Abstract

Background: European countries with established cytology-based screening programs for cervical cancer will soon face decisions about whether to incorporate human papillomavirus (HPV) DNA testing and what strategies will be most cost-effective. We assessed the cost-effectiveness of incorporating HPV DNA testing into existing cervical cancer screening programs in the United Kingdom, The Netherlands, France, and Italy. Methods: We created a computer-based model of the natural history of cervical carcinogenesis for each using country-specific data on cervical cancer risk and compared each country's current screening policy with two new strategies: 1) cytology throughout a woman's lifetime, using HPV DNA testing as a triage strategy for equivocal cytology results (“HPV triage”), as well as 2) cytology until age 30 years and HPV DNA testing in combination with cytology in women more than 30 years of age (“combination testing”). Outcomes included reduction in lifetime cervical cancer risk, increase in life expectancy, lifetime costs, and incremental cost-effectiveness ratios, expressed as cost per year of life saved. We explored alternative protocols and conducted sensitivity analysis on key parameters of the model over a relevant range of values to identify the most cost-effective options for each country. Results: Both HPV DNA testing strategies, HPV triage and combination testing, were more effective than each country's status quo screening policy. Incremental cost-effectiveness ratios for HPV triage were less than $13 000 per year of life saved, whereas those for combination testing ranged from $9800 to $75 900 per year of life saved, depending on screening interval. We identified options that would be very cost-effective (i.e., cost-effectiveness ratio less than the gross domestic product per capita) in each of the four countries. Conclusions: HPV DNA testing has the potential to improve health benefits at a reasonable cost compared with current screening policies in four European countries.

Mortality from invasive cervical cancer has decreased substantially in countries that have implemented a program of cytology screening ( 14 ) . With the establishment of human papillomavirus (HPV) infection as a necessary precursor to cervical cancer ( 5 , 6 ) and the availability of reliable assays to detect high-risk types of HPV, some countries are beginning to incorporate HPV DNA testing into national screening guidelines. For example, in the United States, HPV DNA testing has been approved by the Food and Drug Administration both as a triage strategy in the case of equivocal cytology results and as a test to be used in combination with cytology for primary screening in women more than 30 years of age; national guidelines have been revised accordingly ( 712 ) .

In many European countries, cervical cancer screening guidelines include the use of conventional cytology ( 13 ) , although they vary widely with respect to the frequency of screening, age to start and stop screening, target coverage rates, and follow-up strategies for equivocal or mildly abnormal results ( Table 1 ) ( 1418 ) . These countries will soon face decisions about whether or not to incorporate HPV DNA testing and what types of strategies will be most cost-effective. Although previous studies have evaluated the costs and benefits of alternate strategies for cervical cancer screening in the United Kingdom and The Netherlands ( 1929 ) , to our knowledge, there has not been a comparative analysis that has involved multiple European countries and has focused on integrating HPV DNA testing into cervical cancer screening programs. Our objective was to assess the costs and benefits associated with HPV DNA testing in four European countries (the United Kingdom, The Netherlands, France, and Italy) to assist decision makers faced with choices about the adoption of this new technology.

Table 1.

Country-specific cervical cancer screening policies ( 1318 )

Characteristic United Kingdom The Netherlands France Italy 
Screening ages, y 20–65 30–60 25–65 25–65 
Screening interval, y  3–5 * 
Eligible women, million 14 3.6 17 5.6 
Coverage, %  84 80 60 70 
Follow-up of equivocal cytology results Repeat cytology Repeat cytology None Colposcopy 
Characteristic United Kingdom The Netherlands France Italy 
Screening ages, y 20–65 30–60 25–65 25–65 
Screening interval, y  3–5 * 
Eligible women, million 14 3.6 17 5.6 
Coverage, %  84 80 60 70 
Follow-up of equivocal cytology results Repeat cytology Repeat cytology None Colposcopy 
*

The screening interval in several regions of the United Kingdom differ with age, with a 3-year screening interval for women 20–39 years of age and a 5-year screening interval for women 40–65 years of age ( 15 ) .

Coverage estimates were obtained from Linos et al. ( 13 ) and country-specific policy papers: the U.K. estimate was based on the percentage of women 20–64 years of age who had a Pap smear in the last 5 years ( 14 , 15 ) ; The Netherlands estimate was based on a national report from 1996–1997 and reflects the percentage of women between 30 and 64 years of age who had a Pap smear in the last 5 years ( 16 ) ; the coverage estimate for France was an average of age-specific coverage rates from the Bas-Rhin and Doubs regions and ranged from 82% in women 25 years of age to 37% in women 65 years of age ( 17 ) ; in Italy, approximately 70% of eligible women are covered, ranging from 74% in Turin to 39% in Florence ( 18 ) . Coverage in both France and Italy reflect the percentage of women between 25 and 64 years of age who had a Pap smear in the last 3 years.

