Cost-effectiveness comparison of lamivudine plus adefovir combination treatment and nucleos(t)ide analog monotherapies in Chinese chronic hepatitis B patients

Figures & data

Figure 1 Diagram of CHB patient transition states in the Markov model.

Abbreviations: post-LT, post-liver transplantation; CHB, chronic hepatitis B.

Table 1 Annual transition rates of disease states used in the model (%)

Initial state	Entered state	Model input (range)	Reference numbers
CHB	Compensated cirrhosis	1.0 (0.8, 1.2)	Adjusted based on 43, 44
	Decompensated cirrhosis	0.5 (0.3, 0.7)	Adjusted based on 44, 45
	Hepatocellular carcinoma	0.4 (0.3, 0.5)	Adjusted based on 43, 45
	Death	0.9 (0.8, 1.0)	Adjusted based on 43, 45
Virologic response	Compensated cirrhosis	0.4 (0.2, 0.6)	3
	Hepatocellular carcinoma	0.2 (0.1, 0.3)	3
	Death	Natural cause of death	59
Virologic resistance	Compensated cirrhosis	1.0 (0.8, 1.2)	Assumed equal to CHB
	Decompensated cirrhosis	0.5 (0.3, 0.7)	Assumed equal to CHB
	Hepatocellular carcinoma	0.4 (0.3, 0.6)	Assumed equal to CHB
	Death	0.9 (0.8, 1.0)	Assumed equal to CHB
Compensated cirrhosis	Decompensated cirrhosis	2.6 (1.5, 3.7)	Adjusted based on 45, 46
	Hepatocellular carcinoma	1.8 (0.8, 2.8)	Adjusted based on 45, 46
	Death	2.5 (1.5, 3.5)	Adjusted based on 45, 46
Decompensated cirrhosis	Hepatocellular carcinoma	9.1 (8.2, 10.0)	47
	Liver transplantation	5.5 (1.0, 10.0)	27
	Death	10.4 (9.4, 11.4)	48
Hepatocellular carcinoma	Liver transplantation	5.5 (1.0, 10.0)	27
	Death	52.0 (46.8, 57.2)	48
Liver transplantation	Death	12.0 (10.8, 13.2)	49
Post-liver transplantation	HBV relapse	4.8 (4.3, 5.3)	50
	Death	8.1 (7.3, 8.9)	50

Abbreviations: CHB, chronic hepatitis B; HBV, hepatitis B virus.

Table 2 Treatment-related annual rates used in the model

Treatment	Virologic response (%)		Resistance rate (%)
	Probability (range)	Reference numbers	Probability (range)	Reference numbers
HBeAg-positive
LAM	35 (27, 43)	^Citation9, ^Citation51	17.0 (12.1, 21.9)	^Citation9, ^Citation51
ADV	23 (14, 32)	^Citation8, ^Citation52	3.1 (1.3, 4.9)	^Citation8
TBV	64 (61, 67)	^Citation9, ^Citation17	8.1 (7.5, 8.7)	^Citation9, ^Citation10
ETV	69 (62, 76)	^Citation17, ^Citation51, ^Citation52	0.9 (0.6, 1.2)	^Citation51, ^Citation53
TDF	75 (73, 77)	^Citation17, ^Citation54, ^Citation55	0.5 (0.1, 0.9)	^Citation54, ^Citation56
LAM + ADV	77 (66, 88)	^Citation18^–^Citation20	0.8 (0.1, 1.5)	^Citation18, ^Citation22, ^Citation23
HBeAg-negative
LAM	75 (73, 77)	^Citation9, ^Citation60	17.0 (12.1, 21.9)	^Citation9, ^Citation51
ADV	61 (59, 63)	^Citation52	3.1 (1.3, 4.9)	^Citation8
TBV	85 (80, 90)	^Citation9	8.1 (7.5, 8.7)	^Citation9, ^Citation10
ETV	90 (86, 94)	^Citation17, ^Citation51, ^Citation60	0.8 (0.6, 1.2)	^Citation51, ^Citation53
TDF	94 (92, 96)	^Citation17, ^Citation54, ^Citation55	0.5 (0.1, 0.9)	^Citation54, ^Citation56
LAM + ADV	91 (87, 95)	^Citation18, ^Citation24	0.8 (0.1, 1.5)	^Citation18, ^Citation22, ^Citation23
Rescue strategies
LAM + ADV	63 (52, 74)	^Citation15	6.9 (6.2, 7.6)	^Citation15
ETV + ADV	73 (65, 81)	^Citation15	0.0	^Citation15

Abbreviations: HBeAg, hepatitis B e antigen; LAM, lamivudine; ADV, adefovir; TBV, telbivudine; ETV, entecavir; TDF, tenofovir.

