Almost all cervical cancers and high-grade cancer precursors are caused by specific high-risk types of human papillomavirus (HPV).1,2 The availability of sensitive assays to detect carcinogenic types of HPV has led to substantial interest in the use of HPV DNA testing as a cervical cancer screening tool. Molecular testing for high-risk types of HPV has already been recommended in published clinical guidelines for the triage of women with equivocal results on cervical cytology.3,4 Recently, the Food and Drug Administration approved the use of 1 specific HPV DNA assay for high-risk types of HPV (Hybrid Capture II; Digene Diagnostics, Gaithersburg, MD) as an adjunct to cervical cytology for cervical cancer screening in women aged 30 years or more. Although a number of published studies have shown that screening with a combination of HPV DNA testing and cervical cytology would detect more high-grade cervical cancer precursor lesions, referred to as high-grade cervical intraepithelial neoplasia (CIN 2,3), the potential public health impact of changing how we screen for cervical cancer has not been fully assessed.5,6
Cervical cytology-screening programs, with conventional Papanicolaou (Pap) tests repeated at frequent intervals, have clearly reduced cervical cancer incidence and mortality in the United States.7 Although the use of HPV DNA testing as an adjunctive screening method would be predicted to make screening more sensitive, the combination of HPV DNA testing and cervical cytology appears to be less specific than cervical cytology when used alone. This raises the concern that unless appropriate strategies are developed, the introduction of HPV DNA testing as an adjunct to cervical cytology for screening could dramatically increase both the costs of screening and the number of women being referred for unnecessary additional workups, while having a minimal impact on cervical cancer. Because no one clinical trial will be capable of considering all the risks, benefits, and costs of using HPV DNA testing for primary cervical cancer screening, a decision analytic approach with a mathematical model can be a useful approach to evaluate multiple alternative screening strategies and can extrapolate clinical and economic outcomes beyond the time horizon of a single clinical study.8 To inform the deliberations of professional organizations developing national cervical cancer screening guidelines, we developed such a computer-based model to conduct a comprehensive cost-effectiveness analysis of cervical cytology screening strategies that incorporate HPV DNA testing in women aged 30 years or more.
MATERIALS AND METHODS
Our computer-based model simulates the natural history of cervical carcinogenesis using a sequence of monthly transitions among health states. Biopsy-confirmed cervical disease is defined as either CIN grade 1 (CIN 1) or grade 2,3 (CIN 2,3), whereas cytology results are classified according to the 2001 Bethesda System, which classifies squamous abnormalities into atypical squamous cells of undetermined significance (ASC-US), atypical squamous cells cannot exclude a high-grade lesion (ASC-H), low-grade squamous intraepithelial lesions (LSIL), or high-grade squamous intraepithelial lesions (HSIL).9,10 HPV infection is defined as either detectable or undetectable for high-risk types (defined as HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) to accurately represent what would occur in a clinical setting and to permit calibration to data on the distribution of detectable HPV DNA in women with SIL.11 Invasive cervical cancer is stratified according to the National Cancer Institute's Surveillance, Epidemiology, and End Results program (local = FIGO stage I, regional = FIGO stage II–III, and distant cancer = FIGO stage IV).7,12 A cohort of sexually naive women, free of disease, enter the model at the age of 13 and each month face an age-dependent risk of acquiring HPV. Women with HPV infection or established cervical lesions can regress to normal or progress to higher-grade lesions or cervical cancer. Unique health states are defined to distinguish women with previously abnormal screening tests, prior treatment for CIN, and detected cervical disease (through symptoms or screening). Women at any age may die of a cervical cancer-related illness or other causes.
Strategies are defined by varying the type of cytology test (eg, liquid-based versus conventional cytology), use of HPV testing in combination with cytology after the age of 30, and the frequency of the screening program. The main screening approaches include: 1) conventional cytology (eg, Pap test) for women of all ages; 2) liquid-based cytology for women of all ages (with ASC-US results managed by using reflex HPV DNA testing); and 3) DNA testing for high-risk types of HPV in combination with either conventional or liquid-based cytology for women aged 30 years or more. The use of HPV DNA testing for primary screening was restricted to women aged 30 years or more in the base case. Sensitivity analyses were used to identify the potential consequences associated with HPV DNA testing in younger women.
