Drug therapies for chronic hepatitis C infection: a cost-effectiveness analysis
===============================================================================

* William W. L. Wong
* Karen M. Lee
* Sumeet Singh
* George Wells
* Jordan J. Feld
* Murray Krahn

## Abstract

**Background:** Before 2011, pegylated interferon plus ribavirin was the standard therapy for chronic hepatitis C. Interferon-free direct-acting antiviral agents were then approved. Although these treatments appear to be more effective, they are substantially more expensive. In anticipation of the need for information regarding the comparative cost-effectiveness of new regimens in a recent therapeutic review, we conducted the analysis to inform listing decision in Canada.

**Methods:** A state-transition model was developed in the form of a cost-utility analysis. Regimens included in the analysis were comprehensive. The cohort under consideration had a mean age of 50 years. The cohort was defined by treatment status and cirrhosis status. Inputs for the model were derived from published sources and validated by clinical experts.

**Results:** For each genotype 1 population, at least 1 of the interferon-free agents appeared to be economically attractive compared with pegylated interferon-ribavirin, at a willingness-to-pay of $50 000 per quality-adjusted life-year. The drug that was the most cost-effective varied by population. For genotype 2-4 population, the direct-acting antiviral therapies appeared not to be economically attractive compared with pegylated interferon-ribavirin for the treatment-naive; however, there were direct-acting antiviral therapies that appeared to be attractive when compared with no treatment for the treatment-experienced.

**Interpretation:** Public health policy should be informed by consideration of health benefit, social and ethical values, feasibility and cost-effectiveness. Our analysis assists the development of reimbursements and policies for interferon-free direct-acting antiviral agent regimens for chronic hepatitis C infection by informing the last criterion. Considering the rapid development of treatments for chronic hepatitis C, further update and expanded reviews will be necessary.

Before 2011, pegylated interferon plus ribavirin was the standard therapy for chronic hepatitis C. Since then, substantial advances have been made in the treatment of this disease. Treatment success is measured by a sustained virological response, which is defined as undetectable hepatitis C viral RNA 12 to 24 weeks post-treatment (i.e., effectively a virological cure).1-4 In patients with advanced fibrosis or cirrhosis at baseline, a sustained virological response is associated with reduced liver-related and all-cause mortality, in addition to reduced incidence of liver failure and liver cancer.5 Although treatment with pegylated interferon-ribavirin results in sustained virological response in a proportion of patients, the treatment is less than ideal because of its long duration, numerous associated adverse effects and relatively low efficacy.4 In 2011, the first 2 direct-acting antiviral agents, boceprevir and telaprevir, were approved for use in combination with pegylated interferon-ribavirin for patients with genotype 1 chronic hepatitis C infection. More recently, Health Canada has approved Harvoni (an interferon-free combination of ledipasvir and sofosbuvir),6-8 Holkira Pak, a combination of a dasabuvir tablet and an ombitasvir, paritaprevir and ritonavir tablet,9-11 and daclatasvir in combination with sofosbuvir12 for treating chronic hepatitis C infection. Apart from better tolerability without requiring pegylated interferon-ribavirin, potential benefits of some or all of these regimens are shorter treatment durations and higher efficacy in terms of sustained virological response rates.

Regulatory approvals of these newer regimens have given way to discussions of affordability and accessibility, which pose a challenge for public drug programs in Canada, given the prevalence of chronic hepatitis C infection and the high cost of new treatments compared with pegylated interferon-ribavirin regimens. In anticipation of the need and demand for supporting evidence and information regarding the comparative effectiveness of new regimens for chronic hepatitis C infection, the Canadian Agency for Drugs and Technologies in Health (CADTH) has updated its previous Therapeutic Review13 to include recently approved and emerging regimens for the treatment of chronic hepatitis C infection (genotypes 1-6).

In collaboration with CADTH, the objective of this study was to evaluate the cost-effectiveness of treatment regimens for chronic hepatitis C infection (genotypes 1-4).

## Methods

### Study design

We developed a state-transition model of the hepatitis C virus to assess the cost-effectiveness of alternative treatment strategies for patients with chronic monoinfection from hepatitis C virus genotypes 1 through 4 in Canada. Detailed methodology is reported in Appendix 1, available at [www.cmajopen.ca/content/5/1/E97/suppl/DC1.](http://www.cmajopen.ca/content/5/1/E97/suppl/DC1.)

### Cohort

The cohort under consideration had a mean age of 50 years. A broader age range (40-60 yr) was considered in the sensitivity analyses. Cohorts were defined by age, treatment status (naive v. experienced) and cirrhosis status (no cirrhosis v. cirrhosis).

