Cost-effectiveness of different human papillomavirus vaccines in Singapore

  • Vernon J Lee1, 2Email author,

    Affiliated with

    • Sun Kuie Tay3,

      Affiliated with

      • Yee Leong Teoh4 and

        Affiliated with

        • Mei Yin Tok1

          Affiliated with

          BMC Public Health201111:203

          DOI: 10.1186/1471-2458-11-203

          Received: 26 July 2010

          Accepted: 31 March 2011

          Published: 31 March 2011

          Abstract

          Background

          Human papillomavirus (HPV) vaccines are widely available and there have been studies exploring their potential clinical impact and cost-effectiveness. However, few studies have compared the cost-effectiveness among the 2 main vaccines available - a bivalent vaccine against HPV 16/18, and a quadrivalent vaccine against 6/11/16/18. We explore the cost-effectiveness of these two HPV vaccines in tropical Singapore.

          Methods

          We developed a Markov state-transition model to represent the natural history of cervical cancer to predict HPV infection, cancer incidence, mortality, and costs. Cytologic screening and treatment of different outcomes of HPV infection were incorporated. Vaccination was provided to a cohort of 12-year old females in Singapore, followed up until death. Based on available vaccines on the market, the bivalent vaccine had increased effectiveness against a wider range of HPV types, while the quadrivalent vaccine had effectiveness against genital warts. Incremental cost-effectiveness ratios (ICER) compared vaccination to no-vaccination, and between the two vaccines. Sensitivity analyses explored differences in vaccine effectiveness and uptake, and other key input parameters.

          Results

          For the no vaccination scenario, 229 cervical cancer cases occurred over the cohort's lifetime. The total discounted cost per individual due to HPV infection was SGD$275 with 28.54 discounted life-years. With 100% vaccine coverage, the quadrivalent vaccine reduced cancers by 176, and had an ICER of SGD$12,866 per life-year saved. For the bivalent vaccine, 197 cancers were prevented with an ICER of $12,827 per life-year saved. Comparing the bivalent to the quadrivalent vaccine, the ICER was $12,488 per life-year saved. However, the cost per QALY saved for the quadrivalent vaccine compared to no vaccine was $9,071, while it was $10,392 for the bivalent vaccine, with the quadrivalent vaccine dominating the bivalent vaccine due to the additional QALY effect from reduction in genital warts. The overall outcomes were most sensitive to vaccine cost and coverage.

          Conclusion

          HPV vaccination is a cost-effective strategy, and should be considered a possible strategy to reduce the impact of HPV infection.

          Cervical cancer cervical intraepithelial neoplasia incremental cost effectiveness ratio vaccine

          Background

          Cervical cancer is the second most common cancer in women worldwide [1], affecting 500,000 women annually and resulting in more than 250,000 deaths [2]. In Singapore, despite decreasing incidence of cervical cancer as a result of regular cytological screening, it remains a common gynaecological cancer [3], with 200 cases and about 100 deaths annually [3, 4].

          Human papillomavirus (HPV) infection is the main cause of cervical cancer. There are more than 150 different strains of HPV but only about 15 are high-risk oncogenic strains for cervical cancer. Of these, HPV types 16 and 18 account for about 70% of all cervical cancer cases, while the other oncogenic strains account for the rest [57]. Two prophylactic HPV vaccines, a bivalent vaccine which targets HPV 16/18, and a quadrivalent vaccine which targets 6/11/16/18, are widely available. Both vaccines have shown to be highly effective in clinical trials and economic studies of HPV vaccines have found them to be cost-effective in various countries [8]. As such, many countries are considering universal vaccination of women with the HPV vaccine.

          Before any universal vaccine implementation, it is important for policymakers to understand the long-term benefits (beyond the time horizon of clinical trials) of the vaccine by using mathematical modelling in a decision-analytic framework [917]. Extending previous studies of HPV vaccination, we compare the status quo of cervical cancer screening only and vaccination with a quadrivalent or bivalent vaccine in addition to baseline screening. This allowed us to determine the cost-effectiveness of vaccination over the current screening practices, and the incremental cost-effectiveness of one vaccine over the other.

