Cost-effectiveness of daclatasvir plus sofosbuvir-based regimen for treatment of hepatitis C virus genotype 3 infection in Canada

Abstract

Objective:

New regimens for the treatment of chronic hepatitis C virus (HCV) genotype 3 have demonstrated substantial improvement in sustained virologic response (SVR) compared with existing therapies, but are considerably more expensive. The objective of this study was to evaluate the cost-effectiveness of two novel all-oral, interferon-free regimens for the treatment of patients with HCV genotype 3: daclatasvir plus sofosbuvir (DCV + SOF) and sofosbuvir plus ribavirin (SOF + RBV), from a Canadian health-system perspective.

Methods:

A decision analytic Markov model was developed to compare the effect of various treatment strategies on the natural history of the disease and their associated costs in treatment-naïve and treatment-experienced patients. Patients were initially distributed across fibrosis stages F0–F4, and may incur disease progression through fibrosis stages and on to end-stage liver disease complications and death; or may achieve SVR. Clinical efficacy, health-related quality-of-life, costs, and transition probabilities were based on published literature. Probabilistic sensitivity analysis was performed to assess parameter uncertainty associated with the analysis.

Results:

In treatment-naive patients, the expected quality-adjusted life years (QALYs) for interferon-free regimens were higher for DCV + SOF (12.37) and SOF + RBV (12.48) compared to that of pINF + RBV (11.71) over a lifetime horizon, applying their clinical trial treatment durations. The expected costs were higher for DCV + SOF ($170,371) and SOF + RBV ($194,776) vs pINF + RBV regimen ($90,905). Compared to pINF + RBV, the incremental cost-effectiveness ratios (ICER) were $120,671 and $135,398 per QALYs for DCV + SOF and SOF + RBV, respectively. In treatment-experienced patients, DCV + SOF regimen dominated the SOF + RBV regimen. Probabilistic sensitivity analysis indicated a 100% probability that a DCV + SOF regimen was cost saving in treatment-experienced patients.

Conclusion:

Daclatasvir plus sofosbuvir is a safe and effective option for the treatment of chronic HCV genotype 3 patients. This regimen could be considered a cost-effective option following a first-line treatment of peg-interferon/ribavirin treatment experienced patients with HCV genotype-3 infection.

Keywords::

• Cost-effectiveness
• Daclatasvir
• Sofosbuvir
• Chronic hepatitis C
• Genotype 3
• Canada
• Pegylated interferon

Introduction

The hepatitis C virus (HCV) represents a major public health concern with substantial clinical, economic, and humanistic burden. The Public Health Agency of Canada (PHAC) estimated that 220, 000 people were infected with HCV living in Canada in 2011, and, in 2012, 10,180 new cases of acute or chronic HCV infection were reported1. The acute HCV infection is often asymptomatic (60–75%)2, and at least 21% of HCV-infected patients remain undiagnosed3. Up to 25% of acute infected patients recover within 6 months, but 75–85% become chronically infected1. Of greater concern is that up to 5–20% of individuals with chronic hepatitis C develop cirrhosis after 20–30 years of infection4. Decompensated liver cirrhosis often manifests with ascites, esophageal bleeding, and/or encephalopathy5. When cirrhosis develops, the risk of hepatocellular carcinoma is estimated at 3–4% annually6. Both hepatocellular carcinoma and decompensated liver cirrhosis make chronic hepatitis a leading indication for liver transplantation6.

Early stages of chronic hepatitis C have a modest impact on the quality-of-life7. On the other hand, advanced stages of the disease can have significant negative effects on the quality-of-life and overall survival. HCV infection is compared to a ‘silent epidemic’, with estimated number of deaths surpassing that for human immunodeficiency virus (HIV)8. In Canada, PHAC projects an increase by 20–80% of the burden of illness related to HCV-related end-stage liver disease hepatocellular carcinoma (HCC), liver transplantation and deaths between 1997–20279. Despite the high prevalence of the disease, until 2013, the population of chronic hepatitis C (CHC) patients undergoing treatment in Canada every year remained small (less than 2%)10, mainly due to the limited resources needed to provide for the necessary healthcare for these patients.

The ultimate goal of treatment remains the prevention of complications and death from HCV infections. Because of the slow progression of chronic HCV infections, short-term virological end-points are used as surrogate markers for treatment response instead of clinical end-points11. Sustained virological response (SVR) is considered a marker for cure and defined as the absence of HCV RNA from serum 24 weeks following discontinuation of therapy12. More recently, earlier assessment of serum HCV RNA at 12 weeks (i.e., SVR12) after treatment has been deemed a reliable indicator and predictor of virological success at week 241 2, given the concordance with SVR 24 is 99%12–15.

