Antivirais incorporados no Brasil para hepatite B crônica : análise de custo-efetividade Incorporated antivirals for chronic hepatitis B in Brazil : a cost-effectiveness analysis

MÉTODOS: Utilizando modelo de Markov, construiu-se coorte hipotética de 40 anos para pacientes HBeAg-positivo ou HBeAg-negativo. Foram comparados os usos de adefovir, entecavir, tenofovir e lamivudina (com terapia de resgate em caso de resistência viral) para tratamento de pacientes adultos com hepatite B crônica, virgens de tratamento, com elevados níveis de alanina aminotransferase, sem evidência de cirrose e sem coinfecção por HIV. Valores para custo e efeito foram obtidos da literatura. A medida do efeito foi expressa em anos de vida ganhos (AVG). Taxa de desconto de 5% foi aplicada. Análise de sensibilidade univariada foi conduzida para avaliar incertezas do modelo.

Chronic hepatitis B (CHB) is a highly prevalent disease, with an estimated 350 million cases worldwide. 13ccording to the Information System for Notifi able Diseases (SINAN), between 1999 and 2010 there were 104,454 confi rmed cases in Brazil.In 2009 alone there were 14,468 confi rmed cases, giving a detection rate of 7.6 per 100,000 inhabitants.a Patients with CHB may develop progressive liver disease, which can result in cirrhosis and hepatocellular carcinoma.These stages of the disease are linked to an increased risk of morbidity and mortality, as well as involving considerable health care costs. 21B is caused by the hepatitis B virus (HBV) and diagnosis is confi rmed if the patient has HBV surface antigens (HBsAg) for at least six months, as well as increased liver enzymes and histological fi ndings.These patients can then be further subdivided, based on the presence of the "e" hepatitis B antigen (HBeAg) in the serum, either HBeAg-positive or HBeAg-negative.These groups differ in their natural history and response to antiviral treatment, with HBeAg-negative often associated with worse prognoses and response to treatment. 25CHB treatment aims for the sustained repression of HBV replication, remission from liver disease and preventing cirrhosis, liver failure and hepatocellular carcinoma.In HBeAg-positive patients, durable HBeAg seroconversion to anti-HBe is a signifi cant marker, associated with better prognostics. 11fore 2009, in Brazil, interferon and lamivudine were the only CHB treatments covered by the Brazilian Unifi ed Health System (SUS).Adefovir dipivoxil, entecavir, pegylated interferon and tenofovir were then included in the treatment guidelines for this disease.Interferon was established as the fi rst choice for treating HBeAg-positive patients and tenofovir for those who were HBeAg-negative.b These six drugs were part of the Specialized Component of Pharmaceutical Care (SCPC) and were made available through the Ministério da Saúde National Policy for Pharmaceutical Care.d This situation means that fi nancial resources aimed at health care need to be optimized.
There is little evidence focusing on the use of tenofovir in Brazil.To renew or reject the option set in the treatment guidelines, it is important to carry out studies to

INTRODUCTION
better understand the economic impact and the public health results.
This study aims to assess the cost-effectiveness of different drug therapies for adults with chronic hepatitis B.

