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Cost-effectiveness of Chronic Hepatitis C Treatment with Thymosin Alpha-1
Archives of Medical Research 37 (2006) 663–673
ORIGINAL ARTICLE
Cost-effectiveness of Chronic Hepatitis C Treatment with Thymosin Alpha-1 Fernando Garcı´a-Contreras,a Armando Neva´rez-Sida,a Patricia Constantino-Casas,a Fernando Abud-Bastida,b and Juan Gardun˜o-Espinosaa a
Unidad de Investigacio´n en Economı´a de la Salud, Coordinacio´n de Investigacio´n en Salud, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico b Hospital General de Zona Las Margaritas, IMSS, Mexico City, Mexico Received for publication August 24, 2005; accepted November 30, 2005 (ARCMED-D-05-00336).
Background. More than one million individuals in Mexico are infected with hepatitis C virus (HCV), and 80% are at risk for developing a chronic infection that could lead to hepatic cirrhosis and other complications that impact quality of life and institutional costs. The objective of the study was to determine the most cost-effective treatment against HCV among the following: peginterferon, peginterferon plus ribavirin, peginterferon plus ribavirin plus thymosin, and no treatment. Methods. We carried out cost-effectiveness analysis using the institutional perspective, including a 45-year time frame and a 3% discount rate for costs and effectiveness. We employed a Bayesian-focused decision tree and a Markov model. One- and two-way sensitivity analyses were performed, as well as threshold-oriented and probabilistic analyses, and we obtained acceptability curves and net health benefits. Results. Triple therapy (peginterferon plus ribavirin plus thymosin alpha-1) was dominant with lower cost and higher utility in relationship with peginterferon 1 ribavirin option, peginterferon alone and no-treatment option. In triple therapy the cost per unit of success was of $1,908 [USD/quality-adjusted life years (QALY)] compared with peginterferon plus ribavirin $2,277/QALY, peginterferon alone $2,929/QALY, and no treatment $4,204/QALY. Sensitivity analyses confirmed the robustness of the base case. Conclusions. Peginterferon plus ribavirin plus thymosin alpha-1 option was dominant (lowest cost and highest effectiveness). Using no drug was the most expensive and least effective option. Ó 2006 IMSS. Published by Elsevier Inc. Key Words: Cost effectiveness, Economic evaluation, Chronic hepatitis C, Peginterferon, Ribavirin, Thymosin alpha-1.
Introduction Approximately 170 million persons, i.e., 3.1% of the world population, are infected with hepatitis C virus (HCV) and face the risk of developing hepatic cirrhosis or liver cancer (1). In Mexico, hepatitis C prevalence is estimated at 0.7% (2); therefore, it is considered that there are approximately 700,000 persons infected with HCV and that at least 56,000 suffer from hepatic cirrhosis. In the population covered by
Address reprint requests to: Fernando Garcı´a-Contreras, Reforma 476, 3er piso poniente, Col. Jua´rez, Deleg. Cuauhte´moc, 06600 Me´xico, D.F., Me´xico; E-mail: [email protected]
the Mexican Institute of Social Security (IMSS), it has been estimated that approximately 6,300 individuals develop cancer of the liver as a consequence of HCV-related hepatitis. The objective of therapy in patients with chronic hepatitis C was to inhibit viral replication to diminish disease activity in the liver, which is associated with reduction of the risk for developing hepatic cirrhosis and hepatocellular carcinoma (3). However, viral eradication should not be the sole treatment objective because histological improvement can be achieved with permanent viral therapy (4). The effect of alpha interferon in the treatment of HCVrelated chronic hepatitis has demonstrated its effectiveness
0188-4409/06 $–see front matter. Copyright Ó 2006 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2005.11.010
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Garcı´a-Contreras et al./ Archives of Medical Research 37 (2006) 663–673
with a rapid decrease of HCV-RNA during the first weeks of therapy and with a parallel decrease in serum concentrations of alanine aminotransferase (ALT) (5). Nonetheless, the effectiveness shown is !20%; thus, its use is always recommended in combination with another pharmaceutical (6). Ribavirin is a nucleoside analog similar to guanoside and possesses a broad spectrum of antiviral activity. Ribavirin causes a significant decrease in serum concentrations of ALT in patients with HCV-associated chronic hepatitis (7); nevertheless, studies have not shown a significant reduction of HCV-RNA (8). In addition, previous studies have not demonstrated histological changes with ribavirin (9,10). In patients who relapsed after treatment with alpha interferon, the association with ribavirin induced a sustained response in some (11). A higher percentage of sustained response has been achieved in patients with interferon plus ribavirin-based treatment than with interferon only in never-treated (naı¨ve) patients (12,13). Larger studies have shown that peginterferon plus ribavirin combined therapy during 24–48 weeks achieved sustained response rates of 33–41%, compared with interferon alone, which demonstrated a sustained response rate of 5–15% (9,14,15). Thymosin alpha-1 (TA1) or thymalfasin (Zadaxin, SciClone Pharmaceuticals, San Mateo, CA) is a chemically synthesized polypeptide identical to human TA1 (16) and belongs to a class of products known as biological response modifiers (5). Although its mechanism of action is not clear, it is thought that it modulates the immune system, increasing T-cell function. In vitro studies have shown maturation and T-cell differentiation with an increase in CD41, CD81, and CD31 cells and gamma interferon, interleukin2 (IL-2), and interleukin-3 (IL-3), as well as an increase in TH1 response with a decrease in TH2 response. In addition, antigen-stimulated IL-2 receptor expression has been observed (17). It is estimated that in the U.S., cost of care for HCV-related hepatitis in 1997 was 5.46 billion USD, 33% of which corresponded to direct and 67% to indirect costs. Projections in the U.S. estimate that during the period from 2010 to 2019 there will be 165,000 deaths attributable to chronic diseases of the liver, with a direct medical cost due to the hepatitis C virus of 10.7 billion USD (18). At present, alpha-interferon is the most studied therapy for treatment of chronic hepatitis B and C. However, the low response rate (RR) has led efforts toward alternative therapies including TA1, ribavirin, and other forms of interferon, such as pegylates (19–23). Currently, new drugs are being developed and tested for treatment of HCV, including thymosin alpha-1 (Zadaxin), which is indicated in the treatment of HCV. There are multiple alternatives in HCV-related chronic hepatitis treatment, and the association of pegylated interferon plus ribavirin is the most effective option. However, this continues to possess a high proportion of failures and relapses
that as a whole comprise O50%. Therefore, we considered it relevant to analyze treatment alternatives that also included thymosin alpha-1 as part of the first-line triple therapy option to evaluate their economic impact.
Materials and Methods We conducted a cost-effectiveness analysis that took into account the costs of the alternatives studied as well as results measured in QALY gained. The perspective was that of the public health service provider: the Mexican Institute of Social Security (IMSS). This institution covers the potential health needs of 52,757,684 persons and provides services to 42,519,051 individuals (24). With regard to the time frame, the 75-year time horizon was chosen because that is the approximate life expectancy in Mexico; therefore, the decision to end the analysis at that age would reflect, in a more intuitive manner, the potential result in the cohort. In our model, the majority of patients died before reaching that age. Therefore, we simulated a cohort during 45 years in patients who were 30 years of age at the beginning of the study. We utilized a Bayesian-focused decision tree and a Markov model. For the economic analysis, we applied a 3% discount rate for costs as well as for utilities. Costs were considered at the present value. The discount rate was chosen because we only took into account time preferences. The analysis was carried out in the public sector, and it has been recommended that 3% is a good discount rate, whereas in the private sector the best is 5% (25). Treatment alternatives in the decision tree included the following: a) peginterferon-alpha2a; b) peginterferonalpha2a plus ribavirin, and c) peginterferon-alpha2a plus ribavirin plus thymosin alpha-1 (Figure 1). A Markov model with yearly cycles was connected with the decision-tree nodes that indicated treatment relapse or failure to simulate the natural history of the disease of a hypothetical cohort of 10,000 patients with HCV-associated chronic hepatitis. Health states included in the Markov model are shown in Figure 2; these represent the disease’s natural history and served as the base for model conceptualization. A half cycle correction at the beginning of the states was used because the model included an absorbent state, and this provided a better approach to the real-life processes that occurred in continuous time. We included only direct medical costs in this study. The components used for cost estimation included frequency of resource utilization and unitary costs. Costs and follow-up for each treatment strategy as well as annual cost of each cycle of the Markov model were calculated. HCV-related chronic hepatitis treatment costs included drugs during 48 weeks in addition to medical visits, laboratory and diagnostic tests, and surgical procedures. Table 1 shows treatment costs for each of the studied therapies.
