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. 2017 Feb 3;5(1):E97–E108. doi: 10.9778/cmajo.20160161

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

William W L Wong 1, Karen M Lee 1, Sumeet Singh 1, George Wells 1, Jordan J Feld 1, Murray Krahn 1
PMCID: PMC5378540  PMID: 28401125

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.

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.

Table 1: Treatment included in the base-case analysis.

Treatment comparators Subgroup Description
Genotype 1 N/NC N/C E/NC E/C
PR48 X X X X Pegylated interferon + ribavirin for 48 wk
SOF24 + RBV24 X X Sofosbuvir + ribavirin for 24 wk
SIM12 + SOF12 X X X X Simeprevir + sofosbuvir for 12 wk
SOF12 + LDV12 X X X sofosbuvir + ledipasvir for 12 wk
PAR/RIT12 + OMB12 + DAS12 X X Paritaprevir/ritonavir + ombitasvir + dasabuvir for 12 wk
PAR/RIT12 + OMB12 + DAS12 + RBV12 X X Paritaprevir/ritonavir + ombitasvir + dasabuvir + ribavirin for 12 wk
DCV12 + SOF12 X Daclatasvir and sofosbuvir for 12 wk
T12 PR24-48 RGT q8 X X Telaprevir for 12 wk and PR used as RGT for 24 or 48 wk (750 mg every 8 h)
SOF12 + PR12 X X X X Sofosbuvir + pegylated interferon + ribavirin for 12 wk
SOF12 + PR24-48 RGT X Sofosbuvir for 12 wk and PR used as RGT for 24 or 48 wk
SIM12 + PR24-48 RGT X X X X Simeprevir for 12 wk and PR used as RGT for 24 or 48 wk
B24 + PR28-48 RGT X X Boceprevir for 24 wk and PR used as RGT for 28 or 48 wk
SIM12 + SOF12 + RBV12 X X Simeprevir + sofosbuvir+ ribavirin for 12 wk
SIM12 + PR48 X X Simeprevir for 12 wk and PR for 48 wk
B32 PR36-48 RGT X X Boceprevir for 32 wk and PR used as RGT for 36 or 48 wk
SOF24 + LDV24 X Sofosbuvir + ledipasvir for 24 wk
SOF12 + LDV12 + RBV12 X Sofosbuvir + ledipasvir + ribavirin for 12 wk
T12 PR48 q8 X X Telaprevir for 12 wk and PR for 48 wk (750 mg every 8 h)
Genotype 2
SOF12 + RBV12 X X X X sofosbuvir + ribavirin for 12 wk
SOF12 + PR12 X X X Sofosbuvir + pegylated interferon + ribavirin for 12 wk
PR24 X X Pegylated interferon + ribavirin for 24 wk
SOF16 + RBV16 X Sofosbuvir + ribavirin for 16 wk
Genotype 3
PR48 X X X X Pegylated interferon + ribavirin for 48 wk
DCV12 + SOF12 X X Daclatasvir and sofosbuvir for 12 wk
SOF24 + RBV24 X X X X Sofosbuvir + ribavirin for 24 wk
SOF12 + PR12 X X Sofosbuvir + pegylated interferon + ribavirin for 12 wk
Genotype 4
PR 48 X X Pegylated interferon + ribavirin for 48 wk
SOF12 + PR12 X sofosbuvir + pegylated interferon + ribavirin for 12 wk
SOF24 + RBV24 X X X X Sofosbuvir + ribavirin for 24 wk
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Note: E/C = treatment-experienced with cirrhosis, E/NC = treatment-experienced without cirrhosis, N/C = treatment-naive with cirrhosis, N/NC = treatment-naive without cirrhosis.

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.

Figure 1

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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) 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.

