Dataset Information

Modeling Cervical Cancer Screening Strategies With Varying Levels of Human Papillomavirus Vaccination.

ABSTRACT:

Importance

Cervical cancer screening is a lifesaving intervention, with an array of approaches, including liquid-based cytology (LBC), molecular testing for human papillomavirus (HPV) infection, and combinations via parallel cotesting or sequential triage. Maximizing screening efficacy while minimizing overtreatment is vital, especially when considering how the HPV vaccine will affect the interpretation of results.

Objectives

To estimate the likely outcomes of different screening modalities and to model how the increasing uptake of the HPV vaccine could affect the interpretation of screening results.

Design, setting, and participants

This decision analytic model established a simple Markov model to compare the outcomes of different cervical cancer screening modalities on a simulated population of women (aged ≥25 years), considering different levels of HPV vaccination.

Main outcomes and measures

The number of cases of cervical intraepithelial neoplasia (CIN) grade 2 and 3 detected and missed, the number of false positives, and the number of tests required to achieve a given level of accuracy. Positive and negative predictive values of different modalities were simulated under varying levels of HPV vaccination and therefore HPV prevalence.

Results

In a simulated population of 1000 women aged 25 years and older with an HPV prevalence of 2%, HPV-based modalities outperformed LBC-based approaches, detecting 19% more true positives (HPV test sensitivity, 89.9% [95% CI, 88.6%-91.1%]; LBC test sensitivity, 75.5% [95% CI, 66.6%-82.7%]). While cotesting markedly reduced missed cases, detecting 29% more true positives than LBC alone (19.5 [95% CI, 19.3-19.7] per 1000 women screened vs 15.1 [95% CI, 13.3-16.5] per 1000 women screened), it unacceptably increased excess colposcopy referral by 94% (184.4 [95% CI, 181.8-188.0] false positives per 1000 women screened vs 95.1 [95% CI, 93.1-97.0] false positives per 1000 women screened). By contrast, triage testing with reflex screening substantially reduced false positives by a factor of approximately 10 (eg, HPV with LBC triage, 9.6 [95% CI, 9.3-10.0] per 1000 women screened). Over a lifetime of screening, reflex approaches with appropriate test intervals maximized therapeutic efficacy; as HPV vaccination rates increased, HPV-based screening approaches resulted in fewer unnecessary colposcopies than LBC approaches (HPV testing, 80% vaccine coverage: 44.1 [95% CI, 40-45.9] excess colposcopies; LBC testing, 80% vaccine coverage: 96.9 [95% CI, 96.8-97.0] excess colposcopies).

Conclusions and relevance

In this decision analytic model, the effectiveness of cervical cancer screening was dependent on the prevalence of cervical dysplasia and/or HPV infection or vaccination in a population as well as the sensitivity and specificity of various modalities. Although screening is lifesaving, overtesting or modalities inappropriate to the target population may cause significant harm, including overtreatment.

SUBMITTER: Grimes DR

PROVIDER: S-EPMC8246311 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTo provide quantitative insight into current U.S. policy choices for cervical cancer prevention, we developed a model of human papillomavirus (HPV) and cervical cancer, explicitly incorporating uncertainty about the natural history of disease.MethodsWe developed a stochastic microsimulation of cervical cancer that distinguishes different HPV types by their incidence, clearance, persistence, and progression. Input parameter sets were sampled randomly from uniform distributions, and simulations undertaken with each set. Through systematic reviews and formal data synthesis, we established multiple epidemiologic targets for model calibration, including age-specific prevalence of HPV by type, age-specific prevalence of cervical intraepithelial neoplasia (CIN), HPV type distribution within CIN and cancer, and age-specific cancer incidence. For each set of sampled input parameters, likelihood-based goodness-of-fit (GOF) scores were computed based on comparisons between model-predicted outcomes and calibration targets. Using 50 randomly resampled, good-fitting parameter sets, we assessed the external consistency and face validity of the model, comparing predicted screening outcomes to independent data. To illustrate the advantage of this approach in reflecting parameter uncertainty, we used the 50 sets to project the distribution of health outcomes in U.S. women under different cervical cancer prevention strategies.ResultsApproximately 200 good-fitting parameter sets were identified from 1,000,000 simulated sets. Modeled screening outcomes were externally consistent with results from multiple independent data sources. Based on 50 good-fitting parameter sets, the expected reductions in lifetime risk of cancer with annual or biennial screening were 76% (range across 50 sets: 69-82%) and 69% (60-77%), respectively. The reduction from vaccination alone was 75%, although it ranged from 60% to 88%, reflecting considerable parameter uncertainty about the natural history of type-specific HPV infection. The uncertainty surrounding the model-predicted reduction in cervical cancer incidence narrowed substantially when vaccination was combined with every-5-year screening, with a mean reduction of 89% and range of 83% to 95%.ConclusionWe demonstrate an approach to parameterization, calibration and performance evaluation for a U.S. cervical cancer microsimulation model intended to provide qualitative and quantitative inputs into decisions that must be taken before long-term data on vaccination outcomes become available. This approach allows for a rigorous and comprehensive description of policy-relevant uncertainty about health outcomes under alternative cancer prevention strategies. The model provides a tool that can accommodate new information, and can be modified as needed, to iteratively assess the expected benefits, costs, and cost-effectiveness of different policies in the U.S.