METHODS
Using the Markov model, 29 and the TreeAge Pro Suite 2009 program (TreeAge Software, Inc), a hypothetical cohort of HBeAg positive and another of HBeAg negative patients were created.Both contained four groups using adefovir dipivoxil (ADV), entecavir (ETV), lamivudina (LAM) or tenofovir (TDF).The treatments considered were those appropriate for adults with chronic hepatitis B, treatment-naïve, had high alanine aminotransferase levels, no evidence of cirrhosis and no HIV co-infection.The model had a time horizon of 40 years.Life years (LY) per patient treated were used as a measure of effectiveness.Only direct costs were considered, and these were shown in Brazilian currency (R$).The analysis was from the SUS perspective, in other words, the results of the cost-effectiveness of the treatment were analyzed considering the direct costs of treatment.
The model was made up of seven mutually exclusive transition states, corresponding to the six possible stages of the disease (CHB without complications, effi cacy of treatment, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and death) and HBV resistance to the respective drug.For HBeAg positive patients, seroconversion HBeAg/Anti-HBe was considered to be the outcome of effi cacy.For HBeAg negative patients, the outcome analyzed was undetectable serum HBV DNA (< 400 copies/mL).
Each cycle of the model corresponded to one year of treatment.In the fi rst cycle, the population was composed of individuals with CHB, with no complications or drug resistance.Transition from the fi rst to the second cycle, and so on, occurred according to the probabilities of transition from stage to stage.For those patients who showed viral resistance to the initial treatment, rescue therapy was modelled, representing the insertion of another nucleos(t)ide analogue to the treatment.The probabilities of transition were composed of data on progression of the disease (Table 1) and the effi cacy of the drugs (Table 2) obtained, respectively, from randomized clinical studies and studies on the natural history of CHB.
Literature on the natural history of the disease and the effi cacy and effectiveness of treatment is scarce.The drugs examined in this economic assessment were recently approved by the regulatory body.Thus, studies were selected arbitrarily, based on economic assessments, clinical protocols (such as EASL and AASLD) and published clinical trials.
The modeling was carried out based on the following assumptions: patients who did not respond to treatment continued to receive the drug for the entire period of the cohort if no resistance developed; rescue therapy was given to patients who developed resistance to the initial treatments; resistance to rescue therapy was not included; patients at different stages of the disease followed the natural history of Chronic hepatitis B.
The monetary values of the drug treatments in the study were determined by the Drug Market Regulation Chamber -CMED for 2011, considering factory prices without tax, with the coeffi cient of price adjustment of 24.38% already discounted.e Annual spending per patient, according to the stages of the disease, were obtained from a 2005 study evaluating the direct costs of CHB in Brazil. 3The values were corrected sing the National Consumer Price Index (IPCA) for 2011.The costs included medical fees, laboratory tests, diagnostic and therapeutic procedures, hospitalizations and spending on non-anti-viral medicines.The estimates values were taken primarily from SUS payment tables.
When conducting economic assessments of health care technology, it is recommended to use a discount rate on the cost and the effectiveness.Bearing in mind that there is often a time lag between investment in health care service resources and the associated health care benefi t, an arbitrary rate of 5%, recommended by the Ministry of Health when the time period under analysis lasts for more than a year, was used for costs and effectiveness.f Analyses were also carried out using discount rates of 0% and 10% in order to assess to what extent the arbitrary selection of a discount rate affected the study's conclusions.g At the end of the hypothetical cohort, data on the patients' mean life expectancy and the proportion of patients at each stage of the disease was obtained for each group.Means for cost and effectiveness were calculated according to the intervention.For each intervention, the cost-effectiveness ratio (CER) which determined the mean spending for each LY was calculated.To compare between the alternatives, the incremental cost-effectiveness ratio (ICER) was calculated, which is the difference between the mean cost of two alternative treatments and the respective LY differences.The ICER represents the increment in fi nancial resources necessary to obtain an addition LY in relation to a lower CER alternative.An intervention was deemed to be cost-effective if the value of the ICER was below R$ 57,048.00,d equivalent to triple the per capita Gross Domestic Product (GDP) in Brazil in 2011, adapted according to World Health Organization (WHO) guidelines.h Univariate sensitivity analysis was carried out to assess the uncertainties of the model and assumed values due to the scarcity of data in the literature.To this end, the probabilities of transition and the costs varied between 10% less and 10% more.

RESULTS
At the end of the cohort, treatments which began with ETV and TDF had higher proportions of patients with the effi cacy outcome.Respectively, 44.0% and 44.3% of the HBeAg-positive patients attained HBeAg seroconversion.For the HBeAg-negative patients, 17.7% of patients who started treatment with ETV and 18.3% of those who were initially treated with TDF had undetectable levels of HBV DNA (Table 3).
These treatments also offered more protection in terms of complications of the disease.For the group who started treatment with ETV, 44.1% of HBeAg-positive According to sensitivity analysis, for HBeAg-positive patients, the variation of antiviral costs over the period of the cohort may make ICER lower than the threshold suggested by the WHO.For HBeAg-negative patients, the variation in the cost of antivirals, in the fi rst year and in subsequent years, the ICER for TDF compared to ETV may also be less than triple Brazilian per capita GDP.Alteration in the variables considered in the model for HBeAg-negative patients did not make the ICER for ETV, compared to LAM, higher than three times Brazilian per capita GDP (Figure ).

