- Email: [email protected]
Grazoprevir in Patients with Chronic Hepatitis C Genotype 1 Infection
VALUE IN HEALTH ] (2017) ]]]–]]]
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/jval
Cost-Utility of Elbasvir/Grazoprevir in Patients with Chronic Hepatitis C Genotype 1 Infection Shelby Corman, PharmD, MS, BCPS1,*, Elamin H. Elbasha, PhD2, Steven N. Michalopoulos, MPH1, Chizoba Nwankwo, PhD3 1
Pharmerit International, Bethesda, MD, USA; 2Merck & Co., Inc., North Wales, PA, USA; 3Merck & Co., Inc., Kenilworth, NJ, USA
AB STR A CT
Objective: To evaluate the cost-utility of treatment with elbasvir/ grazoprevir (EBR/GZR) regimens compared with ledipasvir/sofosbuvir (LDV/SOF), ombitasvir/paritaprevir/ritonavir þ dasabuvir ⫾ ribavirin (3D ⫾ RBV), and sofosbuvir/velpatasvir (SOF/VEL) in patients with chronic hepatitis C genotype (GT) 1 infection. Methods: A Markov cohort state-transition model was constructed to evaluate the costutility of EBR/GZR ⫾ RBV over a lifetime time horizon from the payer perspective. The target population was patients infected with chronic hepatitis C GT1 subtypes a or b (GT1a or GT1b), stratified by treatment history (treatment-naive [TN] or treatment-experienced), presence of cirrhosis, baseline hepatitis C virus RNA (o or Z6 million IU/mL), and presence of NS5A resistance-associated variants. The primary outcome was incremental cost-utility ratio for EBR/GZR ⫾ RBV versus available oral direct-acting antiviral agents. One-way and probabilistic sensitivity analyses were performed to test the robustness of the model. Results: EBR/GZR ⫾ RBV was economically dominant versus LDV/SOF in all patient populations. EBR/GZR ⫾ RBV was also less costly than SOF/VEL and 3D ⫾ RBV, but produced fewer quality-adjusted life-years in select populations. In the remaining
Introduction Chronic hepatitis C (CHC) infection affects more than 3.5 million patients in the United States, with an estimated 30,500 new hepatitis C virus (HCV) infections in 2014 [1]. It is estimated that 16% and 41% of patients will progress to cirrhosis within 20 and 30 years, respectively [2]. Of patients who develop cirrhosis, approximately 2% to 4% per year will go on to develop hepatocellular carcinoma (HCC) [3]. HCV infection is the leading indication for liver transplantation in the United States [4]. The total health care cost attributable to HCV infection in the United States was estimated in 2011 at $6.5 billion and was expected to increase until 2024, reaching $9.1 billion. Most of these projected costs are attributable to decompensated cirrhosis (DC) (46%), compensated cirrhosis (20%), and HCC (16%) [5]. Treatment of HCV infection and subsequent achievement of sustained virologic response (SVR) are of critical importance in reducing the clinical and economic burden of HCV. More than half of the patients with cirrhosis who achieve SVR experience
populations, EBR/GZR ⫾ RBV was economically dominant. One-way sensitivity analyses showed varying sustained virologic response rates across EBR/GZR ⫾ RBV regimens, commonly impacted model conclusions when lower bound values were inserted, and at the upper bound resulted in dominance over SOF/VEL in GT1a cirrhotic and GT1b TN noncirrhotic patients. Results of the probabilistic sensitivity analysis showed that EBR/GZR ⫾ RBV was cost-effective in more than 99% of iterations in GT1a and GT1b noncirrhotic patients and more than 69% of iterations in GT1b cirrhotic patients. Conclusions: Compared with other oral direct-acting antiviral agents, EBR/GZR ⫾ RBV was the economically dominant regimen for treating GT1a noncirrhotic and GT1b TN cirrhotic patients, and was cost saving in all other populations. Keywords: hepatitis C virus, elbasvir/grazoprevir, cost-utility, Markov.
Copyright & 2017, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
regression of fibrosis to noncirrhotic stages [6]. Risk of developing HCC is reduced by 65% to 91% in patients who achieve SVR [7]. Mortality is reduced by 67% in patients who achieve SVR in the general population of patients with HCV infection, with greater reductions seen in subgroups of patients with cirrhosis (74%) or HIV co-infection (79%) [8]. Health care costs are also significantly lower in patients achieving SVR compared with patients who are treated but do not achieve SVR [9,10]. Achieving SVR has also been associated with a significant improvement in health-related quality of life [7,11,12]. Before the development of direct-acting antiviral agents (DAAs), the combination of pegylated interferon (PegIFN) and ribavirin (RBV) was the mainstay of HCV infection treatment [13]. Telaprevir and boceprevir were the first NS3/4A protease inhibitor DAAs to be marketed in the United States, but were approved for use only in combination with PegIFN and RBV. These regimens are now considered to be inferior to newer regimens due to higher adverse event rates, longer treatment durations, multiple daily doses, drug interactions, and extensive monitoring [14].
* Address correspondence to: Shelby Corman, 4350 East-West Highway, Suite 1110, Bethesda, MD 20814. E-mail: [email protected]. 1098-3015$36.00 – see front matter Copyright & 2017, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.jval.2017.05.003
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Figure 1 – State transition diagram for chronic HCV and liver disease model. The model consists of the following health states: no fibrosis (F0), portal fibrosis without septa (F1), portal fibrosis with few septa (F2), portal fibrosis with numerous septa without cirrhosis (F3), compensated cirrhosis (F4), two decompensated cirrhosis (DC) states—first year and subsequent years (PDC), two hepatocellular carcinoma (HCC) states—first year and subsequent years (PHCC), two liver transplant states—first year (LT) and subsequent years (PLT), liver-related death (LV-Death), death from all other causes (not shown here), and two sustained virologic response (SVR) status states stratified by fibrosis stage – ‘SVR, F0–F3’ and ‘SVR, F4’. Recently, newer Food and Drug Administration–approved oral DAAs provide more convenient dosing regimens with fewer drugdrug interactions [15]. These drugs allow for IFN-free, RBV-free treatment for many patients, depending on the genotype (GT), severity of liver disease, and treatment history. Newer regimens also allow for shorter treatment durations. It is estimated that with the development of IFN-free, RBV-free regimens, the proportion of patients with CHC who are eligible for treatment has increased from 74% to 98% [16]. In the United States, four all-oral DAA regimens are indicated for GT1 infection, and are now considered standard of care: ledipasvir/sofosbuvir (LDV/SOF; Harvonis), ombitasvir/paritaprevir/ritonavir þ dasabuvir (3D; Viekira Paks), sofosbuvir/velpatasvir (SOF/VEL; Epclusas), and elbasvir/grazoprevir (EBR/GZR; Zepatiers). The objective of this study was to evaluate the costeffectiveness of EBR/GZR treatment regimens compared with oral DAA regimens under different assumptions.
Methods We used a Markov cohort state-transition model to assess the economic benefit of treatment with EBR/GZR-based regimens in patients with HCV GT1 in the United States, from the payer perspective. The model simulates the natural history of HCV infection and its treatment via a series of health states reflecting progression of liver disease and its complications in patients who do and do not achieve SVR following treatment with EBR/GZR or comparators. The model uses a lifetime time horizon and a 3% discount rate for costs and utilities.
Target Population The model simulated cohorts of patients infected with HCV GT1. To accurately simulate treatment schedules and outcomes, we divided patients into cohorts on the basis of characteristics that influence treatment selection and duration including cirrhosis status, HCV subtype (GT1a or 1b), treatment history (treatmentnaive [TN] or treatment-experienced [TE]), presence of baseline NS5A resistance-associated variants (RAVs) for GT1a patients, and baseline HCV RNA (o6 million or Z6 million IU/mL) for TN
patients. Within each subgroup (n ¼ 18), patients were categorized by age and sex to calculate background mortality rates and utility values.
Model Structure The cohort model was designed to be consistent with current understanding of the biology of CHC-related liver disease and its treatment (Fig. 1). The structure of the model was based on other published health economic models of HCV disease [17–21], including four previously published and validated Markov cohort models that compared PegIFN and RBV with and without boceprevir, or no treatment, and treatment with EBR/GZR following testing for RAV [22–25]. The model was developed in accordance with the International Society for Pharmacoeconomics and Outcomes Research good practices for economic modeling [26]. The model consists of 16 health states with a cycle length of 1 year. Hepatic fibrosis stage was based on the METAVIR fibrosis scoring system. The progressive disease model assumes that a person with a given fibrosis score at model entry may progress to more severe stages of liver disease or may remain in that health state. In the absence of successful treatment, regression to less severe health states is not permitted. However, after successful treatment a person can achieve SVR. The Markov transition probabilities were assumed to be fixed over time. Because the likelihood of a chronically infected person spontaneously clearing HCV is very small, this health state, and the transition to it, has not been included in the model. To account for the possibility of HCV reinfection, the model allows for transitions from SVR states to fibrosis states following reinfection and failure to clear the virus during the acute infection state (i.e., chronicity). Only one-time reinfection was considered and future diagnosis and treatment were not accounted for. Patients with compensated cirrhosis were at risk for developing DC and/or HCC. Although there are different modes of decompensation (e.g., ascites, variceal hemorrhage, and encephalopathy), they are modeled as one health state here because these decompensation modes are not mutually exclusive. If a patient develops DC and/or HCC, then the patient may receive a liver transplant. To account for differences in mortality rates over time among patients with advanced liver
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disease (i.e., DC, HCC, recipients of liver transplantation), the mortality rates during year one were different from those after year one. All other patients had the same mortality risk as the general US population.
