Journal of Hepatology

May 2005

"……Our study shows that the increase in morbidity and mortality associated with uncomplicated chronic hepatitis C infection is going to increase in the near future without any type of therapeutic intervention, and how this phenomenon will translate into an important increase in the costs of the disease…..

….. 699,823 subjects were estimated to have active HCV disease and 419,895 to have elevated ALT levels and therefore progressive liver disease…..

….. Hepatitis C related mortality will increase in the future while the overall HCV related morbidity will increase until 2011, followed by a slow decrease over the subsequent years due to the small surviving population. Direct mortality related to hepatitis C progression could exceed 90,000 deaths by 2030. Analyzing only the surviving population, the percentage of liver cirrhosis cases will increase by up to 14% and liver related morbidity by 10% (1% for hepatocellular carcinoma and 9% for other complication) in the next 30 years…..

…… The cumulative effects on the public healthcare budget due to HCV-related complications of the population studied are shown in Table 4. It is estimated that cumulative expenditures for chronic hepatitis C progression will reach 2.7 billion € (Euro) by 2030 (1.2 billion by 2010, 2.2 billion by 2020….

…… A reduction of hepatitis C related morbidity (Fig. 2a) and mortality was observed in model projections when treatment was applied, with the reduction being relative to the proportion of patients treated. Treating 10% of the target population would reduced hepatitis C related morbidity from 17,692 to 17,166 cases and treating 25 and 50% would reduce the figures to 16,253 and 14,811 cases, respectively, by 2030. Over this time period, the reduction in mortality would be from 91,000 to 87,500, 82,300 and 73,500 deaths treating 10, 25 and 50% of the cohort…….

Authors: María Butia, Ramón San Miguelb, Max Brosac, Juan M. Cabasésb, Montserrat Medinab, Miguel Angel Casadoe, Leslie Fosbrookd, Rafael Estebana

a Department of Hepatology, Hospital Vall d'Hebrón, Barcelona, Spain

b Department of Economics, Public University of Navarra, Pamplona, Spain

c GOC-Networking, Barcelona, Spain

d Schering-Plough, Madrid, Spain

e Pharmacoeconomics & Outcomes Research Iberia, Madrid, Spain

Chronic Hepatitis C virus (HCV) infection is common and often produces a progressive disease. Some studies suggest that HCV related complications will increase in the future. Our aim was to estimate the future morbidity, mortality and costs of chronic HCV infection in a cohort of patients infected by HCV and to evaluate the impact of HCV therapy.

A mathematical model was used to project over the next 30 years, the HCV related complications and costs in a cohort of 419,895 infected patients representing the HCV infected population in Spain. The impact of HCV therapy with peginterferon and ribavirin in this population was also projected.

A gradual decline in the infected population is expected in the future, however, the proportion of patients with cirrhosis will increase by up to 14% and morbidity associated with HCV infection by up to 10% by the year 2030 with a subsequent increment in HCV related costs.

However, treating from 10 to 50% of the HCV population will result in a reduction of 6 and 26% in morbidity and 4 and 20% in mortality, respectively.

In the future, HCV infection mortality, morbidity and associated costs will increase.

Hepatitis C virus (HCV) infection is a global health problem. Although the prevalence in the European population is estimated as 3%, the real HCV prevalence is still unknown [1]. There are a significant number of undiagnosed cases and it is unknown whether the distribution of the infection is uniform among the estimated 200 million carriers worldwide [2].

The majority of people infected by HCV acquired the infection 10—20 years ago, before the identification of the virus and the availability of HCV tests for screening and diagnosis. Most patients with chronic hepatitis C are asymptomatic until HCV related complications develop [1]. When complications such as decompensated cirrhosis and hepatocellular carcinoma appear, patients require an increased number of clinical visits, drug therapies and diagnostic tests. Hospitalisation and liver transplantation are also often required. These costs are related to the type of HCV complications and have a direct impact on health care resources. Currently, in developed countries, cirrhosis due to HCV infection and hepatocellular carcinoma are the leading causes of liver transplantation, accounting for 30% of all liver transplantations [2,3]. The total number of liver transplantations is limited by the shortage of organs and in the future, if the number of patients requiring transplantation grows, the shortage will become a major problem despite the increasing number of liver related donors.

Considering the high prevalence of HCV infection, the current cost to the National Health Care System of managing HCV infection is relatively low due to the small number of patients receiving HCV therapy and the high number of asymptomatic patients, but it is clear that these costs will rise in the future.

The purpose of this study is to estimate, using a mathematical model, the morbidity, mortality, and costs of chronic hepatitis HCV infection in Spain over the next 30 years and to evaluate the potential impact of HCV therapy on these projections.