M ETHODS

Cervical Cancer Model

We adapted a previously described computer-based model ( 3034 ) to simulate the natural history of cervical carcinogenesis using a sequence of monthly transitions among health states ( Fig. 1 ). For each analysis, a country-specific cohort of non–HIV infected women entered the model and faced age-dependent probabilities of acquiring HPV, developing cervical intraepithelial neoplasia (CIN), or developing cancer. Women with HPV infection or established cervical lesions can regress to normal or develop higher-grade lesions or cervical cancer. Women at any age may die of cervical cancer or other causes.

Fig. 1.

Natural history model of cervical cancer. Health states were defined using four categories of cervical health (healthy; infection with human papillomavirus [HPV]; grade of cervical intraepithelial neoplasia [CIN]; and stage of invasive cancer). The model simulates the natural history of cervical carcinogenesis using a sequence of monthly transitions among these health states. Women face an age-dependent risk of acquiring HPV and can progress or regress in their cervical disease subject to probabilities that are conditional on their HPV status. Not shown are unique health states, which were defined to distinguish women with detectable or undetectable HPV infection, previously abnormal screening tests, prior treatment for CIN, and detected cervical disease (through symptoms or screening). Women may die from cervical cancer or other causes.

Fig. 1.

Natural history model of cervical cancer. Health states were defined using four categories of cervical health (healthy; infection with human papillomavirus [HPV]; grade of cervical intraepithelial neoplasia [CIN]; and stage of invasive cancer). The model simulates the natural history of cervical carcinogenesis using a sequence of monthly transitions among these health states. Women face an age-dependent risk of acquiring HPV and can progress or regress in their cervical disease subject to probabilities that are conditional on their HPV status. Not shown are unique health states, which were defined to distinguish women with detectable or undetectable HPV infection, previously abnormal screening tests, prior treatment for CIN, and detected cervical disease (through symptoms or screening). Women may die from cervical cancer or other causes.

To calibrate our model, we used country-specific data on the age-specific risk of cervical cancer from years prior to widespread organized screening (1960s for the United Kingdom and The Netherlands, and early-to-mid 1980s for France and Italy) from the International Agency for Research on Cancer (IARC) ( 3538 ) . Although we assumed that the underlying natural history of cervical cancer is fundamentally the same across countries, we acknowledged that patterns of sexual behavior and age of sexual debut vary. To reflect this variation, we adjusted the incidence rates of HPV infection by either shifting the age of initial infection or by decreasing the age-specific rate of infection to calibrate each of the four models to the historic age-specific cancer incidence and mortality rates reported by the IARC ( 35 , 36 ) . We then assessed the face validity of the final country-specific models by simulating the cytology screening patterns in each country and comparing the model predictions with recent data from the IARC ( 37 , 38 ) . We found that the resulting peak age of cancer incidence, shape of the age-specific cancer curve, and overall lifetime risk of cancer closely approximated the empiric data. Model corroboration was assessed by comparing short- and long-term outcomes with those reported in other published studies.

HPV Screening Strategies

We explored two main ways to incorporate HPV DNA testing into screening ( 22 , 41 ) : 1) cytology throughout a woman's lifetime, using HPV DNA testing as a triage strategy for equivocal cytology results (i.e., “HPV triage”) and 2) cytology until age 30 years, followed by HPV DNA testing in combination with cytology in women more than 30 years of age (i.e., “combination testing”). We restricted HPV DNA testing as a primary screening test to women more than 30 years of age because the best available data on HPV DNA test performance are from women more than 30 years of age and because the proportion of women younger than 30 years of age who test positive for HPV DNA would be prohibitively high ( 31 ) . Strategies were compared with the status quo screening policy in each country. We allowed for changes in screening frequency but made the conservative assumption that the screening interval would be no longer than every 5 years and no shorter than every 3 years for women in the general population.

For each country's status quo policy, we assumed the use of conventional cytology at the screening ages, interval, and coverage rate specified in Table 1 ( 1318 ) . Cytology results were classified as atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesions (LSILs), or high-grade squamous intraepithelial lesions (HSILs), consistent with the Bethesda system ( 42 ) . We assumed that a “borderline” result by the European reporting system was equivalent to a result of “ASCUS,” a “mildly abnormal” result was equivalent to “LSIL,” and a “moderate” or “severe” result was equivalent to “HSIL.” Biopsy-confirmed cervical disease was defined as either cervical intraepithelial neoplasia grade 1 (CIN 1) or grade 2,3 (CIN 2,3). We defined coverage as the proportion of eligible women at each scheduled screening interval who were screened.

For the base case, we made the following assumptions: 1) each woman in the cohort, regardless of her underlying risk, is equally likely to miss a scheduled screening examination; 2) an equivocal cytology result is followed by repeat cytology screening every 6 months for 1 year in the United Kingdom and The Netherlands and by colposcopy referral in France and Italy; 3) in the combination testing strategy, cytologically normal women who are HPV DNA positive return at 6 and 12 months for repeat cytology and HPV DNA testing, and those who remain HPV DNA positive after 12 months and/or have subsequent abnormal cytology are referred to colposcopy; 4) for HPV triage, HPV DNA testing is a “reflex” test, in which a sample is co-collected at the time of the cytology screen for an additional cost of $2; 5) colposcopy is performed on all women with cytologic results of HSIL; women without visible lesions on colposcopy do not receive biopsy, and treatment is reserved for biopsy-confirmed CIN 2,3; and 6) women who are treated for CIN 2,3, or have biopsy-confirmed CIN 1 return for a repeat cytology test 12 months later, regardless of the general population screening frequency.