### Strategies

Treatment regimens included in the base-case analysis were those approved in Canada, recommended by major guidelines or considered to have a high likelihood of approval in Canada in the near future. Treatment regimens included: pegylated interferon-ribavirin, boceprevir, telaprevir, simeprevir, sofosbuvir, ledipasvir-sofosbuvir, ombitasvir-paritaprevir-ritonavir and dasabuvir, and daclatasvir-sofosbuvir. Detailed regimens considered for each population are presented in Table 1.

View this table:
[Table 1:](http://www.cmajopen.ca/content/5/1/E97/T1)

Table 1:   Treatment included in the base-case analysis

### Decision model

In our analysis, we developed a cohort-based, state transition model using TreeAge Pro 2014 software.14 In our simulations, cohort members move between predefined health states in weekly cycles until all members die. Health states and allowed transitions among health states are shown in Figure 1.

![Figure 1](http://www.cmajopen.ca/https://www.cmajopen.ca/content/cmajo/5/1/E97/F1.medium.gif)

[Figure 1](http://www.cmajopen.ca/content/5/1/E97/F1)

Figure 1 
State-transition model of hepatitis C virus infection and progression. F0 = no fibrosis, F1 = portal fibrosis without septa, F2 = portal fibrosis with rare septa, F3 = numerous septa without cirrhosis, F4 = cirrhosis, HCC = hepatocellular carcinoma, SVR = sustained virological response.

### Model parameters

Model parameters (Table 2, Table 3 and Appendix 2, available at [www.cmajopen.ca/content/5/1/E97/suppl/DC1](http://www.cmajopen.ca/content/5/1/E97/suppl/DC1)) that included disease progression parameters, transition probabilities to advanced liver disease, mortality, epidemiologic variables and direct medical costs were obtained from the published literature (Appendix 1).5,16-18,20,22-32 All cost data were expressed in Canadian dollars and were inflated to 2015 using the Statistics Canada Consumer Price Index for health care and personal items.33 Treatment efficacy and safety inputs were generated directly from the network meta-analysis model.15 Health states utility data were obtained from the most recent and valid Canadian utility study available, conducted by Hsu and colleagues26 in 2012, using Health Utilities Index Mark 2. The study included 700 patients across different chronic hepatitis C health states.

View this table:
[Table 2:](http://www.cmajopen.ca/content/5/1/E97/T2)

Table 2:  Treatment efficacy (sustained virological response) used in the model

View this table:
[Table 3:](http://www.cmajopen.ca/content/5/1/E97/T3)

Table 3:   Costs, utilities and other important parameters used in the model

### Economic assumptions

The analysis was conducted from the perspective of a provincial Ministry of Health in Canada and was structured as a cost-utility analysis, with outcomes expressed in quality-adjusted life-years and costs. Future costs and health benefits were discounted at 5% annually.34

## Results

### Model validation

In Appendix 3 (available at [www.cmajopen.ca/content/5/1/E97/suppl/DC1](http://www.cmajopen.ca/content/5/1/E97/suppl/DC1)), we compared the predicted outcomes of our model against published studies.20,35,36 These outcomes included: probability of progression to cirrhosis and probability of liver-death. Our model results closely matched the results of the published studies.20,35,36

### Base-case analysis

#### Genotype 1, treatment-naive

Table 4 and Appendix 4 (available at [www.cmajopen.ca/content/5/1/E97/suppl/DC1](http://www.cmajopen.ca/content/5/1/E97/suppl/DC1)) summarize the outcomes associated with the base-case analysis for a cohort of 50-year-old treatment-naive genotype 1 patients without cirrhosis. In this subpopulation, the interferon-free drugs are more costly but more effective than pegylated interferon-ribavirin. Among the interferon-free drugs, paritaprevir-ritonavir plus ombitasvir plus dasabuvir for 12 weeks (PAR/RIT12 + OMB12 + DAS12) was the most cost-effective treatment (incremental cost-utility ratio of $29 354 per quality-adjusted life-year), when compared with pegylated interferon-ribavirin therapy - it was associated with an increase in health (0.996 quality-adjusted life-years) and cost ($29 247) compared with pegylated interferon-ribavirin therapy. Sofosbuvir plus ledipasvir for 12 weeks (SOF12 + LDV12) was the most effective treatment in terms of total quality-adjusted life-years (11.857 quality-adjusted life-years), resulting in an incremental cost utility ratio of $37 951 per quality-adjusted life-year compared with pegylated interferon-ribavirin therapy. For genotype 1, treatment-naive patients with cirrhosis, SOF12 + LDV12 was the most cost-effective treatment (incremental cost utility ratio of $26 261 per quality-adjusted life-year) when compared with pegylated interferon-ribavirin therapy, associated with an increase in health (1.879 quality-adjusted life-years) and cost ($49 344).

