Tenofovir disoproxil fumarate is superior to Entecavir and Tenofovir alafenamide in Cost-Effectiveness of Treatment of Chronic Hepatitis B in China with New Volume-Based Purchasing Policy

Methods

Type of Economic Evaluation

A cost-utility analysis was conducted from the China society perspective. The cost-effectiveness of the strategies was assessed using the predicted number of liver-related diseases and deaths, costs (denominated in US dollars 2020), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs).

Strategies

Three NAs antiviral therapies recommended by the AASLD and CSH guidelines were included: ETV (0.5-mg tablet once daily), TDF (300-mg tablet once daily), and TAF (25-mg tablet once daily) [5, 7]. Non-NAs best supportive care (BSC) was defined as careful monitoring and other essential therapy without antiviral treatment. Generic drugs were assumed as the same quality and efficiency as brand-name drugs.

Cohort And Model Structure

A cost-effectiveness analysis was based on a Markov model simulating a hypothetical cohort of 1,000,000 cases of Chinese CHB patients aged 18 years fulfilling Chinese guidelines criteria for treatment of hepatitis B (Fig. 1). TreeAge Pro Suite 2019 software (TreeAge Software, Inc., Williamstown, MA, USA) was used. Patients were tracked as they moved between the following health states: CHB, compensated cirrhosis (CC), decompensated cirrhosis (DC), HCC, liver transplant (LT), post-liver transplant (PLT), and death. The life expectancy of Chinese people is 77 years [27], and thus, the lifetime horizons of this model were set at 59 years. The cycle length was 1 year. Details of the parameters used to derive transition probabilities between two states and related references are found in Table 1. Model input parameters were mainly derived from published studies. The cumulative probabilities or rates from published original studies were all converted to annual probabilities. The probabilities of liver transplant of DC and HCC were calculated based on the annual liver transplant cases and DC and HCC cases which were reported in the literature (Table 1).

Table 1

Model inputs
Parameter	Base-case	Range	Distribution	Source
Annual transition probabilities
CHB to CC	1.90%	1.0-2.8%	Beta	[30–34]
CHB to HCC	0.59%	0.37%-0.8%	Beta	[30, 31, 35, 36]
CC to DC	5.40%	4.6–6.2%	Beta	[32–34, 37]
CC to HCC	4.27%	1.94–6.6%	Beta	[32, 36, 38]
DC to HCC	6.50%	2.7–10.3%	Beta	[35, 39–42]
Liver transplant of DC	0.05%*	NA	NA	[2, 4, 21, 43, 44]
Death of DC	9.55%	9.0-10.1%	Beta	[41, 42, 45]
Liver Transplant of HCC	0.20%*	NA	NA	[4, 44]
Death of HCC	29.03%	27.45–30.60%	Beta	[46]
Death of Liver Transplant	9.65%	6.3%-13%	Beta	[47–49]
Death of Post-Liver Transplant	6.12%	3.98–8.25%	Beta	[50]
HR of ETV vs. non-NA without Cirrhosis
CHB to CC	0.51	0.22–1.19	lognormal	[12]
CHB to HCC	0.40	0.28–0.57	lognormal	[12]
HR of ETV vs. non-NA with Cirrhosis
CC to DC	0.51	0.34–0.78	lognormal	[12, 51]
Cirrhosis to HCC	0.55	0.31–0.99	lognormal	[12, 51]
Death or transplant of DC	0.26	0.13–0.55	lognormal	[12, 51]
HR of TDF vs. non-NA without Cirrhosis
CHB to CC	0.31	0.13–0.73	lognormal	[12, 52]
CHB to HCC	0.27	0.07–0.98	lognormal	[20, 53, 54]
HR of TDF vs. non-NA with Cirrhosis
CC to DC	0.28	0.11–0.76	lognormal	[52, 55]
Cirrhosis to HCC	0.46	0.29–0.75	lognormal	[20, 53, 55]
Death or transplant of DC	0.10	0.04–0.27	lognormal	[55]
HR of TAF vs. non-NA without Cirrhosis
CHB to CC	0.31**	0.13–0.73	lognormal	[12, 25, 56]
CHB to HCC	0.24	0.06–0.87	lognormal	[25, 53, 54]
HR of TAF vs. non-NA with Cirrhosis
CC to DC	0.28**	0.11–0.76	lognormal	[25, 56, 57]
Cirrhosis to HCC	0.41	0.26–0.67	lognormal	[53, 54]
Death or transplant of DC	0.10**	0.04–0.27	lognormal	[25, 56, 57]
Cost
Disease states(per year)
CHB	1177	589–1766	Gamma	[24]
CC	2000	1000–3000	Gamma	[24]
DC	3601	1801–5402	Gamma	[24]
HCC	12710	6355–19065	Gamma	[24]
Liver transplant	103548	85514–121582	Gamma	[58]
Post-Liver Transplant	23254	20886–25620	Gamma	[59]
ETV	1157	NA	NA	[23, 60]
ETV with NVBPP	11	NA	NA	[23, 26, 60]
TDF	792	NA	NA	[23, 60]
TDF with NVBPP	17	NA	NA	[23, 26, 60]
TAF	1002	NA	NA	[60]
Monitor For TDF use	108	NA	NA	[9, 28]
Monitor For TAF use	68	NA	NA	[9, 28]
Discount Rate	0.05	NA	NA	[29]
Utility scores
CHB (HUI3)	0.87	0.85–0.88	Beta	[61]
CC (HUI3)	0.81	0.75–0.86	Beta	[61]
DC (HUI3)	0.49	0.22–0.75	Beta	[61]
HCC (HUI3)	0.85	0.76–0.95	Beta	[61]
Post-liver transplant (HUI3)	0.72	0.60–0.83	Beta	[61]
CC compensated cirrhosis, CHB chronic hepatitis B, DC decompensated cirrhosis, HCC hepatocellular carcinoma, HUI3 Health Utility Index Mark 3, ETV entecavir, TDF tenofovir disoproxil fumarate, TAF Tenofovir alafenamide, NVBPP new volume-Based Purchasing Policy
*Probability was calculated base the liver-transplant cases and DC & HCC estimated numbers reported in paper in 2011, China.
** Assume TAF equivalent to TDF

