基于Markov模型的2种治疗慢性乙型肝炎药物经济学评价

陈幸, 陈琳

重庆市妇幼保健院药剂科,重庆 400021

CHEN Xing^,, CHEN Lin^,

Department of Pharmacy,Chongqing Health Center for Women and Children,Chongqing 400021,China

通信作者陈琳(1982-),女,重庆人,副主任药师,博士,从事临床药学与药理学方向研究。ORCID:0000-0002-2401-8438。电话:023-60354422,E-mail:11777635@qq.com。

作者简介陈幸(1985-),男,重庆人,主管药师,学士,从事临床药学与药理学方向研究。ORCID:0000-0002-8630-1589。电话:023-60354422,E-mail:woaihippo313@126.com。

基金资助: 重庆市技术创新与应用示范项目(cstc2018jscx-msybX0101)

中图分类号: R956;R978.7 文献标识码: B 文章编号: 1004-0781(2021)04-0519-07

摘要:

目的通过建立Markov模型,对替诺福韦艾拉酚胺与替诺福韦酯两种治疗慢性乙型肝炎的一线用药进行药物经济学评价,为临床用药提供循证依据。方法参考药品价格、治疗成本、健康效用值、状态转移概率建立Markov模型,对2种方案的有效性和经济学进行评价,并进行敏感性分析。结果替诺福韦艾拉酚胺组成本为1 077 244.03元,获得7.89QALYs,替诺福韦酯组成本效果为932 456.65元,获得7.48QALYs,增量成本-效果比为353 139.95元。结论与替诺福韦酯组比较,替诺福韦艾拉酚胺组能获得更长的生存结果,但其付出的增量成本效果大于3倍人均GDP193 932元,不具有经济学效益。

关键词: 慢性乙型肝炎 ; 替诺福韦艾拉酚胺 ; 替诺福韦酯 ; 药物经济学

Abstract:

Objective Through the establishment of the Markov model, the pharmacological economic evaluation of tenofovir alafenamide and tenofovir disoproxil for the first-line treatment of chronic hepatitis B was conducted to provide evidence for clinical drug use. Methods The Markov model was established with reference to drug prices, treatment costs, and health utility values. The effectiveness and economics of the two programs were evaluated and sensitivity analysis was performed. Results The composition of tenofovir alafenamide was 1 077 244.03 yuan, 7.89QALYs was obtained, and the effect of tenofovir disoproxil was 932 456.65 yuan, and 7.48QALYs was obtained. The incremental cost-effective ratio was 353 139.95 yuan. Conclusion Compared with the tenofovir dipivoxil group, the tenofovir alafenamide group can achieve longer survival results, but its incremental cost effect is greater than 3 times GDP per capita, and has no economic benefit.

Key words: Chronic hepatitis B ; Tenofovir alafenamide ; Tenofovir disoproxil ; Pharmacoeconomics

开放科学(资源服务)标识码(OSID)

慢性乙型肝炎(Chronic hepatitis B,CHB)是由乙型肝炎病毒(Hepatitis B Virus,HBV)感染引起慢性传染性疾病,在全球范围内对人类健康造成严重的威胁。据估计,2016年全球慢性乙型肝炎病毒感染率为3.5%,2.57亿人患有慢性感染^[1]。最近的研究显示,病毒性肝炎已成为全球第七大发病和死亡原因,每年死亡145万人,超过艾滋病、疟疾和结核病^[2],由HBV引起的如肝硬化、肝细胞癌等并发症是CHB致死的主要原因^[3],仅在2015年,就有68万人死于乙肝病毒相关的肝硬化和肝癌^[4]。CHB的治疗费用也给患者造成沉重的经济负担,有研究^[5]表明,由CHB导致各类肝脏疾病的治疗费用人均20 818元/年,占家庭年均收入的87.3%,占个人年均收入的261.8%。