Base Case Data

Selected input parameters used for the base case are presented in Table 2 ( 7 , 1320 , 22 , 25 , 2931 , 4372 ) . Input parameters for the natural history of HPV and cervical cancer were based on population studies primarily in the United States ( 62 ) , although age-specific HPV incidence rates were derived for each country by calibrating the models to country-specific cancer data, as described above.

Table 2.

Model parameters: country-specific baseline values *

Model parameter United Kingdom The Netherlands France Italy 
Natural history ( 22 , 4361 )      
    Normal to HPV DNA  0.00028–0.00948 0.00028–0.01896 0.00028–0.00948 0.00028–0.00948 
    HPV DNA to CIN 1 0.0046 0.0046 0.0046 0.0046 
    CIN 1 to CIN 2,3 0.0011–0.0039 0.0011–0.0039 0.0011–0.0039 0.0011–0.0039 
    CIN 2,3 to local invasive cancer 0.0040 0.0040 0.0040 0.0040 
    Local cancer to regional cancer 0.0200 0.0200 0.0200 0.0200 
    Regional cancer to distant cancer 0.0250 0.0250 0.0250 0.0250 
    HPV DNA to normal 0.0028–0.0397 0.0028–0.0397 0.0028–0.0397 0.0028–0.0397 
    CIN 1 to normal 0.0068–0.0128 0.0068–0.0128 0.0068–0.0128 0.0068–0.0128 
    CIN 2,3 to normal 0.0029 0.0029 0.0029 0.0029 
5-y cancer survival rate ( 62 )      
    Local invasive cancer 0.86 0.86 0.86 0.86 
    Regional invasive cancer 0.43 0.43 0.43 0.43 
    Distant invasive cancer 0.11 0.11 0.11 0.11 
Annual symptom detection rate ( 30 , 62 )      
    Local invasive cancer 0.19 0.19 0.19 0.19 
    Regional invasive cancer 0.60 0.60 0.60 0.60 
    Distant invasive cancer 0.90 0.90 0.90 0.90 
Test characteristics, % ( 7 , 19 , 20 , 22 , 25 , 31 , 63 , 64 , 72 )      
    Sensitivity of conventional cytology 58.0 80.0 72.0 61.1 
    Specificity of conventional cytology 98.0 96.0 94.0 93.0 
    Sensitivity of HPV DNA test 88.4 88.4 88.4 88.4 
    Specificity of HPV DNA test 94.7 94.7 94.7 94.7 
    Sensitivity of cytology + HPV DNA test 95.0 96.0 95.0 95.0 
    Specificity of cytology + HPV DNA test 92.9 92.9 92.9 92.9 
Direct medical costs, 2004 USD ( 19 , 20 , 25 , 28 , 29 , 6771 ) §     
    Conventional cytology 40 49 14 29 
    HPV DNA test  42 45 31 32 
    Cytology + HPV DNA test 82 94 45 61 
    Colposcopy 136 106 111 101 
    Colposcopy and biopsy 248 170 202 185 
    CIN 2,3 678 2168 908  908  
    Local invasive cervical cancer 18 616 6642 3726  3726  
    Regional invasive cervical cancer 30 564 13 740 14 451  14 451  
    Distant invasive cervical cancer 32 423 21 466 34 122  34 122  
Model parameter United Kingdom The Netherlands France Italy 
Natural history ( 22 , 4361 )      
    Normal to HPV DNA  0.00028–0.00948 0.00028–0.01896 0.00028–0.00948 0.00028–0.00948 
    HPV DNA to CIN 1 0.0046 0.0046 0.0046 0.0046 
    CIN 1 to CIN 2,3 0.0011–0.0039 0.0011–0.0039 0.0011–0.0039 0.0011–0.0039 
    CIN 2,3 to local invasive cancer 0.0040 0.0040 0.0040 0.0040 
    Local cancer to regional cancer 0.0200 0.0200 0.0200 0.0200 
    Regional cancer to distant cancer 0.0250 0.0250 0.0250 0.0250 
    HPV DNA to normal 0.0028–0.0397 0.0028–0.0397 0.0028–0.0397 0.0028–0.0397 
    CIN 1 to normal 0.0068–0.0128 0.0068–0.0128 0.0068–0.0128 0.0068–0.0128 
    CIN 2,3 to normal 0.0029 0.0029 0.0029 0.0029 
5-y cancer survival rate ( 62 )      
    Local invasive cancer 0.86 0.86 0.86 0.86 
    Regional invasive cancer 0.43 0.43 0.43 0.43 
    Distant invasive cancer 0.11 0.11 0.11 0.11 
Annual symptom detection rate ( 30 , 62 )      
    Local invasive cancer 0.19 0.19 0.19 0.19 
    Regional invasive cancer 0.60 0.60 0.60 0.60 
    Distant invasive cancer 0.90 0.90 0.90 0.90 
Test characteristics, % ( 7 , 19 , 20 , 22 , 25 , 31 , 63 , 64 , 72 )      
    Sensitivity of conventional cytology 58.0 80.0 72.0 61.1 
    Specificity of conventional cytology 98.0 96.0 94.0 93.0 
    Sensitivity of HPV DNA test 88.4 88.4 88.4 88.4 
    Specificity of HPV DNA test 94.7 94.7 94.7 94.7 
    Sensitivity of cytology + HPV DNA test 95.0 96.0 95.0 95.0 
    Specificity of cytology + HPV DNA test 92.9 92.9 92.9 92.9 
Direct medical costs, 2004 USD ( 19 , 20 , 25 , 28 , 29 , 6771 ) §     
    Conventional cytology 40 49 14 29 
    HPV DNA test  42 45 31 32 
    Cytology + HPV DNA test 82 94 45 61 
    Colposcopy 136 106 111 101 
    Colposcopy and biopsy 248 170 202 185 
    CIN 2,3 678 2168 908  908  
    Local invasive cervical cancer 18 616 6642 3726  3726  
    Regional invasive cervical cancer 30 564 13 740 14 451  14 451  
    Distant invasive cervical cancer 32 423 21 466 34 122  34 122  
*