Model Assumptions It was assumed that there is no progression to more severe health states (i.e., cirrhosis) during therapy or subsequent follow-up for patients who respond to treatment. SVR is considered a cure for patients who were originally noncirrhotic (i.e., baseline fibrosis score of F0, F1, F2, or F3). Future re-treatment of patients who failed treatment was not considered, nor was treatment of patients with decompensated cirrhosis. Previously cirrhotic patients (i.e., baseline fibrosis score of F4) were assumed to have an excess risk of DC and HCC even if they achieved SVR with treatment. Progression to DC and/or HCC could only occur in cirrhotic patients (i.e., F4 health states), and liver transplantation is performed for patients with DC or HCC only. Patients who receive a liver transplant are assumed to be at no risk of reactivation and progression to liver disease. Adverse events do not differ significantly by treatment regimens and thus are not included.
Model Comparators Food and Drug Administration–approved regimens of EBR/GZR, with or without RBV, were compared with other regimens indicated for GT1 HCV at the labeled dose and duration for each subpopulation (Table 1). In the EBR/GZR arm, GT1a patients with RAVs received 16 weeks of therapy in combination with RBV, while all other populations were treated for 12 weeks without ribavirin. Duration of therapy for LDV/SOF is 8 weeks in TN patients with low viral load, 24 weeks in TE patients, and 12 weeks in all other populations.
Model Inputs Treatment efficacy and discontinuation rates associated with antiviral therapy were derived from pivotal trials of the model comparators in the respective patient population and regimen (Tables 1 and 2). Clinical inputs that describe the rate of HCV progression, the probability of receiving a liver transplantation, both other-cause and liver-related mortality rates, the progression rates, the likelihood of a patient developing serious complications associated with liver disease, and the probability of requiring a liver transplant were sourced from the published literature (Table 2). The study took a third-party payer perspective and costs were inflated to 2016 US dollars using the Consumer Price Index (Medical Care Component) [27]. The costs of oral DAAs were obtained from the Red Book, and represent wholesale acquisition costs without discounts [28]. Costs of required tests for HCV phenotyping or monitoring reflect median reimbursement for commercial insurance plans [29]. The health state costs associated with disease progression (e.g., outpatient visits, monitoring, and hospitalization) were based on the published literature (Table 2) [30]. Age- and sex-specific utility weights were obtained from the published literature [31]. Utility weights during the treatment phase and for each of the HCV health states and liver disease conditions were used to adjust for quality of life among survivors. An on-treatment disutility was applied to RBV-containing regimens; no disutility was applied to RBV-free regimens.
Model Analyses Cost-utility of an EBR/GZR regimen relative to a comparator was evaluated using the incremental cost-utility ratio (ICUR), which is obtained by dividing the incremental total discounted costs by
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the incremental total discounted number of quality-adjusted lifeyears (QALYs) for the EBR/GZR regimen instead of the comparator. In cases in which the EBR/GZR regimen was less costly and more effective than a given comparator, it was concluded to be economically dominant. In cases in which total costs and QALYs were both lower with EBR/GZR, the results are presented as being cost saving; otherwise, the cost per QALY was presented. In the base-case analysis, aggregated results are presented separately by genotype, cirrhosis status, and treatment history. Subgroups by presence of RAVs and baseline viral load were pooled. One-way sensitivity analyses were conducted for several parameters showing the effect of varying these inputs on the ICUR of EBR/GZR treatment strategies compared with the comparator. We varied efficacy, progression rates, discontinuation rates, unit costs, utility weights, and discount rates using the ranges defined in the inputs tables (Tables 1 and 2; see Appendix Table 1 in Supplemental Materials found at http://dx.doi.org/10. 1016/j.jval.2017.05.003). To quantify the impact of uncertainty in the estimated values of transition probabilities, efficacy, costs, and utility weights on the ICUR of EBR/GZR and other DAAs, we performed probabilistic sensitivity analysis (PSA) by drawing 1000 random samples from predefined distributions. It is important to note that the PSA was conducted using each individual subpopulation (e.g., GT1a with and without RAVs; low and high baseline viral load) and then pooled, as done in the base-case analysis. Results of the PSA were summarized using descriptive statistics and presented using cost-effectiveness acceptability curves.
Results Aggregated results are presented separately by genotype, cirrhosis status, and treatment history (Tables 3 and 4; see Appendix Table 2 in Supplemental Materials found at http://dx.doi.org/10. 1016/j.jval.2017.05.003). Results are weighted by the proportion of patients with RAVs (GT1a TN and TE) and/or low or high baseline viral load (GT1a TN and TE, and GT1b TN). EBR/GZR ⫾ RBV was economically dominant relative to LDV/ SOF in all GT1a and GT1b subpopulations regardless of cirrhosis status, and in five of eight subpopulations when compared with either 3D ⫾ RBV or SOF/VEL (Tables 3 and 4; Appendix Table 2). In cost-saving scenarios, the QALY benefit for any treatment was 0.0938 or lower over the time horizon. In subpopulations of patients in whom EBR/GZR ⫾ RBV was not economically dominant (vs. 3D ⫾ RBV: GT1b TN or TE noncirrhotic and GT1b TE cirrhotic; vs. SOF/VEL, GT1a TN or TE cirrhotic or GT1b TN noncirrhotic), the ICURs for each treatment versus EBR/GZR ⫾ RBV exceeded $178,000 per QALY. SOL/VEL was economically dominant compared with both 3D ⫾ RBV and LDV/SOL when used to treat patients with GT1a CHC, regardless of treatment history and/or cirrhosis status. With respect to patients with GT1b CHC, however, SOL/VEL was economically dominant compared with 3D ⫾ RBV among TN patients and cost saving among TE patients. Relative to LDV/SOF, SOL/VEL was economically dominant for patients with GT1b CHC with no cirrhosis, and provided cost saving as treatment of GT1b CHC with cirrhosis. The total cost to treat patients with GT1a or GT1b CHC was the lowest, and QALYs were highest, across all comparators when treatment was administered before cirrhosis (i.e., during F0–F3). Among patients with no cirrhosis, the lifetime costs of treatment range from $59,111 to $100,423 (difference $41,312), while QALYs range from 15.2677 to 15.3779 (difference 0.1102). EBR/GZR resulted in the lowest costs in all groups (GT1b TE), whereas LDV/SOF contributed to the highest costs (in GT1a TE and GT1b TE). With respect to total QALYs, 3D ⫾ RBV produced the greatest
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Table 1 – Treatment inputs by population. Treatment regimen, by population
Subpopulation
Noncirrhotic Duration (wk)
GT1a, TN EBR/GZR ⫾ RBV LDV/SOF
LDV/SOF 3D þ RBV SOF/VEL GT1b, TN EBR/GZR LDV/SOF 3D SOF/VEL GT1b, TE EBR/GZR LDV/SOF 3D SOF/VEL
SVR (95% CI)
Duration (wk)
References
SVR (95% CI)
RAV RAVþ LVL - HCV RNA o6 million IU/mL HVL - HCV RNA Z6 million IU/mL – –
12 16* 8 12 12* 12
0.980 1.000 0.971 0.953 0.961 0.957
(0.962–0.991) (0.541–1.000) (0.847–0.999) (0.910–0.980) (0.940–0.976) (0.938–0.985)
12 16* 12 12 24* 24
0.980 1.000 0.970 0.970 0.946 1.000
(0.962–0.991) (0.541–1.000) (0.842–0.999) (0.842–0.999) (0.894–0.997) (0.962–1.000)
[39] [39] [40,41] [40,41] [42–45] [46]
RAV RAVþ – – –
12 16* 12 12* 12
0.980 1.000 0.954 0.964 0.957
(0.962–0.991) (0.541–1.000) (0.886–0.987) (0.926–0.985) (0.938–0.993)
12 16* 24* 24 12
0.980 1.000 0.986 1.000 1.000
(0.962–0.991) (0.541–1.000) (0.924–1.000) (0.872–1.000) (0.962–1.000)
[39] [39] [47,48] [44,45,49] [46]
– LVL - HCV RNA o6 million IU/mL HVL - HCV RNA Z6 million IU/mL – –
12 8 12 12 12
0.982 0.971 0.953 0.993 0.984
(0.936–0.998) (0.847–0.999) (0.910–0.980) (0.976–0.999) (0.960–0.996)
12 12 12 12 12
1.000 0.970 0.970 0.942 0.958
(0.936–1.000) (0.842–0.999) (0.842–0.999) (0.892–0.991) (0.789–0.999)
[50] [40] [40] [43,44] [46]
– – – –
12 12 12 12
1.000 0.954 1.000 0.984
(0.900–1.000) (0.886–0.987) (0.960–1.000) (0.960–0.996)
12 24 12 12
1.000 0.980 1.000 0.958
(0.541–1.000) (0.891–0.999) (0.894–1.000) (0.789–0.999)
[39] [47,48] [51,52] [46]
Parameters for the beta distributions can be found in Appendix Table 1. 3D, ombitasvir/paritaprevir/ritonavir þ dasabuvir; CI, confidence interval; EBR, elbasvir, GT, genotype; GZR, grazoprevir; HVL, high viral load; LDV, ledipasvir; LVL, low viral load; RAV, resistanceassociated variant; SOF, sofosbuvir; SVR, sustained virologic response; TE, treatment-experienced; TN, treatment-naive; VEL, velpatasvir. * Used in combination with ribavirin.
