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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Design and methods
  5. Results
  6. Discussion
  7. Author contributions
  8. Acknowledgements
  9. References

Summary

Aim

To estimate the cost-effectiveness over a 4-year duration of lamivudine and adefovir dipivoxil for patients with hepatitis B ‘e’ antigen-negative chronic hepatitis B.

Methods

A decision analysis model has been used to perform a cost-effectiveness analysis of lamivudine and adefovir dipivoxil from the perspective of the Spanish Public Health System. Data were obtained from clinical trials.

Results

For the base-case, the total estimated cost per patient treated with lamivudine or adefovir dipivoxil for 4 years was €11 457 and €21 939 respectively. Virological response at year 4 for the lamivudine arm was 40.4% and 78.0% for the adefovir dipivoxil arm. The average cost-effectiveness ratio (cost per responding patient at year 4) was €28 375 for the lamivudine arm and €28 132 for the adefovir dipivoxil arm. The incremental cost-effectiveness ratio of adefovir dipivoxil vs. lamivudine (cost per additional responding patient with adefovir dipivoxil) was €27 872, demonstrating that this cost was slightly lower than the average cost-effectiveness ratios of adefovir dipivoxil or lamivudine. The sensitivity analysis demonstrated that the factors that most influence the cost-effectiveness were the response to adefovir dipivoxil and lamivudine at year 4.

Conclusion

Long-term treatment with adefovir dipivoxil is a cost-effective strategy in patients with chronic hepatitis B ‘e’ antigen-negative hepatitis.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Design and methods
  5. Results
  6. Discussion
  7. Author contributions
  8. Acknowledgements
  9. References

Hepatitis B ‘e’ antigen (HBeAg)-negative is the most prevalent form of chronic hepatitis B (CHB) in some parts of the world. This is true of the Mediterranean countries where more than 60% of CHB cases are HBeAg-negative.1 Patients with chronic HBeAg-negative hepatitis have a high risk of developing progressive liver disease and cirrhosis, particularly if their alanine aminotransferase (ALT) levels and hepatitis B virus (HBV)-DNA concentrations are persistently elevated or fluctuating.1–3 Currently, there are four drugs approved for treatment of CHB: interferon or pegylated interferon (IFN)-α, lamivudine, adefovir dipivoxil and entecavir. Interferon and pegylated IFN-α are administered subcutaneously while lamivudine, adefovir dipivoxil and entecavir are administered orally. Entecavir has been recently approved in the United States but is not yet approved in the European Union and for this reason, it has not been included in this cost-effectiveness study. There is no general agreement how to treat HBeAg-negative patients.4 In these patients complete viral eradication is very difficult to achieve. For this reason, oral drugs administered for a long duration as maintenance therapy to achieve a continuous suppression of HBV-DNA is recommended. Maintained inhibition of HBV-DNA has been associated with histological improvement and absence of disease progression. The efficacy and safety of lamivudine and adefovir dipivoxil in HBeAg-negative patients have been shown in various studies.5–19 Both drugs are administered once daily with an excellent safety profile. Response to lamivudine is high during the first year but long-term treatment is associated with the emergence of lamivudine-resistant variants which increase with therapy at a rate of approximately 20% per year.20 Clinical studies investigating the extended use of lamivudine therapy show a decrease in the virological response, after 30–48 months of therapy, with approximately 42–60% of patients maintaining a virological response.6, 11, 15 Adefovir dipivoxil has a similar efficacy profile during the first year of therapy. It however, has the advantage of very low resistance, approximately 15% after 4 years of therapy in HBeAg-negative patients, this permits a higher sustained virological response while on therapy.16 The main limitation of adefovir dipivoxil is the higher cost compared with lamivudine. The choice of one of these drugs as initial therapy is still non-standard and clinicians have to balance the efficacy, costs, side-effects and therapy monitoring for each drug. Pharmacoeconomic studies can help decision-making to optimize resources especially from a societal and/or health system point of view. Up to now, information regarding the costs associated with CHB and its progression towards more advanced stages is limited. In a thorough analysis of the literature, we have not found any cost-effectiveness study comparing adefovir dipivoxil and lamivudine in HBeAg-negative patients.