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

Description Baseline* or RR Lower limit
(95% CrI)		 Upper limit
(95% CrI)
Genotype 1: treatment-naive
Noncirrhosis
   Reference baseline PR48 0.4913* 0.4359 0.5456
   SOF24 + RBV24 1.634 1.288 1.899
   SIM12 + SOF12 1.802 0.8004 2.186
   SOF12 + LDV12 1.978 1.78 2.225
   PAR/RIT12 + OMB12 + DAS12 1.932 1.337 2.211
   PAR/RIT12 + OMB12 + DAS12 + RBV12 1.944 1.748 2.18
   T12 PR24-48 RGT q8 1.555 1.312 1.767
   SOF12 + PR12 1.769 1.278 2.065
   SOF12 + PR24-48 RGT 1.727 1.245 2.055
   SIM12 + PR24-48 RGT 1.589 1.411 1.784
   B24 PR28-48 RGT 1.538 1.268 1.777
   SIM12 + SOF12 + RBV12 1.766 0.8601 2.176
   DCV12 + SOF12 1.898 1.276 2.212
Cirrhosis
   Reference baseline PR48 0.3958* 0.3092 0.4906
   SOF24 + RBV24 1.757 0.6207 2.571
   SIM12 + SOF12 2.175 0.9347 2.949
   SOF12 + LDV12 2.408 1.893 3.089
   T12 PR24-48 RGT q8 1.43 0.6368 2.195
   SOF12 + PR12 2.038 1.125 2.749
   SIM12 + PR24-48 RGT 1.695 1.057 2.387
   B24 PR28-48 RGT 0.6456 0.1609 1.653
Genotype 1: treatment-experienced
Noncirrhosis
   Reference baseline PR48 0.2571* 0.2242 0.292
   SIM12 + SOF12 1.023 0.04915 3.635
   SOF12 + LDV12 3.564 2.992 4.151
   PAR/RIT12 + OMB12 + DAS12 3.753 3.204 4.329
   PAR/RIT12 + OMB12 + DAS12 + RBV12 3.818 3.345 4.387
   T12 PR48 q8 3.038 2.405 3.633
   SOF12 + PR12 3.097 2.276 3.768
   SIM12 + PR24-48 RGT 2.587 1.757 3.207
   SIM12 + PR48 3.045 2.152 3.718
   SIM12 + SOF12 + RBV12 2.354 0.2271 3.878
   B32 PR36-48 RGT 2.547 1.692 3.328
Cirrhosis
   Reference baseline PR48 0.1691* 0.1165 0.2334
   SIM12 + SOF12 4.665 1.796 7.161
   SOF24 + LDV24 4.503 1.603 7.215
   SOF12 + LDV12 + RBV12 4.626 2.931 7.005
   T12 PR48 q8 3.027 1.361 5.425
   SOF12 + PR12 2.944 0.3161 6.236
   SIM12 + PR24-48 RGT 3.563 1.608 6.091
   SIM12 + PR48 2.709 0.8918 5.319