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3DþRBV SOF/VEL GT1a, TE EBR/GZR ⫾ RBV
Cirrhotic
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Table 2 – Baseline characteristics of patients with HCV infection, probabilities, cost, and utility inputs. Variable
Age (y) 20–29 30–39 40–49 50–59 Z60 Proportion males Proportion of GT1a patients with NS5A RAVs* Proportion of GT1 patients with viral load o6 million IU/mL* Fibrosis stage at baseline† F0 F1 F2 F3 F4 Fibrosis progression F0 to F1 F1 to F2 F2 to F3 F3 to F4 Cirrhosis regression (SVR, F4 to SVR, F3) Cirrhosis progression F4 to DC F4 to HCC SVR, F4 to DC SVR, F4 to HCC Reinfection Annual probability Probability of chronicity Liver disease progression, DC to HCC Probability of Receiving LT DC HCC Mortality rates Age-/sex-specific all-cause DC (first year) DC (subsequent years) HCC-related LT (first year) LT (subsequent years) Health state costs (annual) F0–F1 F2 F3 F4 DC HCC Liver transplant, year 1 Liver transplant, subsequent years Drug costs (weekly) EBR/GZR LDV/SOF 3D SOF/VEL RBV
Base case
Range
Distribution
Parameter 1
Parameter 2
Reference
0.012 0.101 0.407 0.383 0.097 0.636 0.120
0.003–0.052 0.064–0.156 0.340–0.478 0.316–0.454 0.068–0.136 0.561–0.706 0.09–0.15
[1] [39]
0.572
0.429–0.715
[41]
0.107 0.357 0.232 0.143 0.161
0.000–1.000 0.000–1.000 0.000–1.000 0.000–1.000 0.000–1.000
0.117 0.085 0.120 0.116 0.086
0.104–0.130 0.075–0.096 0.109–0.133 0.104–0.129 0.047–0.142
Beta Beta Beta Beta Beta
274.6 230.3 337.9 292.3 11.7
2072.8 2478.8 2478.2 2227.8 123.4
0.029 0.028 0.008 0.005
0.010–0.039 0.010–0.079 0.002–0.036 0.002–0.013
Beta Beta Beta Beta
14.9 2.4 6348.8 2487.5
498.6 84.4 787,251.2 495,012.5
0.047 0.430 0.068
0.036–0.061 0.29–0.58 0.030–0.083
Beta Beta Beta
51.7 18.8 23.5
1048.5 25.0 322.2
0.023 0.040
0.010–0.062 0.000–0.140
Beta Beta
1.3 3.9
55.4 93.1
– 0.140 0.112 0.427 0.166 0.044
– 0.065–0.190 0.065–0.190 0.330–0.860 0.060–0.420 0.060–0.420
– Beta Beta Beta Beta Beta
– 16.4 28.1 5.3 1.3 4.7
– 101.0 223.0 7.1 9.9 101.6
$739 $749 $1,520 $1,773 $19,702 $36,229 $104,671 $27,492
$554–$924 $562–$936 $1,140–$1,900 $1,330–$2,216 $14,777–$24,628 $27,172–$45,286 $78,503–$130,839 $20,620–$34,366
Gamma Gamma Gamma Gamma Gamma Gamma Gamma Gamma
61.5 61.5 61.5 61.5 61.5 61.5 61.5 61.5
12.0 12.2 24.7 28.8 320.5 589.4 1702.9 447.3
$4,550 $7,875 $6,943 $6,230 $48
$3,413–$5,688 $5,906–$9,844 $5,243–$8,679 $4,673–$7,788 $36–$60
[1]
[53]
[2]
[54]
[55–60] [55,61–63] [64] [60,62] [65–70]
[71] [72–74]
[75] [71] [55] [71] [76] [76] [22,27]
[28]
continued on next page
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Table 2 – continued Variable
Laboratory costs RAV testing ALT Direct bilirubin Utilities Disutility, RBV-containing regimens F0–F3 F4 DC HCC After liver transplant Post-SVR, F0–F4
Base case
Range
Distribution
Parameter 1
Parameter 2
Reference
$563 $28 $19
$422–$704 $21–$35 $14–$24
0.076
0.072–0.080
Beta
1281.3
15,578.4
[77]
0.93 0.90 0.80 0.79 0.84 1.00
0.88–0.98 0.86–0.95 0.76–0.84 0.75–0.83 0.80–0.88 0.95–1.00
Beta Beta Beta Beta Beta Beta
106.6 152.8 306.5 321.9 245.0 100.0
8.0 17.0 76.6 85.6 46.7 0.1
[78] [78] [78] [78] [78] [24]
[29]
3D, ombitasvir/paritaprevir/ritonavir þ dasabuvir; ALT, alanine aminotransferase; DC, decompensated cirrhosis; EBR, elbasvir; F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis with rare septa; F3, numerous septa without cirrhosis; F4, cirrhosis; G, genotype; GZR, grazoprevir; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LDV, ledipasvir; LT, liver transplant; RAV, resistance-associated variant; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response; VEL, velpatasvir. * Because these subpopulations are modeled separately, the proportions are used only for weighting the final results for GT1 by subpopulation. † Sensitivity analyses evaluated cost-effectiveness in patients of a single baseline fibrosis stage, setting its probability equal to 1 and probability of all other stages to 0.
number of QALYs (GT1b TE), whereas LDV/SOF the fewest (GT1a TE). Treatment costs among patients with cirrhosis ranged from $74,557 to $186,774 (difference $112,216) and QALYs ranged from 13.6456 to 14.0206 (difference 0.3751). Costs were lowest for EBR/ GZR (G1b TN or TE) and highest for 3D (GT1a TN), and QALYs were lowest and highest for 3D in GT1a TN and G1b TE, respectively.
Deterministic Sensitivity Analysis Deterministic sensitivity analysis was performed with individual subpopulations (n ¼ 18), with and without pooling of RAVpositive and negative or low and high viral load populations (data not shown). Across all subpopulations, SVR rates and medication costs had the largest impact on the results. Reducing the efficacy of EBR/GZR þ RBV to the lower bound of its confidence interval, an SVR of 54.1%, resulted in a change from
Table 3 – Base-case results, genotype 1a (among all-oral DAAs). Treatment regimen GT1a, TN, NC 3D þ RBV LDV/SOF SOF/VEL EBR/GZR ⫾ RBV GT1a, TE, NC 3D þ RBV LDV/SOF SOF/VEL EBR/GZR ⫾ RBV GT1a, TN, C 3D þ RBV LDV/SOF SOF/VEL EBR/GZR ⫾ RBV GT1a, TE, C 3D þ RBV LDV/SOF SOF/VEL EBR/GZR ⫾ RBV
Incremental QALYs
ICUR, EBR/GZR ⫾ RBV ($/QALY)
Total discounted costs ($)
Total discounted QALYs
Incremental costs ($)
$89,310 $82,416 $80,383 $62,337
15.2802 15.3094 15.3171 15.3308
$26,973 $20,078 $18,046 –
0.0507 0.0215 0.0137 –
Dominant Dominant Dominant –
$89,202 $100,423 $80,383 $62,337
15.2873 15.2677 15.3171 15.3308
$26,865 $38,086 $18,046 –
0.0435 0.0631 0.0137 –
Dominant Dominant Dominant –
$186,774 $116,016 $94,930 $78,201
13.6456 13.8665 14.0198 13.9260
$108,573 $37,815 $16,729 –
0.2804 0.0595 0.0938 –
Dominant Dominant Cost-saving –
$183,555 $180,107 $94,930 $78,201
13.9205 13.8753 14.0198 13.9260
$105,355 $101,906 $16,729 –
0.0055 0.0507 0.0938 –
Dominant Dominant Cost-saving –
Note: EGR/GZR ⫾ RBV is considered the reference treatment. 3D, ombitasvir/paritaprevir/ritonavir þ dasabuvir; DAA, direct-acting antiviral; EBR, elbasvir; GT, genotype; GZR, grazoprevir; ICUR, incremental cost-utility ratio; LDV, ledipasvir; QALY, quality-adjusted life-year; RAV, resistance-associated variant; SOF, sofosbuvir; SVR, sustained virologic response; TE, treatment-experienced; TN, treatment-naive; VEL, velpatasvir.