HCV consists of seven major genotypes (GT) (i.e., GT 1–7), with GT 1 and 3 accounting for more than 80% of all genotypes in Canada16–18. Treatment with pegilated interferon alfa 2a or 2b plus ribavirin (pINF + RBV) regimen has been a standard of care up until 2012 when protease inhibitors were added to pINF + RBV for HCV GT-1 infected patients. However, for GT-3, pINF + RBV has remained the only treatment option achieving the SVR24 rates between 60–70%. For patients who received previous treatment for GT-3 (treatment-experienced) and did not achieve SVR, there were very limited treatment options. In 2013, a sofosbuvir and ribavirin (SOF + RBV) regimen was introduced for HCV GT 2 or 3 infected patients in Canada. However, there remains considerable unmet need for improved therapies for this patient population.

GT-3 is the second most prevalent GT and is associated with an increased likelihood of developing hepatic complications, from steatosis to HCC19. Patients with GT-3 tend to have lower response rates than patients with other HCV genotypes. GT-3 patients show faster progression of fibrosis and liver disease and are likely to have hepatosteatosis (fatty liver), which is thought to contribute to the accelerated disease progression and low SVR rates20. Therefore, there is a need for safe and effective HCV therapies that can be given for shorter treatment durations to both treatment-naive and treatment-experienced GT-3 patients, including those with compensated cirrhosis20.

Modeling chronic hepatitis C in Canada

Several authors have modeled CHC in Canada through different interventions. Early models by Krahn et al.21 evaluated disease progression, and the cost-effectiveness of a hypothetical vaccine22 for HCV infection. El Saadany et al.23 estimated the economic burden of hepatitis C in Canada and the potential impact of prevention. Remis24 estimated population dynamics of CHC in Canada, but did not evaluate any treatment. Werb et al.25 evaluated treating HCV infection in patients who inject drugs. Dryden et al.26 evaluated granulocyte-colony stimulating factor for antiviral-associated neutropenia. Murphy et al.27 compared new direct acting antiviral drugs in HCV GT-1 infected treatment-naive and treatment-experienced patients. For other viral genotypes, only one study conducted by Brady et al.28 evaluated pINF + RBV treatment. No studies are available on the cost-effectiveness of current treatment options in Canadian HCV GT-3 infected patients (either treatment-naive or treatment-experienced).

Daclatasvir is a new direct-acting antiviral agent against HCV that is available in Canada. It has a pan-genotypic activity and is a highly selective inhibitor of the HCV non-structural protein 5A (NS5A) replication complex that demonstrates with high antiviral activity29–31. Currently in Canada, daclatasvir is indicated in treatment naive or treatment-experienced adults with HCV GT 1, 2 or 3 with compensated liver disease (including cirrhosis) in combination with sofosbuvir32. With shorter durations of treatment and better safety profiles for new drugs to treat HCV infection across all genotypes16^,17, physicians may increase the volume of patients treated in their clinical practice as less resources are required to administer and monitor these new therapies. The high cost of current antiviral therapies, increased awareness and public pressure may lead to an increased number of patients treated every year. This expansion could lead to significant budgetary considerations for payers in Canada. The current analysis addresses the cost-effectiveness of the new treatment regimens for a high unmet need population; HCV GT-3 infected patients (both treatment-naive and treatment-experienced) from the Canadian healthcare system perspective.

Objective

The objective of this study was to assess the cost-effectiveness of a daclatasvir plus sofosbuvir-based regimen (DCV + SOF) compared to existing standard of care treatment options for treatment-naive and treatment-experienced chronic hepatitis C patients infected with HCV GT-3 in Canada.

Methods

A decision analytic Markov model was developed to evaluate the cost-effectiveness of treatment strategies. Transition of patients through the various health states represents disease progression. The costs associated with being in the state as well as the quality-of-life (health-related utilities) were estimated over the lifetime of patients infected with HCV GT-3 from the Ministry of Health perspective in Canada. The following treatment options were considered in the model. In treatment-naive CHC GT-3 patients, all approved regimens in Canada were considered (i.e., DCV + SOF, SOF + RBV, pINF + RBV). In treatment-experienced patients (patients not responding, partially responding to, or relapsing after the previous pINF + RBV treatment), only two options (DCV + SOF and SOF + RBV) were considered since re-treatment with pINF + RBV offered a very low response rate and was not considered in current clinical guidelines (Table 1)33–37.

Table 1. Treatment comparators evaluated in the current model.

Previous treatment history	Intervention	Comparator
Treatment-naive	DCV + SOF 12-week regimen	pINF + RBV 24-week regimen SOF + RBV 24-week regimen
Treatment-experienced	DCV + SOF 12-week regimen	SOF + RBV 24-week regimen

DCV, daclatasvir; pINF, peg-interferon; RBV, ribavirin; SOF, sofosbuvir.