DISCUSSION
Considering the clinical evidence used and the cost defi ned by the CMED for nucleos(t)ide analogues, the most cost-effective alternative for HBeAg-positive patients was starting treatment with ETV and it is cost-effective, compared to LAM, for HBeAg-negative patients.
In HBeAg-positive patients, starting treatment with LAM produced higher costs and lower values for LY compared to ETV and TDF, characterizing it as a dominated alternative.For both subtypes of the disease, starting treatment with ADV was also dominated by ETV and TDF.These dominated options are not recommended for starting treatment.
The CER for ETV was lower compared to the other treatments for HBeAg-positive patients, with a cost of R$ 4,010.84 each LY.Treatment with TDF would In HBeAg-negative patients, the lowest CER was for treatment started with LAM.In order to reach one more LY with ETV compared to LAM, an incremental investment of R$ 18,065.14 is necessary.This value is lower than the threshold suggested by the WHO of three times national per capita GDP, which means ETV can be characterized as a cost-effective alternative.
With regards treatment started with TDF, incremental investments of R$ 21,421.93 and R$ 71,956.13 for each LY would be necessary for treatment with LAM or ETV, respectively.Sensitivity analysis shows that, if variations in the costs of ETV and TDF are taken into account, this may also be a cost-effective alternative.
As it has a slight advantage over ETV, the model indicates that starting treatment with TDF gives better clinical results compared with the other treatments.With this treatment, there is a greater probability of obtaining effi cacy as the outcome and a lower chance of progression to HBC complications.
Economic models are simplifi cations of reality.The multifaceted complexity of treating a disease cannot be completely covered using this approach.Economic analyses support the decisions of those responsible for coordinating health care programs and services.These decisions should take into account factors and premises considered in the model, as well as others which are not modelled.Thus, some limitations to this study can be identifi ed, such as obtaining costs from secondary sources, using data for efficacy and effectiveness obtained from studies of international populations, the arbitrary selection of studies to create the model and the extrapolation of clinical data, resistance rates and rescue therapy.
The perspective used for the cost-effectiveness analysis was that of the Brazilian Unifi ed Health System.However, the data used were not obtained from national databases such as the Outpatient Information System -Sistema de Informações Ambulatoriais.Another limitation of this study concerns the data for effi cacy and progression of the disease, which were taken from studies which did not deal with Brazilian patients.These data were used due to the lack of clinical studies on this disease in a national context.There are also few prospective studies for CHB, due to the long follow up period.Thus, the clinical data on response to treatment were extrapolated to the end of the hypothetical cohort.
Estimates of the effectiveness of rescue therapies after one year are few.Therefore, evaluating the data obtained for substituting a therapy due to viral resistance should be approached with caution.
Cost-utility analysis from the perspective of health care services in other countries highlighted TDF as the most cost-effective option compared to ETV and LAM.A study from the Spanish perspective indicated TDF as responsible for higher life expectancy and lower costs compared to the other treatments. 1 A study carried out from the perspective of the Italian national health care system concluded that TDF was the most cost-effective alternative. 6In both of these studies, the annual cost of this drug was lower than other nucleos(t)ide analogues, Sensitivity analysis makes it possible to assess the uncertainties, with a variation of 10% for each value used, allowing the robustness of the study's results in relation to the assumptions adopted to be considered.It was possible to defi ne that the ICER is more sensitive to variations in the costs of the drugs.When the proposed variation is considered, situations in which ETV and TDF may be deemed to be cost-effective appear, with ICER below the threshold recommended for incorporating technologies in Brazil.
Bearing in mind the scientifi c output currently available, the assessment emphasizes incorporating and prioritizing ETV and TDF as nucleos(t)ide analogues in clinical protocol and treatment guideline for Chronic hepatitis B. There are some initiatives which may be important in reducing the prices of these drugs.One of these is incentivizing the use of offi cial laboratories, rather than private, in producing low cost drugs.This would make treatment with TDF, which had the best clinical results, also produce better cost-effectiveness results compared with ETV.This action would lead to better treatment for the population affected by CHB.
Of the antivirals considered, ETV and TDF showed the best clinical results.For HBeAg-positive patients, they are the most cost-effective alternatives.For HBeAgnegative patients, they were reasonably cost-effective for use in Brazil.Thus, taking into account the perspective of the SUS and the data in the model, using ETV and TDF are the recommended options for starting CHB treatment in adult patients with no HIV co-infection.In order to reinforce these fi ndings, more clinical studies -principally in Brazil -are necessary, as are budget impact studies.

HIGHLIGHTS
Considering the limited health care resources available, the increase in life expectancy, the increased mean age of the population, the higher prevalence of chronic compared with non-chronic health problems, and the growing appearance of pharmaceutical innovations, using pharma-economic knowledge and methods has become essential.Within the Brazilian Unifi ed Health System (SUS), spending on medication from the Specialized Component of Pharmaceutical Care has grown without interruption, going from R$ 685 million in 2000 (R$ 4.01 per capita) to R$ 1.41 billion in 2007 (R$ 7.40 per capita).This situation calls for the rationalization and optimization of fi nancial resources dedicated to pharmaceutical care.
Patients with chronic hepatitis B in Brazil have been treated with antivirals without pharma-economic studies being carried out in this context.This article uses a hypothetical cohort of patients with chronic hepatitis, both with and without positive HBeAg, in order to analyze the cost-effectiveness of the different drug therapies available.The outcome used was the life years gained in each of the alternatives.
At current prices, the most cost-effective treatments were Entecavir for HBeAg positive patients and Lamivudine for the HBeAg negative ones.