Costs

This study calculated the direct costs of states within 1 year from the social perspective and literature report, indirect and intangible costs were not included. Direct costs included medical and non-medical costs. The direct medical costs of disease states included outpatient expenditures, inpatient expenditures, and expenditures on medicines self-purchased in retail pharmacies derived from published reports or Fujian Provincial Hospital. Furthermore, the direct medical costs of drugs without NVBPP used in the treatment strategies were calculated based on the current local market. The direct non-medical costs included the family’s travel expenses to get treatment and the patient’s extra health product expenses derived from published reports. The price of ETV(NVBPP), TDF(NVBPP), and the cost of monitoring TDF and TAF adverse drug reactions were evaluated based on the price in Fujian Provincial Hospital [28]. All costs were converted from Chinese Yuan (CNY) to US dollar (USD) at an average exchange rate of 6.35 in 2021. Both costs and quality-adjusted life-years (QALYs) were discounted at an annual rate of 5%, based on China Guidelines for Pharmacoeconomic Evaluations [29].

Utilities

The utilities of the health states were obtained from the literature (Table 1). Health Utility Index Mark 3 (HUI3) scores were the default values adopted in the models, with 1 representing perfect health and 0 representing death.

Sensitivity Analyses

One-way sensitivity analyses were conducted on the majority of parameters used by the model, and the ranges of most parameters analyzed were their range obtained from their sources (Table 1). In multiple strategies Markov model, net monetary benefit (NMB) was evaluated by 100,000 iterations of Monte Carlo simulation which were conducted in the probabilistic sensitivity analysis (PSA) to determine the overall impact of parameter uncertainty on the results.

