Cost-effectiveness of combination daclatasvir-sofosbuvir for treatment of genotype 3 chronic hepatitis C infection in the United States

Abstract

Background: A phase III trial evaluated the efficacy and safety of Daklinza (daclatasvir or DCV) in combination with sofosbuvir (SOF) for treatment of genotype (GT) 3 hepatitis C virus (HCV) patients.

Aim: This study evaluated the cost-effectiveness of DCV + SOF vs SOF in combination with ribavirin (RBV) over a 20-year time horizon from the perspective of a United States (US) payer.

Methods: A published Markov model was adapted to reflect US demographic characteristics, treatment patterns, costs of drug acquisition, monitoring, disease and adverse event management, and mortality risks. Clinical inputs came from the ALLY-3 and VALENCE trials. The primary outcome was the incremental cost-utility ratio. Life-years, incidence of complications, number of patients achieving sustained virological response (SVR), and the total cost per SVR were secondary outcomes. Costs (2014 USD) and quality-adjusted life years (QALYs) were discounted at 3% per year. Deterministic, probabilistic, and scenario sensitivity analyses were conducted.

Results: DCV + SOF was associated with lower costs and better effectiveness than SOF + RBV in the base case and in almost all scenarios (i.e. treatment-experienced, non-cirrhotic, time horizons of 5, 10, and 80 years). DCV + SOF was less costly, but also slightly less effective than SOF + RBV in the cirrhotic and treatment-naïve population scenarios. Results were sensitive to variations in the probability of achieving SVR for both treatment arms. DCV + SOF costs less than $50,000 per QALY gained in 79% of all probabilistic iterations compared with SOF + RBV.

Conclusion: DCV + SOF is a dominant option compared with SOF + RBV in the US for the overall GT 3 HCV patient population.

Keywords:

• Daclatasvir
• Sofosbuvir
• Hepatitis C
• Cost-effectiveness
• Cost-benefit analysis

Introduction

The hepatitis C virus (HCV) represents a major global public health burden. Between 130–210 million people are chronically infected with the disease worldwide^1,2. HCV affects ∼2.7 million people in the United States (US)³, and was responsible for ∼19,368 deaths in the US in 2013⁴. HCV is predominantly transmitted via infected blood, either from intravenous drug use, high-risk sexual activity, or blood transfusion prior to screening⁵. The aim of treatment is the eradication of HCV infection, defined as the absence of HCV ribonucleic acid (RNA) at the end of treatment, and at 12 weeks post-treatment; this is termed “sustained virological response” (SVR). The HCV genotype (GT) and stage of liver fibrosis are the strongest predictors of SVR⁶.

Daklinza (daclatasvir or DCV), a pangenotypic non-structural polymerase 5A (NS5A) protein inhibitor, plays an important role in viral RNA replication and assembly/secretion of infectious particles from hepatic cells⁷. DCV, taken once a day at a recommended dosage of 60 mg, gained its first approval in July 2015 in the US; it was initially approved for treatment of chronic HCV in GT 3 infections in adult patients, based on the ALLY-3 trial. In this study, DCV has been investigated in combination with sofosbuvir (SOF) in patients with GT 3 HCV, a patient population with a unique genotype with a higher risk of fibrosis progression compared with other HCV genotypes. During this trial, the DCV + SOF regimen was administered to treatment-naïve and treatment-experienced patients for 12 weeks. Overall, patients were 59% male, with a median age of 55 years, 78% of them had a fibrosis stage of F0–F3, and 21% had cirrhosis⁸.

The emergence of novel therapeutic approaches capable of achieving SVR probabilities approaching 100%, even in the most difficult-to-treat patients such as those with GT 3 HCV, means that altering the future transmission dynamics of the disease is feasible. However, the cost-effectiveness of these approaches is yet to be ascertained. We describe in this paper a US adaptation of a cohort Markov framework (MONARCH model) and the use of this adaptation to investigate the cost-utility of a 12-week regimen of DCV + SOF compared with a 24-week regimen of SOF in combination with ribavirin (RBV) in patients with GT 3 HCV, the only other approved regimen indicated in the US for treating this population at the time the analyses were conducted.