View this table:
[Table 4:](http://www.cmajopen.ca/content/5/1/E97/T4)

Table 4:   Base-case cost-effectiveness results

#### Genotype 1, treatment-experienced

For genotype 1, treatment-experienced patients without cirrhosis, paritaprevir-ritonavir plus ombitasvir plus dasabuvir for 12 weeks (PAR/RIT12 + OMB12 + DAS12) was the most cost-effective treatment (incremental cost utility ratio of $15 506 per quality-adjusted life-year) when compared with pegylated interferon-ribavirin therapy, associated with an increase in health (1.586 quality-adjusted life-years) and cost ($24 597). For patients with cirrhosis, response-guided therapy with simeprevir-pegylated interferon-ribavirin (SIM12 PR24-48 response-guided therapy) was likely to be the most cost-effective option, followed by sofosbuvir plus ledipasvir plus ribavirin for 12 weeks (SOF12 + LDV12 + RBV12), compared with pegylated interferon-ribavirin alone (Table 4).

#### Genotype 2

Table 4 also summarizes the outcomes associated with the base-case analysis for a cohort of 50-year-old, treatment-naive, genotype 2 patients without cirrhosis. Sofosbuvir plus ribavirin for 12 weeks (SOF12 + RBV12) was associated with an increase in health (0.217 quality-adjusted life-years) and cost ($44 051), resulting in an incremental cost utility ratio of $203 282 per quality-adjusted life-year compared with pegylated interferon-ribavirin therapy. For genotype 2, treatment-naive patients with cirrhosis, SOF12 + RBV12 was associated with an increase in health (0.797 quality-adjusted life-years) and cost ($46 773), resulting in an incremental cost utility ratio of $58 659 per quality-adjusted life-year compared with pegylated interferon-ribavirin therapy.

For genotype 2, treatment-experienced patients without cirrhosis, SOF12 + RBV12 was associated with an increase in health (2.157 quality-adjusted life-years) and cost ($39 355), resulting in an incremental cost utility ratio of $18 247 per quality-adjusted life-year compared with no treatment. For treatment-experienced patients with cirrhosis, sofosbuvir plus pegylated interferon-ribavirin for 12 weeks (SOF12 + PR12) was associated with an increase in health (3.265 quality-adjusted life-years) and cost ($59 508), resulting in an incremental cost utility ratio of $18 226 per quality-adjusted life-year compared with no treatment.

#### Genotype 3

The outcomes associated with the base-case analysis for a cohort of 50-year-old, genotype 3, treatment-naive patients without cirrhosis are shown in Table 4. Daclatasvir and sofosbuvir for 12 weeks (DCV12 + SOF12) was the most cost-effective regimen of those currently approved, with an incremental cost utility ratio of $97 158 when compared with pegylated interferon-ribavirin. Similarly, for genotype 3 treatment-experienced patients without cirrhosis, DCV12 + SOF12 was associated with an increase in health (2.612 quality-adjusted life-years) and cost ($79 544), resulting in an incremental cost utility ratio of $28 151 per quality-adjusted life-year, compared with no treatment. In patients with cirrhosis, sofosbuvir and ribavirin for 24 weeks (SOF24 + RBV24) was the most cost-effective approved option for both treatment-naïve and treatment-experienced patients.

#### Genotype 4

Sofosbuvir plus pegylated interferon-ribavirin for 12 weeks (SOF12 + PR12) was the only approved treatment for genotype 4 infection, and was associated with an incremental cost utility ratio of $63 421 per quality-adjusted life-year compared with pegylated interferon-ribavirin for treatment-naive patients without cirrhosis (Table 4). For patients who are treatment-naive with cirrhosis or those who are treatment-experienced, SOF24 + RBV24 was considered the most cost-effective treatment; however it is not currently approved. SOF12 + PR12 could not be evaluated in these subgroups owing to lack of data.

### Sensitivity analyses

We performed both 1-way sensitivity analyses and probabilistic sensitivity analyses to explore the impact of the model's parameter uncertainty.