   B32 PR36-48 RGT 2.521 0.7132 5.623
Genotype 2: treatment-naive
Noncirrhosis
   SOF12 + RBV12 1.16 1.083 1.244
   SOF12 PR12 1.148 0.4762 1.266
   Reference baseline PR24 0.8191* 0.7687 0.8619
   Cirrhosis
   SOF12 + RBV12 1.375 1.026 1.791
   Reference baseline PR24 0.6209* 0.4966 0.7344
Genotype 2: treatment-experienced
Noncirrhosis
   Reference baseline SOF12 + RBV12 0.9549* 0.9071 0.9829
   SOF12 + PR12 1.006 0.8914 1.071
Cirrhosis
   Reference baseline SOF12 + RBV12 0.7331* 0.579 0.8554
   SOF12 + PR12 1.286 0.9865 1.643
   SOF16 + RBV16 1.052 0.7123 1.414
Genotype 3: treatment-naive
Noncirrhosis
   Reference baseline PR48 0.7051* 0.6393 0.765
   SOF24 + RBV24 1.318 1.177 1.47
   DCV12 + SOF12 1.375 1.233 1.525
Cirrhosis
   Reference baseline PR48 0.6021* 0.5584 0.6441
   SOF24 + RBV24 1.509 1.142 1.702
Genotype 3: treatment-experienced
Noncirrhosis
   Reference baseline PR48 0.6082* 0.5786 0.6374
   SOF24 + RBV24 1.467 1.315 1.591
   SOF12 + PR12 1.384 0.8798 1.62
   DCV12 + SOF12 1.544 1.306 1.667
Cirrhosis
   Reference baseline PR48 0.4777* 0.4382 0.5174
   SOF24 + RBV24 1.465 1.139 1.789
   SOF12 + PR12 1.731 1.09 2.086
Genotype 4: treatment-naive
Noncirrhosis
   Reference baseline PR48 0.6502* 0.6335 0.6668
   SOF24 + RBV24 1.268 0.895 1.465
   SOF12 + PR12 1.482 1.269 1.552
Cirrhosis
   Reference baseline PR48 0.3804* 0.3567 0.4052
   SOF24 + RBV24 2.27 1.361 2.65
Genotype 4: treatment-experienced
Noncirrhosis
   Reference baseline SOF12 + RBV12 0.6345* 0.4483 0.7983
   SOF24 + RBV24 1.28 0.6814 1.905
Cirrhosis
   Reference baseline SOF12 + RBV12 0.5628* 0.2422 0.8484
   SOF24 + RBV24 1.469 0.5728 3.505
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Note: Probability distribution based on network meta-analysis.15 For descriptions or treatment regimens, see Table 1. CrI = credible interval, RR = relative risk.

