Data collection

Much effort has been made to ensure that valid and local inputs are used in the model and that assumptions are made that raise the robustness of the model. To populate the model with adequate inputs, a literature review has been performed. Foremost, systematic reviews and other models have been consulted. These sources have not only been used for data extraction but also to provide guidance on the design of the model. Clinical experts have been contacted in order to fill gaps where published data were missing. Discussion with these clinical experts also raised the acceptability and consensus around the model.

10.3.1 Prevalence

Prevalence of HCV is the proportion of a population who currently are HCV positive. Since the purpose of this study was to take a population-based approach to the burden of HCV, it has been of utmost importance to obtain population-based data rather than subgroup data. Data from both the French and Romanian population have been extracted from nationwide surveys conducted in 2004 and

between 2006 and 2008, respectively [27, 28]. The published numbers have been adjusted to the age groups used in the model (presented in Table 7) by taking the weighted average.

Table 7 Prevalence by age in France and Romania

16-34 0.22% 1.44%

35-64 1.05% 3.43%

65+ 1.00% 6.48%

Besides the crude prevalence, the distribution of prevalent cases across health states is listed in Table 8. Data from France (diagnosed prevalence) has been provided by the French institute for public health surveillance (INVS). Because of missing data from Romania on the prevalence of hepatitis C stratified by health states, experts have been consulted to provide assumptions on this.

Table 8 Distribution by age group and severity

France

Mild 58.0% 40.0% 25.0%

Moderate 40.0% 42.0% 48.0%

Cirrhosis 1.5% 15.0% 20.0%

Decompensated cirrhosis 0.5% 2.5% 5.8%

HCC 0.0% 0.5% 1.2%

Romania

Mild 45.0% 20.0% 10.0%

Moderate 48.0% 65.8% 80.0%

Cirrhosis 4.8% 10.0% 6.4%

Decompensated cirrhosis 2.0% 3.9% 3.0%

HCC 0.2% 0.3% 0.6%

10.3.2 Incidence

Due to the asymptomatic nature of HCV, data on incidence is scarce and any available data will most likely underestimate the true incidence due to under-detection and under-reporting of this disease.

Other available estimates are inferred by back-tracking from observed prevalent cases.

This study has used statistics from WHO and should be updated when more accurate data becomes available for the two countries.

Table 9 Incidence used in model in France and Romania

France 0.37

Romania 0.4

Age France Romania

16-34 35-64 65+

10.3.3 Disease progression

Data on disease progression has been collected from a National institute for Health and Care Excellence Health Technology Assessment that used various sources to populate their model (Table 10). Individuals enter the model according to prevalence and incidence numbers. There are three ways an individual may exit the model; 1) by spontaneously resolving the infection, 2) responding to treatment or 3) death unrelated to hepatitis C. To account for cases of spontaneously resolved infections, 2% of patients have been assumed to annually leave the cohort [30].

Table 10 Transition probabilities between health states

Health states Transition probability

From To

Mild Moderate 0.025

Moderate Cirrhosis 0.037

Cirrhosis Decompensated cirrhosis 0.039

Cirrhosis HCC 0.014

Decompensated cirrhosis HCC 0.014

Decompensated cirrhosis Liver transplantation 0.020

Decompensated cirrhosis Death 0.013

HCC Death 0.430

HCC Liver transplantation 0.020

Liver transplantation Post transplantation 0.790

Liver transplantation Death 0.210

Post liver transplantation Death 0.057

10.3.4 Demographics

Demographic data were extracted from Eurostat.se. The data includes a census on the population from 2013 as well as five-year interval projections from 2015 to 2040. The data used in the model were obtained by extrapolating the five year projections by a polynomial function.

10.3.5 Utility

Utility of each health state was extracted from Shepherd et al., 2007 [31]. To account for the adverse effects associated with treatment, the utility of patients who undergo treatment was reduced by 0.11 points as reported by Grieve, Roberts [32]. The data used in the model is presented in Table 11.

Table 11 Utility by disease stage

Health state Utility

The age-stratified utility in the French population age was extracted from an international study on self-reported quality of life using the EQ-5D [26]. No data was available from Romania, which is why data from Hungary has been used.

Table 12 Utility in general population by age in France and Romania

Age

16-34 0.923 0.923

35-64 0.871 0.810

65+ 0.780 0.678

10.3.6 Treatment

Within the therapeutic field of HCV, there has been substantial progress during the last two decades and today up to 90% of infected patients may be successfully treated and new treatment options currently under development may further increase rates of SVR [4].

