Cost-effectiveness of direct-acting antiviral regimen ombitasvir/paritaprevir/ritonavir in treatment-naïve and treatment-experienced patients infected with chronic hepatitis C virus genotype 1b in Japan

Figures & data

Figure 1. Natural history model schematic. CC, compensated cirrhosis; DCC, decompensated cirrhosis; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; SVR, sustained virologic response. Patients with HCV infection initiated treatment in the first cycle. Health states are depicted by ellipses, while arrows represent permissible transitions between health states. Hashed arrows depict the possibility of achieving SVR. Dotted arrows depict progress to HCC from any recovered states, including without history of cirrhosis and history of compensated cirrhosis. Background mortality is possible from any health state. Liver-related mortality is possible from DCC, HCC, and liver transplantation.

Table 1. Model inputs for the base case, deterministic, and probabilistic sensitivity analyses.

Variable	Base case value	Sensitivity, low	Sensitivity, high	PSA, second statistical moment*	Distribution in PSA	Source
Baseline patient characteristics, treatment-naïve
Age (in years)	61	56	66	5	Gamma	Kumada et al.^23
Male (%)	55%	50%	60%	n = 210	Beta	Yoshida et al.^31
Baseline patient characteristics, treatment-experienced
Age (in years)	61	56	66	5	Gamma	Kumada et al.^23
Male (%)	64%	59%	69%	n = 144	Beta	Yoshida et al.^31
Time horizon (years)	70	0	70		None
Discount rates	2.0%	0.0%	4.0%		None
Transitional probabilities (annual)
Fibrosis progression: without   cirrhosis to CC	0.0190	0.0100	0.0290	0.0048	Beta	Ishida et al.^26
Non-fibrosis progression
Recovered, without history of   cirrhosis, to HCC	0.0020	0.0010	0.0030	0.0005	Beta	Maruoka et al.^27
Recovered, no HCV, history of   CC to HCC	0.0180	0.0090	0.0270	0.0045	Beta	McEwan et al.^17
Without cirrhosis to HCC   (first year)	0.0290	0.0145	0.0435	0.0073	Beta	Suga et al.^29
CC to DCC	0.0560	0.0280	0.0840	0.0140	Beta	Suga et al.^29
CC to HCC (first year)	0.0560	0.0280	0.0840	0.0140	Beta	Suga et al.^29
DCC to HCC (first year)	0.0560	0.0280	0.0840	0.0140	Beta	Suga et al.^29
Liver transplant
DCC to liver transplantation   (first year)	0.0035	0.0018	0.0053	0.0009	Beta	Ishida et al.^26
HCC to liver transplantation   (first year)	0.0034	0.0017	0.0051	0.0009	Beta	Ishida et al.^26
Liver-related mortality
DCC to liver-related mortality	0.1510	0.0755	0.2265	0.0378	Beta	Suga et al.^29
Liver transplantation to   liver-related mortality	0.2090	0.1045	0.3135	0.0523	Beta	Ishida et al.^26
After liver transplantation to   liver-related mortality	0.0180	0.0090	0.0270	0.0045	Beta	Ishida et al.^26
HCC first year to liver-related   mortality	0.1180	0.0590	0.1770	0.0295	Beta	Ishida et al.^26: assume equal to “stage I/II HCC to death”
HCC subsequent year to   liver-related mortality	0.2220	0.1110	0.3330	0.0555	Beta	Ishida et al.^26: assume equal to “stage III/IV HCC to death”
Direct medical costs by health state (annual)
Without cirrhosis	JPY 345,300	JPY 172,700	JPY 518,000	JPY 345,300	Gamma	Ishida et al.^26
CC	JPY 478,600	JPY 239,300	JPY 717,900	JPY 478,600	Gamma	Ishida et al.^26
No HCV	JPY 0	JPY 0	JPY 345,300		None	Model assumption: high value is assumed to be equal to the base value of non-active chronic hepatitis C
Recovered, no HCV, without  history of cirrhosis	JPY 57,186	JPY 0	JPY 345,300	JPY 57,186	Gamma	McEwan et al.^17. Lower bound assumed to be 0; upper bound assumed to be base value of respective health state cost