          Methods

          We developed a deterministic Markov state-transition model based on the natural history of HPV infection and cervical cancer in the tropical South-East Asian city-state Singapore (Figures 1). We assumed that the natural history is relatively long, therefore the cycles were annual [18, 19]. The model was performed on a hypothetical cohort of women in Singapore who turned 12 years old in 2008, which is the typical age of HPV vaccination. This amounted to a mid-year female population of 25,000 [20] and the model followed this cohort until death - 88 cycles, assumed to correspond to the time needed until everyone has died. We assumed that sexual activity and hence HPV infection only occurred after age 12.
          http://static-content.springer.com/image/art%3A10.1186%2F1471-2458-11-203/MediaObjects/12889_2010_2979_Fig1_HTML.jpg
          Figure 1

          Markov model for the history of cervical cancer

          Life expectancies and annual mortality rates for the cohort were obtained from the Singapore Department of Statistics [20]. For the input variables (Table 1) [4, 1829], we obtained data from local sources where available, including disease incidence and costs of interventions and outcomes. Most studies on disease evolution and transition between different disease states were performed by a few large international studies - we therefore relied on these to obtain input parameters. The variables were calibrated to the local setting based on local incidence data.
          Table 1

          Vaccination, screening, cost parameters and transition probabilities

          Parameters

          Base case

          Ranges

          Source

          Vaccination

             

          Cohort size

          25,000

           

          [20]

          Vaccine coverage

          100%

           

          Assumption

          Age at vaccination

          12

            

          Vaccine efficacy* - bivalent vaccine

          87.2%

          70%-95%

          [21, 22]

          Vaccine efficacy* - quadrivalent vaccine

          78.8%

          70%-95%

          [23]

          Duration of efficacy

          Lifetime

          5 years to lifetime

          Assumption

          Vaccine waning + booster

          None

          5, 10, 20 years

          Assumption

          Screening

             

          Screening age range

          25-65

           

          [4]

          Screening interval

          every 3 years

           

          [4]

          Percentage screened per year

          17%

          10-20

          Estimated

          Cytology sensitivity to detect CIN1

          0.58

          none

          [18, 19]

          Cytology sensitivity to detect CIN2/3

          0.61

          none

          [18, 19]

          Compliance to CIN1 treatment

          75%

          50%-100%

          Assumption

          Compliance to CIN2/3 treatment

          75%

          50%-100%

          Assumption

          Cancer detection rate

          Low

          High

           

          Probability Of symptons CC1

          0.075

          0.185

           

          Probability Of symptons CC2

          0.113

          0.3

           

          Probability Of symptons CC3

          0.3

          0.75

          [24, 25]

          Probability Of symptons CC4

          0.45

          0.8

           

          Cost, SGD$ (2008)

           

          (-20%/+50%) except vaccine cost (200-400)

           

          Vaccine cost per vaccinated woman, bivalent vaccine #

          400

            

          Vaccine cost per vaccinated woman, quadrivalent vaccine#

          400

           

          Assumption

          Cytology test^

          40

            

          Colposcopy and Biopsy^

          207

            

          CIN 1 treatment

          1,105

            

          CIN 2/3 treatment

          1,480

            

          Stage 1 Cancer treatment cost

          9,388

           

          Singapore public sector hospitals

          Stage 2 Cancer treatment cost

          9,765

            

          Stage 3 Cancer treatment cost

          9,765

            

          Stage 4 Cancer treatment cost

          11,047

            

          Genital warts

          750

            

          Discounting

             

          Costs, Outcomes

          3%, 3%

          (0%-5%)

          Assumption

          Transition Probabilities

             

          Well to HPV

          0.05

          0-0.2

           

          HPV to clearance

          0.4

          0.29-0.55

           

          HPV to CIN1

          0.05

          0.014-0.14

          [18, 19, 26]

          CIN1 clearance

          0.4

          0.24-0.5

           

          CIN1 to CIN2/3

          0.09

          0.02-0.32

           

          CIN2/3 clearance

          0.25

          0.01-0.45

           

          CIN2/3 to persistent CIN2/3

          0.11

          0.03-0.20

           

          Persistent CIN2/3 to Cancer stage 1

          0.05

          0.001-0.15

           

          Cancer stage 1 to Cancer stage 2

          0.22

          0.11-0.4

           

          Cancer 1 to cancer cured

          0.84

          0.63-0.98

           

          Cancer stage 1 to Cancer stage 3

          0.24

          0.12-0.5

           

          Cancer 2 to cancer cured

          0.66

          0.49-0.83

           

          Cancer stage 3 to Cancer stage 4

          0.24

          0.12-0.8

           

          Cancer 3 to cancer cured

          0.38

          0.28-0.48

          [21, 22, 2426]