Modeling approach

The type of economic evaluation conducted is a cost-utility analysis. It evaluates the progression of liver fibrosis in patients infected with HCV. The model structure replicates the natural history of hepatitis C and its complications via a cohort-based Markov lifetime simulation. As shown in Figure 1, the model includes the following health states: chronic hepatitis C stages from F0–F4; decompensated cirrhosis (DC); hepatocellular carcinoma (HCC); liver transplant (LTx); death; and states of sustained virological response.

Figure 1. Model structure for estimated cost and effects of treating patients with chronic HCV infection. Rectangular area created with dashed lines represents disease states of chronic hepatitis C by the level of liver fibrosis.

The model was run in annual cycles over a variable time horizon (0 to lifetime) with the base case of a lifetime. The starting age of a population was assumed at 50 years, as in Murphy et al.27.

The model used transitional probabilities and therapy-related SVR rates. Transition probabilities were based on the data set from Murphy et al.27, with the exception of a ‘DC to HCC’ state transition. The latter was assumed to be equivalent to a transitional probability ‘F4 to HCC’. The other sources of transitional probabilities22^,38^,39 were evaluated in a sensitivity analysis. The transition matrix was updated every cycle to accommodate the age-depended likelihood of all-cause mortality. The all-cause mortality was only applied to patients achieving SVR and patients remaining in health states of liver fibrosis F0–F4. The probability of all-cause mortality was based on Canadian-specific life tables differentiated for males and females40. Individuals achieving SVR were assumed to have the same life expectancy as the general population.

The distribution of patients by fibrosis level was defined separately for treatment-naïve and treatment-experienced CHC patients and was based on values reported by Murphy et al.27, which were similar to Myers et al.41 and Marotta et al.42. Distribution of patients by fibrosis stage and all other model inputs are summarized in Table 2.

Table 2. Base case model parameters.

Parameters	Values
Transitional probabilities	Mean (SD)
F0 to F1	0.117 (0.006)	Murphy et al.27
F1 to F2	0.085 (0.006)	Murphy et al.27
F2 to F3	0.120 (0.006)	Murphy et al.27
F3 to F4	0.116 (0.006)	Murphy et al.27
F3 to DC, F3 to HCC	0.000 (0)	Murphy et al.27
F4 to DC	0.035 (0.004	Murphy et al.27
F4 to HCC	0.024 (0.004)	Murphy et al.27
F4 to LTx	0.000 (0)	Assumption
DC to HCC	0.024 (0.004)	Assumption (same as F4 –>HCC)
DC to LTx	0.030 (0.012)	Martin et al.38
DC to Death (yr 1), DC to Death (yr 2+)	0.216 (0.027)	Murphy et al.27
HCC to LTx	0.030 (0.012)	Martin et al.38
HCC to Death (yr 2+)	0.411 (0.051)	Murphy et al.27
LTx (Yr 1) to Death	0.142 (0.009)	Murphy et al.27
LTx (Yr 2+) to Death	0.034 (0.005)	Murphy et al.27
F4–>DC relapse	0.002 (0.0015)	Murphy et al.27
F4–>HCC relapse	0.005 (0.002)	Murphy et al.27
Population
– Starting age of the population	50 years old	Murphy et al.27
– Gender distribution (male/female)	50%/50%	Assumption
– Liver fibrosis
F0	8% (1.0%)	Murphy et al.27
F1	20% (2.5%)	Murphy et al.27
F2	35% (4.4%)	Murphy et al.27
F3	21% (2.6%)	Murphy et al.27
F4	17% (2.1%)	Murphy et al.27
– Liver fibrosis: treatment-experienced patients
F0	4% (0.5%)	Murphy et al.27
F1	12% (1.6%)	Murphy et al.27
F2	37% (4.8%)	Murphy et al.27
F3	22% (2.9%)	Murphy et al.27
F4	25% (3.3%)	Murphy et al.27
Efficacy	SVR % (SD)
Treatment-naive
– pINF + RBV 24-week	66.5% (2.1%)	Swallow et al.45
– DCV + SOF 12-week	90.3% (3.0%)	Nelson et al.43
– SOF + RBV 24-week	94.3% (2.3%)	Zeuzem et al.44
Treatment-experienced
– DCV + SOF 12-week	86.3% (4.8%)	Nelson et al.43
– SOF + RBV 24-week	78.6% (3.4%)	Zeuzem et al.44
Safety	Mean % (SD)
– pINF + RBV
Anemia, Rash	0 (0)	Swallow et al.45
Discontinuation	4.3% (0.9%)	Swallow et al.45
– DCV + SOF
Anemia, Rash	0 (0)	Nelson et al.43
Discontinuation	0.4% (0.4%)	Nelson et al.43
– SOF + RBV
Anemia	2.6% (1.3)	Zeuzem et al.44
Rash	0.7% (0.7)	Zeuzem et al.44
Discontinuation	0 (0)	Zeuzem et al.44
Cost	Mean $ (SD)
Health state
SVR - F0- F4; Chronic Hepatitis C F0–F4	4562 (46)	Krajden et al.49
Decompensated Cirrhosis, Hepatocellular Carcinoma	14,511 (605)	Krajden et al.49
Liver Transplantation (initial year)	119,884 (16000)	Murphy et al.27
Liver Transplantation (subsequent years)	19,286 (2424)	Murphy et al.27
Cost of treatment
DCV (1 week)	3000 (0)	BMS Canada
SOF (1 week)	4583.33 (0)	Liste des médicaments50
RBV (1 week)*	253.75 (0)	Liste des médicaments50
pINF + RBV (1 week)†	395.84 (0)	Liste des médicaments50
Cost of adverse events
Anemia (1 week)‡	233.31 (46.66)	Lachaine et al.51
Rash (1 week)‡	1.77 (0.35)	Lachaine et al.51
Utilities	Mean (SD)
Health state (values 0–1)
SVR - F0 - F3	0.80 (0.02)	Murphy et al.27
SVR - F4	0.76 (0.02)	Murphy et al.27
Chronic Hepatitis C F0-F4	0.73 (0.10)	Murphy et al.27
Chronic Hepatitis C (F4 State)	0.69 (0.10)	Murphy et al.27
Decompensated Cirrhosis	0.65 (0.17)	Murphy et al.27
Hepatocellular Carcinoma	0.72 (0.25)	Murphy et al.27
Liver Transplantation	0.75 (0.07)	Murphy et al.27
Adverse events (utility decrements)
Anemia	0.03 (0.02)	Sullivan and Ghushchyan47; Del Rio et al.48
Rash	0.02 (0.02)