CHB的治疗目标是最大限度地长期抑制HBV复制,减轻肝细胞炎性坏死及肝纤维化,延缓和减少肝功能衰竭、肝硬化失代偿、肝细胞癌及其他并发症的发生,从而改善生活质量和延长生存时间,抗病毒是治疗HBV的主要手段^[6]。替诺福韦艾拉酚胺(tenofovir alafenamide,TAF)是一种口服生物利用度有限的核苷酸类似物,可抑制HBV和人类免疫缺陷病毒1型(human immunodeficiency Virus-1,HIV-1)的逆转录,是美国食品药物管理局(FDA)最近批准的一种用于治疗HBV感染的新药,与替诺福韦酯(tenofovir disoproxil fumarate,TDF)均为抗HBV一线用药^[7]。TAF和TDF同为替诺福韦(tenofovir,TFV)的前体药物,它们在细胞内具有相同的活性代谢物二磷酸替诺福韦(tenofovir diphosphate,TFV-DP),TAF在血浆中比TDF更稳定,向靶细胞(HBV感染的肝细胞和HIV感染的淋巴样细胞)提供更高水平的TFV-DP。在治疗活性剂量下,TAF与TDF比较,循环中的TFV水平降低约90%,因此TAF对肾功能和骨密度的不良影响较少^[8]。

TAF是中国近年来唯一获批上市的治疗HBV感染的新药,而TDF在治疗HBV感染方面已被广泛使用,评价治疗策略除了有效性和安全性外,药物经济性也是重要考量因素。强效治疗方案带来更好疗效的同时也可能会增加患者的经济负担,因此通过运用卫生经济学的评价技术,结合决策分析的原理,评价长期治疗 CHB 患者的成本-效果,是十分重要的研究课题。而马尔科夫(Markov)模型由于能通过转移概率矩阵实现在不同疾病状态之间的转归,被认为更加适用于模拟慢性病的病程。国内目前尚未发表关于TAF和TDF治疗HBV感染的相关药物经济学评价,本研究从患者支付角度出发,通过建立Markov模型对两种药物在治疗HBV感染方面进行药物经济学评价,为临床用药提供循证医学证据。

1 资料与方法

1.1 Markov模型设计

Markov模型的基本原理是利用某一变量的现在状态和动向,去预测该变量未来的状态及其动向的一种分析手段。由于其具有的马尔科夫性(无后效性),对历史数据需求不多,预测方法具有很多优点 ,因此在现代统计学中占有重要的地位^[9]。参考RUGGERI等^[10]的研究,使用TreeAgePro2011软件构建Markov模型。由于TAF和TDF在治疗HBV感染时发生耐药的概率极低^[11],同时国内肝移植较少且非常规治疗,故构建模型时未考虑耐药及肝移植两个状态,最终模型包含CHB 、HBeAg 血清学转换( HBeAg 阳性患者独有)、代偿性肝硬化(compensated cirrhosis,CC) 、失代偿性肝硬化(decompensated cirrhosis,DC)、肝癌(hepatocellular carcinoma,HCC)与死亡等6个状态,其中死亡为吸收态。各状态转换关系见图1。

图1 各状态转换关系图

Fig.1 Diagram of state transition

1.2 模型参数

1.2.1 研究对象检索PubMed英文数据库,检索范围“Title/Abstract”,检索词“Chronic hepatitis B、tenofovir alafenamide、tenofovir disoproxil fumarate、randomized controlled trial”及其对应的MeSH词。检索时间为建库至今。由于HBV DNA水平已被确定为与慢性乙型肝炎患者肝并发症有关的重要指标^[12],因此排除HBV DNA报道不足、不良事件发生率报道不全的文献,最终选择样本量较大,且治疗周期长的1篇文献,作为本次研究的数据来源^[13]。该文献是基于两项(GS-US-320-0110和GS-US-320-0108)大规模的、正在进行的、随机、双盲的国际III期试验,旨在比较TAF和TDF在治疗中的疗效和安全性。试验共计纳入门诊患者1 298例,服用TAF患者866例,服用TDF患者432例,每日分别服用TAF25 mg和TDF300 mg,随访时间2年。第96周时,HBeAg阳性患者病毒抑制率差异无统计学意义(P=0.47)、HBeAg阴性患者病毒抑制率差异无统计学意义(P=0.84)。患者数据基线见表1。模型将模拟患者的终身治疗,根据2018年中国统计年鉴数据显示,我国居民平均预期寿命为76.34岁,纳入研究的患者平均年龄40岁,因此设置模型循环40个周期,每个周期代表1年。