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Table 4 – Base-case results, genotype 1b (among all-oral DAAs). Treatment regimen GT1b, TN, NC 3D þ RBV LDV/SOF SOF/VEL EBR/GZR GT1b, TE, NC 3D þ RBV LDV/SOF SOF/VEL EBR/GZR GT1b, TN, C 3D þ RBV LDV/SOF SOF/VEL EBR/GZR GT1b, TE, C 3D þ RBV LDV/SOF SOF/VEL EBR/GZR
Total discounted costs ($)
Total discounted QALYs
Incremental costs ($)
Incremental QALYs
ICUR, EBR/GZR ⫾ RBV ($/QALY)
$87,257 $82,416 $79,485 $59,758
15.3613 15.3094 15.3765 15.3343
$27,499 $22,658 $19,727 –
0.0269 0.0250 0.0422 –
Cost-saving Dominant Cost-saving –
$87,005 $100,423 $79,485 $59,111
15.3779 15.2677 15.3765 15.3771
$27,894 $41,312 $20,374 –
0.0008 0.1094 0.0006 –
Cost-saving Dominant Dominant –
$106,312 $116,016 $97,449 $74,557
13.7234 13.8665 13.8046 14.0203
$31,754 $41,459 $22,892 –
0.2969 0.1538 0.2157 –
$102,832 $180,465 $97,449 $74,557
14.0206 13.8447 13.8046 14.0203
$28,275 $105,908 $22,892 –
0.0003 0.1756 0.2157 –
Dominant Dominant Dominant – Cost-saving Dominant Dominant –
Note: EGR/GZR ⫾ RBV is considered the reference treatment. 3D, ombitasvir/paritaprevir/ritonavir þ dasabuvir; DAA, direct-acting antiviral; EBR, elbasvir; GT, genotype; GZR, grazoprevir; ICUR, incremental cost-utility ratio; LDV, ledipasvir; QALY, quality-adjusted life-year; RAV, resistance-associated variant; SOF, sofosbuvir; SVR, sustained virologic response; TE, treatment-experienced; TN, treatment-naive; VEL, velpatasvir.
economic dominance over each comparator, to inferiority in several GT1a, RAVþ subpopulations. In addition, EBR/GZR was dominant over SOF/VEL in the base-case analysis but had lower costs and QALYs at the lower bound of the SVR in GT1b, TN, cirrhotic and noncirrhotic patients. Increasing the cost of EBR/ GZR to 125% of its base-case value resulted in dominance by the comparator only in GT1a, cirrhotic, RAV-positive patients (vs. SOF/VEL), and G1b, TN patients with HCV RNA of less than 6 million IU/mL (vs. LDV/SOF). When pooling the subgroups, using the lower bounds of SVR rates with EBR/GZR resulted in cost savings in all subpopulations, versus all comparators (base-case SVR rates). When using the upper bound values for SVR, EBR/GZR was economically dominant in all subpopulations versus all comparators, with the exception of SOL/VEL among patients with GT1a with cirrhosis, in whom there were cost savings with decreased QALYs.
Probabilistic Sensitivity Analysis EBR/GZR ⫾ RBV was found to be cost-effective in at least 69.0% of the 1000 PSA iterations run, with a willingness-to-pay threshold up to $100,000 per QALY (Figs. 2 and 3). Regardless of treatment history, among subpopulations of GT1a and GT1b noncirrhotic subpopulation, EBR/GZR ⫾ RBV was cost-effective in more than 99% of the iterations. Among the subpopulations with cirrhosis, it was cost-effective in up to 85% of iterations. Among the other treatments, SOF/VEL was found to be cost-effective in more iterations compared with the other treatments.
Conclusions The cost-utility of approved oral DAAs was evaluated in populations of patients with GT1a and GT1b CHC. The base-case results of this model indicated that EBR/GZR ⫾ RBV is economically dominant or cost saving relative to LDV/SOF, 3D ⫾ RBV, and SOF/
VEL. EBR/GZR ⫾ RBV was dominant over all comparators in GT1a patients without cirrhosis, and in GT1b patients with cirrhosis. SOF/VEL was economically dominant compared with both 3D ⫾ RBV and LDV/SOF in all GT1a, and in GT1b for TN, noncirrhotic patients. The proportions of patients achieving SVR among the comparators in this model ranged from 94% to 100% with their respective regimens, and thus QALY differences between groups were small. Deterministic sensitivity analysis showed that the model was sensitive to EBR/GZR SVR in GT1a patients with NS5A RAVs, largely due to wide confidence intervals around SVR rates resulting from small sample sizes in EBR/GZR trial subgroups. It is estimated that 12% of HCV-infected patients have baseline NS5A RAVs, and require longer treatment duration compared with those without RAVs (16 weeks vs. 12 weeks) and concomitant use of RBV. Nonetheless, the base-case results indicate that EBR/ GZR þ RBV is cost-effective in GT1a patients when patients with and without RAVs are pooled. Conversely, cost differences between treatment arms were considerable and favored EBR/GZR. At equivalent treatment durations, medication cost is 27% lower for EBR/GZR than for the least expensive comparator, SOF/VEL. The additional costs of RAV testing in GT1a patients and required monitoring in patients receiving EBR/GZR were trivial in comparison to the drug cost and thus did little to close this gap. The small differences in SVR rates between comparators did not result in dramatic changes in the cost of treating liver disease in those failing to achieve SVR, and thus drug cost was a key driver of total cost. GT1 accounts for 72.6% of all CHC infections in the United States, or an estimated 2.5 million patients [32]. Among those, it is estimated that one in four patients already has significant liver fibrosis and would benefit from antiviral treatment [33]. Introduction of all-oral DAA regimens and expanded access to these regimens, coupled with universal screening for HCV infection, could make HCV infection a rare disease by 2036 [34]. However,
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Figure 2 – Cost-effectiveness acceptability curves: GT1a patients. Abbreviations: 3D, ombitasvir/paritaprevir/ritonavir þ dasabuvir; EBR, elbasvir; GT, genotype; GZR, grazoprevir; LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir; VEL, velpatasvir.
one study estimated that the cost to provide treatment with SOF/ LDV to all insured patients in the United States who are aware of their disease status is $136 billion over 5 years, and $100 billion for GT1a alone [30]. Selection of cost-effective therapies is an attractive alternative to strategies that delay or withhold treatment in patients with early-stage disease, with fewer patients developing advanced liver disease and requiring transplant. To our knowledge, this is the first analysis comparing the cost-effectiveness of all available DAA regimens in a diverse patient population. Previous models have compared sofosbuvirbased regimens to PegIFN and RBV, with or without boceprevir or telaprevir [30], studied costs and effectiveness only in patients with advanced fibrosis [35] or in a TN veteran population [36], or evaluated the cost-effectiveness of restricting treatment to those with advanced disease compared with full access for all infected patients [37]. Taken collectively, these models indicate that alloral DAA regimens are cost-effective compared with no treatment or to PegIFN-based regimens, and thus we did not include these treatment strategies in our model. This cost-utility analysis has several key strengths. First, the structure of the model is similar to that of other published models [22–24] but it also considered the possibility of reinfection after a patient achieved SVR. Second, the model is flexible enough to allow the simultaneous evaluation of multiple cohorts and several comparators. For example, the base case consisted of 18 patient subgroups, four comparators, and 12 baseline
demographic characteristics (by sex, six age groups). Simultaneously, the model allows for pooling of subgroups to collapse treatment-specific subgroups (i.e., presence of RAVs for GT1a patients receiving EBR/GZR) into populations common to all comparators. The analysis also has some limitations. First, assumptions regarding natural history and management of liver disease (e.g., assuming DC and HCC are mutually exclusive states) may overestimate the clinical benefits of HCV treatment in the model. Also, in the absence of robust evidence showing the effectiveness of all-oral DAAs from the real-world clinical setting, inputs were estimated using results from several clinical trials, without adjustments made for between-trial heterogeneity. Within some subpopulations, treatment efficacy was estimated from subpopulations with small sample sizes, which may affect the generalizability of these results. To evaluate the effect of these factors, a follow-up analysis will be necessary once robust, real-world clinical evidence for all oral DAAs has become available. There were also factors that may influence survival in the model. In the absence of age- and sex-adjusted mortality rates specific to the HCV population, mortality was estimated on the basis of general US population. This approach fails to account for any biological or behavioral factors that are unique to this population that have the potential to decrease survival. Furthermore, it was assumed that patients who were re-infected (with chronicity) after achieving SVR would not receive any subsequent HCV treatment
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Figure 3 – Cost-effectiveness acceptability curves: GT1b patients. Abbreviations: 3D, ombitasvir/paritaprevir/ritonavir þ dasabuvir; EBR, elbasvir; GT, genotype; GZR, grazoprevir; LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir; VEL, velpatasvir.
increasing potential costs while decreasing utility. Finally, in the absence of publicly available reimbursement amounts specific to each treatment, treatment costs were estimated using the most comprehensive and transparent basis, as recommended best practices for economic modeling [38]. Therefore, the results of this analysis are valid only when wholesale acquisition cost is used, exclusive of discounts. Treatment costs in real-world practice may differ because of negotiated agreements that are not publicly disclosed. In conclusion, this model demonstrated EBR/GZR ⫾ RBV to be cost-effective or cost saving relative to LDV/SOF and 3D ⫾ RBV in most patients with GT1a and 1b CHC infection. In cases in which EBR/GZR was associated with lower costs and QALYs, ICURs for comparators were outside conventional ranges of costeffectiveness. Source of Financial Support: Support for this work was provided by Merck & Co., Inc.
Supplemental Materials Supplemental material accompanying this article can be found in the online version as a hyperlink at http://dx.doi.org/10.1016/j. jval.2017.05.003 or, if a hard copy of article, at www.valueinhealth journal.com/issues (select volume, issue, and article).
