP. FINDINGS: With current levels of participation (40%), the NBCSP is expected to prevent 92 200 cancer cases and 59 000 deaths over the period 2015-40; an additional 24 300 and 37 300 cases and 16 800 and 24 800 deaths would be prevented if participation was increased to 50% and 60%, respectively. In 2020, an estimated 101 000 programme-related colonoscopies will be done, associated with about 270 adverse events; an additional 32 500 and 49 800 colonoscopies and 88 and 134 adverse events would occur if participation was increased to 50% and 60%, respectively. The overall number needed to screen (NNS) is 647-788 per death prevented, with 52-59 colonoscopies per death prevented. The programme is cost-effective due to the cancer treatment costs averted (cost-effectiveness ratio compared with no screening at current participation, AUS$3014 [95% uncertainty interval 1807-5583] per life-year saved) in the cost-effectiveness analysis. In the budget impact analysis, reduced annual expenditure on colorectal cancer control is expected by 2030, with expenditure reduced by a cumulative AUS$1·7 billion, AUS$2·0 billion, and AUS$2·1 billion (2015 prices) between 2030 and 2040, at participation rates of 40%, 50%, and 60%, respectively. INTERPRETATION: The NBCSP has potential to save 83 800 lives over the period 2015-40 if coverage rates can be increased to 60%. By contrast, the associated harms, although an important consideration, are at a smaller magnitude at the population level. The programme is highly cost-effective and within a decade of full roll-out, there will be reduced annual health systems expenditure on colorectal cancer control due to the impact of screening. FUNDING: Australia Postgraduate Award PhD Scholarship, Translational Cancer Research Network Top-up scholarship (supported by Cancer Institute NSW) and Cancer Council NSW.

Cost-effectiveness of the next generation nonavalent human papillomavirus vaccine in the context of primary human papillomavirus screening in Australia: a comparative modelling analysis.

BACKGROUND: First generation bivalent and quadrivalent human papillomavirus (HPV) vaccines have been introduced in most developed countries. A next generation nonavalent vaccine (HPV9) has become available, just as many countries are considering transitioning from cytology-based to HPV-based cervical screening. A key driver for the cost-effectiveness of HPV9 will be a reduction in screen-detected abnormalities and surveillance tests. We aimed to evaluate the cost-effectiveness of HPV9 in Australia, a country with HPV vaccination of both sexes that is transitioning to 5-yearly HPV-based screening. METHODS: We used Policy1-Cervix and HPV-ADVISE-two dynamic models of HPV transmission, vaccination, and cervical screening-to estimate the cost-effectiveness of HPV9 versus quadrivalent vaccine (HPV4), assuming lifelong vaccine protection, two vaccine doses, and that additional costs were incurred in girls only. Policy1-Cervix was used to estimate the lifetime risk of cervical cancer diagnosis and death. Probabilistic sensitivity analysis of the cost-effectiveness outcomes was done with both models, and results are presented as the median and 10th to 90th percentiles of simulation runs (referred to as 80% uncertainty intervals [UIs]). FINDINGS: Compared with cytology-based screening, HPV screening is predicted to reduce lifetime risk of cervical cancer diagnosis by 18% and of death by 20%, even in unvaccinated cohorts. Under base-case assumptions (lifelong protection, full efficacy at two doses), HPV4 will provide a further reduction in diagnosis of 54% and in death of 53% and HPV9 will provide a further reduction in both diagnosis and death of 11%, compared with cytology-based screening in unvaccinated cohorts. For HPV9 to remain a cost-effective alternative to HPV4, the incremental cost per dose in girls should not exceed a median of AUS$35·99 (80% UI 28·47-41·18) with Policy1-Cervix or AUS$22·74 (15·49-34·45) with HPV-ADVISE, at a willingness-to-pay threshold of AUS$30 000 per quality-adjusted life-year. INTERPRETATION: Differing methods and assumptions led to some differences in the estimates produced by the two models. However, on the basis of median results, HPV9 will be a cost-effective alternative to HPV4 if the additional cost per dose is AUS$23-36 (US$18-28). These results will be important when determining the optimum price of the vaccine in Australia. FUNDING: National Health and Medical Research Council, Australia.