项目	例数	平均年龄, 岁(范围)	平均HBV DNA, lg/ U·mL^-1(范围)	中位ALT (Q1,Q3)	HBeAg状态	已知肝硬化患者的患者	平均纤维化评分(范围)	纤维化评分≥0.75
TAF 25 mg	866	40(18~80)	7.0(1.8~9.9)	80(56,123)	569(65.7)	297(34.3)	65/636(10)	0.37(0.04~0.98)	76/846(9)
TDF 300 mg	432	41(18~72)	7.0(1.4~9.9)	80(53,130)	290(67.1)	142(32.9)	38/326(12)	0.37(0.03~0.99)	42/421(10)
总数		41(18~80)	7.0(1.4~9.9)	80(54,125)	859(66.2)	439(33.8)	103/962(11)	0.37(0.03~0.99)	118/1267(9)

表1 2组患者基线特征

Tab.1 Baseline characteristics of two groups of patients

1.2.2 健康效用值健康效用值作为衡量疾病治疗效果的指标,其数值介于0(死亡)到1(完全健康)之间。本研究健康效用值参考LEVY等^[14]的研究,结果见表2。

健康状态	效用值(范围)
慢性乙型肝炎	0.52(0.47~0.57)
HBeAg 血清学转换	0.71(0.64~0.78)
代偿性肝硬化	0.57(0.51~0.63)
失代偿性肝硬化	0.26(0.23~0.29)
肝细胞癌	0.31(0.28~0.34)
死亡	0

表2 CHB各状态效用值

Tab.2 Utility value of CHB status

1.2.3 状态转移概率本研究各状态间转移概率来源于临床研究[13,15-18],提取数据,根据公式r=-[ln(1-P₁)]/t₁和P₂=1-exp(-rt₂),其中r为瞬时发生率,P₁为一段观察时限下发生某事件的概率,P₂为一个循环周期下的转移概率,t₁为观察的时限长度,t₂为单个循环周期的时间^[19]。计算结果见表3。

表3 CHB各状态转换率
Tab.3 Transition rate of CHB state %

转移过程	TAF(范围)	TDF(范围)	参考文献
慢性乙型肝炎
→慢性乙型肝炎	74.7(73.6~75.8)	80.7(78.3~83.1)	[13,15]
→HBeAg 血清学转换	18.0(17~19)	12.00(11~13)	[13,15]
→代偿性肝硬化	3.88(3.14~4.62)	3.88(3.14~4.62)	[15-16]
→失代偿性肝硬化	2.17(1.84~2.50)	2.17(1.84~2.50)	[15-16]
→肝癌	0.74(0.49~0.99)	0.74(0.49~0.99)	[15-16]
→死亡	0.51	0.51
HBeAg 血清学转换
→HBeAg 血清学转换	95.29(92.17~98.41)	95.29(92.17~98.41)	[13,15]
→慢性乙型肝炎复发	2.2(1.8~2.6)	2.2(1.8~2.6)	[15-16]
→代偿性肝硬化	0.74(0.56~0.92)	0.74(0.56~0.92)	[17-18]
→肝癌	1.29(0.93~1.65)	1.29(0.93~1.65)	[17-18]
→死亡	0.48	0.48
代偿性肝硬化
→代偿性肝硬化	88.10(84.16~92.04)	88.10(84.16~92.04)	[17-18]
→失代偿性肝硬化	4.77(3.79~5.75)	4.77(3.79~5.75)	[17-18]
→肝癌	2.90(1.86~3.94)	2.90(1.86~3.94)	[17-18]
→死亡	4.23	4.23
失代偿性肝硬化
→失代偿性肝硬化	68.56(64.33~72.79)	68.56(64.33~72.79)	[17-18]
→肝癌	2.81(2.32~3.30)	2.81(2.32~3.30)	[17-18]
→死亡	28.63	28.63
肝癌
→肝癌	43.33(38.17~48.49)	43.33(38.17~48.49)	[17-18]
→死亡	56.67	56.67