#### Deterministic sensitivity analyses

The effect of varying parameters related to chronic hepatitis C, treatment-related parameters and heterogeneity parameters for the treatment-naive and treatment-experienced populations based on the incremental cost utility ratio of the most cost-effective treatment is shown in Appendix 4. For all the subpopulations assessed, baseline age, treatment efficacy and cost of antiviral therapy were the most sensitive parameters.

To further measure the effect of the estimates of relative risk of treatment efficacy used in the model, the parameters were varied by the 95% credible intervals generated by the network meta-analysis, as indicated in Table 2. In this analysis for genotype 1, treatment-naive, noncirrhosis group, the incremental cost utility ratio varied from $25 988 to $92 392 for the most cost-effective treatment (PAR/RIT12 + OMB12 + DAS12) when compared with pegylated interferon-ribavirin. For the genotype 1, treatment-experienced, cirrhosis group, the incremental cost utility ratio varied from $11 517 to $99 452 for the most cost-effective treatment (SIM12 + PR24-48 RGT) when compared with pegylated interferon-ribavirin, which may not be considered economically attractive. The main conclusions for the other subgroups remained unchanged.

To measure the effect of the cost of antiviral therapies used in the model, these parameters were varied by 25%, as indicated in Table 2. For the genotype 2 and genotype 4 treatment-naive cirrhosis groups, the generated incremental cost utility ratio for the most cost-effective treatments (genotype 2, SOF12 + RBV12; genotype 4, SOF24 + RBV24) may be less than $50 000 when compared with pegylated interferon-ribavirin. The main conclusion for other groups remained unchanged.

To measure the effect of age in the model, instead of the baseline values, a broader age range of 40-60 years was evaluated. Appendix 1 summarizes the results. The cost-effectiveness results changed significantly. For the genotype 2 and genotype 4 treatment-naive cirrhosis groups, the generated incremental cost utility ratio for the most cost-effective treatments (genotype 2, SOF12 + RBV12; genotype 4, SOF24 + RBV24) may be less than $50 000 when compared with pegylated interferon-ribavirin in younger patients. The main conclusion for other groups remained unchanged.

Other parameters were assessed in deterministic sensitivity analysis, including: fibrosis stage distribution; costs related to chronic hepatitis C, utilities, mortality, chronic hepatitis C progression; and different risk for adverse events. Varying these parameters did not significantly change the results of the base-case analysis.

#### Probabilistic sensitivity analyses

The results of the probabilistic sensitivity analysis for genotype 1 chronic hepatitis C infection suggest that, for treatment-naive patients without cirrhosis, PAR/RIT12 + OMB12 + DAS12 is likely to remain cost-effective at a willingness-to pay-threshold of $50 000 per quality-adjusted life-year. For treatment-naive patients with cirrhosis, SOF12 + LDV12 is likely to remain cost-effective. For treatment-experienced patients without cirrhosis, PAR/RIT12 + OMB12 + DAS12 is likely to remain cost-effective. For treatment-experienced patients with cirrhosis, owing to the large degree of uncertainty around the efficacy data derived from the network meta-analysis on genotype 1 treatment-experienced patients with cirrhosis, there is significant uncertainty associated with the incremental cost utility ratios for this population.

Results of the probabilistic sensitivity analysis also suggest that, for each genotype 2, genotype 3 and genotype 4 treatment-naive population (with or without cirrhosis), pegylated interferon-ribavirin alone is the most cost-effective option at a willingness-to-pay of $50 000 per quality-adjusted life-year. For genotype 2 chronic hepatitis C infection, the probabilistic sensitivity analysis suggests that, for treatment-experienced patients without cirrhosis, SOF12 + RBV12 is likely to remain cost-effective. For treatment-experienced patients with cirrhosis, SOF12 + PR12 is likely to remain cost-effective (< $50 000/quality-adjusted life-year). For genotype 3 chronic hepatitis C infection, the analysis suggests that for treatment-experienced patients with or without cirrhosis, SOF12 + PR12 is likely to remain cost-effective (< $50 000/quality-adjusted life-year). For genotype 4 chronic hepatitis C infection, the analysis suggests that for treatment-experienced patients with cirrhosis, SOF24 + RBV24 is likely to remain cost-effective. For treatment-experienced patients without cirrhosis, no conclusion about the most cost-effective option can be reached owing to uncertainty. Appendix 4 summarizes the results through cost-effectiveness acceptability curves.

Results of multiple 1-way sensitivity analyses and multiple probabilistic sensitivity analyses provided evidence that there were some subpopulations in which the direct-acting antiviral agents would likely remain cost-effective compared with pegylated interferon-ribavirin alone when the uncertainty of the model's parameters are taken into consideration.