Cost-Effectiveness of Chronic Hepatitis C Treatment
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Without response
Without treatment
Sustained response Peginterferon Without response or relapse Hepatitis C treatments
Sustained response
Peginterferon + Ribavirin
Without response or relapse
Peginterferon + Ribavirin + Thymosin
Sustained response
Without response or relapse Figure 1. Decision tree of treatment alternatives in chronic hepatitis C.
For estimating direct medical annual costs of the different health states (Table 2), we obtained information on institutional resource utilization from the previously mentioned ex profeso panel of experts. Resource use by experts was determined according to their experience at the IMSS. The questionnaire was organized into health states and the experts were asked to comment on their treatment of a typical patient; then, resource use was estimated by use of the mean of their answers. The IMSS is a healthcare institution that belongs to the public sector. IMSS unitary costs were acquired from the official Mexican governmental periodical (Diario Oficial de la
Information concerning resource utilization for this type of patient was obtained from an ex profeso panel of experts. This panel included medical doctors with a specialty in gastroenterology and who were certified by the respective council and had at least 10 years of clinical experience. Drug costs were supplied by the pharmaceutical companies that produce the molecules included in this study (Laboratorio Columbia, S.A. de C.V. for alpha-1 thymosin and Laboratorio Roche Syntex de Me´xico, S.A. de C.V. for peginterferon and ribavirin). Treatment dosage and resource utilization were calculated according to the recommendations of each pharmaceutical company.
Ascitis with response to diuretics
Liver transplant
Refractory ascitis
Compensated cirrhosis
Death Esophageal varices
HCV-related chronic hepatitis
Encephalopathy
Hepatocarcinoma
Figure 2. Markov model.
Garcı´a-Contreras et al./ Archives of Medical Research 37 (2006) 663–673
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Table 1. Treatment costs of chronic hepatitis C
Monotherapy Peginterferon Combined therapy Peginterferon plus ribavirin Triple therapy Peginterferon plus ribavirin plus thymosin
Drug
Other resources
Total
13,037
3,110
16,147
20,484
3,110
23,594
44,169
3,110
47,279
Costs are expressed in U.S. dollars (USD). Other resources: medical visits, laboratory and diagnostic tests, and surgical procedures.
Federacio´ del 9 de Marzo del 2004, Me´xico), as well as from the Finance Department of the Hospital de Especialiades (XXI Century National Medical Center, IMSS, in Mexico City). Follow-up concepts included medical visits/appointments, laboratory and office tests, hospitalization, emergency medical care, intensive care, and surgical procedures. Costs were expressed in USD. We utilized the available information from the international literature for the remaining parameters in the model; however, we found no information for the Mexican population. As we were aware that there might be differences between international and Mexican information, we decided to validate the model’s parameters by using a Mexican expert panel. These experts reviewed the information with regard to our context and to their own experience. In a Delphi panel, we designed sentences with a Likert scale concerning the pertinence of those values in relation with our Mexican population, specifically at the IMSS. When values were not considered pertinent, the option was afforded for suggesting new figures. Treatment effectiveness measurements of mono- and combined therapy were taken from the international literature related to patients with genotype 1. Triple-therapy effectiveness was determined by means of a multicenter Table 2. Direct annual medical costs for health states Health status/Costs Chronic hepatitis receiving drug treatment Chronic hepatitis not receiving drug treatment Hepatocarcinoma Hepatic cirrhosis Ascitis Refractory ascitis Esophageal varices, 1 year Esophageal varices, O1 year Encephalopathy, 1 year Encephalopathy, O1 year Liver transplant, 1 year Liver transplant, O1 year
Minimum
Median
Maximum
2,437
3,110
4,998
1,012
1,207
2,365
5,016 1,464 12,645 17,857 16,113 25,784 13,240 23,992 19,097 17,370
5,523 1,944 14,899 21,275 20,474 28,258 18,313 25,683 21,876 20,149
6,707 2,811 19,445 26,384 22,752 31,640 20,004 29,065 35,102 33,375
Source: Panel of experts at the Mexican Institute of Social Security (IMSS). Costs are expressed in USD.
study carried out in Mexico in patients with failure to respond to pegylated interferon (26). The effectiveness information used from that Mexican trial included only genotype 1 at the 48-week evaluation. This study reported that during the 48-week treatment, normalization was achieved in ALT concentrations and negativization of HCV-RNA was reached in 47.8% of patients who had experienced failure or relapse with the interferon plus ribavirin-based therapy. For this reason, it was assumed that the effectiveness of triple therapy was equal to the probability of therapy response with interferon plus ribavirin (0.46) adding the difference of 1 minus the response of interferon plus ribavirin multiplied by the probability of success with the triple therapy (0.478). This is expressed in Equations 1 and 2: TTE 5 CTE1½ð12CTEÞ TTECTNR
ð1Þ
where TTE 5 triple-therapy effectiveness; CTE 5 combined therapy effectiveness (peginterferon plus ribavirin); and TTECTNR 5 triple-therapy effectiveness in combinedtherapy nonresponders. TTE 5 0:461½ð120:46Þ 0:47850:72
ð2Þ
Based on Equation 2, effectiveness of 0.72 was obtained for triple therapy with peginterferon-alpha2a 1 ribavirin 1 thymosin alpha-1 at 48 weeks of treatment. The effectiveness of monotherapy with peginterferon-alpha2a was 0.28 (19), and the combined therapy with peginterferon-alpha2a plus ribavirin was 0.46 (19). These effectiveness values could be translated as the percentage of patients with sustained response. Transition probabilities were obtained from the international literature and are described in Table 3. These were defined as the probability that a patient possesses of changing from one health state to another in each cycle, which in this case represents 1 year (15,19,20,27–30). The initial probability vector assigned a probability value of one in hepatitis C and zero in the remainder vector, i.e., 10,000 patients began in the heath state denominated chronic hepatitis C and as time passed, they traveled from this state to the remainder of the health states according to the probabilities associated with each cycle of analysis. Treatment effectiveness was expressed in QALYs gained. To carry out this estimation, we used quality-of-life indicators from the literature adjusted by Mexican experts (15,19,20). The value of total health was defined as one and death as zero, with intermediate points along this interval (Table 4). We reviewed the international literature, and information concerning utility was presented to the experts. Likert scale was presented for each utility value in the questionnaire. Each questionnaire item included different categories of agreement. When an expert was in agreement, the value was respected, and when an expert was in disagreement
Cost-Effectiveness of Chronic Hepatitis C Treatment Table 3. Transition probabilities Health state
Probability (%)
Reference
0.1 7.3
19 15, 19, 20
86.0
19, 20
HCV-related chronic hepatitis With hepatocarcinoma With cirrhosis Hepatocarcinoma To death Cirrhosis To hepatocarcinoma To ascitis To esophageal varices To encephalopathy Ascitis To refractory ascitis To transplant To death Refractory ascitis To transplant To death Esophageal varices To transplant To death, first year To death, successive years Encephalopathy To transplant To death, first year To death, successive years Liver transplant To death, first year To death, successive years
1.5 2.5 1.1 0.4
19, 19, 19, 19,
6.7 3.1 11.0
20 20 20 20
19 a
19, 20 a
3.1 33.0
19, 20
3.1 40.0 13.0
19, 20 19, 20
3.1 68.0 40.0
19, 20 19, 20
21.0 5.7
15, 19, 20 15, 19, 20
a
a
Mexican Institute of Social Security (IMSS) statistics.
he/she could change the utility value into his/her own value. Thus, the value of the utility was estimated as the mean of the values of all experts. We calculated average and incremental cost-effectiveness ratios with costs and utilities by means of therapeutic strategy for the entire study period. The combined therapy (peginterferon plus ribavirin) was chosen as the comparator therapy because of its greatest effectiveness in current clinical practice. Table 4. Quality-of-life indicators Health states (quality of life values) Minimum Median Maximum
a
References 15, 15, 15, 15,
34a 34a 34a 34a
0.82 0.1 0.7 0.35 0.3 0.2 0.2 0.5
0.87 0.30 0.77 0.48 0.34 0.28 0.30 0.56
0.96 0.5 0.89 0.65 0.51 0.35 0.4 0.64
19, 20, 33, 19, 20, 33, 19, 20, 33, 19, 20, 33, 15, 20a 20, 33a 20, 33a 15, 19, 20, 33,
0.7
0.75
0.95
15, 19, 20, 33, 34a
0
One-way sensitivity analysis was carried out, adjusting triple-therapy costs and effectiveness independently. We also conducted a two-way analysis in which triple-therapy costs and effectiveness concurrently were adjusted. In addition, probabalistic sensitivity analyses were used by means of a microsimulation with 10,000 patients and second-order Monte Carlo simulation. We used a triangular distribution for the costs for the Monte Carlo simulation. The lower limit was estimated from the least use of resources provided by the experts and the upper limit was the highest value in their answers; consequently, the middle point was the mean. We used a triangular distribution for utility, the lower limit being the lowest value in the experts’ responses and the upper limit the highest value in their responses; the middle point being the mean. For effectiveness, we used a uniform distribution. Net health benefits and 95% confidence interval (CI 95%) of the incremental cost-effectiveness ratio were estimated with the six-component analysis ellipse method. In addition, acceptability curves were derived to observe behaviors with respect to willingness to pay. Net health benefits were calculated according to Equation 3: Costc 2Costa NHB 5 UtilityC 2Utilitya 2 ð3Þ WTP where c 5 control therapy, a 5 alternative therapy, NHB 5 net health benefits, and WTP 5 willingness to pay.