HPV = human papillomavirus; DNA = deoxyribonucleic acid; CIN = cervical intraepithelial neoplasia, grade 1 (CIN 1) and grade 2,3 (CIN 2,3). Estimates are reported as monthly probabilities unless otherwise noted; ranges represent age-specific values and are available from the authors upon request. Parameters for which country-specific data were either unavailable or were very uncertain were varied widely in sensitivity analysis.

The age-specific incidence of HPV infection was varied within the plausible range of the reported literature to calibrate the model to country-specific cervical cancer incidence and mortality. Please see “Methods” for details.

Sensitivity is the probability of a positive test given the presence of CIN 1 or higher; specificity is defined as the probability of a negative test given the absence of CIN 1 or higher. Hybrid Capture (HC) II (Digene Corp., Gaithersburg, MD) was used as the HPV DNA test and assumed to perform similarly in all four countries; country-specific estimates were used in sensitivity analysis.

§

Estimates include the office visit and patient time.

HPV DNA test includes only cost of test and lab (i.e., HPV DNA test is a “reflex” test).

Published estimates for the treatment costs of CIN 2,3 and cancer in Italy were not available; costs from France were used as a proxy in the base case.

Cost data, which were estimated from published cost-effectiveness analyses or costing studies in each of the countries ( 19 , 20 , 25 , 28 , 29 , 6771 ) , included direct medical costs (e.g., cost of screening test, treatment, staff time, and office visits) and patient time costs. In the absence of country-specific data (particularly for France and Italy), we inferred missing costs by leveraging the relationship between known costs in all four countries. For example, published colposcopy costs were not available for France. Based on the relative cost of cytology in France compared with the United Kingdom, we inferred these costs by proportionally scaling down published U.K. estimates. To reflect the uncertainty of colposcopy costs, we then varied these costs from 25% to 200% for all countries in sensitivity analysis. Treatment costs were obtained from the literature and included costs of loop cone, knife cone, laser biopsies, and hysterectomy for CIN 2,3 ( 19 , 25 , 28 ) , and surgery, radiotherapy, chemotherapy, and hysterectomy for cancer ( 25 , 29 , 68 , 70 ) . Costs from the United Kingdom were first updated to 2004 British pounds using the U.K. consumer price index ( 73 ) and then converted to 2004 U.S. dollars (USD) ( 74 ) ; costs from the other three countries were updated to 1999 ( 73 ) , converted to 2004 Euros ( 75 ) , and then converted to 2004 USD ( 74 ) .

Cost-effectiveness Analysis

We adopted a societal perspective for the cost-effectiveness analysis and followed the recommendations of the Panel on Cost-Effectiveness in Health and Medicine ( 39 ) . Costs were expressed in 2004 USD to facilitate comparisons across countries. Because there are uncertainties with respect to quality of life associated with HPV positivity, cervical cancer precursors, and invasive cancer, we conducted the base case analysis using reduction in the risk of cancer and increase in life expectancy as the primary outcomes. Future costs and life-years were discounted at an annual rate of 3%.

The performances of the two alternative screening strategies were measured using the incremental cost-effectiveness ratio, which is defined as the additional cost of a specific screening strategy, divided by its additional clinical benefit compared with the next-most-expensive strategy. Strategies that were defined as dominated (those with higher costs and lower benefits than other options) or weakly dominated (those with higher incremental cost-effectiveness ratios than more effective options) were excluded from the incremental cost-effectiveness calculations.

