economic evaluation, reimbursement and context

Cost-Utility of HPV for Prevention of Cervical Cancer in the State of Roraima (Brazil):

A Markov Model Approach

Giacomo Balbinotto Neto (Ph.D) Allex Jardim da Fonseca (M.D)

Universidade Federal do Rio Grande do Sul – Brazil. Institute for Health Technology Assessment – Brazil

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IntroductionIn Brazil, Cervical Cancer (CC) represents an important public health problem.

It is estimated that 22.000 new cases of CC will arise in 2012, corresponding to an incidence rate of 17.5 cases per 100.000 women and to a mortality rate due to CC of 10.2 deaths per 100,000 women.

In the Brazilian Amazon Region, the problem is even more serious.

Due to a low screening coverage for CC in target population (less than 25%), a high incidence of CC has been registered in Amazonia (up to 46 cases/100,000 women), similar to the incidence rates in low-income countries, such as Uganda and Mali.

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Nacional Institute of Cancer – Brazil, 2011.

Roraima

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Brazilian government programs to control CC are based on secondary prevention and have historically failed to overcome:

(i) geographical isolation in the rain forrest ;

(ii) cultural barriers.

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ObjectiveTo assess cost-utility of the HPV vaccination on the prevention of ICC in Brazilian Amazon Region (State of Roraima).

MethodsA Markov cohort model was developed to simulate the natural history of HPV and its progress to ICC, considering the current preventive programs and treatment costs.

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Analytical Decision ModelThe analysis was performed from the provider’s perspective (Brazil's Unified Health System - SUS).

The target population was preteen girls under 12 years old.

The cohort time horizon was lifetime.

The model simulated the natural history of HPV infection until its progression to invasive cervical cancer, taking into account the prevention programs (Pap test) that are current in Brazil.

For each strategy (screening plus vaccination or screening only), the model incorporated health state transition probabilities and the target population was followed from adolescence until death in a hypothetical cohort.

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The 1-year transition probabilities were based mainly on empirical data of local and national studies.

The model evaluated the addition of the vaccine to 3 cervical cancer screening scenarios (0, 3 or 10 exams throughout life).

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Analytical Decision Model

The model incorporated the transition probabilities of mutually exclusive health states that refer to one-year cycles.

The model simulated the transition probabilities for 70 years from the age of vaccination (12 years old). At each transition, the model attributed the costs, quality of life, and death expectation according to the individual’s health condition.

Analytical Decision ModelThe transition probabilities were based on empirical data from medical literature and referred to transitions from a healthy state to a possible HPV infection and low-grade squamous intraepithelial lesion (LSIL) induction, which could regress over time to normality, persist, or progress to high-grade squamous intraepithelial lesion (HSIL).

This, in turn, could persist, regress to normality, or progress to localized, regional, or metastatic invasive cancer.

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At each screening event, cervical lesions would be found according to the criteria (Pap test sensitivity and specificity) described by national studies.

The detection of cervical lesions would require follow-up evaluations or treatment (colposcopy, cryosurgery, and/or surgery), for which they have been assigned a likelihood of success, costs, and implications for the quality of life of the individuals of the cohort model.

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The economic analysis has adopted a 3% annual discount rate for the cost and outcome, with the intent to convert future values into present values.

The model was calibrated by adjusting the incidence of precursor lesions of CC to adequately simulate the results of cancer incidence as recorded in the Brazilian Amazon Region.

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Analytical Decision ModelThe fundamental structure of the model is based on clinical practice that is consistent with the clinical program procedures advocated by the VIVA MULHER, program from the Brazilian Ministry of Health.

Abnormal screening examinations were forwarded to colposcopy, and tissues were evaluated by biopsy. If HSIL were histologically confirmed, then the patient would be subjected to cryotherapy treatment or surgery.

The costs related to each procedure were taken from the funds allocation table of the Ministry of Health of Brazil.

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The probabilities of death by cancer at each stage were extracted from the global survival curves of longitudinal studies. The five-year survival rate varied from 92.0% for localized cancer to 55.7% for regional cancer and 16.5% for metastatic cancer. The annual incremental costs were estimated at 10% of the initial value of the cancer treatment and refer to screening examinations, control of sequelae, and treatment-related toxicities or costs related to tumor recurrence. Only direct costs that were assigned to cancer were computed and are represented in international dollars (US$).