          Cancer 4 to cancer cured

          0.11

          0.08-0.14

           

          Detected CIN1 to well

          0.9

          0.8-1

           

          Detected CIN1 to Detected CIN2/3

          0.09

          0.02-0.32

           

          Detected CIN2/3 to Well

          0.9

          0.8-1

           

          Detected CIN2/3 to Detected PCIN2/3

          0.11

          0.03-0.20

           

          Detected PCIN2/3 to Cancer 1

          0.05

          0.001-0.15

           

          Mortality of cervical cancer

          0.11

            

          Cervical Warts

             

          Effectiveness of vaccination against warts

          0.90

           

          [27, 28]

          Cost of treatment

          750

            

          Well to low risk HPV

          0.050

            

          Low risk HPV to well

          0.500

            

          Low risk HPV to CIN1 low risk

          0.036

            

          Low risk HPV to warts

          0.027

            

          Warts to well

          0.875

            

          CIN1 low risk to well

          0.500

            

          CIN1 low risk to detected CIN 1 low risk

          0.099

            

          Detected CIN 1 low risk to well

          0.950

            

          QALYs

             

          Disease free

          1

            

          Genital warts

          0.96

          0.91-0.99

          [10, 25, 29]

          Detected CIN

          0.89

          0.84-0.94

           

          Cancer detected

             

          Stage I

          0.65

          0.49-0.81

           

          Stage II

          0.56

          0.42-0.70

           

          Stage III

          0.56

          0.42-0.70

           

          Stage IV

          0.48

          0.36-0.60

           

          Cancer cured

          0.94

            

          *Calculated, refer to Table 1b.

          #including costs of implementing, administration and support for vaccination programme

          ^including admininistrative cost & patient costs

          Transition probabilities

          HPV infection progresses to cervical intraepithelial neoplasia (CIN), the precursor of cervical cancer. The usual progression is from CIN 1 to CIN 2, CIN 3, and persistent forms of the latter 2 CIN stages. CIN 2,3 is grouped together due to similar outcomes and management, while the persistent forms are direct precursors of cervical cancer. Cervical cancers are divided into 4 prognostic stages 1 to 4. Each progressive stage is associated with poorer prognosis, lower treatment success rates, and higher recurrence and relapse rates. The transition probabilities for disease progression were obtained from previously published sources (Table 1). To account for uncertainty, we performed wide sensitivity analyses.

          Screening

          In Singapore, recommended screening for cervical cancer starts at age 25 years for women who have ever had sexual intercourse and at 3 yearly intervals if previous smears were negative, until the age of 69 if all smears are negative. In 2004, a survey showed that across all age groups, only 52% of women had their Pap smear done in the last 3 years, but most women did not undergo regular screening every 3 years [4]. We therefore assumed that Singaporean women would on average start screening at 25 years of age, and 17% of the cohort would undergo screening each year.

          We assumed that the sensitivity of PAP smears were 58% for CIN 1 and 61% for CIN2,3 [30, 31]. If a smear is abnormal, further tests including colposcopy and if necessary biopsy are introduced as per local abnormal pap smear guidelines [41], and treatment performed as clinically indicated. We also assumed that once positive, all CIN states would be confirmed by colposcopy and biopsy, and 75% of CIN1 and 75% of CIN2, 3 cases would comply to treatment with an efficacy of 90% [32].

          Treatment

          For CIN, the chance of cure is almost 100% and we assumed a mean cost of treatment for the various CIN stages. For cervical cancer, the chance of cure depends on the cancer stage, while the treatment cost depends on the treatment type. We also determined the chance of symptoms occurring which would lead to early detection and treatment. We modeled these outcomes and costs based on local data obtained from hospitals. As local data on survival rates together with disease transition probabilities were not available, and overall survival rates in Singapore were comparable to developed countries [42], we used available cancer survival rates from similar developed countries [21, 22]. These survival rates were annualized across 5 years to determine overall cure rates for each year - we assumed that those who survive beyond 5 years were cured. Once cancer was detected, we assumed that all individuals would undergo treatment. We did not model outcomes of treatment as individual state transitions but attributed an overall cost to each state.