For the base case we assume that 1) screening begins at an average age of 18 years; 2) colposcopy is performed for ASC-H or SIL cytology but treatment is reserved for biopsy-confirmed CIN 2,3; 3) women with CIN 1 and previously treated CIN 2,3 are followed with annual cytology; 4) women with liquid-based cytology results of ASC-US are managed by using reflex HPV DNA testing (HPV-positive women undergo colposcopy and HPV-negative women return to routine screening, but women with a cytology result of ASC-US who remain positive for HPV are assigned to annual screening); 5) women with a conventional cytology result of ASC-US undergo a repeat conventional cytology and are referred for colposcopy only if the repeat cytology is ASC-US or greater; 6) in all HPV DNA testing strategies HPV-positive women are referred for colposcopy (women without colposcopically identified lesions who test negative for HPV at their next annual screen return to routine screening whereas those who test positive for HPV are reevaluated annually); 7) in all HPV DNA screening strategies we assume that women with CIN 1 and those with treated CIN 2,3 will be followed with annual HPV testing and cytology; and 8) compliance with primary screening and follow-up is 100% to permit comparisons to other published analyses. Sensitivity analyses and additional analyses examined alternative assumptions to those used in the base case, including initiation of screening 3 years after initiation of sexual activity.13
We adopted a societal perspective and followed the recommendations of the Panel on Cost-Effectiveness in Health and Medicine.14 Costs are expressed in 2001 U.S. dollars and clinical outcomes as a reduction in the lifetime risk of cancer and years of life saved. Future costs and life years are discounted at an annual rate of 3%. The performance of alternative screening strategies is measured by using the incremental cost-effectiveness ratio, which is defined as the additional cost of a specific screening strategy divided by its additional clinical benefit and compared with the next most expensive strategy.
Selected data used for the base case are summarized in Table 1.7,15–64 Our model requires parameters for the natural history of cervical disease conditional on a woman's HPV DNA status. Because some of the required model parameters were not available directly from the literature, average probabilities of progression and regression of CIN were derived by using data that were not stratified by HPV status. Using an independent mathematical model, we applied the relative risk of CIN with detectable HPV and the prevalence of detectable HPV to split out the overall average probabilities of progression and regression of cervical lesions for women with detectable high-risk HPV DNA and women without detectable high-risk HPV DNA. Details of these methods are provided elsewhere.4,11–36
To the extent possible, we used data on screening test performance from the largest clinical trials that evaluated conventional cytology and the combination of both HPV testing and cytology within the same study.43,49,51 Additional estimates for the sensitivity and specificity of conventional and liquid-based cytology were from published studies, comprehensive reviews, and meta-analyses.23,52,55–58 Because there is uncertainty with respect to the quality of life associated with being positive for HPV, having cervical cancer precursors, and having invasive cancer, we conducted the base case analysis using reduction in the risk of cancer and life expectancy as the primary outcomes. In sensitivity analysis we evaluated the impact of adjusting for quality of life on our results.65,66
Direct medical costs for screening and treatment included costs associated with screening (eg, cytology, HPV test, office visit), diagnostic work-up for an abnormal cytology or HPV test result (eg, colposcopy and biopsy), and treatment for precancerous lesions (Table 1). Costs of invasive cancer were obtained from published literature and a published report from the Agency for Health Care Policy and Research based on data from the MEDSTAT MarketScan database.23,59,60
Cytology costs were estimated by allowing the model to directly calculate a weighted average of normal and abnormal cervical cytology results because abnormal results require physician review. Human papillomavirus DNA testing costs were based on current Health Care Financing Administration reimbursement rates (HCPC #87621).60,61 We assumed that all women receiving HPV DNA testing receive brief counseling (10 minutes by a trained counselor) and HPV-positive women receive more extensive counseling (20 minutes by a registered nurse or nurse practitioner). Data from the Bureau of Labor Statistics were used to value the time for each level of provider.63 The time spent undergoing screening was based on a prospective study of time costs associated with cervical cancer screening, and previously published data incorporating time and transportation costs were used in sensitivity analysis.38,62 To account for inflation, all costs were converted to constant dollars by using the Medical Care Component of the Consumer Price Index.64