Materials and methods

Model overview

We adapted an existing cohort Markov framework that was designed to simulate the natural history of HCV, including its complications, and to track the clinical and economic outcomes of a hypothetical cohort of patients with GT 3 HCV being treated with one of two treatment options from a US payer perspective^9–12. The model was implemented in Microsoft Excel using Visual Basic for Applications. Patients were treated with either DCV + SOF for 12 weeks or SOF + RBV for 24 weeks during the first year of the simulation. In the base case, the model tracks patients for 20 years, during which time they initiate treatment and achieve SVR, progress to more severe disease stages, experience complications, or die. Patients start in one of five Metavir chronic hepatitis C (CHC) fibrosis stages (F0 = no fibrosis, F1 = portal fibrosis with no septa, F2 = portal fibrosis with few septa, F3 = portal fibrosis with numerous septa, and F4 = compensated cirrhosis [CC]); a cohort of patients distributed across the fibrosis stages is defined at the beginning of the simulation. Patients who achieve SVR remain in that state until the end of the model time horizon or death.

Achievement of SVR is considered tantamount to a cure; it is assumed that, once SVR has been achieved, patients no longer progress to a more advanced health state. Patients who do not achieve SVR remain at risk of: (1) progressing from their initial fibrosis stage to more severe disease stages; (2) complications such as CC, decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), or liver transplant (LTx); or (3) all-cause mortality or liver-related death (Figure 1). The model combines information on therapy effectiveness, adverse events (AEs), therapy cessations, health state utilities, treatment disutilities, mortality risks, and costs to estimate complications, quality-adjusted life years (QALYs), and total costs.

Figure 1. Flow diagram of the MONARCH model.

The underlying MONARCH model framework has previously been validated against a UK-specific cost-effectiveness model¹³. The model framework has also been validated against other HCV cost-effectiveness models set in Belgium, Japan, Spain, the UK, and the US^14–19.

Patient population

Baseline characteristics for the hypothetical cohort of patients infected with HCV GT 3 used in the base-case analysis are shown in Table 1. These population characteristics were based on data from the US Centers for Disease Control and Prevention (CDC) and on a recent model of a US birth cohort screening program for HCV^20,21.

Table 1. Model inputs.

				Mean	SE		Source
Baseline population characteristics
Age (years)				54.00	10.80		CDC^21
Proportion male				65.10%	13.02%		CDC^21
Chronic HCV distribution
F0				17.00%	3.40%		McGarry et al.^20
F1				30.00%	6.00%
F2				20.00%	4.00%
F3				16.00%	3.20%
CC				17.00%	3.40%
Transition probabilities^a
Chronic HCV
F0 to F1				0.079	0.003		Thein et al.^23
F1 to F2				0.060	0.003
F2 to F3				0.109	0.008
F3 to CC				0.112	0.012
End stage liver disease
CC to DC				0.039	0.010		Martin et al.^22
CC to HCC				0.014	0.010
Complications
DC to HCC				0.014	0.010		Martin et al.^22
DC and HCC to LTx				0.030	0.012
DC to death				0.130	0.010
HCC to death				0.430	0.030
LTx (Year 1) to death				0.210	0.046
LTx (Year 2+) to death				0.057	0.012
SVR, discontinuation, and adverse event probabilities
		SVR			AE (Anemia)
Treatment, trial,duration of treatment	Population	Probability	SE	Discontinuation probability(SE)^b, timing (weeks)	Probability^c	SE	Source
DCV + SOF, ALLY-3, 12 weeks	Overall	0.896	0.026	0.0066 (0.0013) at week 8	0.033	0.007	Nelson et al.^8; Swallow et al.^30
	Treatment-naïve	0.901	0.032	0.0099 (0.0020) at week 8	0.020	0.004
	Treatment-experienced	0.863	0.052	0 (0) at week 8	0.059	0.012
	Non-cirrhotic	0.963	0.021	0.0066 (0.0013) at week 8	0.018	0.004
	Cirrhotic	0.625	0.090	0.0066 (0.0013) at week 8	0.063	0.013
SOF + RBV, VALENCE, 24 weeks	Overall	0.852	0.024	0.016 (0.0032) at week 4	0.060	0.012	Zeuzem et al.^29
	Treatment-naïve	0.933	0.024	0.016 (0.0032) at week 4		0.012
	Treatment-experienced	0.772	0.035	0.016 (0.0032) at week 4		0.012
	Non-cirrhotic	0.905	0.023	0.016 (0.0032) at week 4		0.012
	Cirrhotic	0.683	0.063	0.016 (0.0032) at week 4		0.012
Regimen costs for antiviral therapies
Regimen	Weekly regimen cost^d		SE	Treatment duration	Total regimen cost^e		Source
DCV + SOF	$12,250.00		$2,450.00	DCV: 12 weeks SOF: 12 weeks	$147,000.00		Bristol-Myers Squibb, data on file, 2015.
SOF + RBV	$7,155.88^f		$1,431.18	SOF: 24 weeks RBV: 24 weeks	$171,741.12		Health Analytics^31; Truven^46
Treatment-related monitoring costs
	DCV + SOF			SOF + RBV
Week^g	Mean	SE		Mean	SE		Source
4	$571.35	$114.27		$574.36	$114.87		AASLD^33; CMS^47–49
8	$72.44	$14.49		$72.44	$14.49
12	$72.44	$14.49		$130.88	$26.18
24	$0.00	$0.00		$102.14	$20.43
Annual post-treatment monitoring costs
Population	Stage			Mean	SE		Source
Patients who achieved SVR	F0–F2			$0.00	$0.00		AASLD^33; CMS^47–49
	F3–CC			$356.54	$71.31
Patients who did not achieve SVR	F0–F2			$141.64	$28.33
	F3–CC			$410.78	$82.16
	Average F0–CC			$276.21	$55.24
Health state costs
F0–CC fibrosis stages	F0 and F1			$3,374.85	$674.97		Davis et al.^34
	F2 and F3			$7,608.73	$1,521.75
	CC			$12,037.45	$2,407.49
SVR
Initial year	SVR from F0, F1, F2, F3, and CC			$941.13	$188.23		Davis et al.^34; AASLD^33
Subsequent years	SVR from F0, F1, and F2			$0.00	$0.00
	SVR from F3 and CC			$356.54	$71.31
Complications	DC (Initial year and subsequent years)			$48,039.92	$81.78		McAdam-Marx et al.^35
	HCC (Initial year and subsequent years)			$66,669.23	$210.94
	LTx (Initial year)			$218,758.42	$581.11
	LTx (Subsequent years)			$62,863.20	$319.38
Health state utilities
Health state				Mean	SE		Source
F0–CC Fibrosis stages	F0 and F1			0.77	0.03		Martin et al.^22
	F2 and F3			0.66	0.06
	CC			0.55	0.05
End stage liver disease	DC, HCC and LTx (Year 1)			0.45	0.06
	LTx (Year 2+)			0.67	0.07
SVR	SVR from F0 and F1			0.82	0.04
	SVR from F2, F3, and CC			0.72	0.05