The objective of this study was to analyse the cost-effectiveness of long-term therapy (over 4 years) with adefovir dipivoxil or lamivudine in patients with HBeAg-negative CHB in Spain.

Design and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Design and methods
  5. Results
  6. Discussion
  7. Author contributions
  8. Acknowledgements
  9. References

Decision analysis model design

A decision analysis model has been designed for a panel of experts21 to assess the treatment-related costs and effectiveness of two oral therapies in a cohort of 100 patients with chronic HBeAg-negative CHB. This model was applied to two different treatment strategies, both considered as first-line treatment: (i) lamivudine (100 mg/daily) and (ii) adefovir dipivoxil (10 mg/daily; Figure 1). The probabilities of response, resistance and non-response for each strategy were obtained from the published results from clinical trials.5, 11, 15–19, 22, 23 Transition probabilities included in the analysis are summarized in Table 1.

image

Figure 1. Decision tree of treatment strategies of hepatitis B ‘e’ antigen (HBeAg)-negative patients. The numbers in the branches indicate the percentage of patients in each branch each year. The numbers in the end nodes indicate response at 4 years of treatment.

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Table 1.  Probabilities of the decision analysis
VariableBaseline probabilitiesReferences
Initial treatment with lamivudine
1st year: No resistance (continue treatment with lamivudine)0.7305
1st year: Resistance0.2705
2nd year: Lamivudine branch. No resistance (continue treatment with lamivudine)0.58022
2nd year: Lamivudine branch. Resistance0.42022
2nd year: Adefovir dipivoxil branch (after 1st year lamivudine resistance). Response (continue treatment with adefovir dipivoxil)0.57119
2nd year: Adefovir dipivoxil branch (after 1st year lamivudine resistance). Resistance + no response0.42919
3rd year: Lamivudine branch. No resistance (continue treatment with lamivudine)0.47022
3rd year: Lamivudine branch. Resistance0.53022
3rd year: Adefovir dipivoxil branch (after 2nd year lamivudine resistance). Response (continue treatment with adefovir dipivoxil)0.57119
3rd year: Adefovir dipivoxil branch (after 2nd year lamivudine resistance). Resistance + no response0.42919
3rd year: Adefovir dipivoxil branch (after 1st year lamivudine resistance). Response0.71016; panel of experts
3rd year: Adefovir dipivoxil branch (after 1st year lamivudine resistance). Resistance + no response0.29016; panel of experts
3rd year: No treatment branch. No response1.000Panel of experts
4th year: Lamivudine branch (after treatment with lamivudine in year 3). Response0.37011, 15, 18
4th year: Lamivudine branch (after treatment with lamivudine in year 3). Resistance + no response0.63011, 15, 18
4th year: Adefovir dipivoxil branch (after 3rd year lamivudine resistance). Response0.57119
4th year: Adefovir dipivoxil branch (after 3rd year lamivudine resistance). Resistance + no response0.42919
4th year: Adefovir dipivoxil branch (after treatment with adefovir dipivoxil in year 3). Response0.71016
4th year: Adefovir dipivoxil branch (after treatment with adefovir dipivoxil in year 3). Resistance + no response0.29016
4th year: No treatment branch (after 3rd year adefovir resistance + no response). No response1.000Panel of experts
4th year: Adefovir dipivoxil branch (after treatment with adefovir dipivoxil in years 2 and 3). Response0.71016
4th year: Adefovir dipivoxil branch (after treatment with adefovir dipivoxil in years 2 and 3). Resistance + no response0.29016
4th year: No treatment branch (after 3rd year adefovir resistance + no response). No response1.000Panel of experts
4th year: No treatment branch (after 3rd year no treatment). No response1.000Panel of experts
Initial treatment with adefovir dipivoxil
1st year: No resistance (continue treatment with adefovir dipivoxil)1.00023
1st year: Resistance0.00023
2nd year: Adefovir dipivoxil branch. No resistance (continue treatment with adefovir dipivoxil)0.97516
2nd year: Adefovir dipivoxil branch. Resistance0.02516
2nd year: No treatment branch (after 1st year adefovir dipivoxil resistance). No response1.000Panel of experts
3rd year: Adefovir dipivoxil branch. No resistance (continue treatment with adefovir dipivoxil)0.94116
3rd year: Adefovir dipivoxil branch. Resistance0.05916
3rd year: No treatment branch (after 2nd year adefovir dipivoxil resistance). No response1.000Panel of experts
3rd year: No treatment branch (after 2nd year no treatment). No response1.000Panel of experts
4th year: Adefovir dipivoxil branch. Response0.85017
4th year: Adefovir dipivoxil branch. Resistance + no response0.15017
4th year: No treatment branch (after 3rd year adefovir dipivoxil resistance). No response1.000Panel of experts
4th year: No treatment branch (after 3rd year no treatment). No response1.000Panel of experts
4th year: No treatment branch (after 2nd and 3rd year no treatment). No response1.000Panel of experts