          Vaccination

          In Singapore, the quadrivalent and bivalent vaccines have been licensed since 2006 and 2007 respectively. Vaccination remains voluntary, and privately funded individually. To compare between the vaccines, we assumed that the bivalent vaccine has a higher efficacy against other non-16/18 high-risk HPV types compared with the quadrivalent vaccine [32] using a technique described by Debicki et al [25] and shown in Table 2. However, the quadrivalent vaccine has additional protection against other low-risk HPV-types that cause genital warts and CIN 1 - the bivalent vaccine is assumed to have no such protection.
          Table 2

          Details of efficacy calculations

             

          Source

           

          Bivalent

          vaccine

          Quadrivalent

          vaccine

           

          Reduction in the probability of HPV infection

             

          Assumed proportion of HPV 16/18 in cervical cancer, A

          74.9%

          74.9%

          [7]

          Vaccine efficacy-percent reduction in HPV 16/18 persistent infections, B

          95.0%

          95.0%

          [23, 27, 28, 3240]

          Assumed proportion of other high risk HPV in cervical cancer, C

          23.4%

          23.4%

          [7]

          Vaccine efficacy-percent reduction in other high risk HPV persistent infections, D

          68.4%

          32.5%

          [3032]

          Calculated reduction in the probability of HPV infection (AxB)+(CxD)

          87.2%

          78.8%

           

          Corection factor for CIN1

             

          Percent of HPV 1618 in CIN1 cases which are caused by oncogenic HPV, E

          37.0%

            

          Correction factor for CIN1, A-E

          37.9%

            

          Corection factor for CIN2/3

             

          Percent of HPV 1618 in CIN2/3 cases which are caused by oncogenic HPV, F

          52.0%

            

          Correction factor for CIN2/3 A-F

          22.9%

            

          Based on recent studies, the range of protection for non-16/18 oncogenic HPV types are between 53.0% and 68.2% for the bivalent vaccine [23, 33] and 32.5% for the quadrivalent vaccine [21]. The overall effectiveness for the quadrivalent vaccine has been shown to be about 75% [34]. In addition, the quadrivalent vaccine has a 90% protection against HPV-types that cause genital warts [27, 28]

          Base case vaccine characteristics are assumed as follows: (1) proportion of individuals protected following immunization is 100%; (2) vaccine duration is life-long; (3) effectiveness of both vaccines against HPV types 16/18 are similar at 95% [23, 3340]; (4) to create fair competition, we assumed that the prices of both vaccines were equivalent and includes all vaccination costs; (5) we did not include therapeutic benefits to vaccinated patients already infected and assumed that the natural disease history is unaltered; (6) we assumed that all girls based on the coverage rate would receive the full vaccine course and be immunized after 1 year. We performed sensitivity analyses on these assumptions.

          CIN State Adjustments

          For the CIN states, we had to determine the actual proportion of CIN cases that are reduced by vaccination, as not all CIN states are affected by vaccination as compared to cancer. This is to allow for the reduction proportion to be accurate as this will influence the costs of the different strategies. We used a correction method well described by Debicki et al [25] where we determined the proportion of CIN 1 and CIN2/3 cases that were caused by non-oncogenic viruses in the no vaccine strategy, and added these numbers to those obtained for oncogenic viruses in the vaccination strategy (Table 2).

          Genital Warts

          Genital warts are another manifestation of HPV infection caused by non-oncogenic HPV viruses. Low-oncogenic-risk HPV-6/11 is responsible for >95% percent of genital warts [43, 44]. Genital warts cause superficial symptoms but do not result in cancer, and are therefore a separate outcome of HPV infection.

          The model for the development of genital warts is shown in Figure 2. We assumed that low-oncogenic-risk HPV types can either cause clinical genital warts or CIN 1. Clinical genital warts would be identified clinically and treated. CIN 1 would be detected through the normal screening process and we assumed would be indistinguishable from CIN 1 caused by oncogenic types. A reduction in CIN 1 caused by low-oncogenic-risk HPV types would contribute to the overall reduction in CIN 1 incidence [45].
          http://static-content.springer.com/image/art%3A10.1186%2F1471-2458-11-203/MediaObjects/12889_2010_2979_Fig2_HTML.jpg
          Figure 2

          Markov model for the history of genital warts

          Costs, Utility, and discounting

          Costs of the various interventions and outcomes were obtained from patients with HPV infection, CIN states, and cervical cancer diagnosed in 2004 across public sector hospitals in Singapore (SK Tay, unpublished data). All medical services were traced and costs collected from hospital finance data for the following 5 years or until death, and averaged across all patients. We performed the analysis starting from the year 2008 and all interventions according to technology available in 2008. We adopted the health services perspective and included all direct medical costs and benefits. Vaccination cost includes the vaccine cost and related administrative fees. All costs are represented in 2008 Singapore dollars (2008 exchange rate, USD1: SGD1.416).