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The model multiplies the years of life by the utility implicated in the health status to adjust survival by quality of life, with the final outcome of effectiveness being quality-adjusted life years (QALYs).

In the base case, vaccination coverage was assumed at 70% of the target population.

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In this model, it was determined that the vaccine provides immunity throughout life after three doses in the course of one year. However, simulations on the need for booster doses throughout life to maintain immunity (one booster dose every ten years) were also performed.

The reduction in the incidence of CC-inducing lesions as a result of vaccination was based on studies that originally reported the effectiveness of the quadrivalent vaccine .

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The cost of vaccination (three doses + implementation costs) for the base case was estimated at US$ 268.

There are no references for the price of the vaccine in Brazil for the large-scale public sector; since the vaccine has not been incorporated into public health protocols yet.

However, it was reported that the average price of vaccination (three doses) in the American market is US $360 (LIPPMAN, 2007). For the public sector, the value negotiated by the Centers for Disease Control in the United States was US $290 (CDC, 2010).

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Preventive Strategies Cost per individual

(US$)

Quality-adjusted life years (QALYs)

Incremental cost (US$)

QALYs saved per individual

ICER

(US$/QALY)

Non-screening scenario

Vaccination 467 24.80 -42 0.2 Dominant

No vaccination (natural history) 510 24.60

Scenario of 3 screenings throughout the lifetime (base case)

Vaccination + screening 511 29.6 188 0.2 1,374

Only screening 322 29.4

Scenario of 10 screenings throughout the lifetime



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(US$)




ICER

(US$/QALY)










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(US$)




ICER

(US$/QALY)










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(US$)




ICER

(US$/QALY)










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Sensitivity Analysis

All economic assessments show a certain degree of uncertainty, inaccuracy, or methodological controversy (PETITI, 2000; MUENNING, 2002; RASCATI, 2010).

Therefore, sensitivity analyses (one-way) were performed for variables with uncertainty over the base case values to assess the robustness of the present study findings.

These analyses recalculate the ICER considering the variations in a given parameter.

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Sensitivity Analysis

The variables that were evaluated were the cost of vaccination, the effectiveness of vaccination, the scenario of the pre-existing screening program, vaccination coverage, time of immunity, annual discount rate and the characteristics of the Pap test (sensitivity). For such analyses, the variation values represent our judgment regarding the uncertainty of the study parameter or the variations in the results that have been published in the medical literature.

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ResultsThe primary outcome for the calibration of the model was the incidence of invasive cancer.

In the scenario of the natural history of HPV infection, without screening exams, the model simulated a 4.2% lifetime risk of cancer, which equates to 34.1 invasive CC cases per 100,000 women, considering the demographic structure of the region studied (IBGE, 2007b).

In the scenario with screening three times throughout an individual’s lifetime, the risk of cancer was estimated at 3.4% (equivalent to 27.5 cases per 100,000 women).

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Results

Figure below illustrates the CC incidence rate adjusted for each age group, according to the data of the incidence recorded for the population studied (described as "observed") and compares the simulations of this incidence rate (from the Markov model developed) considering 2 baseline strategies: no screening (natural history) and three screenings throughout a woman’s lifetime.

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The scenario of three Pap tests resulted in satisfactory calibration (base case).

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Prediction

The prediction in the three-screenings scenario corresponded satisfactorily to the gross incidence rate of invasive CC as recorded in Amazon region in 2010 (FONSECA, 2010) (28.2 cases per 100,000 women) and will be considered as the baseline strategy to be compared with the addition of vaccination.

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Base Case Analysis

With a vaccination coverage rate of 70%, the vaccination strategy for preteen girls of the Brazilian Amazon Region would reduce the lifelong incidence of CC by 35% in this population and would reduce the mortality due to CC by approximately 33.4%.

The addition of the vaccine generated an incremental cost of approximately US$ 188 per woman to the current strategy. The incremental cost-effectiveness ratio was US$ 1,374/QALYs saved.

Base Case Analysis

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Base Case Analysis

Figure below compares the reduction in the incidence of CC for the various strategies (combination of cytological screening and vaccination), given the different vaccine coverage levels simulated by this model.

We note that the goal of a 50% reduction in CC incidence could be achieved by combining high vaccination coverage (>70%) with existing screening procedures (>three lifetime Pap tests).