Recovered, no HCV, history  of CC	JPY 124,439	JPY 0	JPY 478,600	JPY 124,439	Gamma	McEwan et al.^17. Lower bound assumed to be 0; upper bound assumed to be base value of respective health state cost
DCC	JPY 706,600	JPY 353,300	JPY 1,059,900	JPY 706,600	Gamma	Ishida et al.^26
HCC (first year)	JPY 1,148,500	JPY 574,300	JPY 1,722,800	JPY 1,148,500	Gamma	Ishida et al.^26: first year assumed to be cost of stage I and II of the Ishida model
HCC (subsequent year)	JPY 1,992,800	JPY 996,400	JPY 2,989,300	JPY 1,992,800	Gamma	Ishida et al.^26: subsequent year assumed to be cost of stage III and IV of the Ishida model
Liver transplantation (first year)	JPY 14,995,200	JPY 7,497,600	JPY 22,492,800	JPY 14,995,200	Gamma	Ishida et al.^28, also used in Ishida et al.^26
Liver transplantation  (subsequent)	JPY 2,019,000	JPY 1,009,500	JPY 3,028,500	JPY 2,019,000	Gamma	Ishida et al.^28, also used in Ishida et al.^26
Health state utilities†
Without cirrhosis	0.854	0.684	0.940	0.097	Beta	Imputed from Ishida et al.^26, using Yoshida et al.^31 fibrosis distribution
CC	0.737	0.680	0.790	0.037	Log-normal	Ishida et al.^26
Recovered, no HCV, without  history of cirrhosis	0.930	0.720	1.000	0.090	Beta	Assumed equal to recovered, no HCV, without history of cirrhosis
Recovered, no HCV, history  of CC	0.930	0.720	1.000	0.090	Beta	Ishida et al.^26
DCC	0.671	0.500	0.700	0.014	Log-normal	Ishida et al.^26
HCC (first year)	0.675	0.500	0.700	0.014	Log-normal	Ishida et al.^26, stage I & II
HCC (subsequent year)	0.428	0.300	0.500	0.014	Log-normal	Ishida et al.^26, stage III & IV
Liver transplantation (first year)	0.600	0.450	0.860	0.038	Log-normal	Ishida et al.^26
Liver transplantation  (subsequent)	0.750	0.620	0.900	0.006	Log-normal	Ishida et al.^26
Treatment-related utility change‡	varies	N/A	N/A	N/A	N/A	Ishida et al.^26
Treatment-naïve patients without cirrhosis; includesIFN-ineligible
OBV/PTV/r	−0.0015	N/A	N/A	N/A	N/A	Data on file
DCV/ASV	−0.0029	N/A	N/A	N/A	N/A	Data on file
Treatment-experienced patients  without cirrhosis; includes  IFN-intolerant
OBV/PTV/r	−0.0076	N/A	N/A	N/A	N/A	Data on file
DCV/ASV	−0.0143	N/A	N/A	N/A	N/A	Data on file
Drug costs (per day)§
OBV/PTV/r	JPY 46,115	N/A	N/A	N/A	N/A	Drug price list of the Japanese National Health Insurance^38
DCV	JPY 7,903	N/A	N/A	N/A	N/A	Drug price list of the Japanese National Health Insurance^38
ASV	JPY 5,695	N/A	N/A	N/A	N/A	Drug price list of the Japanese National Health Insurance^38
SOF/LDV	JPY 54,797					Drug price list of the Japanese National Health Insurance^38
Treatment duration (in days)		N/A	N/A	N/A	N/A
Treatment-naïve patients  without cirrhosis; includes  IFN-ineligible
OBV/PTV/r (84)	83.2	N/A	N/A	N/A	N/A	Kumada et al.^23
DCV/ASV (168)	159.3	N/A	N/A	N/A	N/A	Kumada et al.^34
Treatment-experienced patients  without cirrhosis; includes  IFN-intolerant
OBV/PTV/r	83.2	N/A	N/A	N/A	N/A	Kumada et al.^23
DCV/ASV	156.7	N/A	N/A	N/A	N/A	Kumada et al.^34
Treatment SVR
Treatment-naïve patients  without cirrhosis; includes  IFN-ineligible
OBV/PTV/r	95.5%	91.6%	99.4%	2.0%	Beta	Kumada et al.^23
DCV/ASV	84.7%	77.3%	92.1%	3.8%	Beta	Kumada et al.^34
Treatment-experienced patients  without cirrhosis; includes  IFN-intolerant
OBV/PTV/r	96.5%	91.9%	100.0%	2.4%	Beta	Kumada et al.^23
DCV/ASV	85.9%	77.2%	94.6%	4.5%	Beta	Kumada et al.^34
Y93H mutation-negative  patients¶**
OBV/PTV/r	99.0%	97.0%	100.0%	0.7%	Beta	PMDA website^35
SOF/LDV	100.0%	97.0%	100.0%	0.8%	Beta	PMDA website^35
DCV/ASV	91.3%	86.0%	95.0%	2.1%	Beta	PMDA website^35
Monitoring costs	JPY 0	N/A	N/A	N/A	N/A	Model assumption