Results

Base-case results

The Monte Carlo microsimulation was set up with a 1,000,000 size trial cohort using the parameters (Table 1). The QALYs, life years expectance (LYs), incremental costs, incremental QALYs, and ICERs of the included strategies are summarized in Table 2. For a lifetime therapy, compared to the non-NAs support therapy, the ETV, TDF, and TAF reduced 91,802, 112,360, and 123,231 deaths respectively (Supplement Table 1). All the other clinical outcomes are demonstrated in Supplementary Table 1. Without NVBPP, the strategy of non-NAs support therapy strategy had the lowest life years expectance and QALYs at 16.53 and 14.10 years respectively with the lowest cost at 28,649.94USD. In contrast, The TAF therapy strategy successfully achieved the highest life years expectance and QALYs at 19.14 and 16.50 years respectively with a cost of 46,352.06USD which is even lower than the cost of ETV therapy. Compare to the Non-NAs strategy, the ETV strategy increased 20,173.19USD cost with an increment of 1.77 QALYs and 1.97 LYs, and the calculated ICER was 11,397.28.11USD/QALY. Similarly, the TDF strategy increased a cost of 14,620.26USD with 2.32 QALYs and 2.49 LYs incremental respectively. And the ICER of the TDF strategy was 6,301.84USD/QALY which is lower than the ETV strategy. Although the TAF strategy increased the largest QALYs and LYs which are 2.38 and 2.57 years with a cost of 17,899.62USD, the ICER of the TAF strategy is 7,520.85USD/QALY at a moderate level. With the NVBPP, the cost of ETV and TDF was significantly decreased. On the ground of non-NAs support therapy, the lifetime cost of ETV and TDF strategy was even lower. The ETV(NVBPP) strategy had a 1,082.24 USD decremental and the TDF(NVBPP) strategy had a 154.00 USD decremental. Considering the same gained QALYs with ETV and TDF strategy, the ICER of ETV (NVBPP) and TDF (NVBPP) achieved − 611.44 and − 66.38 USD/QALY. WTP/QALY ratio was highlighted as 1 to 3 times gross domestic product per capita as recommended by the World Health Organization [62]. As the GDP per capita of China in 2020 was 10500.40USD [63], the WTP/QALYs ratios ranged from 10,000.00 to 30,000.00 USD/QALY was reasonable. Except for the ICER of the ETV being higher than the 10,000.00USD/QALY, all the other strategies’ ICER is lower than GDP per capita (Fig. 2).

Table 2

Base-case cost-effectiveness results
Strategy	Cost(USD)	ΔCost(USD)	QALYs	ΔQALYs	ICER(USD/QALY)	LYs	ΔLYs
Non-NAs BSC	28649.94		14.10			16.53
ETV	48625.63	20173.19	15.89	1.77	11397.28	18.54	1.97
ETV(NVBPP)	27370.20	-1082.24	15.89	1.77	-611.44	18.54	1.97
TDF	43072.70	14620.26	16.44	2.32	6301.84	19.06	2.49
TDF(NVBPP)	28298.44	-154.00	16.44	2.32	-66.38	19.06	2.49
TAF	46352.06	17899.62	16.50	2.38	7520.85	19.14	2.57
BSC best supportive care, ETV entecavir, TDF tenofovir disoproxil fumarate, TAF Tenofovir alafenamide, NVBPP New Volume-based purchasing policy, ICER incremental cost-effectiveness ratio, QALY quality-adjusted life-year, LY life year expectancy

Univariate Sensitivity Analysis

A series of univariate sensitivity were performed for all transition probabilities, costs, and utilities. As the multiple strategies model, the tornado graph is based on NMB with a WTP threshold of 30,000USD/QALY and the most influence 15 paraments were present (Fig. 3). The discount and age of starting therapy were the highest impacts on NMB for a lifetime therapy. With the discount rate increasing from 3–6%, the NMB decreased from 660237.87USD to 402993.81USD. On the other hand, the later therapy start, the less NMB the patient gains. Starting therapy at 18 years old will gain 464,803.91USD NMB and only 335,062.11USD NMB was gained when starting therapy at 60 years old. For TDF monotherapy, the HR of TDF vs. non-NAs from CHB to HCC and HR from CHB to CC were the most influence paraments. With the increment of HR of TDF vs. Non-NAs from CHB to HCC and from CHB to CC, the NMB decreased from 472,503.02 to 449,503.50USD and 472,181.54 to 449,655.03USD respectively (expect value 464803.92USD, the percentage NMB change only ranges from − 3.3–1.7%). All parameters excepting the discount and start therapy age had little impact on the robustness of the models.

Probabilistic Sensitivity Analysis

PSA with 100,000 Monte Carlo simulations was conducted to assess the impact of uncertain parameters varying simultaneously within defined distributions. The results are displayed in the cost-effectiveness plane (Figs. 4&5). In pairwise comparison, taking the non-NAs support care therapy as the baseline, over 98.6% of simulations will choose ETV, TDF, ETV(NVBPP), TDF(NVBPP), or TAF respectively as an optimal strategy with a WTP threshold of 30,000USD/QALY. Although the TAF strategy has the highest QALYs and LYs, only 12.34% and 40.16% of simulations will take the TAF strategy as the optimal strategy compare with TDF(NVBPP) and ETV(NVBPP). Without NVBPP, the percentage of TAF as optimal therapy in simulation compering to TDF or ETV will rise to 44.56% and 96.62%.