          For the Quality-Adjusted Life Years (QALYs) calculations, the utility values were obtained from other developed countries as similar data was not available locally (Table 1a). Utility for each health state, which ranged from 1 which corresponded to complete health to 0 for death, were multiplied by the time spent in each state. Genital warts and detected CIN (colposcopy treatment) was given utility values of 0.96 and 0.89 respectively [29]. Quality values for various detected cancer stages differed depending on the cancer stage, while cured cancer was slightly less than complete health [10, 25].

          Since the model ran over a long time-frame, costs and benefits were translated into present values using a discount factor [4649]. Health outcomes and costs were discounted at 3% per annum, similar to previous local economic evaluations.

          Analyses

          The model was run using Excel spreadsheets (Microsoft Corp, Redmond, WA) and @Risk (Palisade, Newfield, NY) simulation add-in. We performed cost-benefit analysis using the costs per life-year saved with individual economic value calculated from the net present value of future annual earnings (earnings-equivalent for the elderly), adjusted for age [50]. We also performed cost-effectiveness analyses; and cost-utility analyses as not all negative health outcomes resulted in death. The incremental cost-effectiveness ratio (ICER) would be acceptable if it is below the per-capita gross domestic product (GDP) for the population. The per-capita GDP for Singapore in 2008 was $53,192.

          All parameters were subject to sensitivity analysis to determine which input variables were most important in determining the final strategy. We performed one-way and two-way sensitivity analyses on vaccination and transition parameters to determine the impact of changes in input variables. This allowed us to determine which parameters had the highest influence on the outcome, and would be priority areas for intervention.

          Results

          Base case analysis

          Table 3 reports the base-case results of estimated cases, non-discounted and discounted total costs, life-years, and QALYs. The model estimates that approximately 86% of cervical cancer, 86% of deaths from cancer, and 47% of CIN 1, 65% of CIN 2/3, and 86% of persistent CIN 2/3 cases could be prevented by the bivalent vaccine vaccination. The quadrivalent vaccine avoids these cases by 2-9% less than the bivalent vaccine. However, the quadrivalent vaccine reduces genital warts cases by 89%. Vaccination with the bivalent or quadrivalent vaccine yielded 634 and 570 respectively more life years than screening alone.
          Table 3

          Summary of estimated cases, non-discounted and discounted total costs and life-years of a single age-cohort (n = 25,000) of 12 year old girls

            

          Screening only

          Bivalent*

          Quadrivalent*

          Cases

              
           

          Cervical cancer

          229

          32

          53

           

          Deaths from cervical cancer

          144

          20

          33

           

          CIN Persistent 2n3 detected

          2,073

          294

          480

           

          CIN 2n3 detected

          382

          135

          168

           

          CIN 1 detected

          2,109

          1,127

          1,293

           

          Genital warts

          4,126

          4,126

          447

          NON-DISCOUNTED

              

          Total costs

           

          21,150,496

          25,020,340

          22,822,396

           

          Vaccine costs

          -

          10,000,000

          10,000,000

           

          Screening costs

          11,006,014

          9,949,324

          10,078,234

           

          CIN1 treatment costs

          2,330,522

          1,245,203

          1,292,796

           

          CIN 2 & 3 treatment costs

          564,776

          199,475

          247,908

           

          CIN Persistent 2 & 3 treatment costs

          3,067,301

          435,141

          710,367

           

          Genital warts treatment costs

          3,094,714

          3,094,714

          335,580

           

          Cervical cancer treatment costs

          1,087,169

          96,483

          157,511

          Life-years (LY)

           

          1,692,651

          1,695,651

          1,695,338

          QALYs

           

          1,717,089

          1,720,571

          1,720,299

          DISCOUNTED

              

          Total costs

           

          6,880,106

          15,034,926

          14,210,399

          Life-years (LY)

           

          711,164

          711,800

          711,734

          QALYs

           

          735,991

          736,775

          736,784

          *In addition to screening

          From the cost-benefit analysis, the incremental savings is $8.23 m with the quadrivalent vaccine and $9.47 m with the bivalent vaccine, or an advantage of $1.24 m for the bivalent over the quadrivalent vaccine. For the cost-effectiveness analysis, the cost per life year saved for the quadrivalent vaccine compared to no vaccine was $12,866, compared to $12,827 for the bivalent vaccine. Comparing the bivalent to the quadrivalent vaccine, the ICER is $12,488, showing that the bivalent vaccine saves more lives for the cost. However, the cost per QALY saved for the quadrivalent vaccine compared to no vaccine was $9,071, while it was $10,392 for the bivalent vaccine, with the quadrivalent vaccine dominating the bivalent vaccine due to the additional QALY effect from reduction in genital warts.