CC, compensated cirrhosis; CHC, chronic hepatitis C; DCC, decompensated cirrhosis; DCV/ASV, daclatasvir/asunaprevir; EQ-5D, EurolQol-5 Dimensions; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IFN, interferon; OBV/PTV/r, ombitasvir/paritaprevir/ritonavir; PMDA, Pharmaceuticals and Medical Devices Agency; PSA, probabilistic sensitivity analysis; SOF/LDV, sofosbuvir/ledipasvir; SVR, sustained virologic response; TP, transitional probability; Treatment-experienced = non-response and prior relapse.

* Second statistical moment was standard error where available. If standard error were not available, standard deviation was used. If neither were available for a beta distribution, the n was used and a binomial distribution was assumed.

† The health state utilities for the PSA were programmed to preserve the ranking. The health state utility for patients without cirrhosis uses the standard error from Ishida et al.²⁶ and a beta distribution. The health state utility for recovered states are anchored to patients without cirrhosis by maintaining the difference in health state utilities between health states from the base model. Health state utilities that are assumed to be equal in the base model are set equal in the PSA. For other health state utilities, the differences with the health state utility for patients without cirrhosis were modeled using a log-normal distribution.

‡ Disutility for DCV/ASV imputed from ABV trial EQ-5D, but annualized using expected treatment duration in each of the relevant DCV/ASV trial arms.

§ Total drug costs were derived from the duration of a therapy in days for each regimen drug multiplied by the daily cost of each regimen. Data for treatment duration were extracted from trial publications.

¶ For OBV/PTV/r, the 95% confidence interval for the SVR rate is based on patients with and without cirrhosis in a primary virologic failure population. The Briggs method was applied to the SVR in the PSA. The SVR standard deviation reported uses the Briggs method⁴⁰.

** The 95% confidence interval was calculated using the same method, exact binomial distribution using the Clopper-Pearson method. The OBV/PTV/r and SOF/LDV report SVR12 results. DCV/ASV data are for SVR24. We assumed concordance between SVR24 and SVR12.

Figure 2. Liver outcomes in (a) treatment-naïve patients; and (b) treatment-experienced patients. CC, compensated cirrhosis; DCC, decompensated cirrhosis; DCV/ASV, daclatasvir/asunaprevir; HCC, hepatocellular carcinoma; OBV/PTV/r, ombitasvir/paritaprevir/ritonavir.

Table 2. Total costs, LYs, QALYs, ICERs, and effectiveness across patient segments.

Patient segment	Cost (JPY)/patient	LY/patient	QALY/patient	All oral DAA (ICER, JPY per QALY)	No treatment (ICER, JPY per QALY)
Treatment-naïve patients without cirrhosis
OBV/PTV/r	JPY 5,410,171	17.80	16.41	JPY 1,684,751*	Dominated by OBV/PTV/r†
DCV/ASV	JPY 4,439,917	17.40	15.83
No treatment	JPY 7,756,050	14.24	11.34
Treatment-experienced patients without cirrhosis
OBV/PTV/r	JPY 5,322,416	17.58	16.22	JPY 1,836,596*	Dominated by OBV/PTV/r†
DCV/ASV	JPY 4,297,182	17.20	15.66
No treatment	JPY 7,660,828	14.09	11.23

DAA, direct-acting antiviral; DCV/ASV, daclatasvir/asunaprevir; ICER, incremental cost-effectiveness ratio; LY, life year; OBV/PTV/r, ombitasvir/paritaprevir/ritonavir; QALY, quality-adjusted life year; Treatment-experienced = non-response and prior relapse; Difference in cost = total direct cost of OBV/PTV/r regimen – total direct cost of comparator; Difference in QALY = OBV/PTV/r regimen QALY – comparator QALY.