A Markov computer simulation was used to model prognosis by following over time a representative cohort of the HCV infected patients for each age group. The Markov model used the software DATA 3.5 (TreeAge software, Williamstown, MA, USA).

The Markov model describes disease progression and determines the long-term morbidity, life expectancy, mortality, and lifetime costs for cohorts of HCV infected subjects. The model (described elsewhere) uses probabilities of progression from chronic hepatitis to cirrhosis, decompensated liver disease and finally death, obtained from data published in the literature, and which has been validated in previous analyses [4—7]. We modified the front end of the model to include patients with normal alanine aminotransferase (ALT) levels and chronic HCV infection, adding the assumption of non-progression of the disease for these patients. Table 1 shows the probabilities of transition between each state [4,6—18]. The model was validated by predicting the 5-year survival rate of a cohort of patients with compensated cirrhosis. Model predictions gave a survival rate in compensated cirrhosis patients of 48%, that was similar to the 50% described by Fattovich et al. [10] and the 55% predicted by Bennett's model [4].

The annual transplantation probability for Spain (www.msc.es/ont) was estimated as Stein et al did for the United Kingdom giving a figure of 2% [13].

The term morbidity was defined as those health states related to decompensated cirrhosis, hepatocellular carcinoma and liver transplantation. Hepatic deaths are considered to be those attributed to liver failure, or liver related complications excluding other common causes of death not related to liver disease. All-cause death rates as described by the Spanish National Institute of Statistics are included in the model (www.ine.es).

The computer model was designed to quantify the expected number of HCV positive patients in various states over time. The study was particularly focused on morbidity because these HCV health states consume the most medical resources in hepatitis C. Once the baseline data had been established using the model, projections were then made to determine the effects of treating a proportion of infected cases.

Spanish population.

The figure of 40 million for the Spanish population was obtained from the National Institute of Statistics. Data on anti-HCV prevalence was obtained from a large study performed in Spain [20]. Anti-HCV prevalence was divided into eight age groups according to the prevalence of anti HCV antibodies in the previously mentioned study.

We assumed that 73% of anti-HCV positive patients had HCV RNA and active disease [21]. Patients who had chronic infection with positive HCV RNA were further assumed to have elevated ALT levels in 60% of cases whereas the remainder would have persistently normal ALT levels. This differentiation is important since progression of the disease is different in these two groups of patients. Patients with elevated ALT levels who have progressive liver disease are treated accordingly, while a conservative scenario is designed for those patients with normal ALT levels. In these patients, no disease progression was considered. As the population under study is the general population, in which many people will never suffer from HCV disease, we have considered a 0.2% rate of spontaneous resolution as in a previous analysis [4,22].

As a result, the cohort of patients chosen to project the consequences of HCV disease was composed of HCV RNA positive patients with elevated ALT levels. This cohort was distributed into the eight age groups described earlier, according to HCV prevalence and then each age group was divided into mild disease, moderate disease and cirrhosis using mathematical estimations based on previously published studies [23,24].

Direct medical care cost estimates were based on actual variable costs for patients with hepatitis C from our previous studies [7,8]. Unit costs for clinical procedures, monitoring tests and hospital admissions, were obtained from a database of health care cost elements in Spain [25]. Only direct health care system costs have been considered in the study in order to view the financial impact from the health care payer viewpoint. Indirect costs such as patient time loss, leisure time loss, and informal care were not included, since the perspective chosen for the estimation of economic consequences of the disease was that of the National Health System which pays only for direct medical costs. Discounting was used to allow for time preference converting future costs (beyond the first year) into present values. A discount rate of 3% was applied to costs and health benefits based on international recommendations.

The following assumptions were considered in the model: (1) patients who achieve a sustained virologic response (SVR) were considered cured, to have no HCV-related complications in the future and therefore to have the same life expectancy as the general population; (2) the study does not include new infections since it is difficult to determine that figures, and their inclusion would not have a major impact until the last years of the study period; (3) the model does not consider the possibility of different prognoses for HCV disease nor the influence of co-factors that result in accelerated progression of the disease such as age, co-infection by hepatitis B or human immunodeficiency virus (HIV), and alcohol consumption. The inclusion of these cofactors, particularly HIV coinfection that represents approximately 10% of the HCV population will increase the morbidity and cost of HCV infection.

One-way sensitivity analysis was performed to test the robustness of the results by changing variables such as the probabilities of illness progression and the discount rate, and to analyse how hypothetical situations would affect morbidity, mortality and cost.

Probabilities of progression.

The probabilities of progression were reduced to the lower rates of progression for HCV published recently. Transition from chronic hepatitis C to liver cirrhosis was reduced by 50%, giving figures of 2% for mild to moderate chronic hepatitis C, 3.6% for moderate hepatitis to cirrhosis and 43% for hepatocellular carcinoma to death [19]. This will be considered in the analysis as the alternative scenario.