          Sensitivity analysis

          For the sensitivity analyses, we compared 3 different outcomes - the quadrivalent vaccine to screening alone, the bivalent vaccine to screening alone and the bivalent vaccine to the quadrivalent vaccine. Table 4 shows selected sensitivity analyses results. Decreasing vaccine coverage while keeping vaccination costs constant (assuming that vaccine purchases are sunk costs) increased the ICER and decreases cost-benefit across the board, especially at vaccine coverage levels ≤40% where vaccination is not cost-effective. If vaccination costs can be capped to only those who receive vaccination, then either vaccine remains cost effective even at 20% vaccination levels.
          Table 4

          Sensitivity analysis for the imput parameters on ICER and Cost-Benefit

          Parameters

          ICER (SGD/LY saved), discounted

          ICER (SGD/QALY saved), discounted

          Cost Benefit Analysis (million SGD), discounted

           

          Quadrivalent vaccine vs No vaccine

          Bivalent vaccine vs No vaccine

          Bivalent vaccine vs Quadrivalent vaccine

          Quadrivalent vaccine vs No vaccine

          Bivalent vaccine vs No vaccine

          Bivalent vaccine vs Quadrivalent vaccine

          Quadrivalent vaccine vs No vaccine

          Bivalent vaccine vs No vaccine

          Bivalent vaccine vs Quadrivalent vaccine

          Base case

          12,866

          12,827

          12,488

          9,071

          10,392

          Dom

          8.23

          9.47

          1.24

          Vaccine coverage (base:100%) - assuming vaccine purchase costs for the cohort are sunk costs

             20%

          86,397

          83,454

          56,178

          61,804

          67,631

          Dom

          -6.25

          -6.57

          -0.33

             40%

          40,444

          39,322

          29,109

          28,847

          31,864

          Dom

          -2.72

          -2.75

          -0.03

             60%

          25,124

          24,607

          19,981

          17,861

          19,938

          Dom

          0.92

          1.21

          0.29

             80%

          17,464

          17,246

          15,337

          12,367

          13,973

          Dom

          4.67

          5.23

          0.63

          Vaccine coverage (base:100%) - assuming vaccine costs are as consumed

             20%

          11,524

          15,873

          56,178

          8,059

          12,818

          Dom

          1.75

          1.43

          -0.33

             40%

          12,804

          14,417

          29,109

          9,010

          11,668

          Dom

          3.38

          3.25

          -0.03

             60%

          13,034

          13,733

          19,981

          9,166

          10,727

          Dom

          4,92

          5.21

          0.29

             80%

          13,003

          13,241

          15,337

          9,185

          11,122

          Dom

          6,67

          7.3

          0.63

          Vaccine efficacy (Bivalent base: 88.3%, Quadrivalent base: 79.4%)

             70%

          15,008

          17,237

          Dom

          10,369

          13,894

          Dom

          6.43

          5.31

          -1.11

             90%

          10,863

          12,326

          Dom

          7,733

          9,932

          Dom

          11.13

          10.17

          -0.96

          Vaccination costs (base: SGD$400 for both)

             Decrease to SGD$300 for both

          8,521

          8,942

          12,572

          5,922

          7,205

          Dom

          10.96

          11.96

          1

             Decrease to SGD$200 for both,

          4,109

          4,988

          12,572

          2,775

          4,019

          Dom

          13.46

          14.46

          1

             Decrease to SGD$100 for both

          Dom

          1,034

          12,572

          Dom

          833

          Dom

          15.96

          16.96

          1

          Booster (base: none)

             5 years

          91,149

          83,707

          19,486

          67,830

          70,487

          Dom

          -36.07

          -35.52

          0.54

             10 years

          47,045

          43,778

          15,584

          36,192

          38,134

          Dom

          -10.94

          -10.14

          0.8

             20 years

          27,321

          26,048

          15,067

          19,483

          21,093

          Dom

          0.3

          1.13

          0.84

          Screening coverage rate (base: 17%)