Although multiple criteria exist for categorizing the cost effectiveness of interventions, most of these criteria have been proposed within the context of a single country ( 39 ) . Because of the comparative nature of our four-country analysis, we chose to use guidelines that are specifically intended for international comparisons. According to these guidelines, which are from the Commission on Macroeconomics and Health, interventions with cost-effectiveness ratios that are less than the gross domestic product per capita are considered very cost-effective and those with ratios that are less than three times the gross domestic product per capita are considered cost-effective ( 40 ) .

Sensitivity Analyses

We performed extensive sensitivity analyses because of the considerable amount of uncertainty and variation in country-specific estimates of screening test performance and costs. Additional analyses were conducted to assess how the results might differ if we: 1) allowed for more frequent screening intervals with cytology alone; 2) assumed different follow-up strategies for HPV DNA–positive women with normal cytology; 3) replaced conventional cytology with liquid-based cytology, which is more costly ($7 additional) per test and has higher sensitivity (68%) and lower specificity (93%) than conventional cytology ( 20 ) ; or 4) included quality-adjusted life expectancy as an outcome. For this last analysis, we applied stage-specific quality weights for time spent with invasive cancer (ranging from 0.48 with distant cancer to 0.68 with local cancer), and age-specific quality weights (ranging from 0.79 to 0.90) for noncancer states to reflect average quality of life decrements in women who were over 40 years of age ( 76 ) . Quality weights were varied ±50% in sensitivity analysis.

R ESULTS

Model Calibration and Corroboration

To evaluate our model calibration, we used number of cases and population size of women in 5-year age intervals from the IARC data ( 3538 ) to calculate the standard error and 95% confidence intervals for the age-specific incidence rates. We found that our model predictions for age-specific cancer incidence fell within or very close to the 95% confidence interval of the IARC data for all age groups.

Model projections of intermediate outcomes were then compared with those from other published models of cervical cancer screening in European countries. Rates of colposcopy referral among women without CIN or cancer for combination testing were approximately 31% greater for 3-year screening compared with 5-year screening in the United Kingdom using our model, compared with 29% that was projected by an independent U.K. model ( 19 ) . When we used this model to simulate a population of U.S. women, the projected reduction in the lifetime cancer risk was 74% with the 3-year combination strategy, similar to the 78% that was projected from an analysis exploring HPV DNA testing options in the U.S. ( 77 ) .

Base Case

The total lifetime discounted costs, life expectancy (discounted and undiscounted), and reduction in lifetime risk of cancer associated with alternative cervical cancer screening strategies for all four countries are shown in Table 3 . In all countries, strategies that incorporated HPV DNA testing were preferable to the status quo strategy. Incremental cost-effectiveness ratios for HPV triage were less than $13 000 per year of life saved, whereas those for combination testing ranged from $9800 to $75 000 per year of life saved, depending on screening interval. In the United Kingdom, both strategies of HPV triage or combination testing every 5 years cost less than $15 000 per year of life saved. At more frequent screening intervals, combination testing ranged from $33 200 (3-, 5-year) to $75 900 (3-year) per year of life saved. All other strategies, including the status quo, were more costly and either less effective (i.e., strongly dominated) or less cost-effective (i.e., weakly dominated). In The Netherlands, France, and Italy, the results were similar to those in the United Kingdom. In The Netherlands, all nondominated strategies cost less than $40 000 per year of life saved, and in France and Italy, all nondominated strategies cost less than $30 000 per year of life saved.

Table 3.

Total lifetime costs, life expectancy, and incremental cost-effectiveness of HPV DNA testing strategies *