Time is represented by annual cycles. The time horizon of the study was limited to 4 years because the results available for these drugs only cover this period. The base-case calculation was carried out by applying a 3% discount rate for all costs during the second, third and fourth year of treatment.24, 25 In addition, a sensitivity analysis was performed without incorporating a temporary adjustment (i.e. 0% discount rate) for costs24, 25 in order to check the variability of the data obtained. No discount rate was applied to the efficacy and response results because as this were obtained from figures published in clinical studies.

Treatment responses

Treatment response and drug resistance rates for each of the strategies were obtained from clinical studies involving HBeAg-negative CHB patients. These studies were selected because they used the same treatment regimen (lamivudine 100 mg orally daily and adefovir dipivoxil 10 mg orally daily) for 4 years.

Definition of health states every year are the following: response was considered as a decrease of serum HBV-DNA to undetectable levels by polymerase chain reaction (PCR) assay and resistance as reappearance of HBV-DNA in serum due to the emergence of drug-resistant HBV mutants.26 Patients with lamivudine drug resistance were switched to adefovir dipivoxil and the response rate to adefovir dipivoxil therapy was also obtained from studies published in the literature.19 The therapeutic end point of this cost-effectiveness study was virological response at year 4 of continuous therapy. Rates observed ranging from 39% to 34% (average = 37%) for those patients treated with lamivudine11, 15, 18 and 85% for those treated with adefovir dipivoxil.17 In the algorithm, patients without HBV drug resistance continued with the same therapy until year 4. If however, lamivudine resistance emerged, treatment was changed at year 2 or 3 or 4 as necessary. In patients with adefovir dipivoxil resistance or non-response, treatment was discontinued and no other therapeutic intervention was started due to insufficient information about alternative therapies. Only some anecdotical cases have been cited in this setting.

Figure 1 shows the number of patients in each branch, based on therapeutic response and HBV drug resistance rates for each drug from published data.

Assumptions

The cost-effectiveness analysis used the following key assumptions. It was assumed that

  • 1
    the treatment population was similar for both lamivudine and adefovir dipivoxil strategies;
  • 2
    in spite virological response of lamivudine and adefovir dipivoxil were evaluated independently in different studies, it is appropriate, for the objective of this analysis, to compare results from both drugs;
  • 3
    the adverse events profile for both drugs is similar and therefore their possible treatment costs have not been considered;27
  • 4
    therapeutic response and HBV drug resistance are evaluated each year and depending on the results, therapy is continuous for the next year in patients without HBV drug resistance or it is changed as depicted in the decision tree (Figure 1). Patients with lamivudine resistance were switched directly to adefovir dipivoxil. In the adefovir dipivoxil strategy, if patients developed resistance, no treatment was considered because there is insufficient evidence regarding the best therapy. Therefore, in the model when there is no clear or demonstrated evidence of the best treatment, a no treatment strategy was adopted. Both drugs were not administered in combination.

Cost-effectiveness ratios

To assess and quantify each branch of the decision tree, a cost-effectiveness analysis was used. This analysis allowed for the calculation of the cost-effectiveness ratios (CER; cost for each unit of effectiveness produced by each drug) of lamivudine or adefovir dipivoxil, using the following formulas: CERlamivudine = Cost lamivudine (4 years)/Effectiveness (response) lamivudine, CERadefovir dipivoxil = Cost adefovir (4 years)/Effectiveness (response) adefovir.