* OBV/PTV/r regimen is cost-effective (higher cost and better QALY outcomes) below a JPY 5 million/QALY threshold.

† OBV/PTV/r regimen dominates (i.e. lower costs and better outcomes).

Figure 3. OBV/PTV/r vs DCV/ASV in HCV GT1b treatment-naïve patients without cirrhosis (base case: JPY 1,684,751). CHC, chronic hepatitis C; HCC, hepatocellular carcinoma; DCV/ASV, daclatasvir/asunaprevir; GT1b, genotype 1b; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ICER, incremental cost-effectiveness ratio; OBV/PTV/r, ombitasvir/paritaprevir/ritonavir; SVR, sustained virologic response.

Figure 4. OBV/PTV/r vs DCV/ASV in HCV GT1b treatment-experienced patients without cirrhosis (base case: JPY 1,836,596). CHC, chronic hepatitis C; HCC, hepatocellular carcinoma; DCV/ASV, daclatasvir/asunaprevir; GT1b, genotype 1b; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ICER, incremental cost-effectiveness ratio; OBV/PTV/r, ombitasvir/paritaprevir/ritonavir; SVR, sustained virologic response.

Figure 5. Probabilistic sensitivity analysis in treatment-naïve HCV GT1b patients without cirrhosis. GT1b, genotype 1b; HCV, hepatitis C virus; ICER, incremental cost-effectiveness ratio; OBV/PTV/r, ombitasvir/paritaprevir/ritonavir; PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life year; WTP, willingness-to-pay. PSA estimated on 500 simulations. OBV/PTV/r is the optimal therapy in at least 86.0% of the simulations, assuming payers have a WTP threshold of JPY 5 million/QALY. The dashed line indicates the JPY 5 million WTP threshold; the data points to right of this line yield ICERs below the WTP threshold.

Figure 6. Probabilistic sensitivity analysis in treatment-experienced patients with HCV GT1b infection without cirrhosis. GT1b, genotype 1b; HCV, hepatitis C virus; ICER, incremental cost-effectiveness ratio; OBV/PTV/r, ombitasvir/paritaprevir/ritonavir; PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life year; WTP, willingness-to-pay. PSA estimated on 500 simulations. OBV/PTV/r is the optimal therapy in at least 88.2% of the simulations, assuming payers have a WTP threshold of JPY 5 million/QALY. The dashed line indicates the JPY 5 million WTP threshold; the data points to right of this line yield ICERs below the WTP threshold.

Table 3. Total costs, QALYs, and ICER results for patients without the Y93H mutation.

Regimen	Total costs (JPY)/patient	QALYs	ICER (JPY per QALY)
OBV/PTV/r	JPY 5,406,235	16.14	NA
DCV/ASV	JPY 4,199,382	15.72	JPY 2,889,945*
SOF/LDV	JPY 6,111,476	16.19	JPY 13,296,227*
No treatment	JPY 7,709,306	10.82	Dominated by OBV/PTV/r†

DCV/ASV, daclatasvir/asunaprevir; ICER, incremental cost-effectiveness ratio; OBV/PTV/r, ombitasvir/paritaprevir/ritonavir; QALY, quality-adjusted life year; SOF/LDV, sofosbuvir/ledipasvir.

* OBV/PTV/r is cost-effective (higher cost and better QALY outcomes; or lower cost and lower QALY outcomes) below a JPY 5 million/QALY threshold.

† OBV/PTV/r dominates (i.e. lower costs and better outcomes).