Available estimates used in previous cost effectiveness models of treatment efficacy in genotype 1 hepatitis C have been rendered obsolete due to the development of new drugs (protease inhibitors).

Additional drugs are under investigation and expected to be launched within the next few years. This model, in order to mirror current standard of care, will therefore use efficacy estimates of protease inhibitors. Moreover, the model may also enable the user to set SVR-rates as these are expected to change with the development and launch of new drugs.

Estimates of the rates of SVR were extracted from various clinical trials. Results from each individual study were pooled and SVR-rates (weighted average) were calculated by the authors of this study. In genotype 1, studies on treatment with a protease inhibitor (Boceprevir and Telaprevir) on top of treatment with Peg interferon alpha 2a or 2b and Ribavirin were consulted [33-37]. Three of these studies reported SVR-rate by fibrosis stage [34, 35, 37] and served as estimates of the SVR rate in cirrhotic patients. For genotypes 2-6, only trials with Peg interferon alpha 2a or 2b with Ribavirin as an active arm were consulted [38-44]. Only treatment-naïve subjects were considered. The SVR-rate in patients with cirrhosis and genotype other than 1 were extracted from a cost-effectiveness-study that used data originating from the Trent HCV cohort [45]. The same rate of SVR was used for genotype 2 or 3 and genotype 4, 5 or 6 due to lack of better data.

Table 13 SVR rates with protease inhibitors by genotype and disease stage

Genotype 1 69% 57%

Genotype 2/3 80% 40%

Genotype 4-6 56% 40%

Table 14 SVR rates without protease inhibitors by genotype and disease stage

Genotype 1 44% 22%

Table 15 SVR rates under increase efficacy by genotype and disease stage

Genotype 1 92% 80%

Genotype 2 or 3 97% 83%

Genotype 4, 5, or 6 96% 80%

No data on the distribution of treatment by age and severity was found. A distribution on treatment was assumed giving preference to treatment in cirrhotic and older patients. The distribution assumed in France and Romania are presented in Table 16 and Table 17.

Table 16 Number of annual treatments in France by age and severity

Mild 0 0 0

Moderate 100 3,000 1,000 Cirrhosis 0 4,000 2,000

Table 17 Number of annual treatments in Romania by age and severity

Mild 0 0 0

Moderate 0 0 0

Cirrhosis 500 3500 2000

10.3.7 Distribution of genotypes

The distribution of genotype in France was extracted from published literature [14]. According to clinical experts, almost the entire infected population (>99.99%) in Romania, has genotype 1, which is why this parameter is set at 100% in the model.

Table 18 Distribution of genotype by country

Genotype 1 56% 100%

Genotype 2 or 3 32% 0%

Genotype 4, 5, or 6 12% 0%

10.3.8 Mortality

Mortality data was extracted from WHO life-tables and adjusted to fit the selected age-groups of this study (Table 19).

Mild/Moderate Cirrhosis

16-34 35-64 65+

16-34 35-64 65+

France Romania

Table 19 Annual probability of death unrelated to hepatitis C

Cost data include health care costs, drug costs and indirect cost.

Health care costs refer to the costs associated with the management of the disease and were extracted from two cost effectiveness studies from France and Romania [46, 47]. Health state costs in Romania were adjusted after discussion with clinical experts. All estimates reflect annual costs.

Table 20 Annual health state costs

Mild 85 € 77 €

Moderate 395 € 77 €

Cirrhosis 1,081 € 582 €

Decompensated cirrhosis 11,719 € 930 € Hepatocellular carcinoma 14,550 € 592 €

Liver transplant 75,494 € 56,699 €

Post liver transplant 3,234 € 6,982 €

Drug costs are the costs of the drugs incurred by those that undergo treatment. Drug costs for France were extracted from a recent cost-effectiveness study while drug costs in Romania have been extracted from listed prices [48, 49]. The price of protease inhibitors refers to the average price of boceprevir and telaprevir. The total drug cost of a treatment regime depends on the duration of treatment, which can be adjusted by the user in the model.

Table 21 Weekly drug costs

*The cost of Ribavirin is included in the price of pegylated interferon

Indirect costs are those associated with the potential productivity shortfall that individuals with hepatitis C may suffer due to the disease. For instance, one study found that the productivity of those with HCV infection was 7.5% lower compared with the general population and that the labour force participation was 20% lower than those not infected [50]. In addition, the cost of premature death is accounted for in individuals who would otherwise be in employable age. The loss of production was quantified in terms of earnings as measured by the current average wage in the country.

Data on wages were extracted from Eurostat.

All costs are expressed in 2013 values.

France Romania

France 312 € - € 1,503 €

Romania 203 € 15 € 1,473 €