Two discount rates were applied to costs: 0 and 5%.

The Markov model was used to estimate the natural history of hepatitis C and also the costs and effects of anti-HCV therapy in the cohort of HCV infected patients. Patients were treated with peginterferon alpha-2b at a dose of 1.5mcg/kg each week and ribavirin at the dose of 800mg/day for 48 weeks in patients with genotype 1 and 24 weeks in patients with genotype 2,3 [26]. Sustained response to therapy was defined as HCV RNA negativity 6 months after discontinuation of treatment and the response rate applied was 54% according to recent studies [26,27].

The proportion of potential patients who would receive therapy is difficult to estimate but some studies suggest that only 30—40% of infected patients would be optimal candidates for treatment [28]. The remaining 70% might have contraindications for HCV drugs, lack of awareness of the disease, or low potential drug benefits. In addition, although treatment is not contraindicated, in patients younger than 18 or older than 65, the sustained virologic response rate is not well documented and treatment is therefore not recommended. Given this uncertainty, several different proportions of infected patients were modeled for evaluating treatment impact. The scenarios analyzed were ‘no treatment’ as the base case, and treatment of 10, 25 and 50% of patients between age 18 and 65, which is also the population usually included in clinical trials.

The model did not consider potential treatment benefits in patients not achieving SVR, because although there are some suggestions supporting a treatment benefit, no long-term evidence is available yet [29].

Additional costs considered in this scenario were drug costs (peginterferon and ribavirin) and treatment monitoring costs. A 3% discount rate was applied to both costs and outcomes.

The total population of Spain, the age distribution, the total number of anti-HCV and HCV RNA cases, those with elevated ALT and the distribution of liver lesions are shown in Table 2. Overall, 699,823 subjects were estimated to have active HCV disease and 419,895 to have elevated ALT levels and therefore progressive liver disease. These figures were used in the model.

The expected burden of hepatitis C infection for the base case and for the alternative scenario is shown in Table 3. Hepatitis C related mortality will increase in the future while the overall HCV related morbidity will increase until 2011, followed by a slow decrease over the subsequent years due to the small surviving population. Direct mortality related to hepatitis C progression could exceed 90,000 deaths by 2030. Analyzing only the surviving population, the percentage of liver cirrhosis cases will increase by up to 14% and liver related morbidity by 10% (1% for hepatocellular carcinoma and 9% for other complication) in the next 30 years (Fig. 1).

The cumulative effects on the public healthcare budget due to HCV-related complications of the population studied are shown in Table 4. It is estimated that cumulative expenditures for chronic hepatitis C progression will reach 2.7 billion € by 2030; 1.2 billion euro by 2010 & 2.2 billion euro by 2020.

Variations of major assumptions were examined to assess their impact on the simulation process. An alternative scenario was projected assuming a slower HCV progression rate, without significant impact on HCV related costs and outcomes (Table 3). The reduction in cumulative costs would be 9% by year 2020 and 13% by 2030.

An important impact on costs was observed with different discount rates, whereby higher discount rates (e.g. 5%) lead to a decrease in future costs (Table 4).

The effect of treating different proportions of patients with chronic hepatitis C was examined. Among the 419,898 patients with positive HCV RNA and high ALT levels included in the model, there were 264,337 subjects between 25 and 64 years old who were primary candidates for HCV therapy. Three different therapeutic scenarios were projected, treating 10, 25 and 50% of these eligible patients, i.e. 26,434, 66,084 and 132,168 patients, respectively.

A reduction of hepatitis C related morbidity (Fig. 2a) and mortality (Fig. 2b) was observed in model projections when treatment was applied, with the reduction being relative to the proportion of patients treated. Treating 10% of the target population would reduced hepatitis C related morbidity from 17,692 to 17,166 cases and treating 25 and 50% would reduce the figures to 16,253 and 14,811 cases, respectively, by 2030. Over this time period, the reduction in mortality would be from 91,000 to 87,500, 82,300 and 73,500 deaths treating 10, 25 and 50% of the cohort.