Project description:The availability of human papillomavirus (HPV) DNA testing and vaccination against HPV types 16 and 18 (HPV-16,18) motivates questions about the cost-effectiveness of cervical cancer prevention in the United States for unvaccinated older women and for girls eligible for vaccination.An empirically calibrated model was used to assess the quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (2004 US dollars per QALY) of screening, vaccination of preadolescent girls, and vaccination combined with screening. Screening varied by initiation age (18, 21, or 25 years), interval (every 1, 2, 3, or 5 years), and test (HPV DNA testing of cervical specimens or cytologic evaluation of cervical cells with a Pap test). Testing strategies included: 1) cytology followed by HPV DNA testing for equivocal cytologic results (cytology with HPV test triage); 2) HPV DNA testing followed by cytology for positive HPV DNA results (HPV test with cytology triage); and 3) combined HPV DNA testing and cytology. Strategies were permitted to switch once at age 25, 30, or 35 years.For unvaccinated women, triennial cytology with HPV test triage, beginning by age 21 years and switching to HPV testing with cytology triage at age 30 years, cost $78,000 per QALY compared with the next best strategy. For girls vaccinated before age 12 years, this same strategy, beginning at age 25 years and switching at age 35 years, cost $41,000 per QALY with screening every 5 years and $188,000 per QALY screening triennially, each compared with the next best strategy. These strategies were more effective and cost-effective than screening women of all ages with cytology alone or cytology with HPV triage annually or biennially.For both vaccinated and unvaccinated women, age-based screening by use of HPV DNA testing as a triage test for equivocal results in younger women and as a primary screening test in older women is expected to be more cost-effective than current screening recommendations.

Project description:Current US cervical cancer screening guidelines do not differentiate recommendations based on a woman's human papillomavirus (HPV) vaccination status. Changes to cervical cancer screening policies in HPV-vaccinated women should be evaluated. We utilized an individual-based mathematical model of HPV and cervical cancer in US women to project the health benefits, costs, and harms associated with screening strategies in women vaccinated with the bivalent, quadrivalent, or nonavalent vaccine. Strategies varied by the primary screening test, including cytology, HPV, and combined cytology and HPV "cotesting"; age of screening initiation and/or switching to a new test; and interval between routine screens. Cost-effectiveness analysis was conducted from the societal perspective to identify screening strategies that would be considered good value for money according to thresholds of $50 000 to $200 000 per quality-adjusted life-year (QALY) gained. Among women fully vaccinated with the bivalent or quadrivalent vaccine, optimal screening strategies involved either cytology or HPV testing alone every five years starting at age 25 or 30 years, with cost-effectiveness ratios ranging from $34 680 to $138 560 per QALY gained. Screening earlier or more frequently was either not cost-effective or associated with exceedingly high cost-effectiveness ratios. In women vaccinated with the nonavalent vaccine, only primary HPV testing was efficient, involving decreased frequency (ie, every 10 years) starting at either age 35 years ($40 210 per QALY) or age 30 years ($127 010 per QALY); with lower nonavalent vaccine efficacy, 10-year HPV testing starting at earlier ages of 25 or 30 years was optimal. Importantly, current US guidelines for screening were inefficient in HPV-vaccinated women. This model-based analysis suggests screening can be modified to start at later ages, occur at decreased frequency, and involve primary HPV testing in HPV-vaccinated women, providing more health benefit at lower harms and costs than current screening guidelines.

Project description:Introduction Determining the high-risk human papillomavirus (HR-HPV) genotypes burden in women with and without cervical cancer afford a direct comparison of their relative distributions. This quest is fundamental to implementing a future population-based cervical cancer prevention strategy in Ghana. We estimated the cervical cancer risk by HPV genotypes, and the HPV vaccine-preventable proportion of cervical cancer diagnosed in Ghana. Materials and methods An unmatched case-control study was conducted at the two largest cervical cancer treatment centres in Ghana from 1st October 2014 to 31st May 2015. Cases were women diagnosed with cervical cancer and controls were women without cervical cancer who were seeking care at the two hospitals. Nested multiplex polymerase chain reaction (NM-PCR) was used to detect HPV infection in cervical samples. Logistic regression was used to determine the association between the risk of cervical cancer and identified HPV infection. P ≤0.05 was considered statistically significant. Results HPV deoxyribonucleic acid (DNA) data were analysed for 177 women with cervical cancer (cases) and 201 without cancer (controls). Cervical cancer was diagnosed at older ages compared to the age at which controls were recruited (median ages, 57 years vs 34 years; p < 0.001). Most women with cervical cancer were more likely to be single with no formal education, unemployed and less likely to live in metropolitan areas compared to women without cervical cancer (all p-value <0.001). HPV DNA was detected in more women with cervical cancer compared to those without cervical cancer (84.8% vs 45.8%). HR-HPV genotypes 16, 18, 45, 35 and 52 were the most common among women with cervical cancer, while 66, 52, 35, 43 and 31 were frequently detected in those without cancer. HPV 66 and 35 were the most dominant non-vaccine genotypes; HPV 66 was more prevalent among women with cervical cancer and HPV 35 in those without cervical cancer. Cervical cancer risk was associated with a positive HPV test (Adjusted OR (AOR): 5.78; 95% CI: 2.92–11.42), infection with any of the HR-HPV genotypes (AOR: 5.56; 95% CI: 3.27–13.16) or multiple HPV infections (AOR: 9.57 95% CI 4.06–22.56). Conclusion Women with cervical cancer in Ghana have HPV infection with multiple genotypes, including some non-vaccine genotypes, with an estimated cervical cancer risk of about six- to ten-fold in the presence of a positive HPV test. HPV DNA tests and multivalent vaccine targeted at HPV 16, 18, 45 and 35 genotypes will be essential in Ghana’s cervical cancer control programme. Large population-based studies are required in countries where cervical cancer is most prevalent to determine non-vaccine HPV genotypes which should be considered for the next-generation HPV vaccines.