Screening strategy Total avg lifetime cost, $ Total discounted life expectancy, y Total undiscounted life expectancy, y Reduction in lifetime risk of cancer, %  Cost-effectiveness ratio, $/YLS  
United Kingdom      
    No screening 102 28.6850 66.6940 — — 
    HPV triage, 5-y 250 28.7119 66.8291 49.3 5500 
    HPV triage, 3-, 5-y 306 28.7149 66.8405 50.7  Dominated  
    Status quo, 3-, 5-y 313 28.7132 66.8319 47.7  Dominated § 
    HPV triage, 3-y 345 28.7183 66.8593 59.5  Dominated  
    Combination testing, 5-y 397 28.7226 66.8829 72.8 13 800 
    Combination testing, 3-, 5-y 498 28.7256 66.8938 73.8 33 200 
    Combination testing, 3-y 601 28.7270 66.9016 78.4 75 900 
The Netherlands      
    No screening 54 28.7850 67.3701 — — 
    HPV triage, 5-y 228 28.8322 67.6110 58.7 3700 
    Status quo, 5-y 236 28.8318 67.6093 58.2  Dominated § 
    HPV triage, 3-y 302 28.8381 67.6400 65.3 12 500 
    Combination testing, 5-y 372 28.8402 67.6497 69.7 32 700 
    Combination testing, 3-y 526 28.8443 67.6685 73.9 37 400 
France      
    No screening 30 29.0913 69.7455 — — 
    HPV triage, 5-y 102 29.1196 69.8930 46.3 2600 
    HPV triage, 3-y 136 29.1254 69.9231 55.8 5900 
    Status quo, 3-y 146 29.1255 69.9234 56.0  Dominated  
    Combination testing, 5-y 192 29.1270 69.9326 62.0  Dominated  
    Combination testing, 3-y 303 29.1317 69.9555 69.3 26 300 
Italy      
    No screening 98 29.0505 68.9557 — — 
    HPV triage, 5-y 132 29.0738 69.0763 40.6 1500 
    HPV triage, 3-y 190 29.0802 69.1100 53.7 9000 
    Status quo, 3-y 202 29.0804 69.1110 54.0  Dominated  
    Combination testing, 5-y 223 29.0836 69.1281 61.9 9800 
    Combination testing, 3-y 359 29.0889 69.1544 72.7 25 600 
Screening strategy Total avg lifetime cost, $ Total discounted life expectancy, y Total undiscounted life expectancy, y Reduction in lifetime risk of cancer, %  Cost-effectiveness ratio, $/YLS  
United Kingdom      
    No screening 102 28.6850 66.6940 — — 
    HPV triage, 5-y 250 28.7119 66.8291 49.3 5500 
    HPV triage, 3-, 5-y 306 28.7149 66.8405 50.7  Dominated  
    Status quo, 3-, 5-y 313 28.7132 66.8319 47.7  Dominated § 
    HPV triage, 3-y 345 28.7183 66.8593 59.5  Dominated  
    Combination testing, 5-y 397 28.7226 66.8829 72.8 13 800 
    Combination testing, 3-, 5-y 498 28.7256 66.8938 73.8 33 200 
    Combination testing, 3-y 601 28.7270 66.9016 78.4 75 900 
The Netherlands      
    No screening 54 28.7850 67.3701 — — 
    HPV triage, 5-y 228 28.8322 67.6110 58.7 3700 
    Status quo, 5-y 236 28.8318 67.6093 58.2  Dominated § 
    HPV triage, 3-y 302 28.8381 67.6400 65.3 12 500 
    Combination testing, 5-y 372 28.8402 67.6497 69.7 32 700 
    Combination testing, 3-y 526 28.8443 67.6685 73.9 37 400 
France      
    No screening 30 29.0913 69.7455 — — 
    HPV triage, 5-y 102 29.1196 69.8930 46.3 2600 
    HPV triage, 3-y 136 29.1254 69.9231 55.8 5900 
    Status quo, 3-y 146 29.1255 69.9234 56.0  Dominated  
    Combination testing, 5-y 192 29.1270 69.9326 62.0  Dominated  
    Combination testing, 3-y 303 29.1317 69.9555 69.3 26 300 
Italy      
    No screening 98 29.0505 68.9557 — — 
    HPV triage, 5-y 132 29.0738 69.0763 40.6 1500 
    HPV triage, 3-y 190 29.0802 69.1100 53.7 9000 
    Status quo, 3-y 202 29.0804 69.1110 54.0  Dominated  
    Combination testing, 5-y 223 29.0836 69.1281 61.9 9800 
    Combination testing, 3-y 359 29.0889 69.1544 72.7 25 600 
*

HPV = human papillomavirus, DNA = deoxyribonucleic acid; HPV triage refers to primary screening with cervical cytology, reserving HPV DNA testing for women with equivocal cytology results—HPV DNA–positive women are then triaged to colposcopy and more frequent follow-up. Combination testing refers to primary screening with cervical cytology alone prior to age 30, and cervical cytology combined with HPV DNA testing in women over the age of 30. All costs expressed in 2004 U.S. dollars. 3-y refers to a 3-year screening interval; 5-y refers to a 5-year screening interval; 3-, 5-y refers to a 3-year screening interval for women 20–39 years of age and a 5-year screening interval for women 40–65 years of age. No screening is the referral group; therefore, reduction in lifetime risk of cancer and cost-effectiveness ratio cannot be computed and is denoted by a dash (—).

Cost-effectiveness ratio calculated as the difference in cost divided by the difference in life expectancy for each strategy compared with the next best strategy; YLS = year of life saved.

Strategy cost more but was less cost-effective than next most expensive strategy and was therefore weakly dominated.

§

Strategy cost more but was less effective than the next most expensive strategy and was therefore strongly dominated.

The preferred screening strategies using thresholds of cost-effectiveness based on each country's gross domestic product per capita ( 78 ) are shown in Table 4 . In the context of the four European countries analyzed in this study, a very cost-effective intervention would fall between $25 600 (Italy) and $31 700 (The Netherlands) per year of life saved. A cost-effective intervention would cost $90 600 (UK), $95 100 (The Netherlands), $87 300 (France), and $76 800 (Italy) per year of life saved.

Table 4.