CC: Compensated cirrhosis; CHC: Chronic hepatitis C; DC: Decompensated cirrhosis; DCV: Daclatasvir; ESLD: End-stage liver disease; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; LTx: Liver transplant; NA: Not available; RBV: Ribavirin; SE: Standard error; SOF: Sofosbuvir; SVR: Sustained virological response.

Note: SE is assumed to be 20% of the mean.

^a The inputs associated with all chronic HCV transition probabilities are based on the Thein et al.²³ meta-analysis of 111 studies that provides a pooled estimate of fibrosis stage progression across GTs.

^b Proportion of patients who discontinued treatment over treatment duration.

^c Proportion of patients who experienced an AE over treatment duration.

^d Based on a weekly cost of $5,250 for DCV, $7,000 for SOF, and $155.88 for RBV.

^e Regimen cost over the entire treatment duration.

^f The cost of ribavirin is a weighted average cost calculated using recent market shares of various ribavirin products.

^g Treatment-related monitoring costs for weeks 16, 20, 28, 32, 36, 40, 44 and 48 are $0.

Transition probabilities

Probabilities of progressing to subsequent fibrosis stages or experiencing a complication were obtained from the literature (Table 1)^22,23. All transition probabilities are conditional on surviving (i.e. all-cause mortality is determined at the beginning of each annual cycle, and the transition probabilities are applied to the living patients only). Patients who do not achieve SVR and do not die can remain in the same health state or progress to a more severe state. As shown in Figure 1, patients in fibrosis stages F0–F3 can transition to the subsequent fibrosis stage (i.e. F1–CC), and those at fibrosis stage CC can transition to DC or HCC. Patients with DC can remain in that state or transition to HCC, receive a LTx, or die from liver-related causes. Patients with HCC can receive an LTx or die from liver-related causes, and those who have received an LTx can die from liver-related causes. Patients who achieve SVR have no increased risk for experiencing complications such as DC and HCC (i.e. transitions from CC to DC or HCC in patients that have achieved SVR are also assumed to be zero)²⁴. Transition probabilities across F0–CC are based on a meta-regression published by Thein et al.²³, and the transition probabilities to end-stage liver disease stages and HCV complications come from a previously published cost-effectiveness analysis of antiviral treatments for HCV by Martin et al.²². The probabilities at which patients progress through fibrosis stages are independent of patient age, presence of comorbid conditions or coinfections, and baseline disease severity. The use of such transition probabilities is a common feature of economic models in HCV²⁴; several recent models^25–27 used the above-mentioned disease progression probabilities published by Thein et al.²³.