The incremental cost-effectiveness ratio (ICER), defined as the additional cost incurred to achieve an extra unit of effectiveness was calculated applying the following formula: ICERadefovir dipivoxil vs. lamivudine = (Cost adefovir − Cost lamivudine)/(Effectiveness adefovir − Effectiveness lamivudine).

Cost estimate, unitary cost, perspective

A cost estimate was performed by means of identification and subsequent quantification of resources used, and assigning unitary cost to each. The costs are presented in € for the year 2003. The chosen perspective (final payer) was the Public Health System, which incurs the following direct health costs: cost of drug acquisition, visits, diagnostic or laboratory tests to determine virological response and HBV drug resistance.

Drug acquisition costs were obtained from the Medicinal Product Catalogue 2003. The costs of the remaining resources were obtained from the database of Spanish health costs (SOIKOS, 2004 version), other publications28 and market prices of Spanish hospitals. In Table 2, the unitary costs (in €) used in the pharmacoeconomic analysis are listed with their respective sources.

Table 2.  Prices of drugs and some diagnostic and therapeutic procedures used in the treatment of CHB. Unitary cost estimate (in €).
ResourcesUnitary cost (€ 2003)References
  1. * Ex-factory price: drugs for hospital use.

  2. † Percentage of patients with decompensation because of cirrhosis (7.3%/year), hepatic encephalopathy (0.4%/year), varicose haemorrhage (1.1%/year), ascites (2.5%/year), hepatocarcinoma (1.6%/year); only for non-treated patients.

  3. CHB, chronic hepatitis B; HBV, hepatitis B virus.

  4. ‡ Glaxo Smith Kline, Greenford, UK; § Gilead Sciences, Foster City, CA, USA.

Lamivudine (Zeffix‡, 100 mg 28 tablets)*55.59Medicinal Product Catalogue
Adefovir dipivoxil (Hepsera§, 10 mg 30 tablets)*428.40Medicinal Product Catalogue
Initial consultation (pre-treatment): hepatology154.2424
Successive consultations: hepatology77.4124
Analyses23.6624
Serology43.73SOIKOS Database 2004
α-Fetoprotein14.2924
Ultrasound scan62.94SOIKOS Database 2004
Biopsy319.1924
HBV-DNA101.18SOIKOS Database 2004
Resistance test118.00Hospital Vall d'Hebrón
Decompensation costs†172.5024

The frequency of out-patient visits and the laboratory tests required for each strategy was estimated by a panel of hepatologists. The European consensus conference and other international recommendations were taken into consideration in these estimates. Table 3 shows the costs of initial assessment visits and the annual cost for each strategy: no treatment, treatment with lamivudine and treatment with adefovir dipivoxil.

Table 3.  Initial assessment costs and follow-up of treatment with lamivudine and adefovir dipivoxil over 4 years (with no discount)
ParameterUnitary cost (€)Number of timesPatients (%)Total
  1. * Percentage of patients with decompensation due to cirrhosis (7.3%/year), hepatic encephalopathy (0.4%/year), varicose haemorrhage (1.1%/year), ascites (2.5%/year), hepatocarcinoma (1.6%/year).

Initial assessment costs
Initial pre-treatment consultation154.241100154
Analyses23.66210047.3
Serology43.73110043.7
α-Fetoprotein14.29110014.3
Ultrasound scan62.94110062.9
Biopsy319.191100319
Treatment costs: lamivudine/year
Successive consultations77.414100309
Analyses23.66410094.6
HBV-DNA101.184100404
α-Fetoprotein14.29110014.3
Ultrasound scan62.94110062.9
Resistance test (year 1)118.0012731.9
Resistance test (year 2)118.0014249.6
Resistance test (year 3)118.0015362.5
Resistance test (year 4)118.0016374.3
Treatment costs: adefovir dipivoxil/year
Successive consultations77.412100154
Analyses23.66210047.3
HBV-DNA101.182100202
α-Fetoprotein14.29110014.3
Ultrasound scan62.94110062.9
Resistance test (year 1)118.00100.00
Resistance test (year 2)118.0012.52.95
Resistance test (year 3)118.0015.96.96
Resistance test (year 4)118.00115.017.7
Costs: no treatment/year
Successive consultations77.414100309
Analyses23.66410094.6
HBV-DNA101.184100404
α-Fetoprotein14.29110014.3
Ultrasound scan62.94110062.9
Decompensation costs*172.50  172