*The average daily dose of ribavirin was assumed to be 1000 mg.

†The average weekly cost of pINF + RBV was estimated from the weekly cost of peg-interferon alfa-2a plus ribavirin kit (Pegasys RBV) as the latter was the most frequently used product between various pINF + RBV kits in the province of Ontario in 2013–2014.

‡The weekly cost of adverse events was assumed from the average cost per case of adverse event reported by Lachaine et al.51 divided by 48, where 48 was the maximum duration of interferon based regimens across all viral genotypes50.

The costs were estimated from a Ministry of Health perspective. The following costs were considered in the model: cost of managing early stages of CHC patients in Canada; cost of anti-HCV therapy; cost of managing adverse events due to anti-HCV therapy; and cost of treating late stages of chronic hepatitis such as decompensated cirrhosis and hepatocellular carcinoma, including liver transplantation and post-transplant care.

Source of efficacy outcomes

Efficacy, expressed as SVR, was translated through transition probability as follows. Patients who achieved SVR were transitioned to recovered health state stratified by fibrosis severity. If treatment were not successful, the individual continued progressing through the natural history of HCV infection. The efficacy outcomes for available treatment options for CHC patients infected with HCV GT-3 came from three sources: the ALLY-3 clinical trial for a 12-week DCV + SOF regimen43; the VALENCE clinical trial for a 24-week SOF + RBV regimen44; and published indirect treatment comparison for a 24-week pINF + RBV regimen45. ALLY-3 and VALENCE were the most recent Phase 3 clinical trials and were considered for the approval of SOF + DCV and SOF + RBV indications in CHC GT-3 in Canada, respectively. These studies did not include a common comparator (i.e., pINF + RBV, a standard of care in CHC GT-3); however, they included patients with similar baseline characteristics. The model implemented only naive indirect treatment comparison because a traditional indirect treatment comparison between those regimens and/or pINF + RBV standard of care was not possible. The efficacy of the pINF + RBV regimen in CHC GT-3 was obtained from the meta-analysis by Swallow et al.45.

Utilities

The model assumed health utilities for viral clearance, CHC, liver transplantation, and hepatocellular carcinoma states from Hsu et al.7 and health utility for decompensated cirrhosis from McLernon et al.46 in a similar fashion to Murphy et al.27. Disutility of adverse events was estimated from the general population experiencing similar symptoms, as appeared in Sullivan and Ghushchyan47 and Del Rio et al.48. The current model did not use disutility of treatment to avoid double counting disutility of adverse events.

Cost

The cost of treating early and late stages of CHC was specified on an annual basis using data from Krajden et al.49. The cost of liver transplantation was also assumed from Murphy et al.27. When patients cleared their infection and transitioned to an SVR state, the model assumed that resource utilization was independent from viral RNA load, and a sero-positive patient with liver fibrosis F0–F4 who had achieved a sustained virological response status would use similar healthcare resources to a compensated CHC patient who had not achieved a sustained virological response status.