表3 CHB各状态转换率

Tab.3 Transition rate of CHB state %

1.2.4 治疗成本因TDF已在国内上市多年,且存在通过一致性评价的仿制药物,故本研究最终选择进口药物作为治疗药物。以2018年重庆市药品挂网价格为准,确定富马酸替诺福韦二吡呋辛酯片(TDF,韦瑞德,Gilead Sciences,Inc,0.3g/p,H20171313)每天治疗成本为人民币10.98元;富马酸丙酚替诺福韦片(TAF,韦立德,Gilead Sciences International Ltd,25 mg/p,H20180060)每天治疗成本为人民币39.33元,根据患者每日服用量确定药品治疗费用。参考文献确定CHB各状态下产生的治疗费用^[20],治疗费用=直接费用+间接费用+隐形费用,成本和效用值年贴现率设置为5%^[21]。治疗过程中有13例(2%)接受TAF治疗和4例(1%)接受TDF治疗的患者因不良事件而停止治疗,比例均较低。两种治疗均耐受良好,大多数患者仅发生轻度至中度的不良反应。不良反应集中表现为头痛TAF98例(11.3%)TDF43例(10%);鼻咽炎TAF105例(12.1%)TDF44例(10.2%);上呼吸道感染、鼻咽炎TAF105例(12.1%)TDF45例(10.4%)。因此由治疗引发的不良反应治疗费用及效用值降低未计算在内,结果见表4。

项目	赋值(元,人民币/年)
药品
TDF	4 007.7
TAF	14 355.45
治疗成本
慢性乙型肝炎	68 506.2
HBeAg 血清学转换	68 506.2
代偿性肝硬化	82 168.9
失代偿性肝硬化	93 150.5
肝癌	131 510.1

表4 各状态成本费用

Tab.4 Costs of each state

1.2.5 评价指标本次研究将质量调整生命年(QALYs)做为评价指标,使用增量成本-效果比(ICER)作为2种药品的药物经济学评价标准。因国内目前尚无具体标准,故本次研究根据世界卫生组织建议,设定ICER<1倍人均GDP为极有成本-效果;1倍人均GDP<ICER<3倍人均GDP为有成本-效果;ICER>3倍人均GDP为不具有成本-效果^[22]。本次研究选定2018年1倍人均GDP即64 644元为阈值标准,数据来源于中国统计年鉴。

1.3 敏感性分析

1.3.1 单因素敏感性分析为了考察模型的稳定性,分别对2种药品的成本、贴现率、各状态治疗费用、各状态效用值进行单因素敏感性分析。各成本值按基线±25%计算,效用值按基线±10%计算,所有费用贴现率浮动0~8%。

1.3.2 概率敏感性分析根据各不确定性因素的参数分布特征进行1 000次二阶Monte Carlo模拟,成本服从Gamma分布,效用值服从Beta分布。根据支付意愿(WTP)绘制成本-效果可接受曲线及散点图。

2 结果

2.1 队列分析

到第40个周期时,TAF组停留在CHB状态概率为2.23%,HBeAg 血清学转换为22.62%,CC概率为2.90%,DC概率为0.66%,HHC概率为0.77%,死亡率为70.83%;TDF组停留在CHB状态概率为2.61%,HBeAg 血清学转换为19.22%,CC概率为2.91%,DC概率为0.70%,HHC概率为0.70%,死亡率为73.87%。见图2,3。

图2 TAF组队列分析模型图

Fig.2 Cohort analysis mdel of TAF group

图3 TDF组队列分析模型

Fig.3 Cohort analysis mdel of TDF group

2.2 回乘分析

对TAF组和TDF组进行回乘分析,成本-效果分析结果见表5。结果显示TAF组成本为1 077 244.03元,获得7.89QALYs,TDF组成本效果为932 456.65元,获得7.48QALYs,增量成本-效果比为353 139.95,大于2018年3倍人均GDP193 932元,说明TAF组相较与TDF组不具有经济学效益。

方案	成本 (C)/元	增量成本 (△C)	效果 (E)/QALYs
TDF	932 456.65		7.48
TAF	1 077 244.03	144 787.38	7.89
方案	增量效果 (△E)	C/E	△C/△E
TDF		124 659.98
TAF	0.41	136 532.83	353 139.95