The cost-effectiveness of each strategy across a range of WTP thresholds is shown in Fig. 6. The TDF(NVBPP) had a 78.29% chance of being the optimal treatment strategy at a WTP threshold of 30,000USD/QALY, and the chances of ETV(NVBPP) and TAF being optimal were 14.23% and 7.48%. Little chance of Non-NAs BSC, ETV, and TDF being optimal. With the decremental WTP threshold, the chance of ETV(NVBPP) being the optimal strategy increased while TAF being optimal decreased. At the threshold of 20,000USD/QALY, ETV(NVBPP) and TAF were 17.34% and 2.69%, and TDF(NVBPP) was 79.87%. Further decreasing the WTP thresholds to 10000USD/QALY, the ETV(NVBPP) increased to 24.83%, and TAF will decrease to only 0.04%, while the TDF(NVBPP) is still predominating which up to 75.13%. Therefore, the TDF(NVBPP) has the highest chance of being the most cost-effective treatment for CHB infections.

Discussion

In this study, we evaluated the cost-effectiveness of the first-line NAs as a lifetime CHB therapy, especially including the ETV and TDF with NVBPP. Our analyses suggested that compare to non-NAs support therapy, all the NAs with or without NVBPP were cost-effective at a WTP threshold of 30,000USD/QALY. The TAF gained the highest QALYs with the second-highest cost which is lower than ETV and higher than TDF. Considering the improvement of renal and bone safety [25], the TAF would be a promising therapy compared to the ETV and TDF. Indeed, our probabilistic sensitivity analysis show in most simulation compare to ETV and nearly half of the simulation compared to TDF, that TAF could be the optimal therapy with a WTP threshold of 30,000USD/QALY.

Tian’s study about the cost-effectiveness of TAF compare to TDF and ETV in Canada, shows a 33.4% reduction in price would be required to make TAF cost-effective [61]. Based on Tian’s study, the price of a unit of ETV, TDF, and TAF were 5.50 Canada Dollars (4.32 USD), 4.89 Canada Dollars (3.84USD), and 19.55 Canada Dollars (15.3 USD) respectively. At the same time, in China, the price of ETV, TDF without NVBPP, and TAF were 3.16USD, 2.17USD, and 2.74USD which means a 26.9%, 43.5%, and 82.1% reduction compared to Tian’s study. This might explain the incremental cost-effectiveness of TAF in China.

However, in 2019, China’s New Volume-Based Purchasing Policy was implemented in Beijing, Shanghai, Tianjin, Chongqing (4 municipalities directly under the Central Government), and other 7 megacities (“4 + 7”). With the NVBPP, brand or generic drug manufacturers will gain the predominant supplier position in public hospitals with a low drug price. In the first turn of purchasing, the price of ETV and TDF was 92.7% and 96.2% reduction [26]. With more cities implementing the NVBPP and annually price refreshing, the price of a unit of ETV and TDF in our hospital were 0.03USD and 0.05USD in 2021 while TAF was still out of the list of NVBPP[28]. In this new background, the ETV(NVBPP) and TDF(NVBPP) dominated the ETV and TDF in our analyses. Even considering the TAF has the highest QALYs gain, our acceptable care analysis demonstrated that the TDF(NVBPP) will be the most people’s optimal strategy followed by ETV(NVBPP), and only a small part of people will choose the TAF.

Our analysis is based on the ground of assuming the generic drugs were the same potent and quality as brand name drugs. NVBPP was open to all generic and brand-name drug manufacturers. However, all the generic drugs on the list were required to pass the generic consistency evaluation (GCE) which was launched by the National Medical Products Administration (NMPA) in 2018[26]. In the GCE, the generic drugs should have comparable quality to brand-name drugs, especially in the bioequivalence trials [64]. It’s reasonable to assume the ETV and TDF provided by generic manufacturers have similar qualities to brand-name ones. However, due to the lack of long-term clinical trials in GCE, whether the generic ETV and TDF with NVBPP are equivalent to brand-name ones in the real world in a long-term therapy still needs to be observed in the future.