a
Chronic hepatitis Hepatocarcinoma Hepatic cirrhosis Ascitis Refractory ascitis Esophageal varices Encephalopathy Liver transplant, 1 year Liver transplant, O1 year Death
667
34a
15, 19, 20, 33a
Panel of experts at the Mexican Institute of Social Security (IMSS).
Results At the end of the cohort simulation, triple therapy was the least expensive alternative ($73,900), with the combined peginterferon plus ribavirin therapy the second least expensive alternative ($74,934). The most expensive alternative was no treatment ($95,074). With respect to effectiveness, we obtained 39 QALYs with triple therapy, followed by peginterferon plus ribavirin with 33, and in last place not offering treatment with only 23 QALYS (Table 5). Triple therapy is the alternative with the lowest cost per QALY ($1,908) followed by the combined peginterferon plus ribavirin therapy at $2,277, monotherapy at $2,929, and not administering treatment, $4,204. Each life year adjusted for quality of life achieved by utilizing triple therapy implied a savings with respect to the next best alternative (peginterferon plus ribavirin) of O$355. Incremental analysis showed that peginterferon plus ribavirin, peginterferon, and the no-treatment-given alternative were dominated by triple therapy. In itself, the latter no-treatment-given alternative was dominated by the remaining alternatives because it is the most expensive and least effective alternative. Therefore, providing treatment implied savings with respect to not providing treatment during the simulation period of approximately $21,099 in the case of triple therapy, as can be observed in Figure 3.
Garcı´a-Contreras et al./ Archives of Medical Research 37 (2006) 663–673
668 Table 5. Cost-effectiveness analysis Alternative Peginterferon 1 ribavirin 1 thymosin Peginterferon 1 ribavirin Peginterferon No treatment
Cost
Incremental cost
Utility (QALY)
73,900
Incremental utility
39
Cost/utility
Incremental cost/utility
1,908
Dominant
74,934
1,034
33
26
2,277
Dominated
84,601 95,074
10,701 21,174
29 23
210 216
2,929 4,204
Dominated Dominated
Costs are expressed in USD.
Figure 4 describes the accumulated costs of treatment options and Figure 5 shows the curves of their cost-utility during follow-up. Sensitivity Analysis The bidimensional 95% CI of the incremental cost-utility ratio was estimated with the ellipse method and is described in Figure 6. Using peginterferon plus ribavirin as comparator and peginterferon plus ribavirin plus thymosin as basal therapy, the bidimensional 95% CI of the incremental costutility ratio was 98% of the points found in the dominance zone, i.e., within quadrant IV and component 1. The remainder of points is also found in the dominance zone within quadrant I and component 2, i.e., nearly 100% of the time we will find greater utility at lesser cost if we use triple therapy compared with the combined therapy. Figure 7 shows an acceptability curve in which the tripletherapy treatment alternative is the most cost-effective option, independent of willingness to pay. With regard to net health benefits using the combined therapy as comparator (Figure 8), the alternatives of not administering treatment and therapy with peginterferon did
not demonstrate positive results independent of willingness to pay; nevertheless, triple therapy showed positive net health benefits. When the combined therapy was used as the comparator, triple therapy achieved positive health benefits independently of willingness to pay. If any of the remaining alternatives were chosen as comparators, positive net health benefits of an even greater magnitude would be obtained. We adjusted the model to different triple-therapy costs to determine the cut-off point at which this alternative was no longer the dominant one with regard to the dominated one (peginterferon plus ribavirin). The decision concerning the best option depended on willingness to pay when triple therapy reached a cost that was $$48,314. Threshold analysis showed that triple therapy was dominated only when effectiveness was #46%. If the effectiveness of triple therapy is higher, there is a range of effectiveness in which the best option will depend on the willingness to pay; in this range, there is no dominance. We can see the dominance area between both alternatives in Figure 9. We considered cost and effectiveness intervals for triple therapy, which allowed us to establish the values among the cost and effectiveness indicators at which this therapy
Cost-Utility Analysis HCV treatments $1,100K
Without treatment
$1,070K
Peginterferon
$1,040K
Peginterferon + Ribavirin Peginterferon + Ribavirin + Thymosin
Cost
$1,010K $980K $950K $920K $890K $860K $830K 22
26
30
34
38
Utility Figure 3. Cost-utility.
Cost-Effectiveness of Chronic Hepatitis C Treatment
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COSTS 100,000 90,000
Accumulated Costs
80,000 70,000 60,000 50,000 40,000 30,000 20,000 10,000 0
2
4
6
8
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
Follow-up (years) Without treatment
Peginterferon
Peginterferon + Ribavirin
Peginterferon + Ribavirin + Thymosin
Figure 4. Accumulated costs for treatment alternatives during follow-up.
would be dominant, dominated, or indifferent. The relationship between effectiveness and cost is described in Figure 9: in the neighborhood of the line, under and to the right areas, triple therapy continued to be dominated. To remain in this situation, for each percentage point that effectiveness decreased it would be necessary to reduce the cost by $1,418 for the therapy to continue as a dominant option.
Discussion The healthcare cost of chronic hepatitis complications is very high (15). Evaluation of consequences as well as costs
of different treatment alternatives will allow us to obtain relevant information for optimizing allocation of resources to different health programs. In this study, direct medical costs of hepatic cirrhosis, ascitis, and esophageal varices bleeding were 29, 31, and 17%, respectively, together representing 77% of total costs. Other studies have shown that complications of chronic hepatitis such as hepatic cirrhosis, ascitis, and portal hypertension-related upper digestive tract bleeding were O90% of costs, whereas costs due to hepatocarcinoma represented !10% (15). The difference between our findings and other studies can be explained mainly by the use of expensive technologies in developed countries.
COST/UTILITY 10,000 9,000 8,000 7,000
C/U
6,000 5,000 4,000 3,000 2,000 1,000 1
3
5
7
9
11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45
Follow-up (years) Without treatment
Peginterferon
Peginterferon + Ribavirin
Peginterferon + Ribavirin + Thymosin
Figure 5. Acceptability curve of treatment alternatives.
Garcı´a-Contreras et al./ Archives of Medical Research 37 (2006) 663–673
670
Incremental Cost-utility Triple therapy versus combined therapy $ 26,596
Peginterferon + Ribavirin + T... vs. Peginterferon + Ribavirin
Incremental Cost
$17,730 $8,856 0 ($8,865) (17,730) (26,596) (35,461) -3
0
3
6
9
12
15
Incremental utility Figure 6. Ellipse graph with 95% confidence interval (CI 95%) for incremental cost-utility.
At the IMSS, unitary costs are low, and this may be related to certain explanations: there can be a slight underestimation because costs do not include profit and certain management costs and the existence of a scale economy (a huge volume in services resulting in lower costs). Another reason for finding that our costs at the IMSS were lower in comparison with other countries (developed countries) is that total costs were not adjusted by purchasing parity power. Transplant cost is low in relation with other decompensated states because experts considered that decompensated patients utilize many resources due to their frequent and lengthy hospital admissions. Consequently, the experts
included several bed-days and medical and nurse-time and careful and close control of drugs and laboratory tests. Although transplant cost is high during and around the surgical event, it decreases after this. Finally, in the long run the cost of decompensated patients will result in a higher cost than the liver transplant. When the risks of transition to decompensated states are high, the correlation with costs will be high also. There is a direct proportional correlation between risk of transition and costs and inversely with utility. Therapy with interferon involves multiple side effects such as fever, nausea, irritability, and depression (7). Combined therapy with interferon plus ribavirin—in addition to
Acceptability curve 1.0 Without treatment
Cost-Utility proportion
0.9
Peginterferon
0.8
Peginterferon + Ribavirin
0.7
Peginterferon + Ribavirin + Thymosin
0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
4,433
8,865
Willingness to pay Figure 7. Acceptability curve of treatment alternatives.