Survival

The model incorporated all-cause and liver-related mortality risks. Annual age- and sex-specific mortality risks came from life tables for the US general population²⁸. In addition to the risk of all-cause mortality, patients who experienced DC, HCC, and LTx also incurred a state-specific risk of liver-related death; the probabilities of liver-related death were obtained from the literature for each of these complications (Table 1)²². Patients who achieved SVR and those who did not achieve SVR but had not yet progressed to DC, HCC, and LTx were not at increased risk of liver-related death and had an all-cause mortality risk equivalent to that of the general population in the US. Patient survival is not directly influenced by treatment.

Treatment effects, AEs, and treatment discontinuations

Clinical inputs for treatment efficacy (i.e. probability of achieving SVR), AEs, and treatment discontinuations were obtained from the ALLY-3 trial, the VALENCE trial, and a published matching-adjusted indirect comparison comparing the efficacy and tolerability of DCV + SOF versus SOF + R in patients infected with GT 3 HCV (Table 1)^8,29,30. ALLY-3 was a phase 3, open-label, two-cohort [treatment-naïve (n = 101) and treatment-experienced (n = 51)] trial evaluating a 12-week regimen of once-daily oral DCV (60 mg) plus SOF (400 mg) in patients with GT 3 HCV. The primary end-point was the proportion of patients achieving SVR12, as evidenced by an undetectable HCV viral load 12 weeks after completion of treatment. VALENCE was a phase 3, multi-center, placebo-controlled randomized controlled trial in which patients with GT 2 (n = 91) or GT 3 (n = 328) HCV were randomized 4:1 to receive once-daily SOF (400 mg) and twice-daily oral RBV (1,000 mg or 1,200 mg daily, depending on body weight) for 24 weeks or placebo. The primary end-point in the VALENCE trial was also SVR12.

Treatments evaluated in this economic evaluation have favorable safety profiles. AEs were mild, did not have any impact on quality-of-life, and were not affected by treatment response and/or discontinuation, but were associated with a one-time management cost. Anemia, the most prevalent AE associated with these two treatments, was the only AE incorporated into the analyses. We did not include other AEs because they are infrequent and associated with minimal management costs. The proportion of patients who experienced anemia in the ALLY-3 and VALENCE trials is reported in Table 1.

In the simulation, patients may have discontinued treatment for various reasons, including due to AEs. Patients who discontinue treatment in the model no longer incur therapy-related costs and disutility. Discontinuation probabilities observed in the ALLY-3 and VALENCE trials are detailed in Table 1.

Costs

Cost inputs include those that are related to the therapies and the health states (Table 1). Therapy-related costs include the costs of the actual antiviral regimens, on-treatment- and post-treatment-related monitoring, and AE management. Antiviral regimen- and monitoring-related costs only apply during those weeks when patients received treatment. SOF costs of $7,000 per week and DCV costs of $5,250 per week are used in the analyses³¹.

The total cost of managing an anemia event, obtained from a recent retrospective database analysis in the US, is estimated at $1,271.21 (standard error [SE]: $254.24)³².

Treatment-related and post-treatment monitoring costs are based on the 2014 recommendations published by the American Association for the Study of Liver Disease (AASLD) and account for general practitioner visit time, HCV-specific tests, general medical work-up, and therapy-specific testing³³. The cost of post-treatment monitoring is independent of the treatment received, but does depend on achieving SVR. Monitoring costs are dependent upon therapy duration, and are no longer accrued once patients discontinue treatment. The 4-week monitoring costs incurred while on treatment, and the annual post-treatment monitoring costs are summarized in Table 1. Annual costs associated with each fibrosis stage, SVR, and each complication were obtained from Davis et al.³⁴, McAdam-Marx et al.³⁵, and the 2014 AASLD recommendations³³ (Table 1). Annual SVR costs depend on the severity of the HCV state from which patients achieved SVR and whether the patient has been in that state for 1 year or more. All costs were converted to and reported in 2014 US dollars³⁶.

Health-state utilities

The model incorporates health-related quality-of-life for all health states via utility values that are used to compute QALYs. Utilities for health states were obtained from Martin et al.²². The utilities for patients achieving SVR depended on the fibrosis stage from which SVR was achieved. The health utility values are shown in Table 1.

As AEs were assumed to be usually mild, the impact of treatment-related AEs on quality-of-life was incorporated into a treatment-related disutility adjustment, rather than via an AE disutility. The treatment-related disutility was not incurred following therapy discontinuation. The disutilities for DCV + SOF and SOF + RBV, both of which are peginterferon alfa-free regimens, were estimated to be 0.070 (SE = 0.014) per Younossi et al.³⁷.