R EF E R EN C ES
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Cost-Utility of Elbasvir/Grazoprevir in Patients with Chronic Hepatitis C Genotype 1 Infection Shelby Corman, PharmD, MS, BCPS1,*, Elamin H. Elbasha, PhD2, Steven N. Michalopoulos, MPH1, Chizoba Nwankwo, PhD3 1
Pharmerit International, Bethesda, MD, USA; 2Merck & Co., Inc., North Wales, PA, USA; 3Merck & Co., Inc., Kenilworth, NJ, USA
AB STR A CT
Objective: To evaluate the cost-utility of treatment with elbasvir/ grazoprevir (EBR/GZR) regimens compared with ledipasvir/sofosbuvir (LDV/SOF), ombitasvir/paritaprevir/ritonavir þ dasabuvir ⫾ ribavirin (3D ⫾ RBV), and sofosbuvir/velpatasvir (SOF/VEL) in patients with chronic hepatitis C genotype (GT) 1 infection. Methods: A Markov cohort state-transition model was constructed to evaluate the costutility of EBR/GZR ⫾ RBV over a lifetime time horizon from the payer perspective. The target population was patients infected with chronic hepatitis C GT1 subtypes a or b (GT1a or GT1b), stratified by treatment history (treatment-naive [TN] or treatment-experienced), presence of cirrhosis, baseline hepatitis C virus RNA (o or Z6 million IU/mL), and presence of NS5A resistance-associated variants. The primary outcome was incremental cost-utility ratio for EBR/GZR ⫾ RBV versus available oral direct-acting antiviral agents. One-way and probabilistic sensitivity analyses were performed to test the robustness of the model. Results: EBR/GZR ⫾ RBV was economically dominant versus LDV/SOF in all patient populations. EBR/GZR ⫾ RBV was also less costly than SOF/VEL and 3D ⫾ RBV, but produced fewer quality-adjusted life-years in select populations. In the remaining
Introduction Chronic hepatitis C (CHC) infection affects more than 3.5 million patients in the United States, with an estimated 30,500 new hepatitis C virus (HCV) infections in 2014 [1]. It is estimated that 16% and 41% of patients will progress to cirrhosis within 20 and 30 years, respectively [2]. Of patients who develop cirrhosis, approximately 2% to 4% per year will go on to develop hepatocellular carcinoma (HCC) [3]. HCV infection is the leading indication for liver transplantation in the United States [4]. The total health care cost attributable to HCV infection in the United States was estimated in 2011 at $6.5 billion and was expected to increase until 2024, reaching $9.1 billion. Most of these projected costs are attributable to decompensated cirrhosis (DC) (46%), compensated cirrhosis (20%), and HCC (16%) [5]. Treatment of HCV infection and subsequent achievement of sustained virologic response (SVR) are of critical importance in reducing the clinical and economic burden of HCV. More than half of the patients with cirrhosis who achieve SVR experience
populations, EBR/GZR ⫾ RBV was economically dominant. One-way sensitivity analyses showed varying sustained virologic response rates across EBR/GZR ⫾ RBV regimens, commonly impacted model conclusions when lower bound values were inserted, and at the upper bound resulted in dominance over SOF/VEL in GT1a cirrhotic and GT1b TN noncirrhotic patients. Results of the probabilistic sensitivity analysis showed that EBR/GZR ⫾ RBV was cost-effective in more than 99% of iterations in GT1a and GT1b noncirrhotic patients and more than 69% of iterations in GT1b cirrhotic patients. Conclusions: Compared with other oral direct-acting antiviral agents, EBR/GZR ⫾ RBV was the economically dominant regimen for treating GT1a noncirrhotic and GT1b TN cirrhotic patients, and was cost saving in all other populations. Keywords: hepatitis C virus, elbasvir/grazoprevir, cost-utility, Markov.
Copyright & 2017, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
regression of fibrosis to noncirrhotic stages [6]. Risk of developing HCC is reduced by 65% to 91% in patients who achieve SVR [7]. Mortality is reduced by 67% in patients who achieve SVR in the general population of patients with HCV infection, with greater reductions seen in subgroups of patients with cirrhosis (74%) or HIV co-infection (79%) [8]. Health care costs are also significantly lower in patients achieving SVR compared with patients who are treated but do not achieve SVR [9,10]. Achieving SVR has also been associated with a significant improvement in health-related quality of life [7,11,12]. Before the development of direct-acting antiviral agents (DAAs), the combination of pegylated interferon (PegIFN) and ribavirin (RBV) was the mainstay of HCV infection treatment [13]. Telaprevir and boceprevir were the first NS3/4A protease inhibitor DAAs to be marketed in the United States, but were approved for use only in combination with PegIFN and RBV. These regimens are now considered to be inferior to newer regimens due to higher adverse event rates, longer treatment durations, multiple daily doses, drug interactions, and extensive monitoring [14].
* Address correspondence to: Shelby Corman, 4350 East-West Highway, Suite 1110, Bethesda, MD 20814. E-mail: [email protected]. 1098-3015$36.00 – see front matter Copyright & 2017, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.jval.2017.05.003
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Figure 1 – State transition diagram for chronic HCV and liver disease model. The model consists of the following health states: no fibrosis (F0), portal fibrosis without septa (F1), portal fibrosis with few septa (F2), portal fibrosis with numerous septa without cirrhosis (F3), compensated cirrhosis (F4), two decompensated cirrhosis (DC) states—first year and subsequent years (PDC), two hepatocellular carcinoma (HCC) states—first year and subsequent years (PHCC), two liver transplant states—first year (LT) and subsequent years (PLT), liver-related death (LV-Death), death from all other causes (not shown here), and two sustained virologic response (SVR) status states stratified by fibrosis stage – ‘SVR, F0–F3’ and ‘SVR, F4’. Recently, newer Food and Drug Administration–approved oral DAAs provide more convenient dosing regimens with fewer drugdrug interactions [15]. These drugs allow for IFN-free, RBV-free treatment for many patients, depending on the genotype (GT), severity of liver disease, and treatment history. Newer regimens also allow for shorter treatment durations. It is estimated that with the development of IFN-free, RBV-free regimens, the proportion of patients with CHC who are eligible for treatment has increased from 74% to 98% [16]. In the United States, four all-oral DAA regimens are indicated for GT1 infection, and are now considered standard of care: ledipasvir/sofosbuvir (LDV/SOF; Harvonis), ombitasvir/paritaprevir/ritonavir þ dasabuvir (3D; Viekira Paks), sofosbuvir/velpatasvir (SOF/VEL; Epclusas), and elbasvir/grazoprevir (EBR/GZR; Zepatiers). The objective of this study was to evaluate the costeffectiveness of EBR/GZR treatment regimens compared with oral DAA regimens under different assumptions.
Methods We used a Markov cohort state-transition model to assess the economic benefit of treatment with EBR/GZR-based regimens in patients with HCV GT1 in the United States, from the payer perspective. The model simulates the natural history of HCV infection and its treatment via a series of health states reflecting progression of liver disease and its complications in patients who do and do not achieve SVR following treatment with EBR/GZR or comparators. The model uses a lifetime time horizon and a 3% discount rate for costs and utilities.
Target Population The model simulated cohorts of patients infected with HCV GT1. To accurately simulate treatment schedules and outcomes, we divided patients into cohorts on the basis of characteristics that influence treatment selection and duration including cirrhosis status, HCV subtype (GT1a or 1b), treatment history (treatmentnaive [TN] or treatment-experienced [TE]), presence of baseline NS5A resistance-associated variants (RAVs) for GT1a patients, and baseline HCV RNA (o6 million or Z6 million IU/mL) for TN
patients. Within each subgroup (n ¼ 18), patients were categorized by age and sex to calculate background mortality rates and utility values.
Model Structure The cohort model was designed to be consistent with current understanding of the biology of CHC-related liver disease and its treatment (Fig. 1). The structure of the model was based on other published health economic models of HCV disease [17–21], including four previously published and validated Markov cohort models that compared PegIFN and RBV with and without boceprevir, or no treatment, and treatment with EBR/GZR following testing for RAV [22–25]. The model was developed in accordance with the International Society for Pharmacoeconomics and Outcomes Research good practices for economic modeling [26]. The model consists of 16 health states with a cycle length of 1 year. Hepatic fibrosis stage was based on the METAVIR fibrosis scoring system. The progressive disease model assumes that a person with a given fibrosis score at model entry may progress to more severe stages of liver disease or may remain in that health state. In the absence of successful treatment, regression to less severe health states is not permitted. However, after successful treatment a person can achieve SVR. The Markov transition probabilities were assumed to be fixed over time. Because the likelihood of a chronically infected person spontaneously clearing HCV is very small, this health state, and the transition to it, has not been included in the model. To account for the possibility of HCV reinfection, the model allows for transitions from SVR states to fibrosis states following reinfection and failure to clear the virus during the acute infection state (i.e., chronicity). Only one-time reinfection was considered and future diagnosis and treatment were not accounted for. Patients with compensated cirrhosis were at risk for developing DC and/or HCC. Although there are different modes of decompensation (e.g., ascites, variceal hemorrhage, and encephalopathy), they are modeled as one health state here because these decompensation modes are not mutually exclusive. If a patient develops DC and/or HCC, then the patient may receive a liver transplant. To account for differences in mortality rates over time among patients with advanced liver
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disease (i.e., DC, HCC, recipients of liver transplantation), the mortality rates during year one were different from those after year one. All other patients had the same mortality risk as the general US population.