Cost-Effectiveness of Chronic Hepatitis C Treatment
671
Net health benefits 11.0
Without treatment vs Peginterferon+ Ribavirin Peginterferon vs Peginterferon + Ribavirin
Net health benefits
7.0
Peginterferon + Ribavirin+ Thymosin vs Peginterferon+Ribavirin
3.0 -1.0 -5.0 -9.0 -13.0 -17.0 -21.0 1.8K
4.2K
6.5K
8.9K
Willingness to pay Figure 8. Willingness to pay vs. net health benefits in the parallel model.
the effects of interferon—can present side effects due to ribavirin that include hemolytic anemia. This disappears with treatment cessation; thus, dose adjustment may be necessary when hematocrit diminution exists (7). Use of interferon plus ribavirin is contraindicated in the presence of anemia, hemolysis, renal insufficiency, coronary artery disease, vascular cerebral disease, gout, and contraception (11). Thymosin alpha-1 is generally well tolerated and, in the majority of clinical studies, the findings were only irritation at punction site (31). When TA1 was used in combination with IFN-alpha2b, fever, fatigue, muscular pain, nausea, vomiting, and neutropenia were reported at higher rates than with the use of interferon alone or placebo (32). Despite the fact that therapy for HVC-related chronic hepatitis achieves a gain in patient quality of life and savings in treatment complications costs, this alternative is not innocuous. Consequently, there is a need to carry out adequate economic evaluations that permit comparison of
alternatives for a better-informed decision with regard to allocation. In the model used, although liver transplant is not a health state it is considered as such due to the fact that a patient with important hepatocellular damage has the possibility of accessing this. Liver transplant was also not included among therapeutic alternatives because it is not considered a treatment option for patients with chronic hepatitis. With regard to real patient evolution, there is a lack of knowledge concerning what occurs with certainty in patients who did not respond to the previously mentioned therapies or who experienced relapse. Questions arise with relationship to the delay in the appearance of complications due to hepatitis related with viral load diminution, and concern whether—in patients who responded to treatment— some complications of chronic hepatitis will occur, among other concerns.
Sensitivity analysis Triple therapy cost and utility 600K
Without treatment Peginterferon
550K
Peginterferon + Ribavirin
Cost
500K
Peginterferon + Ribavirin + Thymosin
450K
400K
350K
300K 0.45
0.55
0.65
0.75
0.85
Utility Figure 9. Bivariate analysis.
672
Garcı´a-Contreras et al./ Archives of Medical Research 37 (2006) 663–673
Published literature on HCV-associated chronic hepatitis in general takes into consideration responders who are cured and nonresponders or those who experience relapse as if the treatment had not affected the viral load (15,19,33,34); thus, more clinical studies are required that allow us to model these behaviors more precisely. This study shows that triple therapy that includes peginterferon plus ribavirin plus thymosin alpha-1 has the higher incremental cost-utility ratio. Although triple therapy had highest initial costs due to the cost of its components in this analysis, in the long term its cost was $1,034 lower than therapy with peginterferon plus ribavirin, whereas not administering treatment was approximately $20,140 more expensive than therapy with peginterferon plus ribavirin. Figure 4 describes triple therapy as the most cost-effective alternative at the end of the follow-up. This could be interpreted as triple therapy being the best option when used in young people, because its economical advantages will be present after 29 years of follow-up. However, triple therapy starts showing lower cost per unit of success in relationship with others strategies after 21 years of follow-up. The cost of no-treatment option at the end of the followup is high as can be seen in Figure 5. No-treatment option starts showing greater cost in relationship with other strategies after 21 years of follow-up. The results of this study have shown that triple therapy is dominant when it is evaluated at the end of the cohort. Those findings are explained by the overall impact in costs resulting from the lower cost because there are fewer complications during the follow-up and the high cost of triple therapy at the beginning of the study. One limitation of this study was to consider effectiveness in week 48 of treatment. Although the ideal is to consider effectiveness to week 72, we did not have the complete information for all study alternatives that would have allowed us to render a fair comparison. In addition, the effectiveness considered in the triple therapy model assumed that effectiveness was the sum of therapeutic effectiveness with pegylated interferon plus ribavirin plus percentage of patients with failure who had a response; this is due to the fact that there were no studies in which triple therapy was considered as the initial treatment therapy. Due to the weakness of the true effectiveness of triple therapy, we carried out a threshold-type sensitivity analysis to determine at which moment the results changed the direction of the conclusions. Analysis showed that triple therapy effectiveness had to be the same as that of double therapy so that it would turn to be dominated. This implies that only if thymosin alpha-1 added no effect on the peginterferon plus ribavirin therapy would it turn triple therapy into a dominated or losing therapy. In two-way analysis, we found that in the case that triple therapy had lower effectiveness, it would be necessary to decrease the cost by $1,498 for each percentage point of effectiveness in order for it to continue being the dominant
therapy. With regard to costs, the possibility that triple therapy was more expensive was considered; therefore, we carried out one-way analysis in which triple therapy costs were increased. However, this analysis showed that despite an increase in cost to nearly double the amount, this therapy could not be dominated due to its greater effectiveness. Uncertainty concerning the incremental cost-effectiveness ratio was evaluated by determination of bidimensional 95% CI by ellipse method. In 10,000 simulations, 98% of the time triple therapy was dominant and in the remaining 2%, the decision fell within the willingness-to-pay sector. These results confirm and provide robustness to the conclusions obtained in the basal study. For cases in which simulations fell within the willingness-to-pay sector, the acceptability curve showed that the triple alternative was the most cost-effectiveness option independently of willingness to pay. Once again, this lends robustness to the basal study conclusions. To confirm that triple therapy with thymosin alpha-1 was the most cost-effective alternative, we analyzed all therapies employing net health benefits as another outcome option. We recognize that because of expert opinion and other aspects of the methods for this study, the underlying limitations in the evidence base for the clinical effectiveness of triple therapy suggest that considerable uncertainty remains about the cost effectiveness of triple therapy. The costeffectiveness ratio (Figure 5) shows that triple therapy is not the most cost-effective alternative in most of the follow-up. This would suggest that for health care systems, only under specific characteristics of patients triple therapy would be the most cost-effective option. However, it should not be considered as a public policy for general patients. With the previously mentioned results, we can conclude that therapy with peginterferon plus ribavirin plus thymosin alpha-1 was the most cost-effective option. Sensitivity analyses showed that the basal study results are robust.
Acknowledgments This work was performed within the IMSS and was supported in part by Laboratorio Columbia, S.A. de C.V. The opinions presented in this paper are those of the authors and do not represent the opinion of the IMSS.
References 1. http://www.who.int/mediacentre/factsheets/fs164/en/ (accessed September 2004). 2. World Health Organization. Weekly Epidemiological Record. 10 December 1999, 74th year. http://www.who.int/wer (accessed September 2004). 3. Liaw YF. Current therapeutic trends in therapy for chronic viral hepatitis. J Gastroenterol Hepatol 1997;12(suppl):S346–S353. 4. Hoofnagle JH, Di Bisceglie AM. The treatment of chronic viral hepatitis. N Engl J Med 1997;226:347–356. 5. Christian T, Fabien Z, Pierre P. Viral hepatitis. Curr Opin Infect Dis 1999;12:481–490.