*Baseline probability.

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

Fibrosis distribution
Treatment status and fibrosis stage Base estimate Lower limit
(-25%)		 Upper limit
(+25%)		 Probability distribution
Treatment-naive16
F0 0.08 0.06 0.1 Beta (58.8-676.2)
F1 0.20 0.15 0.25 Beta (51-204)
F2 0.35 0.2625 0.4375 Beta (41.25-76.61)
F3 0.21 0.1575 0.2625 Beta (50.35-189.41)
F4 0.16 0.12 0.2 Beta (53.6-281.4)
Treatment-experienced17
F0 0.04 0.03 0.05 Beta (61.4-1473.6)
F1 0.13 0.0975 0.1625 Beta (55.55-371.76)
F2 0.38 0.285 0.475 Beta (39.3-64.12)
F3 0.23 0.1725 0.2875 Beta (49.05-164.21)
F4 0.22 0.165 0.275 Beta (49.7-176.2)
Natural history parameters
Description Base estimate Lower limit
(95% CI)		 Upper limit
(95% CI)		 Probability distribution
Annual probability for fibrosis progression
F0-F118 0.117 0.104 0.13 Beta (285.9-2158.3)
F1-F218 0.085 0.075 0.096 Beta (218.5-2351.6)
F2-F318 0.12 0.109 0.133 Beta (299.8-2198.6)
F3-F418 0.116 0.104 0.129 Beta (281.4-2144.7)
Genotype 3 accelerated fibrosis progression (OR)19 1.52 1.12 2.07 Exp [normal (0.419-0.154)]
Annual probability for cirrhosis progression
F4-decompensated (non-SVR)5 0.035 0.027 0.043 Beta (73.8-2036.1)
F4-decompensated (SVR)5 0.002 0.0001 0.005 Beta (1.77-884.3)
F4-HCC (non-SVR)5 0.024 0.018 0.031 Beta (45.9-1865.3)
F4-HCC (SVR)5 0.005 0.001 0.009 Beta (6.21-1236.5)
Annual probability for liver transplantation20
From decompensated cirrhosis 0.033 0.017 0.049 Beta (16.42-481.19)
From HCC 0.033 0.017 0.049 Beta (16.42-481.19)
Chronic hepatitis C-related mortality
Description Base estimate Lower limit
(-25%)		 Upper limit
(+25%)		 Probability distribution
HCC21 0.411 0.31 0.51 Beta (38.6-55.3)
Decompensated cirrhosis22 0.216 0.162 0.27 Beta (49.96-181.3)
Liver transplant (first yr)23 0.142 0.124 0.159 Beta (213.4-1289.7)
Liver transplant (> 1 yr)23 0.034 0.024 0.043 Beta (44.6-1268.1)
Therapy cost, Can$
PAR/RIT+ OMB + DAS (Holkira Pak) 12 wk24 55 860 41 895 69 825 -
LDV + SOF (Harvoni) 12 wk24 67 000 50 250 83 750 -
DCV (Daklinza) 12 wk24 36 000 27 000 45 000 -
SOF(Sovaldi) 12 wk24 55 000 41 250 68 750 -
SIM (Galexos) 12 wk24 36 502 27 377 45 628 -
PR 24 wk24 9500 7125 11 875 -
Telaprevir (Incivek)
Pegylated interferon/ribavirin 24 to 48 wk24 		44 468-53 968 33 351-40 476 55 585-67 460 -
Boceprevir
Pegylated interferon alfa-2b/ribavirin 24 to 44 wk24 		31 831-59 972 23 873-44 979 39 789 -74 965 -
Chronic hepatitis C-related utilities
Canadian population average25
Age 45-54 yr 0.86 0.83 0.88 Beta (459.34-74.78)
Utility for CHC infection-related health states26
Non-irrhosis 0.73 0.69 0.77 Beta (358.98-132.77)
Compensated cirrhosis 0.69 0.65 0.73 Beta (368.29-165.46)
Hepatocellular carcinoma 0.69 0.65 0.73 Beta (368.29-165.46)
Decompensated cirrhosis27 0.65 0.61 0.69 Beta (369.04-198.71)
Post-transplant 0.75 0.70 0.79 Beta (224.25-74.75)
Noncirrhosis on-treatment (apply only to regimens contains pegylated interferon or ribavirin) 0.71 0.67 0.75 Beta (364.76-148.99)
Noncirrhosis viral clearance 0.80 0.76 0.84 Beta (319.2-79.8)
Compensated cirrhosis on-treatment (apply only to regimens contains pegylated interferon or ribavirin) 0.67 0.63 0.71 Beta (369.67-182.08)
Compensated cirrhosis viral clearance 0.76 0.72 0.80 Beta (345.8-109.2)
One-time disutility associated with adverse event28,29
Anemia -0.03 -0.0375 -0.0225 -Beta (62.05-2006.28)
Depression -0.0625 -0.0781 -0.0468 -Beta (59.94-899.06)
Rash -0.0213 -0.0267 -0.0159 -Beta (62.62-2006.28)
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Note: For descriptions of treatment regimens, see Table 1. CI = confidence interval, OR = odd ratio, SVR = sustained viral response.

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), 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) 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).