Table 1 .
Annual rates of progression of the disease.

Table 2 .
Annual probabilities associated with the treatments used in the model.and18.2% of HBeAg-negative patients did not develop CC, DC or HC, die or develop viral resistance to treatment.In the group initially treated with TDF, 44.4% of HBeAg-positive and 19.0% of HBeAg-negative patients did not develop these complications.Treatment with ADV resulted in higher costs and worse results.This alternative was, therefore, dominated by the other strategies.When a 5% discount rate for the costs and effects is considered, treatment with LAM was also dominated by ETV and TDF for HBeAg-positive patients.In these patients, a lower CER was observed for ETV (R$ 4,010.84/LY).The ICER for TDF, compared with ETV (R$ 162,735.04/LY) was more than treble per capita GDP in Brazil.For HBeAg-negative patients, treatment with LAM gave the lowest CER (R$ 6,205.08/LY),followedbyETV(R$ 6,532.04/LY)andTDF(R$6,651.64/LY).The ICER for ETV compared to that of LAM (R$ 18,065.14/LY)waslowerthanper capita GDP in Brazil.Compared with ETV, TDF had a CER of R$ 71,956.13 per LY, which is higher than the limit suggested by the WHO (Table4).When a discount rate of 10% was applied to costs and effects, the CER for ETV and TDF was R$ 4,665.08/LYand R$ 4,838.21/LYrespectively for HBeAg-positive patients.The ICER for TDF compared to ETV was R$ 433,119.83 per LY.For HBeAg-negative patients, the lowest CER was for LAM (R$ 5,999.10/LY),followed by ETV (R$ 6,701.40/LY)and TDF (R$ 6,953.76/LY).The ICER for ETV compared to LAM was R$ 55,668.84 per LY.Considering TDF compared to ETV, the ICER was R$ 354,997.16 per LY.
When the situation is analyzed without applying discount rates, the CER of ETV (R$ 3,141.17/LY)for HBeAg-positive patients was lower than that of TDF (R$ 3,219.87/LY).The ICER for TDF in relation to ETV was R$ 52,966.58per LY.For HBeAg-negative patients, treatment with LAM was dominated by ETV and TDF.The CER for ETV (R$ 5,894.36/LY)was lower than that of TDF (R$ 6,079.00/LY).The ICER for TDF compared to ETV was R$ 81,081.06 per LY.

Table 3 .
Proportions of patients at each stage of the disease at the end of the cohort, by treatment.
ADV: adefovir; CC: compensated cirrhosis; CD: decompensated cirrhosis, HCC: hepatocellular carcinoma; ETV: entecavir; LAM: lamivudine; TDF: tenofovir a In HBeAg-positiv patients, response was defi ned as seroconversion HBeAg.In HBeAg-negative patients, response was defi ned as undetectable levels of hepatitis B virus DNA.necessitate an incremental investment of R$ 162,735.04 per additional LY.Although this value is above the threshold set by the WHO, sensitivity analysis indicates that this situation may be reversed if the cost of the drug decreases, or if the cost of ETV increases.If these variations in cost are taken into account, starting treatment with TDF may also be considered the most cost-effective alternative.

Table 4 .
7esults for cost-effectiveness with a discount rate of 5% on the costs and effects.rangingbetween 66.6% and 73.2% of the annual cost for ETV.In Brazil, according to the values set by the CMED, the annual cost of TDF is 107.9% that of ETV.In concordance with the results of this study, cost-effectiveness analysis comparing ETV and LAM from the perspective of the Brazilian Unifi ed Health System concluded that treatment with ETV is the most cost-effective treatment.7 a Treatments listed in order of increasing cost, according to the disease subtype.b Exchange rate as of 29/12/2011: US$ 1.00 = R$ 1.87.c Values regarding the non-dominated drug with the closest cost.CC: compensated cirrhosis; CD: Incremental cost-effectiveness ratio decompensated cirrhosis, HCC: hepatocellular carcinoma; ETV: entecavir; CHB: Chronic Hepatitis B, no complications; LAM: lamivudine; TDF: tenofovir Figure.Univariate sensitivity analysis between non-dominated treatment strategies.A) TDF versus ETV, HBeAg-positive; B) ETV versus LAM, HBeAg-negative; C) TDF versus LAM, HBeAg-negative; D) TDF versus ETV, HBeAg-negative.Continuation