Cost-Effectiveness of Chronic Hepatitis C Treatment 6. Chemello L, Cavalletto L, Casarin C, Bonetti P, Bernardinello E, Pontisso P, et al. Persistent hepatitis C viremia predicts late relapse after sustained response to interferon-a in chronic hepatitis C. Ann Intern Med 1996;124:1058–1060. 7. Reichard O, Andersson J, Schvarcz R, Weiland O. Ribavirin treatment for chronic hepatitis C. Lancet 1991;337:1058–1061. 8. Thomas HC, Torok ME, Forton DM, Taylor-Robinson SD. Possible mechanisms of action and reasons for failure of antiviral therapy in chronic hepatitis C. J Hepatol 1999;31(suppl 1):152–159. 9. Dusheiko G, Main J, Thomas H, Reichard O, Lee C, Dhillon A, et al. Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study. J Hepatol 1996;25:591–598. 10. Di Bisceglie AM, Conjeevaram HS, Fried MW, Sallie R, Park Y, Yurdaydin C, et al. Rivabirin as therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123:897–903. 11. Brillanti S, Garson J, Foli M, Whitby K, Deaville R, Masci C, et al. A pilot study of combination therapy with ribarivin plus interferon alpha for interferon alpha-resistant chronic hepatitis C. Gastroenterology 1994;107:812–817. 12. Lai MY, Kao JH, Yang PM, Wang JT, Chen PJ, Chan KW, et al. Longterm efficacy of ribavirin plus interferon alpha in the treatment of chronic hepatitis C. Gastroenterology 1996;11I:1307–1312. 13. Reichard O, Norkrans G, Fryden A, Braconier JH, Sonnerborg A, Weiland O for the Swedish Study Group. Randomised, double-blind, placebo-controlled trial of interferon (alpha2b) with and without ribavirin for chronic hepatitis C. Lancet 1998;351:83–87. 14. Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of interferon a2b plus ribavirin for 48 weeks or for 24 weeks versus interferon a2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998;352: 1426–1432. 15. Younossi ZM, Mendel ES, McHutchison JG, Shermock KM. Cost effectiveness of interferon a2b combined with ribavirin for the treatment of chronic hepatitis C. Hepatology 1999;30:1318–1324. 16. McHutchison JG, Hoofnagle JH. Therapy of chronic hepatitis C. In: Liang TJ, Hoofnagle JH, eds. Hepatitis C: Biomedical Research Reports. New York: Academic Press;2000. pp. 203–239. 17. Ancell C, Phipps J, Young L. Thymosin alpha-1. Am J Health System Pharmacy 2001;58:879–888. 18. Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the US. Am J Public Health 2000;90:1562–1569. 19. Siebert U, Sroczynski G, Rossol S, Waseon J, Ravens-Sieberer U, Kurth B, et al. Cost effectiveness of peginterferon a-2b plus ribavirin versus interferon a-2b plus ribavirin for initial treatment of chronic hepatitis C. Gut 2003;52:425–432.
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ORIGINAL ARTICLE
Cost-effectiveness of Chronic Hepatitis C Treatment with Thymosin Alpha-1 Fernando Garcı´a-Contreras,a Armando Neva´rez-Sida,a Patricia Constantino-Casas,a Fernando Abud-Bastida,b and Juan Gardun˜o-Espinosaa a
Unidad de Investigacio´n en Economı´a de la Salud, Coordinacio´n de Investigacio´n en Salud, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico b Hospital General de Zona Las Margaritas, IMSS, Mexico City, Mexico Received for publication August 24, 2005; accepted November 30, 2005 (ARCMED-D-05-00336).
Background. More than one million individuals in Mexico are infected with hepatitis C virus (HCV), and 80% are at risk for developing a chronic infection that could lead to hepatic cirrhosis and other complications that impact quality of life and institutional costs. The objective of the study was to determine the most cost-effective treatment against HCV among the following: peginterferon, peginterferon plus ribavirin, peginterferon plus ribavirin plus thymosin, and no treatment. Methods. We carried out cost-effectiveness analysis using the institutional perspective, including a 45-year time frame and a 3% discount rate for costs and effectiveness. We employed a Bayesian-focused decision tree and a Markov model. One- and two-way sensitivity analyses were performed, as well as threshold-oriented and probabilistic analyses, and we obtained acceptability curves and net health benefits. Results. Triple therapy (peginterferon plus ribavirin plus thymosin alpha-1) was dominant with lower cost and higher utility in relationship with peginterferon 1 ribavirin option, peginterferon alone and no-treatment option. In triple therapy the cost per unit of success was of $1,908 [USD/quality-adjusted life years (QALY)] compared with peginterferon plus ribavirin $2,277/QALY, peginterferon alone $2,929/QALY, and no treatment $4,204/QALY. Sensitivity analyses confirmed the robustness of the base case. Conclusions. Peginterferon plus ribavirin plus thymosin alpha-1 option was dominant (lowest cost and highest effectiveness). Using no drug was the most expensive and least effective option. Ó 2006 IMSS. Published by Elsevier Inc. Key Words: Cost effectiveness, Economic evaluation, Chronic hepatitis C, Peginterferon, Ribavirin, Thymosin alpha-1.
Introduction Approximately 170 million persons, i.e., 3.1% of the world population, are infected with hepatitis C virus (HCV) and face the risk of developing hepatic cirrhosis or liver cancer (1). In Mexico, hepatitis C prevalence is estimated at 0.7% (2); therefore, it is considered that there are approximately 700,000 persons infected with HCV and that at least 56,000 suffer from hepatic cirrhosis. In the population covered by
Address reprint requests to: Fernando Garcı´a-Contreras, Reforma 476, 3er piso poniente, Col. Jua´rez, Deleg. Cuauhte´moc, 06600 Me´xico, D.F., Me´xico; E-mail: [email protected]
the Mexican Institute of Social Security (IMSS), it has been estimated that approximately 6,300 individuals develop cancer of the liver as a consequence of HCV-related hepatitis. The objective of therapy in patients with chronic hepatitis C was to inhibit viral replication to diminish disease activity in the liver, which is associated with reduction of the risk for developing hepatic cirrhosis and hepatocellular carcinoma (3). However, viral eradication should not be the sole treatment objective because histological improvement can be achieved with permanent viral therapy (4). The effect of alpha interferon in the treatment of HCVrelated chronic hepatitis has demonstrated its effectiveness
0188-4409/06 $–see front matter. Copyright Ó 2006 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2005.11.010
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with a rapid decrease of HCV-RNA during the first weeks of therapy and with a parallel decrease in serum concentrations of alanine aminotransferase (ALT) (5). Nonetheless, the effectiveness shown is !20%; thus, its use is always recommended in combination with another pharmaceutical (6). Ribavirin is a nucleoside analog similar to guanoside and possesses a broad spectrum of antiviral activity. Ribavirin causes a significant decrease in serum concentrations of ALT in patients with HCV-associated chronic hepatitis (7); nevertheless, studies have not shown a significant reduction of HCV-RNA (8). In addition, previous studies have not demonstrated histological changes with ribavirin (9,10). In patients who relapsed after treatment with alpha interferon, the association with ribavirin induced a sustained response in some (11). A higher percentage of sustained response has been achieved in patients with interferon plus ribavirin-based treatment than with interferon only in never-treated (naı¨ve) patients (12,13). Larger studies have shown that peginterferon plus ribavirin combined therapy during 24–48 weeks achieved sustained response rates of 33–41%, compared with interferon alone, which demonstrated a sustained response rate of 5–15% (9,14,15). Thymosin alpha-1 (TA1) or thymalfasin (Zadaxin, SciClone Pharmaceuticals, San Mateo, CA) is a chemically synthesized polypeptide identical to human TA1 (16) and belongs to a class of products known as biological response modifiers (5). Although its mechanism of action is not clear, it is thought that it modulates the immune system, increasing T-cell function. In vitro studies have shown maturation and T-cell differentiation with an increase in CD41, CD81, and CD31 cells and gamma interferon, interleukin2 (IL-2), and interleukin-3 (IL-3), as well as an increase in TH1 response with a decrease in TH2 response. In addition, antigen-stimulated IL-2 receptor expression has been observed (17). It is estimated that in the U.S., cost of care for HCV-related hepatitis in 1997 was 5.46 billion USD, 33% of which corresponded to direct and 67% to indirect costs. Projections in the U.S. estimate that during the period from 2010 to 2019 there will be 165,000 deaths attributable to chronic diseases of the liver, with a direct medical cost due to the hepatitis C virus of 10.7 billion USD (18). At present, alpha-interferon is the most studied therapy for treatment of chronic hepatitis B and C. However, the low response rate (RR) has led efforts toward alternative therapies including TA1, ribavirin, and other forms of interferon, such as pegylates (19–23). Currently, new drugs are being developed and tested for treatment of HCV, including thymosin alpha-1 (Zadaxin), which is indicated in the treatment of HCV. There are multiple alternatives in HCV-related chronic hepatitis treatment, and the association of pegylated interferon plus ribavirin is the most effective option. However, this continues to possess a high proportion of failures and relapses
that as a whole comprise O50%. Therefore, we considered it relevant to analyze treatment alternatives that also included thymosin alpha-1 as part of the first-line triple therapy option to evaluate their economic impact.