Figure 7. Probabilistic sensitivity analysis: results using MCID of ±0.05 in QALYs between OBV/PTV/r and SOF/LDV. MCID, minimally clinical important difference; OBV/PTV/r, ombitasvir/paritaprevir/ritonavir; PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life year; SOF/LDV, sofosbuvir/ledipasvir. PSA estimated on 500 simulations. OBV/PTV/r is a dominant strategy (i.e. less costly and more effective) vs SOF/LDV in 25.6% of simulations (i.e. MCID ≥0). In addition, when we varied the MCID in QALYs from 0.05 to –0.05, OBV/PTV/r dominates SOF/LDV in 7.0–73.0% of simulations.

Figure 8. Model and published estimates of cumulative compensated cirrhosis estimates.

Kumada H, Chayama K, Rodrigues L Jr, et al. Randomized phase 3 trial of ombitasvir/paritaprevir/ritonavir for hepatitis C virus genotype 1b-infected Japanese patients with or without cirrhosis. Hepatology 2015;62:1037-46

 PubMed Web of Science ®Google Scholar

Yoshida H, Shiratori Y, Moriyama M, et al. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of Hepatocarcinogenesis by Interferon Therapy. Ann Intern Med 1999;131:174-81

 PubMed Web of Science ®Google Scholar

Ishida H, Yotsuyanagi H. Examination of the cost-effectiveness of the standard of care for chronic HCV treatment. Research on health-economics of various initiatives related to viral liver diseases, Ministry of Health, Labour and Welfare, Japan (PI: Hirao T) 2014;127-192 (Japanese Only). http://mhlw-grants.niph.go.jp/niph/search/Download.do?nendo=2013&jigyoId=135013&bunkenNo=201333004A&pdf=201333004A0005.pdf. Accessed January 6, 2016

 Google Scholar

Maruoka D, Imazeki F, Arai M, Kanda T, Fujiwara K, Yokosuka O. Long–term cohort study of chronic hepatitis C according to interferon efficacy. J Gastroenterol Hepatol. 2012;27:291-9.

 PubMed Web of Science ®Google Scholar

McEwan P, Ward T, Webster S, et al. Estimating the long-term clinical and economic outcomes of daclatasvir plus asunaprevir in difficult-to-treat Japanese patients chronically infected with Hepatitis C Genotype 1b. Value Health Regional Issues 2014;3:136-45

 PubMedGoogle Scholar

Suga M, et al. Development of the fundamental model for HCV. Research on health-economics of various initiatives related to viral liver diseases, Ministry of Health, Labour and Welfare, Japan (PI: Hirao T), 2014;76-95 (Japanese Only). http://mhlw-grants.niph.go.jp/niph/search/Download.do?nendo=2013&jigyoId=135013&bunkenNo=201333004A&pdf=201333004A0004.pdf. Accessed January 6, 2016

 Google Scholar

Ishida K, Imai H, Ogasawara K, et al. Cost-utility of living donor liver transplantation in a single Japanese center. Hepatogastroenterology 2006;53:588-91

 PubMed Web of Science ®Google Scholar

Ministry of Health Labour and Welfare. Japanese National Health Insurance drug price list, effective April 2016. Japan: Ministry of Health Labour and Welfare; 2016. http://www.mhlw.go.jp/topics/2014/03/tp0305–01.html (Japanese only). Accessed March 4, 2016

 Google Scholar

Kumada H, Suzuki Y, Ikeda K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology 2014;59:2083-91

 PubMed Web of Science ®Google Scholar

BMS KK, AbbVie GK, Gilead Sciences KK, Interview Form available from PMDA website (in Japanese only). Daklinza Interview Form: http://www.info.pmda.go.jp/go/interview/1/670605_6250040F1020_1_005_1F. Viekirax Interview Form: http://www.info.pmda.go.jp/go/interview/1/112130_62501A2F1027_1_1F. Harvoni Interview Form: http://www.info.pmda.go.jp/go/interview/1/230867_62501A1F1022_1_001_1F.pdf. 2015. Japan. Accessed January 6, 2016

 Google Scholar

Briggs AH, Ades AE, Price MJ. Probabilistic sensitivity analysis for decision trees with multiple branches: use of the Dirichlet distribution in a Bayesian framework. Med Decis Making 2003;23:341-50

 PubMed Web of Science ®Google Scholar