Model outcomes

The primary outcomes of the model were QALYs, direct costs, and the incremental cost-utility ratio (ICUR). The ICUR is defined as the ratio of incremental total direct costs incurred to incremental QALYs gained associated with DCV + SOF compared with SOF + RBV. Secondary outcomes include life years (LYs) gained; the incremental cost-effectiveness ratio (ICER; defined as the ratio of incremental total direct costs incurred to incremental LYs gained); and event counts for CC, DC, HCC, LTx, and liver-related deaths. Additional outcomes include direct costs and therapy-related costs (including costs related to drug acquisition, monitoring, and AE management) per SVR.

Analyses

The base-case analysis evaluated a hypothetical cohort of 1,000 patients over a 20-year time horizon from a US payer perspective. Costs and health benefits were both discounted at 3.0% annually³⁸. A range of additional analyses were conducted to evaluate the robustness of the results and identify the model parameters which, when varied, exhibited the greatest effect on model results. These analyses included deterministic sensitivity analyses (DSA), probabilistic sensitivity analyses (PSA), and scenario analyses.

One-way DSA were conducted to evaluate how the model outcomes changed as selected model parameters were varied. These analyses were conducted by individually varying the SVR probabilities (by ± 10%), health state costs (by ± 20%), DCV weekly therapy cost (by ± 20%), and SOF weekly therapy cost (by ± 20%) while holding all others constant. Results reported from the DSA are the differences in costs, QALYs, as well as the ICUR between the two treatment arms calculated with all parameters set to their minimum or maximum values.

PSA were conducted to account for joint parameter uncertainty by simultaneously varying age, sex, initial fibrosis stage distribution, efficacy, costs, treatment discontinuation probabilities, disutilities, transition probabilities, costs and utilities for all health states, AE incidence, and AE cost. Transition probabilities and health utilities were sampled from a beta distribution, and costs were sampled from a gamma distribution. One thousand bootstrap replications with a cohort size of 1,000 patients were used in the PSA. Results of the PSA are displayed in a scatterplot and a cost-effectiveness acceptability curve (CEAC), with willingness-to-pay (WTP) ranging from $0–$100,000 per additional QALY.

Eight alternate scenarios evaluated the sensitivity of the results to differences in population (treatment-naïve, treatment-experienced, non-cirrhotic, cirrhotic), comparators (no treatment as control arm), and time horizon (5, 10, and 80 years).

Results

Base-case analysis

Treatment with DCV + SOF resulted in lower costs, from a payer’s perspective ($161,504 vs $190,146), and more QALYs gained (10.54 vs 10.44) over 20 years than SOF + RBV (i.e. DCV + SOF dominated SOF + RBV) in the overall GT 3 HCV patient population in the US (Table 2). Patients treated with DCV + SOF gained 0.03 more LYs than patients treated with SOF + RBV (13.95 vs 13.92, respectively) and they also experienced 14 fewer cases of CC, seven fewer cases of DC, three fewer cases of HCC, one fewer LTx, and seven fewer liver-related deaths (per 1,000 patients) than patients treated with SOF + RBV.

Table 2. Base-case discounted results.

Outcomes	DCV + SOF	SOF + RBV	Difference
Per patient
Total costs^a	$161,504	$190,146	–$28,642
Cost of AEs^a	$42	$76	–$34
Monitoring costs^a	$441	$603	–$162
Antiviral costs^a	$146,677	$169,451	–$22,775
Disease management costs^a	$14,344	$20,015	–$5,672
LYs^a	13.95	13.92	0.03
QALYs^a	10.54	10.44	0.10
Total number achieving SVR	896	852	44
Total cost per SVR	$180,250	$223,176	–$42,926
Antiviral cost per SVR	$164,241	$199,684	–$35,443
Incremental total costs per QALY	—	—	Dominant
Per 1,000 patients
CC	34	48	−14
DC	17	24	−7
HCC	7	10	−3
LTx	2	3	−1
Liver-related deaths	16	22	−7

AE: Adverse event; CC: Compensated cirrhosis; DC: Decompensated cirrhosis; DCV: Daclatasvir; HCC: Hepatocellular carcinoma; ICER: Incremental cost-effectiveness ratio; ICUR: Incremental cost-utility ratio; LTx: Liver transplant; LY: Life-year; QALY: Quality-adjusted life year; RBV: Ribavirin; SOF: Sofosbuvir; SVR: Sustained virological response.

^a Discounted using an annual rate of 3%.