Materials and Methods We conducted a cost-effectiveness analysis that took into account the costs of the alternatives studied as well as results measured in QALY gained. The perspective was that of the public health service provider: the Mexican Institute of Social Security (IMSS). This institution covers the potential health needs of 52,757,684 persons and provides services to 42,519,051 individuals (24). With regard to the time frame, the 75-year time horizon was chosen because that is the approximate life expectancy in Mexico; therefore, the decision to end the analysis at that age would reflect, in a more intuitive manner, the potential result in the cohort. In our model, the majority of patients died before reaching that age. Therefore, we simulated a cohort during 45 years in patients who were 30 years of age at the beginning of the study. We utilized a Bayesian-focused decision tree and a Markov model. For the economic analysis, we applied a 3% discount rate for costs as well as for utilities. Costs were considered at the present value. The discount rate was chosen because we only took into account time preferences. The analysis was carried out in the public sector, and it has been recommended that 3% is a good discount rate, whereas in the private sector the best is 5% (25). Treatment alternatives in the decision tree included the following: a) peginterferon-alpha2a; b) peginterferonalpha2a plus ribavirin, and c) peginterferon-alpha2a plus ribavirin plus thymosin alpha-1 (Figure 1). A Markov model with yearly cycles was connected with the decision-tree nodes that indicated treatment relapse or failure to simulate the natural history of the disease of a hypothetical cohort of 10,000 patients with HCV-associated chronic hepatitis. Health states included in the Markov model are shown in Figure 2; these represent the disease’s natural history and served as the base for model conceptualization. A half cycle correction at the beginning of the states was used because the model included an absorbent state, and this provided a better approach to the real-life processes that occurred in continuous time. We included only direct medical costs in this study. The components used for cost estimation included frequency of resource utilization and unitary costs. Costs and follow-up for each treatment strategy as well as annual cost of each cycle of the Markov model were calculated. HCV-related chronic hepatitis treatment costs included drugs during 48 weeks in addition to medical visits, laboratory and diagnostic tests, and surgical procedures. Table 1 shows treatment costs for each of the studied therapies.
Cost-Effectiveness of Chronic Hepatitis C Treatment
665
Without response
Without treatment
Sustained response Peginterferon Without response or relapse Hepatitis C treatments
Sustained response
Peginterferon + Ribavirin
Without response or relapse
Peginterferon + Ribavirin + Thymosin
Sustained response
Without response or relapse Figure 1. Decision tree of treatment alternatives in chronic hepatitis C.
For estimating direct medical annual costs of the different health states (Table 2), we obtained information on institutional resource utilization from the previously mentioned ex profeso panel of experts. Resource use by experts was determined according to their experience at the IMSS. The questionnaire was organized into health states and the experts were asked to comment on their treatment of a typical patient; then, resource use was estimated by use of the mean of their answers. The IMSS is a healthcare institution that belongs to the public sector. IMSS unitary costs were acquired from the official Mexican governmental periodical (Diario Oficial de la
Information concerning resource utilization for this type of patient was obtained from an ex profeso panel of experts. This panel included medical doctors with a specialty in gastroenterology and who were certified by the respective council and had at least 10 years of clinical experience. Drug costs were supplied by the pharmaceutical companies that produce the molecules included in this study (Laboratorio Columbia, S.A. de C.V. for alpha-1 thymosin and Laboratorio Roche Syntex de Me´xico, S.A. de C.V. for peginterferon and ribavirin). Treatment dosage and resource utilization were calculated according to the recommendations of each pharmaceutical company.
Ascitis with response to diuretics
Liver transplant
Refractory ascitis
Compensated cirrhosis
Death Esophageal varices
HCV-related chronic hepatitis
Encephalopathy
Hepatocarcinoma
Figure 2. Markov model.
Garcı´a-Contreras et al./ Archives of Medical Research 37 (2006) 663–673
666
Table 1. Treatment costs of chronic hepatitis C
Monotherapy Peginterferon Combined therapy Peginterferon plus ribavirin Triple therapy Peginterferon plus ribavirin plus thymosin
Drug
Other resources
Total
13,037
3,110
16,147
20,484
3,110
23,594
44,169
3,110
47,279
Costs are expressed in U.S. dollars (USD). Other resources: medical visits, laboratory and diagnostic tests, and surgical procedures.
Federacio´ del 9 de Marzo del 2004, Me´xico), as well as from the Finance Department of the Hospital de Especialiades (XXI Century National Medical Center, IMSS, in Mexico City). Follow-up concepts included medical visits/appointments, laboratory and office tests, hospitalization, emergency medical care, intensive care, and surgical procedures. Costs were expressed in USD. We utilized the available information from the international literature for the remaining parameters in the model; however, we found no information for the Mexican population. As we were aware that there might be differences between international and Mexican information, we decided to validate the model’s parameters by using a Mexican expert panel. These experts reviewed the information with regard to our context and to their own experience. In a Delphi panel, we designed sentences with a Likert scale concerning the pertinence of those values in relation with our Mexican population, specifically at the IMSS. When values were not considered pertinent, the option was afforded for suggesting new figures. Treatment effectiveness measurements of mono- and combined therapy were taken from the international literature related to patients with genotype 1. Triple-therapy effectiveness was determined by means of a multicenter Table 2. Direct annual medical costs for health states Health status/Costs Chronic hepatitis receiving drug treatment Chronic hepatitis not receiving drug treatment Hepatocarcinoma Hepatic cirrhosis Ascitis Refractory ascitis Esophageal varices, 1 year Esophageal varices, O1 year Encephalopathy, 1 year Encephalopathy, O1 year Liver transplant, 1 year Liver transplant, O1 year
Minimum
Median
Maximum
2,437
3,110
4,998
1,012
1,207
2,365
5,016 1,464 12,645 17,857 16,113 25,784 13,240 23,992 19,097 17,370
5,523 1,944 14,899 21,275 20,474 28,258 18,313 25,683 21,876 20,149
6,707 2,811 19,445 26,384 22,752 31,640 20,004 29,065 35,102 33,375
Source: Panel of experts at the Mexican Institute of Social Security (IMSS). Costs are expressed in USD.
study carried out in Mexico in patients with failure to respond to pegylated interferon (26). The effectiveness information used from that Mexican trial included only genotype 1 at the 48-week evaluation. This study reported that during the 48-week treatment, normalization was achieved in ALT concentrations and negativization of HCV-RNA was reached in 47.8% of patients who had experienced failure or relapse with the interferon plus ribavirin-based therapy. For this reason, it was assumed that the effectiveness of triple therapy was equal to the probability of therapy response with interferon plus ribavirin (0.46) adding the difference of 1 minus the response of interferon plus ribavirin multiplied by the probability of success with the triple therapy (0.478). This is expressed in Equations 1 and 2: TTE 5 CTE1½ð12CTEÞ TTECTNR
ð1Þ
where TTE 5 triple-therapy effectiveness; CTE 5 combined therapy effectiveness (peginterferon plus ribavirin); and TTECTNR 5 triple-therapy effectiveness in combinedtherapy nonresponders. TTE 5 0:461½ð120:46Þ 0:47850:72
ð2Þ
Based on Equation 2, effectiveness of 0.72 was obtained for triple therapy with peginterferon-alpha2a 1 ribavirin 1 thymosin alpha-1 at 48 weeks of treatment. The effectiveness of monotherapy with peginterferon-alpha2a was 0.28 (19), and the combined therapy with peginterferon-alpha2a plus ribavirin was 0.46 (19). These effectiveness values could be translated as the percentage of patients with sustained response. Transition probabilities were obtained from the international literature and are described in Table 3. These were defined as the probability that a patient possesses of changing from one health state to another in each cycle, which in this case represents 1 year (15,19,20,27–30). The initial probability vector assigned a probability value of one in hepatitis C and zero in the remainder vector, i.e., 10,000 patients began in the heath state denominated chronic hepatitis C and as time passed, they traveled from this state to the remainder of the health states according to the probabilities associated with each cycle of analysis. Treatment effectiveness was expressed in QALYs gained. To carry out this estimation, we used quality-of-life indicators from the literature adjusted by Mexican experts (15,19,20). The value of total health was defined as one and death as zero, with intermediate points along this interval (Table 4). We reviewed the international literature, and information concerning utility was presented to the experts. Likert scale was presented for each utility value in the questionnaire. Each questionnaire item included different categories of agreement. When an expert was in agreement, the value was respected, and when an expert was in disagreement
Cost-Effectiveness of Chronic Hepatitis C Treatment Table 3. Transition probabilities Health state
Probability (%)
Reference
0.1 7.3
19 15, 19, 20
86.0
19, 20
HCV-related chronic hepatitis With hepatocarcinoma With cirrhosis Hepatocarcinoma To death Cirrhosis To hepatocarcinoma To ascitis To esophageal varices To encephalopathy Ascitis To refractory ascitis To transplant To death Refractory ascitis To transplant To death Esophageal varices To transplant To death, first year To death, successive years Encephalopathy To transplant To death, first year To death, successive years Liver transplant To death, first year To death, successive years
1.5 2.5 1.1 0.4
19, 19, 19, 19,
6.7 3.1 11.0
20 20 20 20
19 a
19, 20 a
3.1 33.0
19, 20
3.1 40.0 13.0
19, 20 19, 20
3.1 68.0 40.0
19, 20 19, 20
21.0 5.7
15, 19, 20 15, 19, 20
a
a
Mexican Institute of Social Security (IMSS) statistics.