The model predicts an age-specific prevalence of high-risk HPV infection that is within a plausible range of results observed in studies using sensitive assays to detect high-risk types of HPV DNA.67–72 Prevalence for all CIN predicted by the model is within the range of estimates reported in other clinical studies, with a peak prevalence of CIN of approximately 7.1% early in the third decade.73–75 In the absence of screening, the model predicts a 3.3% lifetime risk of cervical cancer and a peak annual incidence of 67 per 100,000.76,77 In an exercise to ascertain the face validity of the model, the predictive value of cytology and HPV DNA testing closely approximated data from an independent prospective cohort study (Figure 1). 78
Table 2 depicts the reduction in cervical cancer, gains in life expectancy and quality-adjusted life expectancy, and total lifetime costs associated with different screening strategies. The reduction in lifetime risk of cervical cancer varies from 81.3% to 93.4%, and the discounted average total per-woman lifetime costs from $1,009 to $3,575, depending on the screening frequency, type of cytology, and test strategy. The discounted quality-adjusted life expectancy gains exceed the comparable life expectancy gains, because, in addition to averting cervical cancer-related mortality, a proportion of the screening benefit is realized from improving quality of life with a shift to diagnosis of earlier stages of cancer.
Annual cervical cancer screening with conventional cytology serves as a useful benchmark with which to compare newer strategies. Figure 2 shows the discounted per-woman average lifetime costs and reduction in cervical cancer incidence associated with selected screening strategies recommended by various professional organizations.79,80 A program of annual conventional Pap tests costs $2,457 over the lifetime of a woman and reduces cervical cancer by 89%, whereas triennial liquid-based cytology (using HPV DNA testing only for women with ASC-US) costs $1,358 per woman over her lifetime and reduces cervical cancer incidence by 90%. Similarly, triennial screening with HPV DNA testing combined with cytology in women aged 30 years or more reduces cancer incidence by 90% to 92% and is about 30% less costly than annual conventional cytology.
Strategies shown in Figure 3 differ by type of cytology test (eg, liquid-based versus conventional cytology), use of HPV testing in women aged more than 30 in combination with cytology, and the frequency of the screening program. Strategies lying on the efficiency curve dominate those lying to the right of the curve because they are more effective and either cost less or have a more attractive cost-effectiveness ratio than the next best strategy.
The incremental cost-effectiveness ratio for triennial screening with liquid-based cytology and reflex HPV DNA testing for ASC-US is $95,300 per year of life saved compared with the next best nondominated strategy. In comparison, triennial HPV DNA testing combined with cytology administered to women aged 30 years or more (with liquid-based cytology before the age of 30) costs an additional $289 per lifetime, reduces the lifetime risk of cancer by an additional 2%, and has an incremental cost-effectiveness ratio of $228,700 per year of life saved. Biennial screening with liquid-based cytology reserving HPV DNA testing for women with ASC-US provides similar benefits, although it is slightly more costly, with a cost-effectiveness ratio of $257,400 per year of life saved. Increasing screening frequency when HPV DNA testing is combined with cytology after age 30 from every 3 years to every 2 years costs $452,600 per year of life saved. Screening annually with HPV DNA testing combined with cytology administered to women aged 30 years or more provides an additional reduction in lifetime risk of cancer of approximately 0.5%, costs an average additional $1,400 per woman, and has an incremental cost-effectiveness ratio of more than $2 million per year of life saved compared with the next-best strategy. Analyses in which health states reflecting invasive cancer were adjusted for quality of life reflected cost-effectiveness ratios that were approximately 20% lower.