All the ETV, TDF, and TAF are highly effective in suppressing HBV DNA replication and improving the outcome of CHB, especially in preventing HCC occur [12–15]. However, none of them can eliminate cccDNA [10]. Researches show HBV viremia typically recurs upon treatment cessation despite successful virus suppression during therapy [11]. Some studies indicate that long-term NAs therapy can reduce the mortality and HCC incidence in CHB patients [12, 15, 16, 65–67]. Based on these, we assume a lift-time therapy in our model, to evaluate the cost-effectiveness on a whole life scale. As expected, the ETV, TDF, and TAF therapy has a higher cost compare to non-NAs support therapy with a cost-effect ICER. Interestedly, the whole life cost of ETV and TDF with NVBPP were even lower than the non-NAs BSC. Given that we assume the ETV and TDF with NVBPP have the same efficiency as ETV and TDF without NVBPP, and the ETV and TDF reduce the clinical outcome of CHB such as DC, HCC, and liver transplant. The lower cost may be a result of improvement in the outcome of CHB compare to non-NAs support therapy.

As a developing country, the Chinese per capita spending on health care was 4,702.8 CNY (737.9USD) in 2019[68]. In contrast, the US. per capita spending on health care reach 10,623USD in 2018[69]. On the other hand, 84 million Chinese are living with HBsAg [2] while 1.59 million Americans live with HBsAg [70]. Therefore, affordable long-term NAs for CHB patients in China is a critical issue. In our study, the ETV(NVBPP) and TDF(NVBPP) strategies have a lower cost than non-NAs BCS, and TDF(NVBPP) has the highest acceptability probability. It’s reasonable to expect the TDF(NVBPP), followed by ETV(NVBPP), would improve the outcome of CHB patients without increasing the health care burden. ETV and TDF with NVBPP could be the optimal strategies to alleviate the CHB burden.

Declarations

Ethics approval and consent to participate：All methods were carried out in accordance with relevant guidelines and regulations or declaration of Helsinki (not applicable, the data in this paper were from published articles and do not involve patients, so ethical approval and informed consent are not required）.

Consent for publication: Not Applicable.

Availability of data and materials: All data generated or analysed during this study are included in this published article.

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Competing interests: The authors have no competing interests.

Founding: This study is supported by Fujian Provincial Natural Science Foundation, Grant No. 2020J05264 & Science and Technology Planning Project of Fujian Provincial Health Commission, Grant No. 2020GGA002 & Qihang Foundation of Fujian Medical University, Grant No. 2019QH1167.

Author’s contributions: Lin Y, Lin XY and Chen J designed the study, collected and analyzed the data, and wrote the manuscript, the authors have contributed equally to this work; Lin ZH and Lin Y contributions to conception, design, and coordination of the study and gave final approval of the version to be published.

Acknowledgements: This study was supported by the Fujian Provincial Natural Science Foundation (2020J05264), Science and Technology Planning Project of Fujian Provincial Health Commission (2020GGA002), and Qihang Foundation of Fujian Medical University (2019QH1167). The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Authors' information:

1.Yi Lin, M.D., Ph.D. Department of Gastroenterology and Hepatology, Fujian Provincial Hospital; The Shengli Clinical Medical College, Fujian Medical University.

2.Zhihui Lin, Department of Gastroenterology and Hepatology, Fujian Provincial Hospital; The Shengli Clinical Medical College, Fujian Medical University.

3.Xueyan Lin, Department of Gastroenterology and Hepatology, Fujian Provincial Hospital; The Shengli Clinical Medical College, Fujian Medical University.

4.Juan Chen, Department of Gastroenterology and Hepatology, Fujian Provincial Hospital; The Shengli Clinical Medical College, Fujian Medical University.

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Tenofovir disoproxil fumarate is superior to Entecavir and Tenofovir alafenamide in Cost-Effectiveness of Treatment of Chronic Hepatitis B in China with New Volume-Based Purchasing Policy

Abstract

Background/Aim:

Methods

Results

Conclusion

Introduction

Methods

Type of Economic Evaluation

Strategies

Cohort And Model Structure

Costs

Utilities

Sensitivity Analyses

Results

Base-case results

Univariate Sensitivity Analysis

Probabilistic Sensitivity Analysis

Discussion

Conclusion

Declarations

References