表5 2种方案成本-效果分析

Tab.5 Cost-effectiveness analysis of two regimens

2.3 敏感性分析

2.3.1 单因素敏感性分析由于本研究中的数据均来源于文献,为检验变量对模型稳定性是否有影响,本研究对各状态成本±25%及效用值±10%进行单因素敏感性分析,所得结果与原模型一致,龙卷风图见图4。分析结果说明对模型影响最大的因素为两种药品的成本,其它因素影响较小。

图4 敏感性分析龙卷风图
Cta:TAF药品成本;Ctd:TDF药品成本;Cc:代偿性肝硬化治疗成本;Uchb:CHB效用值;dls:贴现率;Uc:代偿性肝硬化效用值;Cd:失代偿性肝硬化治疗成本;Ud:失代偿性肝硬化效用值;Ch:肝癌治疗成本;Uh:肝癌效用值。

Fig.4 Tornado graph of sensitivity analysis
Cta:cost of TAF;Ctd:cost of TDF;Cc:treatment cost of compensated cirrhosis;Uchb:utility value of CHB;dls:discount rate;Uc:utility value of compensated cirrhosis;Cd:treatment cost of decompensated cirrhosis;Ud:utility value of decompensated cirrhosis;Ch:treatment cost of hepatocellular carcinoma;Uh:utility value of hepatocellulav carcinoma.

2.3.2 概率敏感性分析通过二阶Monte Carlo模拟1 000次进行概率敏感性分析,阈值标准为64 644元。成本-效果可接受曲线图5所示。结果显示,TAF的接受率随着WTP的增加而上升,但仍低于TDF。模拟1 000次的散点分布图如图6所示,结果显示TDF较TAF更具有经济学优势。

图5 成本-效果可接受曲线

Fig.5 Acceptance curve of cost-effectiveness

图6 增量成本散点图

Fig.6 Scatter plot of incremental cost

3 讨论

相关研究表明,TDF比较与其他核苷酸类似物具有更好的病毒学应答,不良反应少,耐药率低等优点^[23]。2008年FDA批准TDF用于CHB治疗,2014年中国食品药品监督管理局批准TDF用于CHB患者抗病毒治疗^[24]。TAF比较TDF具有更高的生物利用度,TAF25 mg与TDF300 mg的抗病毒作用无明显差异。MURAKAMI等^[25]的实验结果显示,TAF系孵育的肝细胞中 TFV-DP的浓度分别是TFV系和TDF系的120倍和5倍,说明TAF的抗病毒复制的活性最强。而正是由于起给药剂量远低于TDF,因此TAF对肾和骨骼的毒性较小,安全性较高^[26]。

TAF作为近年国内唯一获准上市的抗HBV感染药物,且和TDF同为TFV的前体药物,国内目前尚无文献对两者进行比较。参考加拿大卫生部药品和技术局(Canadian Agency for Drugs and Technologies in Health,CADTH)的TAF药物经济学报告^[27],采用TAF治疗的患者(7 137美元·人^-1)比采用TDF治疗的患者(1 784美元·人^-1)每年治疗费用多出5 353美元·人^-1,报告结果提示TAF比较TDF并不具有成本效益。本研究采用增量成本-效果做为评价标准,从药物经济学的角度出发对TAF和TDF进行评价,结果提示现阶段TAF较TDF并不具有经济学效益,结果与CADTH一致。

本研究尚存在以下不足:①因国内缺乏TAF和TDF的大型随机对照试验,本研究采用的是多地区、多种族的文献资料,与国内患者的身体体质可能存在一定差异。②采纳文献目前仅报道96周的治疗效果,尚需后续报道对模型进行论证。③研究过程对疾病临床状态及计算进行了简化,死亡状态仅考虑与疾病相关死亡率,实际结果可能会存在一定偏倚。

本研究结果提示虽然TAF较TDF具有更好的抗病毒活性、安全性以及更长的生产结局,但从药物经济学角度考虑TDF更具有经济学效益。本研究旨在为临床治疗慢性乙型肝炎选择治疗方案时提供一定的循证医学证据。