Model Assumptions It was assumed that there is no progression to more severe health states (i.e., cirrhosis) during therapy or subsequent follow-up for patients who respond to treatment. SVR is considered a cure for patients who were originally noncirrhotic (i.e., baseline fibrosis score of F0, F1, F2, or F3). Future re-treatment of patients who failed treatment was not considered, nor was treatment of patients with decompensated cirrhosis. Previously cirrhotic patients (i.e., baseline fibrosis score of F4) were assumed to have an excess risk of DC and HCC even if they achieved SVR with treatment. Progression to DC and/or HCC could only occur in cirrhotic patients (i.e., F4 health states), and liver transplantation is performed for patients with DC or HCC only. Patients who receive a liver transplant are assumed to be at no risk of reactivation and progression to liver disease. Adverse events do not differ significantly by treatment regimens and thus are not included.
Model Comparators Food and Drug Administration–approved regimens of EBR/GZR, with or without RBV, were compared with other regimens indicated for GT1 HCV at the labeled dose and duration for each subpopulation (Table 1). In the EBR/GZR arm, GT1a patients with RAVs received 16 weeks of therapy in combination with RBV, while all other populations were treated for 12 weeks without ribavirin. Duration of therapy for LDV/SOF is 8 weeks in TN patients with low viral load, 24 weeks in TE patients, and 12 weeks in all other populations.
Model Inputs Treatment efficacy and discontinuation rates associated with antiviral therapy were derived from pivotal trials of the model comparators in the respective patient population and regimen (Tables 1 and 2). Clinical inputs that describe the rate of HCV progression, the probability of receiving a liver transplantation, both other-cause and liver-related mortality rates, the progression rates, the likelihood of a patient developing serious complications associated with liver disease, and the probability of requiring a liver transplant were sourced from the published literature (Table 2). The study took a third-party payer perspective and costs were inflated to 2016 US dollars using the Consumer Price Index (Medical Care Component) [27]. The costs of oral DAAs were obtained from the Red Book, and represent wholesale acquisition costs without discounts [28]. Costs of required tests for HCV phenotyping or monitoring reflect median reimbursement for commercial insurance plans [29]. The health state costs associated with disease progression (e.g., outpatient visits, monitoring, and hospitalization) were based on the published literature (Table 2) [30]. Age- and sex-specific utility weights were obtained from the published literature [31]. Utility weights during the treatment phase and for each of the HCV health states and liver disease conditions were used to adjust for quality of life among survivors. An on-treatment disutility was applied to RBV-containing regimens; no disutility was applied to RBV-free regimens.
Model Analyses Cost-utility of an EBR/GZR regimen relative to a comparator was evaluated using the incremental cost-utility ratio (ICUR), which is obtained by dividing the incremental total discounted costs by
3
the incremental total discounted number of quality-adjusted lifeyears (QALYs) for the EBR/GZR regimen instead of the comparator. In cases in which the EBR/GZR regimen was less costly and more effective than a given comparator, it was concluded to be economically dominant. In cases in which total costs and QALYs were both lower with EBR/GZR, the results are presented as being cost saving; otherwise, the cost per QALY was presented. In the base-case analysis, aggregated results are presented separately by genotype, cirrhosis status, and treatment history. Subgroups by presence of RAVs and baseline viral load were pooled. One-way sensitivity analyses were conducted for several parameters showing the effect of varying these inputs on the ICUR of EBR/GZR treatment strategies compared with the comparator. We varied efficacy, progression rates, discontinuation rates, unit costs, utility weights, and discount rates using the ranges defined in the inputs tables (Tables 1 and 2; see Appendix Table 1 in Supplemental Materials found at http://dx.doi.org/10. 1016/j.jval.2017.05.003). To quantify the impact of uncertainty in the estimated values of transition probabilities, efficacy, costs, and utility weights on the ICUR of EBR/GZR and other DAAs, we performed probabilistic sensitivity analysis (PSA) by drawing 1000 random samples from predefined distributions. It is important to note that the PSA was conducted using each individual subpopulation (e.g., GT1a with and without RAVs; low and high baseline viral load) and then pooled, as done in the base-case analysis. Results of the PSA were summarized using descriptive statistics and presented using cost-effectiveness acceptability curves.
Results Aggregated results are presented separately by genotype, cirrhosis status, and treatment history (Tables 3 and 4; see Appendix Table 2 in Supplemental Materials found at http://dx.doi.org/10. 1016/j.jval.2017.05.003). Results are weighted by the proportion of patients with RAVs (GT1a TN and TE) and/or low or high baseline viral load (GT1a TN and TE, and GT1b TN). EBR/GZR ⫾ RBV was economically dominant relative to LDV/ SOF in all GT1a and GT1b subpopulations regardless of cirrhosis status, and in five of eight subpopulations when compared with either 3D ⫾ RBV or SOF/VEL (Tables 3 and 4; Appendix Table 2). In cost-saving scenarios, the QALY benefit for any treatment was 0.0938 or lower over the time horizon. In subpopulations of patients in whom EBR/GZR ⫾ RBV was not economically dominant (vs. 3D ⫾ RBV: GT1b TN or TE noncirrhotic and GT1b TE cirrhotic; vs. SOF/VEL, GT1a TN or TE cirrhotic or GT1b TN noncirrhotic), the ICURs for each treatment versus EBR/GZR ⫾ RBV exceeded $178,000 per QALY. SOL/VEL was economically dominant compared with both 3D ⫾ RBV and LDV/SOL when used to treat patients with GT1a CHC, regardless of treatment history and/or cirrhosis status. With respect to patients with GT1b CHC, however, SOL/VEL was economically dominant compared with 3D ⫾ RBV among TN patients and cost saving among TE patients. Relative to LDV/SOF, SOL/VEL was economically dominant for patients with GT1b CHC with no cirrhosis, and provided cost saving as treatment of GT1b CHC with cirrhosis. The total cost to treat patients with GT1a or GT1b CHC was the lowest, and QALYs were highest, across all comparators when treatment was administered before cirrhosis (i.e., during F0–F3). Among patients with no cirrhosis, the lifetime costs of treatment range from $59,111 to $100,423 (difference $41,312), while QALYs range from 15.2677 to 15.3779 (difference 0.1102). EBR/GZR resulted in the lowest costs in all groups (GT1b TE), whereas LDV/SOF contributed to the highest costs (in GT1a TE and GT1b TE). With respect to total QALYs, 3D ⫾ RBV produced the greatest
4
Table 1 – Treatment inputs by population. Treatment regimen, by population
Subpopulation
Noncirrhotic Duration (wk)
GT1a, TN EBR/GZR ⫾ RBV LDV/SOF
LDV/SOF 3D þ RBV SOF/VEL GT1b, TN EBR/GZR LDV/SOF 3D SOF/VEL GT1b, TE EBR/GZR LDV/SOF 3D SOF/VEL
SVR (95% CI)
Duration (wk)
References
SVR (95% CI)
RAV RAVþ LVL - HCV RNA o6 million IU/mL HVL - HCV RNA Z6 million IU/mL – –
12 16* 8 12 12* 12
0.980 1.000 0.971 0.953 0.961 0.957
(0.962–0.991) (0.541–1.000) (0.847–0.999) (0.910–0.980) (0.940–0.976) (0.938–0.985)
12 16* 12 12 24* 24
0.980 1.000 0.970 0.970 0.946 1.000
(0.962–0.991) (0.541–1.000) (0.842–0.999) (0.842–0.999) (0.894–0.997) (0.962–1.000)
[39] [39] [40,41] [40,41] [42–45] [46]
RAV RAVþ – – –
12 16* 12 12* 12
0.980 1.000 0.954 0.964 0.957
(0.962–0.991) (0.541–1.000) (0.886–0.987) (0.926–0.985) (0.938–0.993)
12 16* 24* 24 12
0.980 1.000 0.986 1.000 1.000
(0.962–0.991) (0.541–1.000) (0.924–1.000) (0.872–1.000) (0.962–1.000)
[39] [39] [47,48] [44,45,49] [46]
– LVL - HCV RNA o6 million IU/mL HVL - HCV RNA Z6 million IU/mL – –
12 8 12 12 12
0.982 0.971 0.953 0.993 0.984
(0.936–0.998) (0.847–0.999) (0.910–0.980) (0.976–0.999) (0.960–0.996)
12 12 12 12 12
1.000 0.970 0.970 0.942 0.958
(0.936–1.000) (0.842–0.999) (0.842–0.999) (0.892–0.991) (0.789–0.999)
[50] [40] [40] [43,44] [46]
– – – –
12 12 12 12
1.000 0.954 1.000 0.984
(0.900–1.000) (0.886–0.987) (0.960–1.000) (0.960–0.996)
12 24 12 12
1.000 0.980 1.000 0.958
(0.541–1.000) (0.891–0.999) (0.894–1.000) (0.789–0.999)
[39] [47,48] [51,52] [46]
Parameters for the beta distributions can be found in Appendix Table 1. 3D, ombitasvir/paritaprevir/ritonavir þ dasabuvir; CI, confidence interval; EBR, elbasvir, GT, genotype; GZR, grazoprevir; HVL, high viral load; LDV, ledipasvir; LVL, low viral load; RAV, resistanceassociated variant; SOF, sofosbuvir; SVR, sustained virologic response; TE, treatment-experienced; TN, treatment-naive; VEL, velpatasvir. * Used in combination with ribavirin.