Although an incremental cost-effectiveness ratio of less than $50,000 per year of life saved gained would, in general, be considered attractive for preventive health measures in the United States, the clinical benefits associated with cervical cancer strategies found to be less than $50,000 per year of life saved (eg, every 4-year screening strategies) are lower than those provided by annual conventional cytology. One could therefore argue that cervical cancer screening strategies with incremental cost-effectiveness ratios less than $250,000 per year of life saved would be considered cost-effective in that they provide equal or better cancer protection and are less costly than the status quo.
The rank-ordering of strategies is not sensitive to plausible changes in the natural history parameters, cost of the diagnostic work-up for an abnormal screening test result, and costs associated with CIN 2,3 and cancer. However, the choice between triennial liquid-based cytology with HPV DNA testing for ASC-US results versus HPV testing combined with cytology for primary screening in women aged 30 years or more is dependent on the relative performance and cost of each test.
If the cost of the HPV test is reduced by 25%, lifetime liquid-based cytology alone is dominated by strategies with primary HPV DNA testing in women aged 30 years or more at nearly all screening intervals. In addition, the incremental cost-effectiveness ratio of HPV DNA testing in combination with cytology administered to women aged 30 years or more is reduced by 30% compared with the same strategy conducted every 4 years. When counseling costs associated with HPV DNA testing are increased by 25%, the incremental cost of triennial screening with HPV DNA testing in combination with cytology in women aged 30 years or more remains below $250,000 per year of life saved. However, if the cost of the HPV DNA test increased by 50%, liquid-based cytology alone—reserving HPV DNA testing for triage of ASC-US results—dominates strategies that use HPV DNA testing for primary screening.
We varied the sensitivity and specificity of liquid-based cytology to identify the specific values at which triennial liquid-based cytology with reflex HPV DNA testing for ASC-US is preferred to triennial HPV DNA testing in combination with cytology in women aged 30 years or more. When the sensitivity and specificity of liquid-based cytology are above 87% and 91%, respectively, liquid-based cytology is nearly always preferred. However, provided the sensitivity and specificity of liquid-based cytology are below 79% and 86%, respectively, HPV testing is nearly always preferred.
Because of the limited data available that directly compare the performance of conventional and liquid-based cytology and the uncertainty that exists as to the incremental additional benefits one obtains with the use of liquid-based cytology, we also conducted an analysis that assumes the use of conventional cytology alone. Table 3 shows the costs, benefits, and cost-effectiveness of strategies that use conventional cytology alone versus conventional cytology combined with HPV DNA testing. Strategies that involve less-frequent screening with combined HPV testing and cytology in women aged 30 years or more are more effective and less costly than annual conventional cytology.
The cumulative lifetime risk of detecting HPV DNA in the absence of a cytological abnormality when HPV testing is initiated in women when they are aged 18 is shown in Figure 4. Even when screening is performed relatively infrequently, the cumulative lifetime risk of being classified as HPV DNA positive in the absence of a cytological abnormality ranges from 60% to 80%. In contrast, if HPV testing is initiated at the age of 30, the comparable risk ranges between 15% and 20%. The costs associated with initiating HPV testing at the age of 18 substantially exceed the costs of initiating HPV testing at the age of 30. For example, the total lifetime cost associated with annual screening using HPV testing and cytology in combination in women of all ages approaches $4,500, nearly $1,000 more than an otherwise-identical strategy limiting the use of HPV DNA testing to women aged 30 years or more.