Compared with patients receiving SOF + RBV, patients receiving DCV + SOF incurred lower costs for anti-viral therapy ($146,677 vs $169,451), management of AEs ($42 vs $76), monitoring ($441 vs $603), and disease management ($14,344 vs $20,015). Treatment with DCV + SOF was, therefore, associated with lower total direct and therapy-related costs per SVR ($180,250 vs $223,176).

Deterministic sensitivity analyses

DSA results showed that DCV + SOF dominated SOF + RBV in the majority of the analyses (Table 3). The incremental cost of DCV + SOF vs SOF + RBV was most sensitive to variations in both DCV + SOF and SOF + RBV weekly therapy costs. Variations in SVR probabilities in the two arms had substantial effects on incremental QALYs and ICURs. While DCV + SOF dominated SOF + RBV in most analyses, it no longer dominated if the SVR for DCV + SOF were decreased by 10%, if SVR for SOF + RBV were increased by 10%, if DCV + SOF treatment costs increased by 20%, or if SOF + RBV treatment costs decreased by 20%.

Table 3. DSA discounted results.

	Difference between arms
	Costs^a		QALYs^a		ICUR
	Minimum^b	Maximum^c	Minimum^b	Maximum^c	Minimum^b	Maximum^c
Base-case	−$28,642		0.10		Dominant
SVR probabilities for DCV + SOF	−$17,093	−$40,192	−0.07	0.27	$234,221	Dominant
SVR probabilities for SOF + RBV	−$39,625	−$17,660	0.26	−0.06	Dominant	$277,037
Disease state costs	−$27,500	−$29,785	0.10	0.10	Dominant	Dominant
Weekly therapy cost for DCV + SOF	−$57,978	$693	0.10	0.10	Dominant	$6,916
Weekly therapy costs for SOF + RBV	$5,248	−$62,533	0.10	0.10	$52,378	Dominant

DCV: Daclatasvir; DSA: Deterministic sensitivity analyses; ICUR: Incremental cost-utility ratio; LY: Life-year; QALY: Quality-adjusted life-year; RBV: Ribavirin; SOF: Sofosbuvir; SVR: Sustained virological response.

^a Discounted using an annual rate of 3%.

^b Results based on the minimum value in the range.

^c Results based on the maximum value in the range.

Probabilistic sensitivity analyses

In most of the PSA iterations, DCV + SOF provided better health outcomes (i.e. more QALYs) at lower costs than SOF + RBV, and DCV + SOF dominated SOF + RBV in ∼75% of the simulations (Figure 2). DCV + SOF was cost-effective compared with SOF + RBV in 79% of the PSA iterations at a WTP threshold of $50,000 per QALY (Figure 3).

Figure 2. PSA scatterplot results—discounted costs vs QALYs.PSA: probabilistic sensitivity analysis; QALY: quality-adjusted life years.Note: Costs and QALYs have been discounted using a 3% annual rate.

Figure 3. Cost-effectiveness acceptability curve.

Scenario analyses

The results of the scenario analysis are detailed in Table 4. DCV + SOF dominated SOF + RBV in every scenario tested except for treatment-naïve and cirrhotic patients, for which DCV + SOF was less costly but also slightly less effective, and in the scenario where DCV + SOF is compared with no treatment, for which DCV + SOF has an ICUR of $18,371 per QALY.

Table 4. Scenario analysis discounted results.

Scenario (population, comparator, time horizon)	Total costs (per patient)^a		QALYs (per patient)^a		ICUR of DCV + SOF versus comparator
	DCV + SOF	Comparator	DCV + SOF	Comparator
Base-case analysis	$161,504	$190,146	10.54	10.44	Dominant
Treatment-naïve, SOF + RBV, 20 years	$160,682	$179,705	10.55	10.60	DCV regimen is less costly but also slightly less effective
Treatment-experienced, SOF + RBV, 20 years	$166,113	$200,458	10.48	10.29	Dominant
Non-cirrhotic, SOF + RBV, 20 years	$152,043	$181,247	10.82	10.72	Dominant
Cirrhotic, SOF + RBV, 20 years	$236,329	$245,621	8.58	8.79	DCV regimen is less costly but also slightly less effective
Overall population, SOF + RBV, 5 years	$151,626	$176,090	3.50	3.47	Dominant
Overall population, SOF + RBV, 10 years	$155,303	$181,322	6.39	6.34	Dominant
Overall population, SOF + RBV, 80 years	$167,418	$198,563	13.64	13.49	Dominant
Overall population, No treatment, 20 years	$161,504	$129,839	10.54	8.82	$18,371

DCV: Daclatasvir; ICUR: Incremental cost-utility ratio; LY: Life-year; QALY: Quality-adjusted life-year; RBV: Ribavirin; SOF: Sofosbuvir.

^a Discounted using an annual rate of 3%.