Table 3 Annual costs (US dollars, 2014 values) and disease-state utilities

Average disease costs (per patient/year)	Base case (range)	Reference numbers
Drug costs
LAM	913 (822, 1,004)	^Citation33
ADV	1,059 (953, 1,165)	^Citation33
TBV	1,314 (1,183, 1,445)	^Citation33
ETV	2,044 (1,840, 2,248)	^Citation33
TDF	3,176 (2,858, 3,494)	Local pharmacy
Disease-state costs
CHB	1,876 (1,688, 2,064)	^Citation57
Virologic response	1,876 (1,688, 2,064)	Assumed equal to CHB
Virologic resistance	1,876 (1,688, 2064)	Assumed equal to CHB
Compensated cirrhosis	2,853 (2,568, 3,138)	^Citation57
Decompensated cirrhosis	5,274 (4,747, 5,801)	^Citation57
Hepatocellular carcinoma	7,930 (7,137, 8,723)	^Citation57
Liver transplantation	62,001 (55,801, 68,201)	^Citation58
Post-liver transplantation	9,391 (8,452, 10,330)	^Citation58
Disease-state utilities (QALYs)
CHB	0.52 (0.47, 0.57)	^Citation34
Virologic response	0.71 (0.64, 0.78)	^Citation34
Virologic resistance	0.52 (0.47, 0.57)	Assumed equal to CHB
Compensated cirrhosis	0.57 (0.51, 0.63)	^Citation34
Decompensated cirrhosis	0.26 (0.23, 0.29)	^Citation34
Hepatocellular carcinoma	0.31 (0.28, 0.34)	^Citation34
Liver transplantation	0.41 (0.37, 0.45)	^Citation34
Post-liver transplantation	0.55 (0.49, 0.61)	^Citation34

Notes: All drug costs and direct disease-state costs are expressed in 2014 US dollars ($, USD) per patient/year.

Abbreviations: LAM, lamivudine; ADV, adefovir; TBV, telbivudine; ETV, entecavir; TDF, tenofovir; CHB, chronic hepatitis B; QALYs, quality-adjusted life years.

Table 4 Base-case cost and effectiveness of treatment strategies

Drug	ETVa	LAM	ADV	TBV	TDF	LAM + ADV
HBeAg-positive patients
Cost (×$1,000)	72.15	83.48	81.24	76.63	82.64	74.45
QALYs	10.88	10.55	10.59	10.68	10.93	10.98
LYS	15.84	15.64	15.66	15.73	15.87	15.90
Incremental cost (×$1,000)	–	−11.33	−9.09	−4.48	−10.49	−2.30
Incremental LYS	–	0.20	0.18	0.11	−0.03	−0.06
Incremental QALYs	–	0.33	0.29	0.20	−0.05	−0.10
CER (×$1,000/QALYs)	6.63	7.91	7.67	7.18	7.56	6.78
ICER (×$1,000/QALYs)	–	Dominated	Dominated	Dominated	209.80	23.00
HBeAg-negative patients
Cost (×$1,000)	67.15	78.30	69.92	72.82	80.99	69.84
QALYs	11.00	10.62	10.76	10.74	11.05	11.02
LYS	15.92	15.70	15.78	15.77	15.94	15.93
Incremental cost (×$1,000)	–	−11.15	−2.77	−5.67	−13.84	2.69
Incremental LYS	–	0.22	0.14	0.15	−0.02	−0.01
Incremental QALYs	–	0.38	0.24	0.26	−0.05	−0.02
CER (×$1,000/QALYs)	6.10	7.37	6.50	6.78	7.33	6.34
ICER (×$1,000/QALYs)	–	Dominated	Dominated	Dominated	276.80	134.50

Notes:

a The therapy used as a reference treatment. All costs are expressed in 2014 US dollars ($). Dominated: The therapy has higher cost and lower efficacy in comparison with the reference treatment. ICER is calculated by using the formula ICER = Incremental cost/Incremental QALYs. “–” ETV was the baseline comparator.

Abbreviations: ETV, entecavir; LAM, lamivudine; ADV, adefovir; TBV, telbivudine; TDF, tenofovir; HBeAg, hepatitis B e antigen; QALYs, quality-adjusted life years; LYS, life years saved; ICER, incremental cost-effectiveness rate.

Figure 2 Ten-year cumulative incidence of advanced liver diseases for HBeAg-positive (A) and -negative (B) CHB patients after different therapy strategies.

Abbreviations: LAM, lamivudine; ADV, adefovir; TBV, telbivudine; ETV, entecavir; TDF, tenofovir; HBeAg, hepatitis B e antigen; CHB, chronic hepatitis B.