Previously, we have shown that biennial or triennial screening with liquid-based cytology coupled with “reflex” HPV DNA testing for evaluating women with ASC-US results is both more effective and less costly than annual conventional cytology.4 Now that HPV DNA testing has been approved by the Food and Drug Administration for use as an adjunct to cervical cytology in women aged 30 years or more, the critical issue for clinicians and payers is whether additional benefits are accrued through using HPV DNA testing in conjunction with cervical cytology for primary screening as opposed to limiting HPV DNA testing to selected women with equivocal cytologic results. Compared with annual conventional cytology, we found that screening at 2- or 3-year intervals with either liquid-based cytology (with HPV DNA testing used only for ASC-US management) or HPV DNA testing combined with cytology in women aged 30 years or more would provide increased protection against cervical cancer while reducing the average per-woman lifetime costs associated with screening.
It is important to note that some screening strategies perceived as providing maximum protection against cervical cancer would actually provide minimal additional protection yet drastically increase costs. These include primary screening with cytology and HPV DNA testing in younger women. A strategy that relies on annual screening and uses HPV DNA testing and cytology in combination provides only a few hours of additional life-expectancy gain and has a cost-effectiveness ratio of more than $2,000,000 per year of life saved. Similarly, if biennial HPV DNA testing were begun in women at the age of 18, 60% to 80% of all women would be found to be positive for high-risk types of HPV at some point in their lifetime. In view of the transient nature of most HPV infections, the uncertain psychological impact of telling a woman that she is infected with a high-risk type of HPV, and the potential for unnecessary intervention and overtreatment of women who are positive for HPV DNA but cytology negative, it is unlikely that the benefits associated with such strategies would outweigh the risks.
Our analysis has a number of limitations. First, there is considerable uncertainty with respect to the longitudinal nature of HPV infection and the prevalence of high-risk HPV infections among women in the general U.S. screening population. Second, unknown factors that contribute to population heterogeneity and possible cofactors that contribute to an individual's risk of disease progression could not be modeled.81 Third, there are no empiric data suitable for inclusion into this decision analytic model on the cost and quality of life decrement associated with women being told they have high-risk types of HPV. Fourth, we elected to conservatively assume that HPV DNA-positive women would receive at least 1 colposcopy and then would be followed annually because there is still considerable uncertainty with respect to the optimal management of HPV DNA-positive but cytology-negative women. Finally, it is important to stress that these results assume a particular screening frequency throughout each woman's lifetime. If a woman is at particularly high risk (eg, she has only received 1 or 2 screenings before the age of 30), HPV DNA testing combined with cytology will be more effective and more cost effective.
Our general results are consistent with others who have reported that less frequent screening with more sensitive tests is likely to provide a reasonable balance between costs and benefits.23,24,82–87 However, our model and analysis permit a more comprehensive assessment of the value of HPV DNA testing compared with existing alternatives. Our model is particularly flexible with respect to its capability to assign different strategies for the management of ASC-US and LSIL. This is important because the overall performance of cytology is significantly enhanced by the use of reflex HPV testing for ASC-US results, and without its inclusion the incremental benefits of HPV testing for primary screening could be overestimated. Our model also distinguishes the health states representing detectable HPV and LSIL to capture the different practice patterns and costs associated with the diagnostic work-up and follow-up in response to each. In addition, we specifically included the recent consensus practice recommendations for the management and accompanying cost estimates for LSIL.3
These results support the recently recommended strategies that include the use of HPV DNA testing considered by professional societies and organizations to be appropriate for routine clinical practice: liquid-based cytology coupled with “reflex” HPV DNA testing for ASC-US and high-risk HPV DNA testing in conjunction with cytology (either liquid-based or conventional) after women reach the age of 30.79,80 HPV DNA testing has not only the potential to improve the effectiveness of cervical cancer prevention programs but also the potential to drastically increase cervical cancer-screening costs and lead to unnecessary interventions and over treatment if used inappropriately. Using cost-effectiveness modeling, we have been able to define screening options that are more effective than conventional annual cytology, capitalize on the availability of sensitive HPV tests, and are cost effective. These options would improve the performance of screening for clinical care from an individual perspective and would enhance the efficiency and cost-effectiveness of screening for the U.S. population from a broad public health perspective, permitting resources to be redirected toward efforts to reduce disparities and expand screening coverage.
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