Sensitivity analysis

Because of the variations in published data and expert estimates, the most important variables were adjusted over a wide range and their effect on the results analysed. The scenarios that were considered are: (i) not applying a discount rate to the costs (0%); (ii) increasing the dosage of lamivudine from 100 to 150 mg/day;6 (iii) considering decompensation costs to be zero; (iv) increasing from two to four times per year the number of visits and laboratory tests investigating adefovir resistance in patients treated with this drug to be equal to those treated with lamivudine; (v) reducing by half the cost of the diagnostic test of HBV drug resistance; (vi) adjusting the lamivudine arm response rate at year 4 with the intention of achieving the ‘threshold value’.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Design and methods
  5. Results
  6. Discussion
  7. Author contributions
  8. Acknowledgements
  9. References

Base-case

Table 4 shows the results of the base-case analysis. The estimated total costs for 4 years of treatment for lamivudine or adefovir dipivoxil arms as initial therapies, applying a 3% discount rate was €11 457 and €21 939 respectively. The lamivudine arm has demonstrated an efficacy of 40.4% and the adefovir dipivoxil arm of 78.0%. This gave a CER (average cost per patient with successful therapy response at year 4) of €28 375 for the lamivudine arm (€11 457 divided by 0.40) and €28 132 for the adefovir dipivoxil arm (€21 939 divided by 0.78). Despite the higher costs associated with adefovir dipivoxil the ICER of adefovir dipivoxil vs. lamivudine (as initial therapies; cost per each additional patient with response to adefovir dipivoxil) is €27 872 and demonstrating that the incremental cost with adefovir dipivoxil per additional patient with virological response is slightly lower than the cost per responding patient with either adefovir dipivoxil (€28 132) or lamivudine (€28 375).

Table 4.  Summary of results (3% discount for costs; all costs in €)
 LamivudineAdefovir dipivoxil
  1. * Pharmacological cost + other costs.

Cost (4 years treatment)*11 457.1521 939.21
Effectiveness (virological response at 4 years; %)40.478.0
Incremental effectiveness adefovir dipivoxil vs. lamivudine 37.6
Cost-effectiveness ratio (cost per patient with virological response at 4 years)28 374.8328 132.46
Incremental cost-effectiveness ratio (cost per incremental virological response of adefovir dipivoxil vs. lamivudine at 4 years) 27 872.24

The average cost per patient in the lamivudine arm increased from €2259 at year 1 to €3303 at year 4 while that of adefovir dipivoxil arm decreased from €6321 at year 1 to €4856 at year 4 (Figure 2). These changes were due to the loss of therapy response during long-term treatment with lamivudine. If the cost of the lamivudine arm in the first year is considered to be representative of 100% (€2259) of the cost, the respective cost of the adefovir dipivoxil arm is represented by a cost of 280% (€6321). However, at year 4, the cost of adefovir dipivoxil decreases to 147% (€4856) in relation to lamivudine (Figure 3).

image

Figure 2. Annual and total average cost of the therapeutic alternatives (3% discount for costs). LAM, lamivudine; ADV, adefovir dipivoxil.

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image

Figure 3. Expected costs and efficacy of adefovir dipivoxil in percentages. The comparison considers a 100% lamivudine value and shows the adefovir dipivoxil value as increases or decreases regarding lamivudine.

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As expected, despite the initial benefits of lamivudine treatment, a decrease in the rate of HBV suppression over time was observed due to the emergence of HBV drug resistance. For patients treated for 4 years evaluated in this algorithm, which maintained viral suppression, defined by undetectable HBV-DNA, was 40.4% for the lamivudine arm and 78.0% for the adefovir dipivoxil arm. Therefore, the virological response achieved with adefovir dipivoxil as first-line treatment was 1.9 times greater than that of lamivudine (Figure 3).