               

             10%

          12,424

          12,398

          12,171

          9,120

          10,409

          Dom

          9.2

          10.29

          1.08

             25%

          13,670

          13,558

          12,593

          9,199

          10,552

          Dom

          7.68

          8.63

          0.95

             40%

          15,200

          14,845

          11,783

          9,628

          10,977

          Dom

          6.43

          7.35

          0.92

          Effectiveness against viral warts

               

             70%

          13,348

          12,827

          8,996

          9,665

          10,392

          57,447

          8.23

          9.46

          1.23

             80%

          13,143

          12,827

          10,768

          9,366

          10,392

          640,633

          8.35

          9.46

          1.11

             100%

          12,721

          12,827

          14,408

          8,777

          10,392

          Dom

          8.59

          9.46

          0.86

          Dom = Dominated by quadrivalent vaccine

          Lowering the overall vaccine efficacy increases ICER and decreases cost-benefit for both vaccination strategies compared to no vaccination, but vaccination still remains cost-effective even if no cross-reactivity against low-risk HPV types is present. In the latter scenario, the quadrivalent vaccine dominates the bivalent vaccine even for the additional cost per life year saved, due to the additional reduction on genital warts.

          Decreasing vaccination costs for both vaccines decreases the overall ICER and increases the cost-benefit of the vaccination strategy. Conversely, overall ICER for all comparisons increases and cost-benefit decreases when vaccine waning and administering a booster in the future are considered, although the vaccination strategies are still cost-effective up to 10 yearly boosters.

          Changing the cervical cancer screening rates through pap smears affects the outcomes - increasing screening coverage rates increases ICER and decreases cost-benefit for vaccination due to the higher rates of early detection of CIN states which can be treated before they develop cancer. Increasing screening coverage also decreases the cost per life year saved for the bivalent vaccine compared to the quadrivalent vaccine because screening reduces CIN cases and therefore the advantage that the quadrivalent vaccine has in reducing the number of CIN cases due to non-oncogenic HPV.

          The ICER for the quadrivalent vaccine vs. no vaccine increases with reduced effectiveness of the quadrivalent vaccine against genital warts. At 100% effectiveness the quadrivalent vaccine vs. no vaccine is more cost-effective compared to the bivalent vaccine vs. no vaccine across all 3 measures. Changing the sensitivity of the pap- smear tests, the compliance to treatment, or the cost of the interventions does not change the outcome substantially - vaccination remains cost-effective and the bivalent vaccine remains the more cost-beneficial strategy compared to the quadrivalent vaccine, and more-cost effective per life year saved. However, when using cost-per QALY saved, the quadrivalent vaccine dominates the bivalent vaccine across the board due to the additional QALYs saved from reducing genital warts.

          The results of the one-way sensitivity analysis on ICER are shown in Figures 3 and 4. It is evident that the primary outcome is most affected by the vaccine effectiveness and the percentage of vaccine coverage. This means that vaccine parameters are the most important factors in the overall outcomes. The probability of infection with HPV, the probability of conversion from HPV to CIN1, and the transition probabilities between the CIN states and back to the well state also have some impact on the outcome. This is likely due to the importance of these parameters on the number of CIN cases that require treatment, and the eventual number of cancer cases. This also means that prevention of HPV infection and CIN is important to reduce the impact from the disease.
          http://static-content.springer.com/image/art%3A10.1186%2F1471-2458-11-203/MediaObjects/12889_2010_2979_Fig3_HTML.jpg
          Figure 3

          One-way sensitivity analysis tornado diagrams for the quadrivalent vaccine

          http://static-content.springer.com/image/art%3A10.1186%2F1471-2458-11-203/MediaObjects/12889_2010_2979_Fig4_HTML.jpg
          Figure 4

          One-way sensitivity analysis tornado diagrams for the bivalent vaccine

          Discussion

          During the last few decades, cervical cytology programmes have demonstrated their usefulness in reducing cervical cancer mortality and morbidity in many developed countries. However, it is a well-established fact that to be successful in population-based cervical screening, the coverage of the population screened must be adequate and this has often proved difficult to achieve. Although the incidence has declined over the years, cervical cancer, which is a preventable cancer, is still a common gynecological cancer in Singapore. With the global arrival of HPV vaccines, vaccination may be a successful complement to screening and decision on adoption of HPV vaccination will need to be made across individual countries.