Preferred screening strategies with different willingness-to-pay thresholds *

Country  GDP per capita ( 78 ) , 2004 USD   Most effective strategy less than 1× GDP per capita   Most effective strategy less than 3× GDP per capita  
United Kingdom 30 200 Combination test (5-y) Combination test (3-y) 
The Netherlands 31 700 HPV triage (3-y) Combination test (3-y) 
France 29 100 Combination test (3-y) Combination test (3-y) 
Italy 25 600 Combination test (3-y) Combination test (3-y) 
Country  GDP per capita ( 78 ) , 2004 USD   Most effective strategy less than 1× GDP per capita   Most effective strategy less than 3× GDP per capita  
United Kingdom 30 200 Combination test (5-y) Combination test (3-y) 
The Netherlands 31 700 HPV triage (3-y) Combination test (3-y) 
France 29 100 Combination test (3-y) Combination test (3-y) 
Italy 25 600 Combination test (3-y) Combination test (3-y) 
*

Combination test refers to primary screening with cervical cytology alone prior to age 30, and cervical cytology combined with HPV DNA testing in women over the age of 30. HPV triage refers to primary screening with cervical cytology, reserving HPV DNA testing for women with equivocal cytology results—HPV DNA–positive women are then triaged to colposcopy and more frequent follow-up. 3-y refers to a 3-year screening interval; 5-y refers to a 5-year screening interval; 3-, 5-y refers to a 3-year screening interval for women 20–39 years of age and a 5-year screening interval for women 40–65 years of age. GDP = gross domestic product; USD = United States dollars.

The Commission on Macroeconomics and Health has defined interventions that have a cost-effectiveness ratio less than the gross domestic product per capita as very cost-effective, and less than three times the gross domestic product per capita as cost-effective ( 40 ) .

Sensitivity Analyses

Results were most sensitive to changes in the relative performance and costs of the different screening tests. Results were less sensitive to changes within the plausible range of natural history parameters and to changes in costs of diagnostic workup and treatment for CIN and cancer.

Screening with the combination strategy every 5 years was very cost-effective (i.e., less than the country-specific gross domestic product), provided that its sensitivity exceeded 85% in the United Kingdom and Italy, and 90% in The Netherlands and France; HPV triage strategies at these thresholds consistently cost less than $15 000 per year of life saved with either 3- or 5-year screening. If the sensitivity fell below 65%, combination testing cost more than three times the gross domestic product per capita in all four countries. Using the most optimistic estimates for combined cytology and HPV DNA testing in the literature (sensitivity 100%, specificity 94%) ( 65 ) , the cost per year of life saved for 5-year combination testing was reduced by approximately 9% in all four countries, compared with the base case results.

Varying the cost of screening changed the cost-effectiveness outcome. When the cost of both HPV DNA testing and cytology in women more than 30 years of age was reduced by 25%, the combination strategy every 3 years cost less than the per capita gross domestic product per year of life saved in all countries. When these costs were doubled, ratios for every 3-year combination strategies exceeded the gross domestic product per capita, and HPV triage became the preferred strategy; however, when using the threshold of three times the gross domestic product per capita, the combination strategy was still preferred.

Because of the variation in colposcopy and biopsy costs and management protocols for CIN in European countries, we varied these costs in our model from 25% to 200% of their base case values; however, the rank ordering of strategies did not change and the cost-effectiveness ratios varied minimally. For example, in Italy and France, the cost of the HPV triage strategy every 5 years ranged from $1100 per year of life saved and $1700, respectively, when colposcopy costs decreased by 75%, to $2400 per year of life saved and $3800, respectively, when colposcopy costs were doubled.

We evaluated how more frequent screening with cytology alone (i.e., status quo strategies every 1 or 2 years for all four countries, as well as 3 years for the United Kingdom and The Netherlands) compared with strategies that incorporated HPV DNA testing. In most analyses, frequent screening with cytology alone was either strongly or weakly dominated; in Italy, annual screening with cytology alone was not dominated but cost more than $3 million per year of life saved. Moreover, unless the sensitivity of the cytology test was greater than 95% in the United Kingdom, The Netherlands, and France, the status quo strategies were always strongly dominated by HPV triage. In Italy, when sensitivity of cytology exceeded 90%, the status quo strategy every 3 years cost $67 200 per year of life saved.

We explored the impact of the following alternative protocols for the management of women who are cytologically normal and HPV DNA positive: 1) colposcopy and more frequent follow-up screening (yearly or biennially); 2) HPV DNA test at 6 and/or 12 months, followed by more frequent screening for 5 years; and 3) combination of cytology and HPV DNA testing at 6 and/or 12 months, followed by more frequent screening for 5 years. Under all of these assumptions, combination testing in women more than 30 years of age was the most cost-effective strategy compared with HPV triage testing.

When conventional cytology was replaced with liquid-based cytology in the model, the cost-effectiveness ratios associated with combined HPV DNA testing and cytology in women more than 30 years of age were reduced by approximately 20% compared with the base case. Analyses in which health states were adjusted for quality of life resulted in cost-effectiveness ratios that were approximately 15% lower than in the base case.