Discussion

The ICUR representing the comparison of DCV + SOF with SOF + RBV for the treatment GT 3 HCV was estimated using a validated cohort-based Markov model designed to simulate the natural history of HCV from chronic infection to end-stage liver disease and mortality^9–11,13,39. The new oral therapy, DCV, which lacks an interferon component, is associated with a shorter treatment duration than the standard of care in the US (i.e. SOF + RBV) and constitutes the only regimen available without RBV for the majority of patients with GT 3 HCV at the time these analyses were conducted⁸. As part of its clinical development, DCV has been studied in the ALLY-3 trial, a phase 3 evaluation of DCV + SOF in treatment-naive and treatment-experienced subjects with GT 3 HCV. Data from ALLY-3 on treatment effects, discontinuations, and AEs associated with DCV + SOF were used in the model⁸. Data for SOF + RBV came from the phase-3 VALENCE trial²⁹.

The model analyses indicated that DCV + SOF was clearly a cost-effective treatment option compared with SOF + RBV for treatment of GT 3 HCV. Results also showed that the DCV + SOF regimen was associated with lower HCV-related morbidity and mortality. The primary drivers of cost-savings associated with the DCV + SOF regimen were the shorter treatment duration, which led to lower costs for antiviral therapy, and the reduced incidence of HCV-related complications, which led to lower disease management costs. The reduced number of HCV-related complications (CC, DC, HCC, LTx, and liver-related deaths) associated with the DCV-based regimen led to medical care cost savings and gains in LYs and QALYs. The DCV + SOF regimen was also associated with fewer AEs than the therapeutic strategy available at the time these analyses were conducted.

Comprehensive sensitivity analyses were performed to better characterize the robustness of the base-case estimates in response to uncertainty in various model inputs. Several deterministic and probabilistic analyses were conducted, and a number of alternate scenarios were evaluated. DCV + SOF dominated SOF + RBV in almost all sensitivity analyses, indicating that the findings were robust to individual and joint changes in a range of key parameters. The DSA indicated that incremental costs and QALYs generated by the model were most sensitive to assumptions concerning weekly therapy costs and SVR probabilities in both treatment arms. In the PSA, DCV + SOF was cost-effective relative to SOF + RBV at a WTP threshold of $50,000 per QALY in almost 79% of the replications. DCV + SOF dominated SOF + RBV in five of the eight scenarios evaluated. However, in the cirrhotic and treatment-naïve population scenarios, DCV + SOF was less costly, but also slightly less effective than SOF + RBV. DCV + SOF was associated with an ICUR of $18,371 per QALY compared with no treatment.

Findings of other economic models evaluating the DCV + SOF regimen for treatment of GT 3 HCV depend on the data sources used and the other therapies evaluated, as well as the patient population studied. Overall, published results of economic analyses in other countries were aligned with our findings, particularly when SOF + RBV was used as the comparator and when efficacy data from the ALLY-3 trial were used, as shown in Table 5^40–43.

Table 5. Summary of published economic studies in GT 3 HCV.

Study	Country	Population	Treatments	Data sources	QALYs	Costs	ICER
Najafzadeh et al.^40	US	TN	• DCV + SOF (24 weeks) • pINF + RBV (24 weeks) • SOF + RBV (24 weeks) • SOF + LDV + RBV (12 weeks)	• AI444040 • FISSION • ELECTRON 2 • VALENCE	• DCV + SOF: 12.16 • pINF + RBV: 11.50 • SOF + RBV: 11.37 • SOF + LDV + RBV: 12.35	• DCV + SOF: USD 317,830 • pINF + RBV: USD 58,323 • SOF + RBV: USD 207,872 • SOF + LDV + RBV: USD 120,464	• DCV + SOF vs pINF + RBV:USD 396,229 per QALY • SOF + RBV was more costly and less effective than pINF + RBV • SOF + LDV + RBV vs pINF + RBV: USD 73,236 per QALY
McEwan et al.^41	UK	TN patients with advanced fibrosis stages (≥3)	• DCV + SOF (24 weeks) • pINF + RBV (24 weeks) • No treatment	• AI444040 • ACCELERATE	Not reported (only incremental outcomes were reported)	Not reported (only incremental outcomes were reported)	• DCV + SOF vs pINF + RBV: £30,871 per QALY • DCV + SOF vs no treatment: £13,442 per QALY
McEwan et al.^42	UK	TN, TE, and INF-ineligible patients	• DCV + SOF (12 weeks) • SOF + RBV (24 weeks) • No treatment (for IFN-ineligible patients)	Matching-adjusted indirect comparison of the ALLY-3 and VALENCE trials	Not reported (only incremental outcomes were reported)	Not reported (only incremental outcomes were reported)	• DCV + SOF dominatedSOF + RBV for TN, TE, and IFN-ineligible patients • DCV + SOF vs no treatment: £7,736 per QALY for IFN-ineligible patients
Moshyk et al.^43	Canada	TN and TE	• DCV + SOF (12 weeks) • pINF + RBV (24 weeks) • SOF + RBV (24 weeks)	• ALLY-3 • VALENCE	TN: • DCV + SOF: 12.37 • pINF + RBV: 11.71 • SOF + RBV: 12.48 TE: • DCV + SOF: 12.11 • SOF + RBV: 11.87	TN: • DCV + SOF: CDN 170,371 • pINF + RBV: CDN 90,905 • SOF + RBV: CDN 194,775 TE: • DCV + SOF: CDN 170,575 • SOF + RBV: CDN 196,437	• DCV + SOF vs pINF + RBVin TN patients:CAN$120,671 per QALY • DCV + SOF dominated SOF + RBV in TE patients