Figure 3 Cost-effectiveness of different treatment strategies for HBeAg-positive (A) and -negative (B) chronic hepatitis B patients.

Notes: The x-axis represents the life-time QALYs for each treatment, and the y-axis indicates the life-time costs (US dollars). The straight lines represent the cost-effectiveness frontier, which joins the treatments that are not dominated by any other treatment. The slope of this line at any point represents the ICER for the comparison between the treatments at either end of the line.
Abbreviations: LAM, lamivudine; ADV, adefovir; TBV, telbivudine; ETV, entecavir; TDF, tenofovir; QALYs, quality-adjusted life years; HBeAg, hepatitis B e antigen; ICER, incremental cost-effectiveness ratio.

Table 5 Alternative cost and effectiveness of five treatment strategies

Drug	LAM + ADVa	LAM	ADV	TBV	ETV	TDF
HBeAg-positive patients
Cost (×$1,000)	74.45	99.88	96.42	89.47	78.84	87.68
QALYs	10.98	10.70	10.73	10.79	10.94	10.98
LYS	15.90	15.72	15.74	15.79	15.87	15.90
Incremental cost (×$1,000)	–	−25.43	−21.97	−15.02	−4.39	−13.23
Incremental LYS	–	0.18	0.16	0.11	0.03	<0.01
Incremental QALYs	–	0.28	0.25	0.19	0.04	<0.01
CER (×$1,000/QALYs)	6.78	9.33	8.99	8.29	7.21	7.99
ICER (×$1,000/QALYs)	–	Dominated	Dominated	Dominated	Dominated	Dominated
HBeAg-negative patients
Cost (×$1,000)	69.84	92.69	80.21	83.93	70.36	82.72
QALYs	11.02	10.75	10.85	10.84	11.03	11.06
LYS	15.93	15.76	15.82	15.81	15.93	15.95
Incremental cost (×$1,000)	–	−22.85	−10.37	−14.09	−0.52	−12.88
Incremental LYS	–	0.17	0.11	0.12	<0.01	−0.02
Incremental QALYs	–	0.27	0.17	0.18	−0.01	−0.04
CER (×$1,000/QALYs)	6.34	8.62	7.39	7.74	6.38	7.48
ICER (×$1,000/QALYs)	–	Dominated	Dominated	Dominated	52.00	322.00

Notes:

a The therapy used as a reference treatment. All costs are expressed in 2014 US dollars ($). Dominated: The therapy has higher cost and lower efficacy in comparison with the reference treatment. ICER is calculated by using the formula ICER = Incremental cost/Incremental QALYs. “–” LAM+ADV is the baseline comparator.

Abbreviations: LAM, lamivudine; ADV, adefovir; TBV, telbivudine; ETV, entecavir; TDF, tenofovir; HBeAg, hepatitis B e antigen; QALYs, quality-adjusted life years; LYS, life years saved; ICER, incremental cost-effectiveness rate.

Figure 4 Results of one-way sensitivity analysis for HBeAg-positive (A) and -negative (B) CHB patients at a threshold of $20,466/QALY gained.

Note: The vertical dotted line represents the base-case results where ETV was the most cost-effective strategy.
Abbreviations: LAM, lamivudine; ADV, adefovir; ETV, entecavir; VR, virologic response; HCC, hepatocellular carcinoma; CC, compensated cirrhosis; CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; QALYs, quality-adjusted life years.

Figure 5 Cost-effectiveness acceptability curves of different strategies for HBeAg-positive (A) and -negative (B) chronic hepatitis B patients.

Notes: The y-axis indicates the probability that the therapy is a cost-effective strategy. The x-axis represents the WTP threshold to pay one additional QALY.
Abbreviations: ADV, adefovir; ETV, entecavir; LAM, lamivudine; TBV, telbivudine; TDF, tenofovir; HBeAg, hepatitis B e antigen; WTP, willingness-to-pay; QALY, quality-adjusted life year.

Figure 6 Probabilistic results for incremental cost-effectiveness comparisons between treatment with entecavir and (A) lamivudine monotherapy, (B) adefovir monotherapy, (C) telbivudine monotherapy, (D) tenofovir monotherapy, and (E) lamivudine plus adefovir combination therapy for a simulation involving 1,000 patients.

Notes: The y- and x-axes represent the incremental costs and incremental QALYs gained, respectively. Dots below the ICER threshold reflect simulations in which cost per QALYs gained with entecavir are below the Chinese threshold of $20,466/QALY gained.
Abbreviations: QALYs, quality-adjusted life years; ICER, incremental cost-effectiveness ratio.

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