Sensitivity analysis

The sensitivity analysis demonstrates the robustness of the results obtained with the base-case with only two variables significantly impacting the results: the virological response rates to adefovir dipivoxil and lamivudine. If the percentage of the lamivudine arm response at year 4 increases above 40.7%, there is a favourable impact in the average cost-effectiveness analysis for lamivudine strategy. Table 5 shows the impact on the incremental cost-effectiveness by varying each of these variables over a wide range and comparing them with the base-case.

Table 5.  Sensitivity analysis: cost-effectiveness ratio (CER; cost per patient with virological response at 4 years) and incremental cost-effectiveness ratio (ICER; incremental cost per incremental response) of adefovir dipivoxil vs. lamivudine (all costs in €)
 LamivudineAdefovir dipivoxil
CERCERICER
0% discount for costs29 819.8729 321.3428 786.08
Lamivudine dose = 150 mg30 424.0828 132.4625 672.04
Decompensation costs = 028 214.0128 110.5527 999.47
Adefovir dipivoxil follow-up consultations, analyses and HBV-DNA four times per year28 374.8330 075.0731 900.55
Resistance cost/228 293.6428 130.7527 955.86
Percentage response in lamivudine arm at year 4 = 40.728 150.2528 132.4628 113.05

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Design and methods
  5. Results
  6. Discussion
  7. Author contributions
  8. Acknowledgements
  9. References

There is still no, well defined, standard anti-viral therapy for HBeAg-negative CHB and therefore available drugs such as IFN-α, lamivudine and adefovir dipivoxil, are used as first-line treatments for these patients; however, all of them have limitations. Interferons or pegylated interferons are subcutaneous drugs with adverse effects and its use is limited in patients with advanced or decompensated liver diseases. Lamivudine and adefovir dipivoxil are oral drugs without important side-effects. The main limitation of lamivudine therapy is the emergence of HBV drug resistance, associated with a loss of virological response. The main disadvantages of adefovir dipivoxil are cost of the drug and the still relatively short experience with the drug (around 4 years). Currently, there is another drug, entecavir, approved for the treatment of CHB in the United States and some new nucleos(t)ides analogues in development (phase III) that show an important activity against HBV. All of the new drugs for CHB act via inhibition of HBV replication, and need to be administered as maintenance therapy. Therefore, cost-effectiveness studies have a particular relevance in this setting but a relatively short half-life, assuming that new drugs such as entecavir will be soon available in Europe. These drugs will probably display different virological rates, drug resistance patterns and rates. In addition, the prolongation of therapy currently available will provide more results that also need to be considered. All of these factors will certainly influence the results of cost-effectiveness studies in HBeAg-negative CHB patients.

The timeline of this study was limited to 4 years, as this is the period for which published data are available for adefovir dipivoxil. The low cost of lamivudine is weighed by the high risk of developing resistance while the higher cost of adefovir dipivoxil is offset by the low risk of developing resistance.

Currently, treatment with lamivudine in patients with CHB is limited due to the increased risk of HBV drug resistance when therapy is extended. Usually HBV drug resistance is associated with reduced clinical benefit often demonstrating a rebound in HBV-DNA concentrations and ALT levels, increasing the risk of disease progression. The appearance of HBV mutants resistant to lamivudine is the main disadvantage of this drug, increasing from 27% at year 1 to around 75% after 4 years of therapy.5, 11, 15, 18, 22 Comparatively, adefovir dipivoxil has a more favourable long-term resistance profile and therefore a higher efficacy in HBeAg-negative patients. Adefovir dipivoxil has a safety profile, tolerability and favourable form of administration (oral) similar to those of lamivudine. Adefovir dipivoxil demonstrates an extremely high threshold to the development of resistance: 0% at year 1, 2.5% at year 2 and 15% after 4 years of therapy.16, 17, 23 This low rate of resistance is significantly beneficial, as it is therefore possible to maintain the initial anti-viral effect over long-time frames, optimizing the clinical advantages of adefovir dipivoxil.