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The addition of HPV vaccination would reduce by 45% the incidence of invasive CC (70% vaccination coverage).

Base Case

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Results

The sensitivity analyses reveal that vaccination tends to provide a favorable profile from a cost-effectiveness point of view despite changes in the base case parameters proposed by the sensitivity analysis.

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Base Case Analysis

The population vaccination coverage implies wide variations in ICER, surpassing US$ 2,150/QALYs for vaccine coverage levels of less than 50%.

The vaccination strategy tends to dominate the cytological screening (3x) in isolation, i.e., it is less costly and more effective (ICER ≤ 0) for vaccination costs lower than US$ 53 (all doses for primary immunization).

For vaccination costs in excess of US$ 537, the vaccination strategy requires approximately US$ 3,225to save 1 QALY.

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Base Case Analysis

A vaccination effectiveness (reduction in the incidence of precursor lesions) of above 40% maintains the ICER below US$1,612/QALY compared to the basal strategy. Increases in the sensitivity of the Pap test tends to modestly increase the ICER of added vaccination by improving the efficiency of the baseline strategy and leading to a relative reduction in the additional benefit of the vaccine.

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DiscussionThe present study revealed that the addition of HPV vaccination to the existing preventive strategy exhibits a favorable cost-effectiveness and cost- utility profile in the Brazilian Amazon Region (State of Romaima).

Except for the simulation of vaccination coverage rates below 30%, the ICER of the addition of vaccination does not exceed the conventional limit of the GDP value per capita (about US$ 10,000 for Brazil) for any other uncertainty simulation. If the cost of vaccination is reduced to US$53 or less, with a vaccination coverage rate of 70%, then adding vaccination tends to dominate the cytological screening strategy alone.

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Limitations to the Present Study(i) First, because of the lack of national data, some parameters have been calibrated based on international data.

(ii) Second, the adherence to strategic programs in Brazil tends to be opportunistic (VALE, 2010), favoring the vaccination of women who would have good adherence to existing cytological screening to the detriment of non-participating women in higher-risk situations.

(iii) Finally, the Markov assumption itself establishes that transition probabilities depend exclusively on the current health state, not on a sequence of past health states (DRUMMOND, 2001).

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Therefore …

The results of the present study should be considered as a conservative estimate of ICER of HPV vaccination in a Brazilian Amazon Region (State of Roraima) with a high incidence of CC.

However, the satisfactory calibration of the proposed model parameters and the alignment with other researchers’ studies strengthen the results that vaccination is cost-effective in the Brazilian Amazon Region (GOLDIE, 2007; GOLDIE, 2008; COLANTÔNIO, 2009).

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Political Implications

The high risk of invasive CC in Amazon Region implies an urgent need to rethink the current CC preventive policy, especially for underprivileged regions of the country.

The present study was the first cost-effectiveness analysis of a CC preventive strategy that was directed toward a specific region of the country (State of Roraima).

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Political Implications

The cost-efectiveness analysis of HPV vaccine for Amazon Region showed a better profile when compared to studies addressing this topic to Brazil as a whole, as in the analysis published by Colantônio et al. (ICER = US$10,181/QALY) and Goldie et al. (ICER = US$9,600/QALY).

Regarding public health, these results lead to the conclusion that public policies on women's health, particularly on CC prevention programs, should be decentralized (adjusted to territorial reality) and not uniform since the heterogeneity inherent in a country of continental proportions, such as Brazil.

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Political ImplicationsLarge-scale preteen vaccination in the Amazon region can be considered an investment in the future to prevent the premature deaths of hundreds of women in the coming decades, who have historically been neglected in preventive government programs.

Although it is difficult to accurately measure and evaluate this benefit, it would translate into families and children who would not lose their mothers to CC and resources that would not be allocated to the treatment of this disease (direct and indirect costs) (COLANTÔNIO, 2008).

These results may provide the basis for accelerating the incorporation of the vaccine for HPV 16 and 18 in preventive programs that serve underprivileged women in disadvantaged regions of Brazil like Amazon Region.

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Conclusions

Vaccination has a favorable profile in terms of cost-utility in the State of Roraima (Amazon Region in Brazil).

Its inclusion in the immunization schedule would result in substantial reduction in incidence and mortality of invasive CC in Brazilian Amazon region.

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Thanks !Obrigado !Gracias !

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economic evaluation, reimbursement and context

Health & Medicine