he/she could change the utility value into his/her own value. Thus, the value of the utility was estimated as the mean of the values of all experts. We calculated average and incremental cost-effectiveness ratios with costs and utilities by means of therapeutic strategy for the entire study period. The combined therapy (peginterferon plus ribavirin) was chosen as the comparator therapy because of its greatest effectiveness in current clinical practice. Table 4. Quality-of-life indicators Health states (quality of life values) Minimum Median Maximum
a
References 15, 15, 15, 15,
34a 34a 34a 34a
0.82 0.1 0.7 0.35 0.3 0.2 0.2 0.5
0.87 0.30 0.77 0.48 0.34 0.28 0.30 0.56
0.96 0.5 0.89 0.65 0.51 0.35 0.4 0.64
19, 20, 33, 19, 20, 33, 19, 20, 33, 19, 20, 33, 15, 20a 20, 33a 20, 33a 15, 19, 20, 33,
0.7
0.75
0.95
15, 19, 20, 33, 34a
0
One-way sensitivity analysis was carried out, adjusting triple-therapy costs and effectiveness independently. We also conducted a two-way analysis in which triple-therapy costs and effectiveness concurrently were adjusted. In addition, probabalistic sensitivity analyses were used by means of a microsimulation with 10,000 patients and second-order Monte Carlo simulation. We used a triangular distribution for the costs for the Monte Carlo simulation. The lower limit was estimated from the least use of resources provided by the experts and the upper limit was the highest value in their answers; consequently, the middle point was the mean. We used a triangular distribution for utility, the lower limit being the lowest value in the experts’ responses and the upper limit the highest value in their responses; the middle point being the mean. For effectiveness, we used a uniform distribution. Net health benefits and 95% confidence interval (CI 95%) of the incremental cost-effectiveness ratio were estimated with the six-component analysis ellipse method. In addition, acceptability curves were derived to observe behaviors with respect to willingness to pay. Net health benefits were calculated according to Equation 3: Costc 2Costa NHB 5 UtilityC 2Utilitya 2 ð3Þ WTP where c 5 control therapy, a 5 alternative therapy, NHB 5 net health benefits, and WTP 5 willingness to pay.
a
Chronic hepatitis Hepatocarcinoma Hepatic cirrhosis Ascitis Refractory ascitis Esophageal varices Encephalopathy Liver transplant, 1 year Liver transplant, O1 year Death
667
34a
15, 19, 20, 33a
Panel of experts at the Mexican Institute of Social Security (IMSS).
Results At the end of the cohort simulation, triple therapy was the least expensive alternative ($73,900), with the combined peginterferon plus ribavirin therapy the second least expensive alternative ($74,934). The most expensive alternative was no treatment ($95,074). With respect to effectiveness, we obtained 39 QALYs with triple therapy, followed by peginterferon plus ribavirin with 33, and in last place not offering treatment with only 23 QALYS (Table 5). Triple therapy is the alternative with the lowest cost per QALY ($1,908) followed by the combined peginterferon plus ribavirin therapy at $2,277, monotherapy at $2,929, and not administering treatment, $4,204. Each life year adjusted for quality of life achieved by utilizing triple therapy implied a savings with respect to the next best alternative (peginterferon plus ribavirin) of O$355. Incremental analysis showed that peginterferon plus ribavirin, peginterferon, and the no-treatment-given alternative were dominated by triple therapy. In itself, the latter no-treatment-given alternative was dominated by the remaining alternatives because it is the most expensive and least effective alternative. Therefore, providing treatment implied savings with respect to not providing treatment during the simulation period of approximately $21,099 in the case of triple therapy, as can be observed in Figure 3.
Garcı´a-Contreras et al./ Archives of Medical Research 37 (2006) 663–673
668 Table 5. Cost-effectiveness analysis Alternative Peginterferon 1 ribavirin 1 thymosin Peginterferon 1 ribavirin Peginterferon No treatment
Cost
Incremental cost
Utility (QALY)
73,900
Incremental utility
39
Cost/utility
Incremental cost/utility
1,908
Dominant
74,934
1,034
33
26
2,277
Dominated
84,601 95,074
10,701 21,174
29 23
210 216
2,929 4,204
Dominated Dominated
Costs are expressed in USD.
Figure 4 describes the accumulated costs of treatment options and Figure 5 shows the curves of their cost-utility during follow-up. Sensitivity Analysis The bidimensional 95% CI of the incremental cost-utility ratio was estimated with the ellipse method and is described in Figure 6. Using peginterferon plus ribavirin as comparator and peginterferon plus ribavirin plus thymosin as basal therapy, the bidimensional 95% CI of the incremental costutility ratio was 98% of the points found in the dominance zone, i.e., within quadrant IV and component 1. The remainder of points is also found in the dominance zone within quadrant I and component 2, i.e., nearly 100% of the time we will find greater utility at lesser cost if we use triple therapy compared with the combined therapy. Figure 7 shows an acceptability curve in which the tripletherapy treatment alternative is the most cost-effective option, independent of willingness to pay. With regard to net health benefits using the combined therapy as comparator (Figure 8), the alternatives of not administering treatment and therapy with peginterferon did
not demonstrate positive results independent of willingness to pay; nevertheless, triple therapy showed positive net health benefits. When the combined therapy was used as the comparator, triple therapy achieved positive health benefits independently of willingness to pay. If any of the remaining alternatives were chosen as comparators, positive net health benefits of an even greater magnitude would be obtained. We adjusted the model to different triple-therapy costs to determine the cut-off point at which this alternative was no longer the dominant one with regard to the dominated one (peginterferon plus ribavirin). The decision concerning the best option depended on willingness to pay when triple therapy reached a cost that was $$48,314. Threshold analysis showed that triple therapy was dominated only when effectiveness was #46%. If the effectiveness of triple therapy is higher, there is a range of effectiveness in which the best option will depend on the willingness to pay; in this range, there is no dominance. We can see the dominance area between both alternatives in Figure 9. We considered cost and effectiveness intervals for triple therapy, which allowed us to establish the values among the cost and effectiveness indicators at which this therapy
Cost-Utility Analysis HCV treatments $1,100K
Without treatment
$1,070K
Peginterferon
$1,040K
Peginterferon + Ribavirin Peginterferon + Ribavirin + Thymosin
Cost
$1,010K $980K $950K $920K $890K $860K $830K 22
26
30
34
38
Utility Figure 3. Cost-utility.
Cost-Effectiveness of Chronic Hepatitis C Treatment
669
COSTS 100,000 90,000
Accumulated Costs
80,000 70,000 60,000 50,000 40,000 30,000 20,000 10,000 0
2
4
6
8
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
Follow-up (years) Without treatment
Peginterferon
Peginterferon + Ribavirin
Peginterferon + Ribavirin + Thymosin
Figure 4. Accumulated costs for treatment alternatives during follow-up.
would be dominant, dominated, or indifferent. The relationship between effectiveness and cost is described in Figure 9: in the neighborhood of the line, under and to the right areas, triple therapy continued to be dominated. To remain in this situation, for each percentage point that effectiveness decreased it would be necessary to reduce the cost by $1,418 for the therapy to continue as a dominant option.
Discussion The healthcare cost of chronic hepatitis complications is very high (15). Evaluation of consequences as well as costs
of different treatment alternatives will allow us to obtain relevant information for optimizing allocation of resources to different health programs. In this study, direct medical costs of hepatic cirrhosis, ascitis, and esophageal varices bleeding were 29, 31, and 17%, respectively, together representing 77% of total costs. Other studies have shown that complications of chronic hepatitis such as hepatic cirrhosis, ascitis, and portal hypertension-related upper digestive tract bleeding were O90% of costs, whereas costs due to hepatocarcinoma represented !10% (15). The difference between our findings and other studies can be explained mainly by the use of expensive technologies in developed countries.