The cost of drugs came from the Liste des médicaments (RAMQ)50 and did not include wholesaler markup and dispensing fee. Administration cost for peg-interferon alfa 2a/2b was not considered as self-injection was foreseeable. The cost of antiviral treatment was linked to the duration of a regimen. If a patient discontinued treatment, the cost of therapy and the cost of associated adverse events were lower. When a patient discontinued therapy due to other reasons (i.e., side-effects), the model assumed that the particular patient had not achieved an SVR health state. The cost of adverse events (anemia and rash) was based on the estimated frequency of resources used from Lachaine et al.51 and was based on Quebec administrative healthcare data. A 5% discount was used for both costs and utilities in future years in line with Canadian guidelines52.

Validation of the model

The current model was presented in three peer-reviewed publications39^,53–55. Canadian adaptation of the model was additionally validated by comparing the predicted disease state-specific incidence rates and cost-effectiveness ratios to several published sources. The starting age of the model population (liver fibrosis stage F0) was set at 40, 60, and 67 years, and the model was run for 20 and 30 years and lifetime horizon. The cumulative probabilities of developing liver cirrhosis and/or liver death were similar to historical progression estimates by Salomon et al.56; Krahn et al.21; and Murphy et al.27. The validation was also repeated for a population of compensated cirrhosis patients (liver fibrosis stage F4) with model horizon of 10 and 20 years. The cumulative probabilities of developing liver failure, HCC, and liver-related mortality were similar to historical estimates from van der Meer et al.57.

Analysis

The base case analysis of the model assumed the treatment-naive population of CHC GT-3 was treated by either pINF + RBV 24-week, SOF + RBV 24-week, or DCV + SOF 12-week regimen and was followed over the lifetime. Incremental cost-utility ratio was calculated by dividing the difference in cost and the difference in utilities. The reference treatment option was the least expensive and the least efficacious one. Deterministic sensitivity analyses were conducted using alternative values of model parameters like age, discounting factor for costs and utilities, the cost of CHC management (excluding antiviral medication cost), transition rates, health utilities, and cost of managing adverse events. For the probabilistic sensitivity analysis, the model was run for 1000 iterations. The draw of random values was done using a beta distribution for transition probabilities and utilities and a gamma distribution for costs.

Results

The main cost-effectiveness results are presented in Table 3. It was found that, over a lifetime horizon, the expected LYs and QALYs were higher for treatment-naive chronic hepatitis C patients receiving treatment with either a DCV + SOF 12-week or SOF + RBV 24-week regimen compared to a pINF + RBV 24-week regimen. Patients on a DCV + SOF 12-week regimen were also predicted to accrue lower costs than patients on a SOF + RBV 24-week regimen, for both treatment-naive and treatment-experienced patients. Based on the probabilistic sensitivity analysis, newer treatment regimens (DCV + SOF 12-week and SOF + RBV 24-week) would be considered cost-effective in treatment-naive patients infected with HCV genotype 3 if society were willing to pay over $100,000 per QALY (Figure 2). When only two regimens were compared, in treatment-naive patients a SOF + RBV 24-week regimen was more effective but more costly than a DCV + SOF 12-week regimen (Figure 3). In treatment-experienced patients, a DCV + SOF 12-week regimen dominated a SOF + RBV 24-week regimen in patients infected with HCV genotype 3 (Figure 4).

Figure 2. Cost-effectiveness acceptability curve for treatment-naive chronic hepatitis C patients infected with HCV genotype 3. DCV, daclatasvir; pINF, peg-interferon alfa; QALY, quality-adjusted life years; RBV, ribavirin; SOF, sofosbuvir.

Figure 3. Cost-effectiveness plane for the treatment-naive chronic hepatitis C patients infected with HCV genotype 3. DCV, daclatasvir; pINF, peg-interferon alfa; QALY, quality-adjusted life years; RBV, ribavirin; SOF, sofosbuvir.

Figure 4. Cost-effectiveness plane for the treatment-experienced chronic hepatitis C patients infected with HCV genotype 3. DCV, daclatasvir; QALY, quality-adjusted life years; RBV, ribavirin; SOF, sofosbuvir.

Table 3. Treatment-naive and treatment-experienced HCV G3 infected patients.

Treatment	Cost ($)	LY	QALY	ΔCost ($)	ΔLY	ΔQALY	ICER ($/LY)	ICER ($/QALY)
Treatment naïve
pINF + RBV 24-week	90,904.77	15.23	11.71	Ref.	Ref.	Ref.	Ref.	Ref.
DCV + SOF 12-week	170,370.64	15.73	12.37	79,465.86	0.5	0.66	159,290	120,671
SOF + RBV 24-week	194,776.41	15.82	12.48	103,871.64	0.59	0.77	176,755	135,398
Treatment-experienced
DCV + SOF 12-week	170,574.97	15.52	12.11	−25,862.10	0.19	0.24	Dominates	Dominates
SOF + RBV 24-week	196,437.07	15.33	11.87	Ref.	Ref.	Ref.	Ref.	Ref.