参考文献

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[13]	AGARWAL K,BRUNETTO M,SETO W K,et al.96 weeks treatment of tenofovir alafenamide vs.tenofovir disoproxil fumarate for hepatitis B virus infection[J].J Hepatol,2018,68(4):672-681. BACKGROUND & AIMS: Tenofovir alafenamide (TAF) is a new prodrug of tenofovir developed to treat patients with chronic hepatitis B virus (HBV) infection at a lower dose than tenofovir disoproxil fumarate (TDF) through more efficient delivery of tenofovir to hepatocytes. In 48-week results from two ongoing, double-blind, randomized phase III trials, TAF was non-inferior to TDF in efficacy with improved renal and bone safety. We report 96-week outcomes for both trials. METHODS: In two international trials, patients with chronic HBV infection were randomized 2:1 to receive 25mg TAF or 300mg TDF in a double-blinded fashion. One study enrolled HBeAg-positive patients and the other HBeAg-negative patients. We assessed efficacy in each study, and safety in the pooled population. RESULTS: At week 96, the differences in the rates of viral suppression were similar in HBeAg-positive patients receiving TAF and TDF (73% vs. 75%, respectively, adjusted difference -2.2% (95% CI -8.3 to 3.9%; p=0.47), and in HBeAg-negative patients receiving TAF and TDF (90% vs. 91%, respectively, adjusted difference -0.6% (95% CI -7.0 to 5.8%; p=0.84). In both studies the proportions of patients with alanine aminotransferase above the upper limit of normal at baseline, who had normal alanine aminotransferase at week 96 of treatment, were significantly higher in patients receiving TAF than in those receiving TDF. In the pooled safety population, patients receiving TAF had significantly smaller decreases in bone mineral density than those receiving TDF in the hip (mean % change -0.33% vs. -2.51%; p<0.001) and lumbar spine (mean % change -0.75% vs. -2.57%; p<0.001), as well as a significantly smaller median change in estimated glomerular filtration rate by Cockcroft-Gault method (-1.2 vs. -4.8mg/dl; p<0.001). CONCLUSION: In patients with HBV infection, TAF remained as effective as TDF, with continued improved renal and bone safety, two years after the initiation of treatment. Clinicaltrials.gov number: NCT01940471 and NCT01940341. LAY SUMMARY: At week 96 of two ongoing studies comparing the efficacy and safety of tenofovir alafenamide (TAF) to tenofovir disoproxil fumarate (TDF) for the treatment of chronic hepatitis B patients, TAF continues to be as effective as TDF with continued improved renal and bone safety. Registration: Clinicaltrials.gov number: NCT01940471 and NCT01940341. DOI:10.1016/j.jhep.2017.11.039 PMID:29756595 URL [本文引用:1]
[14]	LEVY A R,KOWDLEY K V,ILOEJE U,et al.The impact of chronic hepatitis B on quality of life:a multinational study of utilities from infected and uninfected persons[J].Value Health,2008,11(3):527-538. Abstract Objectives Chronic hepatitis B (CHB) is a condition that results in substantial morbidity and mortality worldwide because of progressive liver damage. Investigators undertaking economic evaluations of new therapeutic agents require estimates of health-related quality of life (HRQOL). Recently, evidence has begun to accumulate that differences in cultural backgrounds have a quantifiable impact on perceptions of health. The objective was to elicit utilities for six health states that occur after infection with the hepatitis B virus from infected and uninfected respondents living in jurisdictions with low and with high CHB endemicity. Methods Standard gamble utilities were elicited from hepatitis patients and uninfected respondents using an interviewer-administered survey in the United States, Canada, United Kingdom, Spain, Hong Kong, and mainland China. Generalized linear models were used to the effect on utilities of current health, age and sex, jurisdiction and, for infected respondents, current disease state. Results The sample included 534 CHB-infected patients and 600 uninfected respondents. CHB