The prolongation of treatment with adefovir dipivoxil for 4 years achieves the suppression of viral replication in a high percentage of HBeAg-negative patients, making treatment with adefovir dipivoxil especially useful for these patients. Also, by decreasing the need to monitor drug resistance, the demand on health resources during follow-up is reduced. However, its high acquisition cost makes it necessary to consider whether its use in first-line treatment is compensated for by the increased response witnessed. Cost-effectiveness analyses are a type of complete economic assessment permitting the evaluation of the possible economic impacts that effective interventions have on society, improving the efficiency of the health system, as well as being an indicator of the priorities in distribution of health expense. To our knowledge, this is the first cost-effectiveness analysis comparing lamivudine and adefovir dipivoxil in HBeAg-negative patients.

The results obtained indicate that at the end of 4-year treatment, suppression of viral replication is achieved in almost twice the number of HBeAg-negative patients treated with adefovir dipivoxil when compared to patients treated with lamivudine. Furthermore, patients with suppression of viral replication have less possibility of disease progression. Although the costs associated with 4 years of therapy with adefovir dipivoxil are more or less double those of lamivudine, the cost per responding patient with adefovir dipivoxil is slightly less than with lamivudine. Moreover, the results are robust, and are evident in the sensitivity analysis.

Therefore, this study demonstrates for the first time that long-term therapy, over a period of 4 years, with adefovir dipivoxil as first-line treatment for HBeAg-negative patients can be considered a cost-effective strategy. There is, however, a series of limitations to be considered in the study. Our model represents a simplified perspective of the treatment in normal clinical practice according to the data available at 4 years. The type of pharmacoeconomic analysis that should be used in each situation depends on existing efficacy and safety data of the therapeutic alternatives. One limitation is the absence of a direct comparative study between lamivudine and adefovir dipivoxil. Ideally, to improve the decision-making process, it would be important to have a comparative study assessing the efficacy and safety of both drugs as well as the data on resource use and costs associated with these treatments.29 Another approach to studying cost-effectiveness and particularly the impact on life expectancy and quality of life would be to base the study on the natural history of CHB using a Markov model.27, 30–32 These models analyse, in a hypothetical cohort of patients, the evolution of CHB from the initial stages of the disease, through severe complications, such as hepatic cirrhosis or development of hepatocarcinoma, up to the death of the patient due to liver failure. Including liver failure in the analysis would help determine the cost-effectiveness of preventing the progression of the disease and its complications (specifically, hepatocarcinoma and liver transplantation). Unfortunately, there is no validated model for HBeAg-negative CHB patients at this time.

Recently, a cost-effectiveness study evaluating different treatment alternatives for patients with CHB has been published.20This study stratified patients according to HBeAg and HBeAg status and the results, using a Markov model for a lifetime, horizon, demonstrate that the use of adefovir dipivoxil in lamivudine-related viral resistance patients may be a highly cost-effective strategy. Our study approaches the cost-effectiveness of oral therapies during a period of 4 years, time with virological response rates published for both drugs and using the current clinical practice approach.

In conclusion, therapy for 4 years with adefovir dipivoxil would improve the clinical benefits in HBeAg-negative patients with compensated CHB resulting from a larger proportion of patients with suppression of viral replication at 4 years and a slowing down of the progression of the disease. From an economical point of view, the results suggest that adefovir dipivoxil is a cost-effective strategy in first-line treatment with oral anti-viral drugs.

Author contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Design and methods
  5. Results
  6. Discussion
  7. Author contributions
  8. Acknowledgements
  9. References

Study concept and design: Buti, Casado, Calleja, Salmerón, Aguilar, Rueda, Esteban; literature review: Buti, Calleja, Salmerón, Aguilar, Esteban; design and development of the model: Casado; analysis and interpretation of data: Casado; drafting of the manuscript: Buti, Casado; critical revision of the manuscript: Buti, Casado, Calleja, Salmerón, Aguilar, Rueda, Esteban.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Design and methods
  5. Results
  6. Discussion
  7. Author contributions
  8. Acknowledgements
  9. References

The study was supported in part by a research grant from Gilead Sciences. The authors had independence from the funding company in study design, analysis and interpretation of the data, report writing and publication, regardless of the results. One of the authors (MR) is an employee of Gilead Sciences.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Design and methods
  5. Results
  6. Discussion
  7. Author contributions
  8. Acknowledgements
  9. References
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