DCV, daclatasvir; ICER, incremental cost-effectiveness ratio; LY, life years; pINF, peg-interferon; QALY quality-adjusted life years; RBV, ribavirin; Ref., reference; SOF, sofosbuvir.

The cost and utility values from the deterministic sensitivity analysis are shown in Table 4 for treatment-naive patients and in Table 5 for treatment-experienced patients. The range of ICER values for each pair-wise comparison is presented in Table 6. In one-way sensitivity analyses, changes in key model parameters did not change the conclusions of the base case. Using Chong et al.58 for health utilities input increased the ICER, and utilities from Martin et al.38 decreased the ICER. Using transitional probabilities from McEwan et al.39 increased the ICER, whereas transitional probabilities from Krahn et al.22 decreased the ICER. Changing the model time horizon from 50 to 20 years increased the ICER the most. Changing discount rate from 5% to 0% decreased the ICER and contributed to the lowest ICER values in Table 6.

Table 4. Sensitivity analysis for treatment-naive patients.

Parameter	pINF + RBV 24-week			SOF + RBV 24-week			DCV + SOF 12-week
	Cost ($)	LY	QALY	Cost ($)	LY	QALY	Cost ($)	LY	QALY
Base case	90,904.77	15.23	11.71	194,776.41	15.82	12.48	170,370.64	15.73	12.37
Model horizon
– 20 years	74,047.68	12.23	9.39	177,876.41	12.46	9.82	153,495.46	12.43	9.76
Starting age
– 40 years old	97,903.39	16.52	12.71	202,251.17	17.31	13.65	177,771.05	17.19	13.52
– 60 years old	78,549.90	13.21	10.15	182,605.57	13.58	10.70	158,182.46	13.52	10.63
Fibrosis stage
– Experienced	90,700.42	15.03	11.51	194,679.10	15.72	12.34	170,251.64	15.61	12.23
Cost of being in the state
– Brady 2007*	24,665.97	15.23	11.71	123,638.08	15.82	12.48	99,972.53	15.73	12.37
– HCV + only†	42,698.34	15.23	11.71	126,417.51	15.82	12.48	105,056.36	15.73	12.37
– SVR 1 year = CHC‡	45,726.51	15.23	11.71	130,711.60	15.82	12.48	109,159.19	15.73	12.37
– Krajden 2010 net cost$	30,193.21	15.23	11.71	124,017.96	15.82	12.48	101,130.06	15.73	12.37
Transition rates
– Murphy et al.27	89,852.97	15.21	11.69	194,550.52	15.82	12.47	170,039.81	15.73	12.36
– Martin et al.38	92,977.55	15.53	11.92	195,246.30	16.01	12.62	171,083.73	15.94	12.52
– McEwan et al.39	93,017.15	15.67	12.05	195,241.65	16.04	12.64	171,075.65	15.98	12.56
– Krahn et al.22	102,969.04	15.41	11.86	196,740.54	15.99	12.61	173,678.98	15.90	12.50
AE costs
– Murphy et al.27	90,904.77	15.23	11.71	194,776.41	15.82	12.48	170,310.75	15.73	12.37
Discount
– 0%	174,333.45	30.22	23.27	277,093.37	32.19	25.41	252,772.57	31.90	25.10
– 3%	113,502.96	19.32	14.86	216,994.65	20.25	15.97	192,627.86	20.11	15.81
Utilities
– Chong et al.58	90,904.77	15.23	11.51	194,776.41	15.82	12.13	170,370.64	15.73	12.04
– Martin et al.38	90,904.77	15.23	10.83	194,776.41	15.82	11.71	170,370.64	15.73	11.59

CHC, chronic hepatitis C; DCV, daclatasvir; LY, life years; pINF, peg-interferon; QALY, quality-adjusted life years; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virological response.

*The inputs are based on the Brady et al.28.

†Cost of CHC management from Krajden et al.49 are attributed only to HCV + patients.

‡Cost of CHC management from Krajden et al.49 are attributed only to HCV + patients and successfully treated patients in the first year.

$Cost of CHC management (net cost only) from Krajden et al.49 are attributed to HCV + patients.

Table 5. Sensitivity analysis for treatment-experienced patients.