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3DþRBV SOF/VEL GT1a, TE EBR/GZR ⫾ RBV
Cirrhotic
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Table 2 – Baseline characteristics of patients with HCV infection, probabilities, cost, and utility inputs. Variable
Age (y) 20–29 30–39 40–49 50–59 Z60 Proportion males Proportion of GT1a patients with NS5A RAVs* Proportion of GT1 patients with viral load o6 million IU/mL* Fibrosis stage at baseline† F0 F1 F2 F3 F4 Fibrosis progression F0 to F1 F1 to F2 F2 to F3 F3 to F4 Cirrhosis regression (SVR, F4 to SVR, F3) Cirrhosis progression F4 to DC F4 to HCC SVR, F4 to DC SVR, F4 to HCC Reinfection Annual probability Probability of chronicity Liver disease progression, DC to HCC Probability of Receiving LT DC HCC Mortality rates Age-/sex-specific all-cause DC (first year) DC (subsequent years) HCC-related LT (first year) LT (subsequent years) Health state costs (annual) F0–F1 F2 F3 F4 DC HCC Liver transplant, year 1 Liver transplant, subsequent years Drug costs (weekly) EBR/GZR LDV/SOF 3D SOF/VEL RBV
Base case
Range
Distribution
Parameter 1
Parameter 2
Reference
0.012 0.101 0.407 0.383 0.097 0.636 0.120
0.003–0.052 0.064–0.156 0.340–0.478 0.316–0.454 0.068–0.136 0.561–0.706 0.09–0.15
[1] [39]
0.572
0.429–0.715
[41]
0.107 0.357 0.232 0.143 0.161
0.000–1.000 0.000–1.000 0.000–1.000 0.000–1.000 0.000–1.000
0.117 0.085 0.120 0.116 0.086
0.104–0.130 0.075–0.096 0.109–0.133 0.104–0.129 0.047–0.142
Beta Beta Beta Beta Beta
274.6 230.3 337.9 292.3 11.7
2072.8 2478.8 2478.2 2227.8 123.4
0.029 0.028 0.008 0.005
0.010–0.039 0.010–0.079 0.002–0.036 0.002–0.013
Beta Beta Beta Beta
14.9 2.4 6348.8 2487.5
498.6 84.4 787,251.2 495,012.5
0.047 0.430 0.068
0.036–0.061 0.29–0.58 0.030–0.083
Beta Beta Beta
51.7 18.8 23.5
1048.5 25.0 322.2
0.023 0.040
0.010–0.062 0.000–0.140
Beta Beta
1.3 3.9
55.4 93.1
– 0.140 0.112 0.427 0.166 0.044
– 0.065–0.190 0.065–0.190 0.330–0.860 0.060–0.420 0.060–0.420
– Beta Beta Beta Beta Beta
– 16.4 28.1 5.3 1.3 4.7
– 101.0 223.0 7.1 9.9 101.6
$739 $749 $1,520 $1,773 $19,702 $36,229 $104,671 $27,492
$554–$924 $562–$936 $1,140–$1,900 $1,330–$2,216 $14,777–$24,628 $27,172–$45,286 $78,503–$130,839 $20,620–$34,366
Gamma Gamma Gamma Gamma Gamma Gamma Gamma Gamma
61.5 61.5 61.5 61.5 61.5 61.5 61.5 61.5
12.0 12.2 24.7 28.8 320.5 589.4 1702.9 447.3
$4,550 $7,875 $6,943 $6,230 $48
$3,413–$5,688 $5,906–$9,844 $5,243–$8,679 $4,673–$7,788 $36–$60
[1]
[53]
[2]
[54]
[55–60] [55,61–63] [64] [60,62] [65–70]
[71] [72–74]
[75] [71] [55] [71] [76] [76] [22,27]
[28]
continued on next page
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Table 2 – continued Variable
Laboratory costs RAV testing ALT Direct bilirubin Utilities Disutility, RBV-containing regimens F0–F3 F4 DC HCC After liver transplant Post-SVR, F0–F4
Base case
Range
Distribution
Parameter 1
Parameter 2
Reference
$563 $28 $19
$422–$704 $21–$35 $14–$24
0.076
0.072–0.080
Beta
1281.3
15,578.4
[77]
0.93 0.90 0.80 0.79 0.84 1.00
0.88–0.98 0.86–0.95 0.76–0.84 0.75–0.83 0.80–0.88 0.95–1.00
Beta Beta Beta Beta Beta Beta
106.6 152.8 306.5 321.9 245.0 100.0
8.0 17.0 76.6 85.6 46.7 0.1
[78] [78] [78] [78] [78] [24]
[29]
3D, ombitasvir/paritaprevir/ritonavir þ dasabuvir; ALT, alanine aminotransferase; DC, decompensated cirrhosis; EBR, elbasvir; F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis with rare septa; F3, numerous septa without cirrhosis; F4, cirrhosis; G, genotype; GZR, grazoprevir; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LDV, ledipasvir; LT, liver transplant; RAV, resistance-associated variant; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response; VEL, velpatasvir. * Because these subpopulations are modeled separately, the proportions are used only for weighting the final results for GT1 by subpopulation. † Sensitivity analyses evaluated cost-effectiveness in patients of a single baseline fibrosis stage, setting its probability equal to 1 and probability of all other stages to 0.
number of QALYs (GT1b TE), whereas LDV/SOF the fewest (GT1a TE). Treatment costs among patients with cirrhosis ranged from $74,557 to $186,774 (difference $112,216) and QALYs ranged from 13.6456 to 14.0206 (difference 0.3751). Costs were lowest for EBR/ GZR (G1b TN or TE) and highest for 3D (GT1a TN), and QALYs were lowest and highest for 3D in GT1a TN and G1b TE, respectively.
Deterministic Sensitivity Analysis Deterministic sensitivity analysis was performed with individual subpopulations (n ¼ 18), with and without pooling of RAVpositive and negative or low and high viral load populations (data not shown). Across all subpopulations, SVR rates and medication costs had the largest impact on the results. Reducing the efficacy of EBR/GZR þ RBV to the lower bound of its confidence interval, an SVR of 54.1%, resulted in a change from
Table 3 – Base-case results, genotype 1a (among all-oral DAAs). Treatment regimen GT1a, TN, NC 3D þ RBV LDV/SOF SOF/VEL EBR/GZR ⫾ RBV GT1a, TE, NC 3D þ RBV LDV/SOF SOF/VEL EBR/GZR ⫾ RBV GT1a, TN, C 3D þ RBV LDV/SOF SOF/VEL EBR/GZR ⫾ RBV GT1a, TE, C 3D þ RBV LDV/SOF SOF/VEL EBR/GZR ⫾ RBV
Incremental QALYs
ICUR, EBR/GZR ⫾ RBV ($/QALY)
Total discounted costs ($)
Total discounted QALYs
Incremental costs ($)
$89,310 $82,416 $80,383 $62,337
15.2802 15.3094 15.3171 15.3308
$26,973 $20,078 $18,046 –
0.0507 0.0215 0.0137 –
Dominant Dominant Dominant –
$89,202 $100,423 $80,383 $62,337
15.2873 15.2677 15.3171 15.3308
$26,865 $38,086 $18,046 –
0.0435 0.0631 0.0137 –
Dominant Dominant Dominant –
$186,774 $116,016 $94,930 $78,201
13.6456 13.8665 14.0198 13.9260
$108,573 $37,815 $16,729 –
0.2804 0.0595 0.0938 –
Dominant Dominant Cost-saving –
$183,555 $180,107 $94,930 $78,201
13.9205 13.8753 14.0198 13.9260
$105,355 $101,906 $16,729 –
0.0055 0.0507 0.0938 –
Dominant Dominant Cost-saving –
Note: EGR/GZR ⫾ RBV is considered the reference treatment. 3D, ombitasvir/paritaprevir/ritonavir þ dasabuvir; DAA, direct-acting antiviral; EBR, elbasvir; GT, genotype; GZR, grazoprevir; ICUR, incremental cost-utility ratio; LDV, ledipasvir; QALY, quality-adjusted life-year; RAV, resistance-associated variant; SOF, sofosbuvir; SVR, sustained virologic response; TE, treatment-experienced; TN, treatment-naive; VEL, velpatasvir.