Our study shows that the increase in morbidity and mortality associated with uncomplicated chronic hepatitis C infection is going to increase in the near future without any type of therapeutic intervention, and how this phenomenon will translate into an important increase in the costs of the disease. The large pool of patients with chronic hepatitis C and progressive liver disease will require bigger Health Care System budgets. The projected HCV disease scenario used in this study is quite conservative. Only patients with elevated ALT levels and positive HCV RNA were considered to have progressive disease and new cases of HCV disease were excluded. Co-factors that can accelerate the progression of the disease such as gender, age at the time of infection, IV drug use, co-infection by hepatitis B or human immunodeficiency virus (HIV), active hepatic inflammation and alcohol consumption were not considered. Although some studies suggest a decrease in the incidence and prevalence of HCV infection as a result of the application of better prophylactic measures over the next few years, this will not translate into a disappearance of the disease. On the contrary, HCV related complications will continue to rise, since it may take two or more decades for a chronic hepatitis to turn into serious liver disease. Thus, the number of patients with liver cirrhosis due to HCV infection may increase by 14% in the next three decades. As the model does not represent the real scenario for HCV infection in our country because only a specific cohort of uncomplicated chronic hepatitis C is modeled. Other forms of HCV infection such as patients with HIV and HCV coinfection, decompensated cirrhosis or hepatocellular carcinoma are not included in the initial cohort of this model. With the inclusion of all forms of disease caused by HCV, the outcomes would have been worse and would translate into a higher morbidity and mortality rates.

Efforts to reduce morbidity resulting from liver disease should be a Health Care priority in the immediate future.

Similar results were obtained in studies that projected the consequences and costs of HCV disease in other countries such as France, Canada and the United States [23,30—33]. However, none of these studies can be directly compared to ours because they made different assumptions, and some did not analyze costs, presented the results differently, and some otherwise accumulated mortality than others employed cross-sectional analysis. Although studies showed an increase in HCV related morbidity and mortality and suggest that HCV may lead to a substantial health and economic burden in the future [30,33]. In addition to the high costs incurred, interventions such as liver transplant have some limitations, the most important of which is the shortage of donor organs and this will significantly decrease the number of liver transplantations.

Treatment for chronic hepatitis C has improved considerably in the past decade. The current standard of care is the combination of pegylated interferon alpha and ribavirin. A sustained virologic response (SVR), defined as an absence of circulating virus 6 months after stopping therapy, was achieved in approximately 54% of treated patients. The SVR rate was close to 80% in favourable genotypes (2 and 3) and approximately 45% in unfavourable genotypes (1 and 4). However, in the majority of western countries, genotype 1 is the most prevalent type and patients have less than a 50% chance of achieving a SVR. In addition, both pegylated interferon and ribavirin are associated with substantial adverse effects and high costs.

A number of different studies have shown that therapy costs for chronic hepatitis C with peginterferon alpha and ribavirin are below the limit of well-accepted medical interventions, particularly for younger patients [7,34]. Our study shows that, even treating a low proportion of the HCV infected population, treatment is capable of reducing the morbidity and mortality from HCV and should be considered a cost-effective intervention. Sensitivity analyses confirmed that the results derived from the model are robust.

One of the limitations of applying cost-effectiveness studies to a large proportion of the target population is that all of the patients are considered to be treated during the first year. Although unrealistic, this conservative scenario is the most appropriate way of estimating the cost-effectiveness ratio, and the impact of HCV therapy on the infected population. Another limitation is that the ribavirin was used at a dose of 800mg/day for 48 weeks and in clinical practice, higher dose are being used. Thus, better dosing of therapy such as weight-adjusted therapeutic regimens when appropriate and sustained adherence to therapy are two important factors which will lead to an increase in SVR, and thus would improve the cost-effectiveness ratio [35]. If these strategies are complemented with good patient selection (not treating patients who are unable to adhere to treatment regimens, or those who are expected to receive a low benefit) and applying stopping rules for non-responders, treatment outcomes and cost-effectiveness ratios would improve [34].

Two points have to be mentioned in relation to the cost-effectiveness ratios observed in this study. Firstly, the correlation between the cost-effectiveness ratio and the patients age at the time of starting therapy, which had been seen in previous studies [7,8], showing that therapy for younger infected patients is more cost-effective than for older patients is now not so clear and it does not appear until middle age (49 years) is reached. The reason for this discrepancy might be the introduction in the current analysis of an age-specific distribution of the HCV infection rate, with lower infection rates in younger patients. This variable was not used in previous studies, in which constant infection rates were assumed. Secondly, the cost per year of life gained in this study is within the range of that considered acceptable for medical intervention in Western countries [36].

From the Health Care System decision making perspective, the high cost of treating 50% of the infected population is partially compensated by the cost savings from the lower future number of HCV related complications avoided by successful treatments.

In conclusion, this study shows a future increase in HCV related morbidity and mortality even without counting new cases of HCV infection. This increase in the consequences of chronic HCV infection will be associated with higher costs for the Health Care System. The implementation of therapy for chronic hepatitis C in this population can modify the HCV scenario increasing patient survival, decreasing morbidity and mortality and reducing the need for liver transplantation, all of which will help to contain Health Care Costs associated with HCV disease.

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