COST/UTILITY 10,000 9,000 8,000 7,000
C/U
6,000 5,000 4,000 3,000 2,000 1,000 1
3
5
7
9
11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45
Follow-up (years) Without treatment
Peginterferon
Peginterferon + Ribavirin
Peginterferon + Ribavirin + Thymosin
Figure 5. Acceptability curve of treatment alternatives.
Garcı´a-Contreras et al./ Archives of Medical Research 37 (2006) 663–673
670
Incremental Cost-utility Triple therapy versus combined therapy $ 26,596
Peginterferon + Ribavirin + T... vs. Peginterferon + Ribavirin
Incremental Cost
$17,730 $8,856 0 ($8,865) (17,730) (26,596) (35,461) -3
0
3
6
9
12
15
Incremental utility Figure 6. Ellipse graph with 95% confidence interval (CI 95%) for incremental cost-utility.
At the IMSS, unitary costs are low, and this may be related to certain explanations: there can be a slight underestimation because costs do not include profit and certain management costs and the existence of a scale economy (a huge volume in services resulting in lower costs). Another reason for finding that our costs at the IMSS were lower in comparison with other countries (developed countries) is that total costs were not adjusted by purchasing parity power. Transplant cost is low in relation with other decompensated states because experts considered that decompensated patients utilize many resources due to their frequent and lengthy hospital admissions. Consequently, the experts
included several bed-days and medical and nurse-time and careful and close control of drugs and laboratory tests. Although transplant cost is high during and around the surgical event, it decreases after this. Finally, in the long run the cost of decompensated patients will result in a higher cost than the liver transplant. When the risks of transition to decompensated states are high, the correlation with costs will be high also. There is a direct proportional correlation between risk of transition and costs and inversely with utility. Therapy with interferon involves multiple side effects such as fever, nausea, irritability, and depression (7). Combined therapy with interferon plus ribavirin—in addition to
Acceptability curve 1.0 Without treatment
Cost-Utility proportion
0.9
Peginterferon
0.8
Peginterferon + Ribavirin
0.7
Peginterferon + Ribavirin + Thymosin
0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
4,433
8,865
Willingness to pay Figure 7. Acceptability curve of treatment alternatives.
Cost-Effectiveness of Chronic Hepatitis C Treatment
671
Net health benefits 11.0
Without treatment vs Peginterferon+ Ribavirin Peginterferon vs Peginterferon + Ribavirin
Net health benefits
7.0
Peginterferon + Ribavirin+ Thymosin vs Peginterferon+Ribavirin
3.0 -1.0 -5.0 -9.0 -13.0 -17.0 -21.0 1.8K
4.2K
6.5K
8.9K
Willingness to pay Figure 8. Willingness to pay vs. net health benefits in the parallel model.
the effects of interferon—can present side effects due to ribavirin that include hemolytic anemia. This disappears with treatment cessation; thus, dose adjustment may be necessary when hematocrit diminution exists (7). Use of interferon plus ribavirin is contraindicated in the presence of anemia, hemolysis, renal insufficiency, coronary artery disease, vascular cerebral disease, gout, and contraception (11). Thymosin alpha-1 is generally well tolerated and, in the majority of clinical studies, the findings were only irritation at punction site (31). When TA1 was used in combination with IFN-alpha2b, fever, fatigue, muscular pain, nausea, vomiting, and neutropenia were reported at higher rates than with the use of interferon alone or placebo (32). Despite the fact that therapy for HVC-related chronic hepatitis achieves a gain in patient quality of life and savings in treatment complications costs, this alternative is not innocuous. Consequently, there is a need to carry out adequate economic evaluations that permit comparison of
alternatives for a better-informed decision with regard to allocation. In the model used, although liver transplant is not a health state it is considered as such due to the fact that a patient with important hepatocellular damage has the possibility of accessing this. Liver transplant was also not included among therapeutic alternatives because it is not considered a treatment option for patients with chronic hepatitis. With regard to real patient evolution, there is a lack of knowledge concerning what occurs with certainty in patients who did not respond to the previously mentioned therapies or who experienced relapse. Questions arise with relationship to the delay in the appearance of complications due to hepatitis related with viral load diminution, and concern whether—in patients who responded to treatment— some complications of chronic hepatitis will occur, among other concerns.
Sensitivity analysis Triple therapy cost and utility 600K
Without treatment Peginterferon
550K
Peginterferon + Ribavirin
Cost
500K
Peginterferon + Ribavirin + Thymosin
450K
400K
350K
300K 0.45
0.55
0.65
0.75
0.85
Utility Figure 9. Bivariate analysis.
672
Garcı´a-Contreras et al./ Archives of Medical Research 37 (2006) 663–673
Published literature on HCV-associated chronic hepatitis in general takes into consideration responders who are cured and nonresponders or those who experience relapse as if the treatment had not affected the viral load (15,19,33,34); thus, more clinical studies are required that allow us to model these behaviors more precisely. This study shows that triple therapy that includes peginterferon plus ribavirin plus thymosin alpha-1 has the higher incremental cost-utility ratio. Although triple therapy had highest initial costs due to the cost of its components in this analysis, in the long term its cost was $1,034 lower than therapy with peginterferon plus ribavirin, whereas not administering treatment was approximately $20,140 more expensive than therapy with peginterferon plus ribavirin. Figure 4 describes triple therapy as the most cost-effective alternative at the end of the follow-up. This could be interpreted as triple therapy being the best option when used in young people, because its economical advantages will be present after 29 years of follow-up. However, triple therapy starts showing lower cost per unit of success in relationship with others strategies after 21 years of follow-up. The cost of no-treatment option at the end of the followup is high as can be seen in Figure 5. No-treatment option starts showing greater cost in relationship with other strategies after 21 years of follow-up. The results of this study have shown that triple therapy is dominant when it is evaluated at the end of the cohort. Those findings are explained by the overall impact in costs resulting from the lower cost because there are fewer complications during the follow-up and the high cost of triple therapy at the beginning of the study. One limitation of this study was to consider effectiveness in week 48 of treatment. Although the ideal is to consider effectiveness to week 72, we did not have the complete information for all study alternatives that would have allowed us to render a fair comparison. In addition, the effectiveness considered in the triple therapy model assumed that effectiveness was the sum of therapeutic effectiveness with pegylated interferon plus ribavirin plus percentage of patients with failure who had a response; this is due to the fact that there were no studies in which triple therapy was considered as the initial treatment therapy. Due to the weakness of the true effectiveness of triple therapy, we carried out a threshold-type sensitivity analysis to determine at which moment the results changed the direction of the conclusions. Analysis showed that triple therapy effectiveness had to be the same as that of double therapy so that it would turn to be dominated. This implies that only if thymosin alpha-1 added no effect on the peginterferon plus ribavirin therapy would it turn triple therapy into a dominated or losing therapy. In two-way analysis, we found that in the case that triple therapy had lower effectiveness, it would be necessary to decrease the cost by $1,498 for each percentage point of effectiveness in order for it to continue being the dominant
therapy. With regard to costs, the possibility that triple therapy was more expensive was considered; therefore, we carried out one-way analysis in which triple therapy costs were increased. However, this analysis showed that despite an increase in cost to nearly double the amount, this therapy could not be dominated due to its greater effectiveness. Uncertainty concerning the incremental cost-effectiveness ratio was evaluated by determination of bidimensional 95% CI by ellipse method. In 10,000 simulations, 98% of the time triple therapy was dominant and in the remaining 2%, the decision fell within the willingness-to-pay sector. These results confirm and provide robustness to the conclusions obtained in the basal study. For cases in which simulations fell within the willingness-to-pay sector, the acceptability curve showed that the triple alternative was the most cost-effectiveness option independently of willingness to pay. Once again, this lends robustness to the basal study conclusions. To confirm that triple therapy with thymosin alpha-1 was the most cost-effective alternative, we analyzed all therapies employing net health benefits as another outcome option. We recognize that because of expert opinion and other aspects of the methods for this study, the underlying limitations in the evidence base for the clinical effectiveness of triple therapy suggest that considerable uncertainty remains about the cost effectiveness of triple therapy. The costeffectiveness ratio (Figure 5) shows that triple therapy is not the most cost-effective alternative in most of the follow-up. This would suggest that for health care systems, only under specific characteristics of patients triple therapy would be the most cost-effective option. However, it should not be considered as a public policy for general patients. With the previously mentioned results, we can conclude that therapy with peginterferon plus ribavirin plus thymosin alpha-1 was the most cost-effective option. Sensitivity analyses showed that the basal study results are robust.
Acknowledgments This work was performed within the IMSS and was supported in part by Laboratorio Columbia, S.A. de C.V. The opinions presented in this paper are those of the authors and do not represent the opinion of the IMSS.
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