Parameter	SOF + RBV 24-week			DCV + SOF 12-week
	Cost ($)	LY	QALY	Cost ($)	LY	QALY
Base case	196,437.07	15.33	11.87	170,574.97	15.52	12.11
Model horizon
– 20 years	179,805.20	12.25	9.47	153,936.49	12.33	9.61
Starting age
– 40 years old	203,479.41	16.67	12.92	177,771.32	16.92	13.21
– 60 years old	184,351.86	13.26	10.26	158,533.22	13.38	10.44
Fibrosis stage
– Naive	196,587.54	15.49	12.04	170,713.60	15.65	12.26
Cost of being in the state
– Brady 2007*	128,946.70	15.33	11.87	101,581.32	15.52	12.11
– HCV + only†	139,845.58	15.33	11.87	108,439.54	15.52	12.11
– SVR 1 year = CHC‡	143,423.72	15.33	11.87	112,368.21	15.52	12.11
– Krajden 2010 net cost$	131,728.71	15.33	11.87	103,068.17	15.52	12.11
Transition rates
– Murphy et al.27	195,587.25	15.31	11.86	170,054.38	15.51	12.10
– Martin et al.38	198,090.05	15.66	12.12	171,721.22	15.82	12.34
– McEwan et al.39	198,198.91	15.76	12.20	171,754.25	15.89	12.39
– Krahn et al.22	205,352.76	15.57	12.07	175,802.18	15.77	12.31
AE costs
– Murphy et al.27	196,215.90	15.33	11.87	170,515.09	15.52	12.11
Discount
– 0%	278,587.48	30.61	23.75	252,329.06	31.23	24.41
– 3%	218,682.00	19.49	15.10	192,696.87	19.78	15.45
Utilities
– Chong et al.58	196,437.07	15.33	11.65	170,574.97	15.52	11.85
– Martin 20123 8	196,437.07	15.33	10.91	170,574.97	15.52	11.18

CHC, chronic hepatitis C; DCV, daclatasvir; LY, life years; pINF, peg-interferon; QALY, quality-adjusted life years; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virological response.

*The inputs are based on the Brady et al. (2007)28

†Cost of CHC management from Krajden et al.49 are attributed only to HCV + patients.

‡Cost of CHC management from Krajden et al.49 are attributed only to HCV + patients and successfully treated patients in the first year.

$Cost of CHC management (net cost only) from Krajden et al.49 are attributed to HCV + patients.

Table 6. ICER range in the sensitivity analyses.

Treatment	Basecase ICER ($/QALY)	Range of ICER ($/QALY)	Basecase ICER ($/LY)	Range of ICER ($/LY)
Treatment naïve
DCV + SOF 12 wk vs pINF + RBV	120,671	42,863–214,724	159,290	46,690–397,239
SOF + RBV 24 wk vs pINF + RBV	135,398	48,019–241,462	176,755	52,162–451,429
SOF + RBV 24 wk vs DCV + SOF 12 wk	224,017	78,454–406,349	274,081	83,865–812,698
Treatment-experienced
DCV + SOF 12 wk vs SOF + RBV 24 wk	Dominates	Dominates	Dominates	Dominates

DCV, daclatasvir; ICER, incremental cost-effectiveness ratio; LY, life years; pINF, peg-interferon; QALY, quality-adjusted life years; RBV, ribavirin; SOF, sofosbuvir.

Discussion

The current study assessed the cost-effectiveness of a daclatasvir plus sofosbuvir base regimen in treatment-naive and treatment-experienced CHC patients infected with HCV GT-3 in Canada. The CHC GT-3 patients at various stages of liver fibrosis were allowed to progress through different health states in the model. Successful treatment of viral infection (an SVR state) would result in ceasing disease progression and preventing development of advanced stages of liver disease. A daclatasvir-based regimen was compared to a sofosbuvir plus ribavirin regimen in treatment-naive and treatment-experienced CHC GT-3 patients and to a peg-interferon plus ribavirin regimen in treatment-naive patients; the only two other regimens approved for the treatment of HCV G3 infections.

The treatment paradigm in chronic hepatitis C is evolving very rapidly, and now that the therapeutic gap for the treatment of CHC GT-1 may have been somewhat filled with the newer agents, there is an immediate need to assess the comparable benefits, harms, and cost-effectiveness of the antiviral regimens that are currently approved for use in Canada. Accordingly, the current analysis is limited to treatment regimens with approved marketing authorization in Canada and considered by reimbursement agencies for listing recommendations.

Interferon has been the mainstay of CHC treatment for the past two decades. Combination therapy with pINF + RBV has resulted in SVR of up to 40–50% for genotype 1 and up to 70–80% in genotypes 2 and 3 in clinical trials. However, interferon is often poorly tolerated, and recent ‘real-life’ studies have found SVR rates ∼20% lower than those reported in clinical trials among patients who initiated treatment for CHC59.