Table 4: Base-case cost-effectiveness results.
Treatment Versus pegylated interferon-ribavirin alone
Total cost, $ Total quality adjusted life-years Incremental cost, $ Incremental quality-adjusted life-years Incremental cost utility ratio Sequential incremental cost utility ratio, $
Genotype 1: treatment-naive noncirrhosis*
(0) No treatment 104 904 9.734 - - - -
(1) PR48 114 132 10.839 - - - 8 353
(14) PAR/RIT12 + OMB12 + DAS12 143 379 11.835 29 247 0.996 29 354 48 060
(6) SOF12 + LDV12 152 762 11.857 38 631 1.018 37 951 435 528
Genotype 1: treatment-naive cirrhosis*
No treatment 101 355 7.043 - - - -
PR48 120 140 8.659 - - - 11 628
SOF12 + LDV12 169 483 10.538 49 344 1.879 26 261 26 261
Genotype 1: treatment-experienced noncirrhosis*
No treatment 104 668 9.596 - - - -
PR48 118 321 10.282 - - - ext. dominated
PAR/RIT12 + OMB12 + DAS12 142 917 11.868 24 597 1.586 15 506 16 836
PAR/RIT12 + OMB12 + DAS12 + RBV12 145 743 11.898 27 422 1.616 16 965 93 872
Genotype 1: treatment-experienced cirrhosis*
No treatment 101 355 7.043 - - - -
PR48 119 828 7.924 - - - ext. dominated
SIM12 PR24-48 RGT 148 780 9.326 28 953 1.402 20 655 20 774
SOF12 + LDV12 + RBV12 172 976 9.933 53 148 2.009 26 456 39 845
SIM12 + SOF12 193 052 9.966 73 225 2.041 35 870 618 881
Genotype 2: treatment-naive noncirrhosis*
PR24 99 904 11.532 - - - -
SOF12 + RBV12 143 955 11.749 44 051 0.217 203 282 203 282
Genotype 2: treatment-naive cirrhosis
No treatment 101 355 7.043 - - - -
PR24 112 767 9.384 - - - 4 876
SOF12 + RBV12 159 541 10.181 46 773 0.797 58 659 58 659
Genotype 2: treatment-experienced noncirrhosis*
No treatment 104 668 9.596 - - - -
SOF12 + RBV12 144 023 11.753 39 355 2.157 18 247 18 247
Genotype 2: treatment-experienced cirrhosis*
No treatment 101 355 7.043
SOF12 + PR12 160 863 10.308 59 508 3.265 18 226 18 226
Genotype 3: treatment-naive noncirrhosis*
No treatment 104 183 9.314 - - - -
PR48 110 387 11.156 - - - 3 367
DCV12 + SOF12 175 987 11.832 65 600 0.675 97 158 97 158
Genotype 3: treatment-naive cirrhosis
No treatment 101 355 7.043 - - - -
PR48 120 843 9.335 - - - 8 504
SOF24 + RBV24 215 437 10.362 94 594 1.027 92 117 92 117
Genotype 3: treatment-experienced noncirrhosis*
No treatment 103 932 9.167 - - - -
PR48 112 301 10.879 8 368 1.712 4 888 4 888
SOF12 + PR12 149 249 11.51 45 316 2.343 19 339 58 535
DCV12 + SOF12 177 476 11.78 73 544 2.612 28 151 104 857
Genotype 3: treatment-experienced cirrhosis
No treatment 101 355 7.043 -
PR48 120 880 8.936 19 525 1.893 10 317 10 317
SOF12 + PR12 163 647 10.082 62 292 3.039 20 496 37 319
SOF24 + RBV24 214 706 9.661 113 351 2.618 43 292 Dominated
Genotype 4: treatment-naive noncirrhosis*
No treatment 104 904 9.734 - - - -
PR48 111 493 11.158 - - - 4 627
SOF12 + PR12 145 731 11.698 34 239 0.54 63 421 63 421
Genotype 4: treatment-naive cirrhosis
No treatment 101 355 7.043 - - - -
PR48 120 087 8.608 - - - 11 970
SOF24 + RBV24 215 281 10.208 95 194 1.6 59 492 59 492
Genotype 4: treatment-experienced noncirrhosis
No treatment 104 668 9.596 - - -
SOF24 + RBV24 201 763 11.503 97 095 1.907 50 913 NA
Genotype 4: treatment-experienced cirrhosis
No treatment 101 355 7.043 - - - NA
SOF24 + RBV24 215 142 10.093 113 787 3.05 37 303
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Note: For description of treatment regimens, see Table 1.

*Refer to Appendix 4 for dominated or extendedly dominated treatments.

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

Supplementary Material

Online Appendices
supp_5_1_E97__index.html (1.3KB, html)

Acknowledgements

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

Footnotes

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

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Supplementary Materials

Online Appendices
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