## Discussion

For each genotype 1 population, at least 1 of the interferon-free therapies appeared to be economically attractive compared with pegylated interferon-ribavirin alone, at a willingness-to-pay of $50 000 per quality-adjusted life-year. The conventional upper limit of applied cost effectiveness thresholds37-39 varies among countries from $50 000 to $120 000 per quality-adjusted life-year. The drug that was the most cost-effective varied by population. For each genotype 2-4 treatment-naive population, the interferon-free or the pegylated interferon-ribavirin-based direct-acting antiviral therapies appeared not to be economically attractive compared with pegylated interferon-ribavirin alone at a willingness-to-pay of $50 000 per quality-adjusted life-year. For each genotype 2-4 treatment-experienced population, there were interferon-free or pegylated interferon-ribavirin-based direct-acting antiviral therapies that appeared to be attractive at a willingness to pay of $50 000 per quality-adjusted life-year when compared with no treatment.

A number of studies reported incremental cost-effectiveness ratios of about Can$40 000 per quality-adjusted life-year for the interferon-free direct-acting antiviral regimens compared with pegylated interferon-ribavirin-based direct-acting antiviral regimens.40-43 Most studies concluded that it is cost-effective to treat genotype 1 with interferon-free direct-acting antiviral agents compared with pegylated interferon-ribavirin-based direct-acting antiviral agents. More recently, additional studies have reported incremental cost-effectiveness for other genotypes.41,42,44-46 Most of the studies concluded that it is not cost-effective to treat genotypes 2-4 with the interferon-free direct-acting antiviral agents at a willingness-to-pay of $50 000 per quality-adjusted life-year.

### Limitations

As with all economic models, a number of assumptions were made in this economic evaluation. First, comparative efficacy and adverse events was based on findings for fibrosis subgroups from a network meta-analysis, which have been stratified by cirrhosis and noncirrhosis. Ideally, the network meta-analysis should have been stratified by individual fibrosis stages. Furthermore, there were very few data available in the literature on the disutility associated with adverse events. The costs related to chronic hepatitis C that we used were not fibrosis-specific; they may overestimate the cost of mild or no fibrosis and underestimate the cost of severe fibrosis. The utilities of patients with chronic hepatitis C who have late-stage liver disease (decompensated cirrhosis and hepatocellular carcinoma) used in the model were based on very small sample sizes and may not cover the full spectrum of the severity of the disease. The pharmacoeconomic analyses do not account for any confidential prices potentially negotiated for therapies. Finally, our analyses do not consider patients with coinfections and subsequent treatment of reinfection.

### Conclusion

Public health policy should be informed by consideration of health benefit, social and ethical values, feasibility and cost-effectiveness. Our analysis assists the development of hepatitis C virus reimbursements and policies for direct-acting antiviral-based regimens for chronic hepatitis C infection by informing the last criterion. We believe that it offers scientifically valid projections mainly based on Canadian data and a network meta-analysis. The CADTH Canadian Drug Expert Committee has issued a recommendation partly based on our findings.47

Considering the rapid pace of development of treatments for chronic hepatitis C, updated and expanded reviews will be necessary. Finally, although shown to be cost-effective, the high cost of direct-acting antiviral agents seriously restricts treatment access in Canada, with further pressure from screening efforts to identify many more patients. To seriously effect the disease, ensure equitable access and help policy-makers meet budgetary challenges, fair and efficient screening and treatment strategies are needed.

### Supplemental information

For reviewer comments and the original submission of this manuscript, please see [www.cmajopen.ca/content/5/1/E97/suppl/DC1](http://www.cmajopen.ca/content/5/1/E97/suppl/DC1)

## Acknowledgements

Acknowledgments: The authors thank L. Chen, S. Hsieh, B. Farah, S. Kelly and A. Ramji for their valuable suggestions and insight.

## Footnotes

*   **Competing interests:** Jordan Feld reports grants and personal fees from Abbvie, Gilead, Janssen and Merck; grants from Abbott and Regulus; and personal fees from Bristol-Myers Squibb. No other competing interests were declared.

*   **Contributors:** William Wong implemented the model, collected and analyzed the data, and drafted the manuscript. Sumeet Singh and Jordan Feld contributed to the interpretation of data. George Wells and his team conducted the network meta-analysis. Karen Lee and Murray Krahn contributed to design of the study, analysis and interpretation of the data. All of authors contributed in revision of the manuscript, approved the final version to be published and agreed to act as guarantors of the results.

*   **Funding:** This study was supported by the Canadian Agency for Drugs and Technologies in Health (CADTH).

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