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Table 4 – Base-case results, genotype 1b (among all-oral DAAs). Treatment regimen GT1b, TN, NC 3D þ RBV LDV/SOF SOF/VEL EBR/GZR GT1b, TE, NC 3D þ RBV LDV/SOF SOF/VEL EBR/GZR GT1b, TN, C 3D þ RBV LDV/SOF SOF/VEL EBR/GZR GT1b, TE, C 3D þ RBV LDV/SOF SOF/VEL EBR/GZR
Total discounted costs ($)
Total discounted QALYs
Incremental costs ($)
Incremental QALYs
ICUR, EBR/GZR ⫾ RBV ($/QALY)
$87,257 $82,416 $79,485 $59,758
15.3613 15.3094 15.3765 15.3343
$27,499 $22,658 $19,727 –
0.0269 0.0250 0.0422 –
Cost-saving Dominant Cost-saving –
$87,005 $100,423 $79,485 $59,111
15.3779 15.2677 15.3765 15.3771
$27,894 $41,312 $20,374 –
0.0008 0.1094 0.0006 –
Cost-saving Dominant Dominant –
$106,312 $116,016 $97,449 $74,557
13.7234 13.8665 13.8046 14.0203
$31,754 $41,459 $22,892 –
0.2969 0.1538 0.2157 –
$102,832 $180,465 $97,449 $74,557
14.0206 13.8447 13.8046 14.0203
$28,275 $105,908 $22,892 –
0.0003 0.1756 0.2157 –
Dominant Dominant Dominant – Cost-saving Dominant Dominant –
Note: EGR/GZR ⫾ RBV is considered the reference treatment. 3D, ombitasvir/paritaprevir/ritonavir þ dasabuvir; DAA, direct-acting antiviral; EBR, elbasvir; GT, genotype; GZR, grazoprevir; ICUR, incremental cost-utility ratio; LDV, ledipasvir; QALY, quality-adjusted life-year; RAV, resistance-associated variant; SOF, sofosbuvir; SVR, sustained virologic response; TE, treatment-experienced; TN, treatment-naive; VEL, velpatasvir.
economic dominance over each comparator, to inferiority in several GT1a, RAVþ subpopulations. In addition, EBR/GZR was dominant over SOF/VEL in the base-case analysis but had lower costs and QALYs at the lower bound of the SVR in GT1b, TN, cirrhotic and noncirrhotic patients. Increasing the cost of EBR/ GZR to 125% of its base-case value resulted in dominance by the comparator only in GT1a, cirrhotic, RAV-positive patients (vs. SOF/VEL), and G1b, TN patients with HCV RNA of less than 6 million IU/mL (vs. LDV/SOF). When pooling the subgroups, using the lower bounds of SVR rates with EBR/GZR resulted in cost savings in all subpopulations, versus all comparators (base-case SVR rates). When using the upper bound values for SVR, EBR/GZR was economically dominant in all subpopulations versus all comparators, with the exception of SOL/VEL among patients with GT1a with cirrhosis, in whom there were cost savings with decreased QALYs.
Probabilistic Sensitivity Analysis EBR/GZR ⫾ RBV was found to be cost-effective in at least 69.0% of the 1000 PSA iterations run, with a willingness-to-pay threshold up to $100,000 per QALY (Figs. 2 and 3). Regardless of treatment history, among subpopulations of GT1a and GT1b noncirrhotic subpopulation, EBR/GZR ⫾ RBV was cost-effective in more than 99% of the iterations. Among the subpopulations with cirrhosis, it was cost-effective in up to 85% of iterations. Among the other treatments, SOF/VEL was found to be cost-effective in more iterations compared with the other treatments.
Conclusions The cost-utility of approved oral DAAs was evaluated in populations of patients with GT1a and GT1b CHC. The base-case results of this model indicated that EBR/GZR ⫾ RBV is economically dominant or cost saving relative to LDV/SOF, 3D ⫾ RBV, and SOF/
VEL. EBR/GZR ⫾ RBV was dominant over all comparators in GT1a patients without cirrhosis, and in GT1b patients with cirrhosis. SOF/VEL was economically dominant compared with both 3D ⫾ RBV and LDV/SOF in all GT1a, and in GT1b for TN, noncirrhotic patients. The proportions of patients achieving SVR among the comparators in this model ranged from 94% to 100% with their respective regimens, and thus QALY differences between groups were small. Deterministic sensitivity analysis showed that the model was sensitive to EBR/GZR SVR in GT1a patients with NS5A RAVs, largely due to wide confidence intervals around SVR rates resulting from small sample sizes in EBR/GZR trial subgroups. It is estimated that 12% of HCV-infected patients have baseline NS5A RAVs, and require longer treatment duration compared with those without RAVs (16 weeks vs. 12 weeks) and concomitant use of RBV. Nonetheless, the base-case results indicate that EBR/ GZR þ RBV is cost-effective in GT1a patients when patients with and without RAVs are pooled. Conversely, cost differences between treatment arms were considerable and favored EBR/GZR. At equivalent treatment durations, medication cost is 27% lower for EBR/GZR than for the least expensive comparator, SOF/VEL. The additional costs of RAV testing in GT1a patients and required monitoring in patients receiving EBR/GZR were trivial in comparison to the drug cost and thus did little to close this gap. The small differences in SVR rates between comparators did not result in dramatic changes in the cost of treating liver disease in those failing to achieve SVR, and thus drug cost was a key driver of total cost. GT1 accounts for 72.6% of all CHC infections in the United States, or an estimated 2.5 million patients [32]. Among those, it is estimated that one in four patients already has significant liver fibrosis and would benefit from antiviral treatment [33]. Introduction of all-oral DAA regimens and expanded access to these regimens, coupled with universal screening for HCV infection, could make HCV infection a rare disease by 2036 [34]. However,
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Figure 2 – Cost-effectiveness acceptability curves: GT1a patients. Abbreviations: 3D, ombitasvir/paritaprevir/ritonavir þ dasabuvir; EBR, elbasvir; GT, genotype; GZR, grazoprevir; LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir; VEL, velpatasvir.
one study estimated that the cost to provide treatment with SOF/ LDV to all insured patients in the United States who are aware of their disease status is $136 billion over 5 years, and $100 billion for GT1a alone [30]. Selection of cost-effective therapies is an attractive alternative to strategies that delay or withhold treatment in patients with early-stage disease, with fewer patients developing advanced liver disease and requiring transplant. To our knowledge, this is the first analysis comparing the cost-effectiveness of all available DAA regimens in a diverse patient population. Previous models have compared sofosbuvirbased regimens to PegIFN and RBV, with or without boceprevir or telaprevir [30], studied costs and effectiveness only in patients with advanced fibrosis [35] or in a TN veteran population [36], or evaluated the cost-effectiveness of restricting treatment to those with advanced disease compared with full access for all infected patients [37]. Taken collectively, these models indicate that alloral DAA regimens are cost-effective compared with no treatment or to PegIFN-based regimens, and thus we did not include these treatment strategies in our model. This cost-utility analysis has several key strengths. First, the structure of the model is similar to that of other published models [22–24] but it also considered the possibility of reinfection after a patient achieved SVR. Second, the model is flexible enough to allow the simultaneous evaluation of multiple cohorts and several comparators. For example, the base case consisted of 18 patient subgroups, four comparators, and 12 baseline
demographic characteristics (by sex, six age groups). Simultaneously, the model allows for pooling of subgroups to collapse treatment-specific subgroups (i.e., presence of RAVs for GT1a patients receiving EBR/GZR) into populations common to all comparators. The analysis also has some limitations. First, assumptions regarding natural history and management of liver disease (e.g., assuming DC and HCC are mutually exclusive states) may overestimate the clinical benefits of HCV treatment in the model. Also, in the absence of robust evidence showing the effectiveness of all-oral DAAs from the real-world clinical setting, inputs were estimated using results from several clinical trials, without adjustments made for between-trial heterogeneity. Within some subpopulations, treatment efficacy was estimated from subpopulations with small sample sizes, which may affect the generalizability of these results. To evaluate the effect of these factors, a follow-up analysis will be necessary once robust, real-world clinical evidence for all oral DAAs has become available. There were also factors that may influence survival in the model. In the absence of age- and sex-adjusted mortality rates specific to the HCV population, mortality was estimated on the basis of general US population. This approach fails to account for any biological or behavioral factors that are unique to this population that have the potential to decrease survival. Furthermore, it was assumed that patients who were re-infected (with chronicity) after achieving SVR would not receive any subsequent HCV treatment
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Figure 3 – Cost-effectiveness acceptability curves: GT1b patients. Abbreviations: 3D, ombitasvir/paritaprevir/ritonavir þ dasabuvir; EBR, elbasvir; GT, genotype; GZR, grazoprevir; LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir; VEL, velpatasvir.
increasing potential costs while decreasing utility. Finally, in the absence of publicly available reimbursement amounts specific to each treatment, treatment costs were estimated using the most comprehensive and transparent basis, as recommended best practices for economic modeling [38]. Therefore, the results of this analysis are valid only when wholesale acquisition cost is used, exclusive of discounts. Treatment costs in real-world practice may differ because of negotiated agreements that are not publicly disclosed. In conclusion, this model demonstrated EBR/GZR ⫾ RBV to be cost-effective or cost saving relative to LDV/SOF and 3D ⫾ RBV in most patients with GT1a and 1b CHC infection. In cases in which EBR/GZR was associated with lower costs and QALYs, ICURs for comparators were outside conventional ranges of costeffectiveness. Source of Financial Support: Support for this work was provided by Merck & Co., Inc.
Supplemental Materials Supplemental material accompanying this article can be found in the online version as a hyperlink at http://dx.doi.org/10.1016/j. jval.2017.05.003 or, if a hard copy of article, at www.valueinhealth journal.com/issues (select volume, issue, and article).
R EF E R EN C ES
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