          The results of this study conclusively shows that HPV vaccination is a cost effective strategy at the population level, as the ICERs across most vaccination strategies were much lower than the per-capita GDP for Singapore, and the vaccine strategies were more cost-beneficial under a wide range of circumstances. This is similar to a recent study in Taiwan which showed the cost-effectiveness of universal vaccination of adolescent girls [51].

          As a base case, the cost per life year saved for the bivalent vaccine was slightly lower compared to the quadrivalent vaccine, and the cost-benefit higher. At the same time, the cost per QALY saved is slightly lower for the quadrivalent vaccine compared to the bivalent vaccine. This is because the quadrivalent vaccine resulted in benefits from reduction in genital warts and CIN, but the bivalent vaccine increased life-years saved. Policy makers will therefore have to consider these factors (higher reduction in QALY versus more lives saved) in choosing between the 2 vaccines, but either option is much better than no vaccination at all.

          The bivalent vaccine is most cost-beneficial at higher vaccine coverage rates of >40%, while the quadrivalent vaccine is more cost-effective and cost-beneficial at lower coverage rates as the number of lives saved are reduced. The quadrivalent vaccine also dominates the bivalent vaccine in the absence of cross-reactivity against non-16/18 oncogenic HPV types, due to the additional reduction on genital warts. This is similar to another study in Ireland which shows that the quadrivalent vaccine was more cost-effective assuming both vaccines have similarly high protective efficacy against HPV [29].

          Of interest, if vaccine purchases are a priori and are sunk costs, the ICER increases substantially for both vaccines as vaccine coverage decreases, and cost-benefit decreases. Under this assumption, vaccine coverage of ≤40% would render vaccination not cost-effectiveness as an overall strategy. It is therefore important for policy makers rolling out universal vaccination strategies with stockpiled vaccines to ensure sufficient vaccine uptake to maintain high societal economic benefit, or to purchase vaccines on an as required basis based on vaccination uptake.

          In addition, the waning of immunity and additional vaccinations contribute substantial to the vaccination costs. Boosters at intervals of once every 20 years still maintain the cost-effectiveness of vaccination. However, more frequent boosters of less than 10 years render vaccination a non-cost-effective strategy. Waning of immunity results in costs far greater compared to the absence of cross-protection to non-16/18 oncogenic HPV types or to genital warts. It is therefore more important for vaccine manufacturers to increase the efficacy of their vaccines in terms of long-term immunity.

          This study does not take into account the dynamics of viral transmission and thus underestimating the impact of herd immunity. Transmission models that accounted for herd immunity suggest that vaccination and screening strategy would be much more attractive compared to screening-only - Chesson et al [9] further demonstrated that herd immunity could reduce ICER by 37.9%. In addition, women who adhere to previous cervical screening tests may have better compliance with subsequent tests, but with the lack of information in the local context, we did not perform individual-based modelling. Also, the model does not take into consideration the potential reduction of other HPV-related cancers like adenocarcinoma of the cervix, vulvar carcinoma or laryngeal papillomatosis. Indirect costs such as absence of work or transportation costs for patients with cervical cancer are also excluded. Given that this study did not include herd immunity effects, we did not study the outcomes of vaccinating boys or optimal catch-up strategies, and we did not consider catch up vaccination, which could increase the immediate benefits of vaccination programs.

          Conclusions

          We demonstrate that vaccination of adolescent girls, in addition to current cytology-based screening, is a cost-effective use of healthcare resources. The bivalent vaccine saves more lives compared to the quadrivalent vaccine, while the quadrivalent vaccine has lower cost per QALYs saved compared to the bivalent vaccine. The main advantage of vaccination will be to reduce cervical cancer mortality but the full benefits of vaccination will be observed 10-20 years after its introduction. Further studies should focus on quantifying the duration of vaccine protection, and use dynamic models to examine the efficiencies of different screening and vaccine strategies in reducing HPV-related disease. Studies should also focus on optimal synergies between screening and vaccination and on affordability and equity in delivery.

          Declarations

          Authors’ Affiliations

          (1)
          Center for Health Services Research, National University of Singapore
          (2)
          Department of Epidemiology and Public Health, National University of Singapore
          (3)
          Department of Obstetrics & Gynaecology, Singapore General Hospital
          (4)
          GlaxoSmithKline Biologicals

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          Copyright

          © Lee et al; licensee BioMed Central Ltd. 2011

          This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.