Cirrhotic patients generally do much worse than non-cirrhotic patients with current therapies. Hence, there still remains the unmet medical need for CHC GT-3 patients with liver cirrhosis where the SVR rates are significantly lower than SVR rates in non-cirrhotic patients prompting either increasing duration of treatment or the addition of ribavirin37.

Key challenges for treatment include selection of optimal combinations of drugs, optimizing durations of treatment, and also careful development of new treatments in order to minimize the risk of development of drug resistance. Careful consideration of these factors would realize the goal of providing curative management for the majority of patients with HCV, particularly in GT-3 patients59.

At a $50,000 per QALY willingness-to-pay threshold, a pINF + RBV 24-week regimen is an attractive treatment option in treatment-naive CHC GT-3 patients, although it is considered therapeutically sub-optimal. In treatment-experienced patients, where a pINF + RBV regimen is no longer available, a DCV + SOF 12-week regimen dominates a SOF + RBV 24-week regimen.

Previous Canadian health economic studies did not compare antiviral regimens in CHC GT-3 patients. In patients infected with HCV GT-1, new treatment options replaced either pINF + RBV alone or pINF-based treatment regimens. There are more antiviral regimens available in CHC GT-1 than in CHC GT-3. An SVR rate of a pINF-RBV regimen in CHC GT-1 would be ∼50%, whereas an SVR rate of a pINF-RBV regimen in CHC GT-3 would be ∼60–70%. Therefore, the current model still supports a pINF + RBV regimen in treatment-naive patients if the willingness-to-pay threshold is below $50,000 per QALY.

The current study results should be considered within its strengths and limitations. First, the model assumes that natural disease progression in CHC genotype 3 is similar to one in CHC genotype 1. However, HCV GT3 infection is progressing faster than other genotypes19. However, the model results did not change significantly in a deterministic sensitivity analysis with alternative inputs for transition probabilities. Therefore, the current estimates are conservative as a rapid progression of a disease may improve the cost-effectiveness ratio.

The authors assumed that a successfully treated patient with compensated liver disease would generate the same costs as a patient with HCV infection unless the disease progresses into advanced stages. However, when the cost of being in a state of compensated liver disease was less than the cost of being in a state of compensated liver disease with HCV infection, the benefit of new advanced treatment options over pINF + RBV increased. The cost of monitoring was not included in the evaluation. All these are conservative assumptions.

Quality-of-life estimates were based on the most recent Canadian source. The base case used Hsu et al.7, which was not the most conservative of all considered alternatives. However, alternative sources of quality-of-life data did not significantly change model results.

The model used clinical inputs like SVR rates from several sources. With the exception of genotype and treatment history, baseline characteristics of the patients were not controlled. Swallow et al.45 presented a matched-adjusted indirect treatment comparison between pINF + RBV, DCV + SOF, and SOF + RBV regimens. The estimated SVR rate for a DCV + SOF treatment regimen in the indirect treatment comparison is numerically higher than the one reported in a clinical trial. Therefore, the clinical assumptions regarding a DCV + SOF regimen were conservative.

The model considered only the Ministry of Health perspective due to limited information on indirect costs. Federico et al.60 estimated the annual time spent on managing the disease which allowed to estimate productivity loss in working individuals. However, there was uncertainty regarding whether such cost would be alleviated by achieving SVR states and whether such findings reflected interferon-free antiviral regimens. With introduction of all oral therapies, which did not require extensive monitoring, additional time loss due to treatment should not be significant. The cost of drug only included acquisition cost, because wholesale mark-up, dispensing fees, and patients’ co-pay were not homogeneous among the provinces in Canada.

Conclusion

Daclatasvir plus sofosbuvir based regimen represents a cost-effective option compared to the existing standard-of-care treatment option for treatment-experienced chronic hepatitis C patients infected with HCV GT-3 in Canada. Although therapeutically sub-optimal, peg-interferon alfa plus ribavirin is the most cost-effective option in treatment-naive patients if the willingness-to-pay is less than $50,000 per QALY. Daclatasvir plus sofosbuvir would be the most cost-effective option after a peg-interferon/ribavirin treatment failure, or in patients with a contraindication or intolerance to peg-interferon and/or ribavirin therapy.

Acknowledgments

The authors would like to thank Thomas Ward and Yong Yuan for guidance in model customization and advice on handling transitional probabilities.

Transparency

Declaration of funding

Development of the model and all analyses were sponsored by Bristol-Myers Squibb.

Declaration of financial/other relationships

AM, MJM and AATM are employees of the Canadian subsidiary of Bristol-Myers Squibb, a pharmaceutical company that manufactures daclatasvir. RG is Professor at the department of Clinical Epidemiology and Biostatistics at McMaster University (Hamilton, Canada). Ron Goeree received financial support from BMS to provide scientific support and expert advice during the development of the health economic project. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.