CDN: Canadian dollar; DCV: daclatasvir; ICER: incremental cost-effectiveness ratio; IFN: interferon; LDV: ledipasvir; QALY: quality-adjusted life-year; RBV: ribavirin; SOF: sofosbuvir; TE: treatment-experienced; TN: treatment-naïve; UK: United Kingdom; US: United States; USD: United States dollar.

At the time we conducted these analyses, daily SOF in combination with RBV for 24 weeks was the recommended regimen for patients with HCV genotype 3 infection according to 2014 AASLD guidelines³³. Furthermore, the results from the ASTRAL-3 phase III trial⁴⁴ evaluating velpatasvir (VEL) in combination with SOF in this population of patients were not yet available. For these reasons, SOF + RBV was chosen as the comparator to DCV + SOF in this study. Our results confirm the 2016 AASLD guidelines⁴⁵, in the sense that SOF + RBV should not be used as a treatment option for patients with HCV GT 3 infection.

Limitations

One of the strengths of our analyses was the consideration of the complexity of the HCV disease and the fact that analyses were performed for various sub-groups of patients. However, the results of our analyses are limited by the lack of head-to-head comparisons for many drugs, which might compromise the conclusions of this cost-effectiveness study. No mixed-treatment comparisons evaluating the efficacy and safety of various HCV treatment options for patients with GT 3 HCV were available at the time of these analyses. However, the various clinical trials considered in our analyses were conducted over the same period of time, so it can reasonably be assumed that the patients enrolled in the various clinical trials had similar baseline characteristics and are, therefore, likely to be comparable.

Our analyses relied on a number of simplifying assumptions. First, patients achieving SVR from chronic HCV remained in a state of SVR; following attainment of SVR, patients were assumed to not progress to end-stage liver disease complications such as DC or HCC. Second, as AEs were typically mild, the impact of treatment-related AEs on quality-of-life was incorporated via the application of a treatment-specific disutility adjustment. Therefore, no AE-specific disutilities were applied. Third, AE risks were assumed to be independent of patient age or initial disease severity. Finally, we considered only one AE, namely anemia, in the analyses and ignored others. Including other AEs, which occur infrequently and are inexpensive to manage, would not likely impact the cost-effectiveness results in any significant way.

Conclusion

Conditional on the assumptions applied, results from this economic model provide strong evidence that DCV in combination with SOF is a dominant strategy over SOF + RBV for treatment of GT 3 HCV in the US, as it is a less expensive and more effective regimen. The provision of an interferon-free treatment alternative such as DCV + SOF could offer valuable benefit in reducing the rate of life-threatening liver complications and increasing patients’ quality-of-life.

Transparency

Declaration of funding

Funding for this study was provided by Bristol-Myers Squibb. The funder provided support in the form of consulting fees for some authors [CST, DM, and MLG] and salaries for other authors [BS, SH, YY, and BG].

Declaration of financial/other interests

CST and MLG are employees of Evidera, Inc., an independent research organization that received consulting fees from Bristol-Myers Squibb for the development of this paper. BS, SH, and YY are employees of Bristol-Myers Squibb, the manufacturer of daclatasvir. At the time of this research project, DM and BG were employees of Evidera and Bristol-Myers Squibb, respectively, but are currently employed elsewhere. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Previous presentation

Presented at the AASLD conference, San Francisco, CA, November 13–17, 2015.

Acknowledgments

The authors would like to acknowledge Michael Byrnes from Evidera for his help in writing this manuscript, as well as Lisa Rosenblatt from Bristol-Myers Squibb for her help in reviewing this paper.