D ISCUSSION

Using a computer-based model of cervical cancer and country-specific data on screening practices and costs and cancer risk in the United Kingdom, The Netherlands, Italy, and France, we found that incorporating HPV DNA testing, either for triage of women of any age with equivocal cytology results or for primary screening in conjunction with cytology in women more than 30 years of age, would provide greater benefit than the status quo screening strategy in all four countries. Although the average per-woman lifetime costs and cost-effectiveness ratios varied across countries, the rank ordering of strategies was similar. In addition, these results were stable over a wide range of sensitivity analyses in which we varied the natural history parameters, treatment patterns for CIN, and cancer costs. Provided that the sensitivity of cytology alone was lower than 90%, both HPV DNA testing strategies were more cost-effective than cytology alone; this finding held true even when we directly compared more frequent cytology to less frequent HPV DNA testing.

In all four countries, the choice between using HPV DNA testing as triage or in combination with cytology was most sensitive to changes in the relative performance and costs of the different screening tests. In particular, using the threshold of gross domestic product per capita for defining cost-effectiveness, we found that, if the sensitivity of the combination test decreased by 5%–10% or the cost of combination test doubled, HPV triage became the most attractive strategy. If we used both cost-effectiveness and the rate of colposcopy referrals as independent criteria that influence the choice between HPV triage and combination testing, HPV triage had a substantially lower referral rate. The enhanced sensitivity of combination testing was associated with decreased specificity compared with HPV triage, resulting in more than a twofold increase in colposcopy referral rate. If this increase in referral rate is associated with quality of life decrements and/or if the capacity to manage the increased referrals is lacking, these factors will need to be weighed against the added benefits of the more sensitive test.

No universal criterion exists that defines a threshold “cost-effectiveness” ratio (i.e., above which an intervention would not be cost-effective and below which it would be cost-effective). Because of the comparative nature of our four-country analysis, we chose to use guidelines specifically intended for international comparisons that were proposed by the Commission on Macroeconomics and Health ( 40 ) . Individual countries may have a different willingness to pay for a year of life saved. For example, in the United States, a threshold of $50 000 per year of life saved is often cited. Interestingly, even using this more generous criterion would not change the results of our analysis. For a variety of reasons, European countries might elect to use stricter thresholds than those implied by the Commission definition; in such a situation, the choice between HPV triage and combination testing could change. We emphasize that our analysis is not intended to provide the correct choice for any particular country; rather, our objective is to provide transparent information about the relationship between the relative costs and effects for each screening strategy so that decision makers from specific countries might use this information in their deliberations about the adoption of HPV DNA technology.

Our analysis has several limitations. Country-specific data were not available for all of the input parameters required for the model, and unknown factors that contribute to population heterogeneity could not be modeled. Similarly, there are no empiric country-specific data suitable for inclusion in this model on the cost and quality of life decrements associated with women being informed that they have high-risk types of HPV. Therefore, we purposefully did not conduct a detailed analysis of every potential strategy that would be of interest within each country—such analyses require detailed country-specific data and careful consideration of regional practice patterns. With ongoing prospective studies in country-specific settings, we anticipate that better data will be available in the future, and it will be an important priority to assimilate these data and refine analyses.

The long-term outcomes associated with different strategies for managing HPV DNA–positive women are not known. Consequently, we focused our analysis on relatively few strategies and also omitted strategies that are largely untested, such as screening at intervals double and triple the length of the status quo (e.g., every 10–15 years). Strategies with lengthened screening intervals will be relevant to women with several consecutive negative cytology and HPV DNA testing results, but better data are needed on their long-term safety to merit serious consideration in countries with established cytology screening programs.

With respect to European countries in particular, a cost-effectiveness analysis in the United Kingdom ( 19 ) and exploratory work assessing the potential value of HPV testing ( 2123 , 25 ) have been published, as have an overview of cervical cancer screening policies and identification of influential parameters on cost-effectiveness ( 27 ) , and cost-effectiveness analyses of different cervical cancer screening strategies using cytology throughout Europe ( 20 , 24 , 26 , 28 , 29 ) . Our results, which suggest that improved outcomes and cost-effectiveness are associated with HPV DNA testing, are consistent with these other published analyses. By including the United Kingdom and The Netherlands, in which previous cervical cancer screening analyses have been conducted, we were able to ensure model corroboration prior to adapting them to France and Italy, which have rarely been the focus of published cost-effectiveness analyses. The unique contribution of this four-country analysis that extends the prior work of others is the provision of a broad comparative overview of the potential value of HPV DNA testing across countries with different epidemiologic profiles and budgets.

The development of sound clinical guidelines and public health policy requires careful consideration of the incremental benefits, harms, and costs that are associated with new technology and its adoption into existing screening strategies, compared with the status quo. As a result of the rapid infusion of new technologies for cervical cancer screening, there is an increased need for policy evaluation to guide such investments. Even before definitive long-term data are available for different HPV DNA testing strategies, cost-effectiveness analyses can be used to explore the implications of changes in broad national screening policies. We found that HPV DNA testing not only has the potential to improve the effectiveness of cervical cancer prevention programs but may also be more cost-effective than current status quo policies that rely solely on conventional cytology.

Supported by the National Cancer Institute (R01-CA93435).

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