and compensated cirrhosis had a moderate impact on HRQOL with utilities ranging from 0.68 to 0.80. Decompensated cirrhosis and hepatocellular carcinoma had a stronger impact with utilities ranging from 0.35 to 0.41. Significant variation was observed between countries, with both types of respondents in mainland China and Hong Kong reporting systematically lower utilities. Conclusions Health states related to CHB infection have substantial reductions in HRQOL and the utilities reported in this study provide valuable information for comparing new treatment options. The observed intercountry differences suggest that economic evaluations may benefit from country-specific utility estimates. The extent that systematic intercountry differences in utilities hold true for other infectious and chronic diseases remains an open question and has considerable implications for the proper conduct and interpretation of economic evaluations. DOI:10.1111/j.1524-4733.2007.00297.x URL [本文引用:1]
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[17]	赵景民,周光德,孙艳玲,等.25946例行肝穿刺检查肝病病例的临床病理、流行病学及转归的研究[J].解放军医学杂志,2008,33(10):1183-1187. [本文引用:0]
[18]	黄海,朱畴文,于晓峰,等.慢性乙型肝炎并发肝硬化的转归研究[J].肝脏,2007,12(6):437-440. [本文引用:0]
[19]	周挺,马爱霞,付露阳,等.药物经济学评价Markov模型中转移概率计算的探讨[J].中国卫生经济,2017,36(12):40-42. [本文引用:1]
[20]	马起山,梁森,肖和卫,等.中国12个地区乙型肝炎相关疾病住院患者经济负担调查[J].中华流行病学杂志,2017,38(7):868-876. [本文引用:1]
[21]	沈科书,王峰,李艳玲,等.运用Markov模型对恩替卡韦治疗慢性乙型肝炎的成本效果分析[J].肝脏,2010,15(6):406-408. [本文引用:1]
[22]	刘国恩,胡善联,吴久鸿.中国药物经济学评价指南(2011版)[J].中国药物经济学,2011(3):6-9,11-48. [本文引用:1]
[23]	BUTI M,FUNG S,GANE E,et al.Long-term clinical outcomes in cirrhotic chronic hepatitis B patients treated with tenofovir disoproxil fumarate for up to 5 years[J].Sprihger Open Choice,2015,9(2):243-250. [本文引用:1]
[24]	替诺福韦酯治疗慢性HBV感染临床应用专家委员会.替诺福韦酯治疗慢性HBV感染临床应用专家共识[J].中华实验和临床感染病杂志:电子版,2015,9(1):120-125. [本文引用:1]
[25]	MURAKAMI E,WANG T,PARK Y,et al.Implications of efficient hepatic delivery by tenofovir alafenamide(GS-7340) for hepatitis B virus therapy[J].Antimicrob Agents Chemother,2015,59(6):3563-3569. Tenofovir alafenamide (TAF) is a prodrug of tenofovir (TFV) currently in clinical evaluation for treatment for HIV and hepatitis B virus (HBV) infections. Since the target tissue for HBV is the liver, the hepatic delivery and metabolism of TAF in primary human hepatocytes in vitro and in dogs in vivo were evaluated here. Incubation of primary human hepatocytes with TAF resulted in high levels of the pharmacologically active metabolite tenofovir diphosphate (TFV-DP), which persisted in the cell with a half-life of >24 h. In addition to passive permeability, studies of transfected cell lines suggest that the hepatic uptake of TAF is also facilitated by the organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3, respectively). In order to inhibit HBV reverse transcriptase, TAF must be converted to the pharmacologically active form, TFV-DP. While cathepsin A is known to be the major enzyme hydrolyzing TAF in cells targeted by HIV, including lymphocytes and macrophages, TAF was primarily hydrolyzed by carboxylesterase 1 (CES1) in primary human hepatocytes, with cathepsin A making a small contribution. Following oral administration of TAF to dogs for 7 days, TAF was rapidly absorbed. The appearance of the major metabolite TFV in plasma was accompanied by a rapid decline in circulating TAF. Consistent with the in vitro data, high and persistent levels of TFV-DP were observed in dog livers. Notably, higher liver TFV-DP levels were observed after administration of TAF than those given TDF. These results support the clinical testing of once-daily low-dose TAF for the treatment of HBV infection. DOI:10.1128/AAC.00128-15 PMID:25870059 URL [本文引用:1]
[26]	STEO W K,ASAHINA Y,BROWN TT,et al.Improved bone safety of tenofovir alafenamide compared to tenofovir disoproxil fumarate over 2 years in patients with chronic HBV infection[J].Clin Gastroenterol Hepatol,2018,S1542-3565(18)30633-5. [本文引用:1]
[27]	.Canadian Agency for Drugs and Technologies in Health.Pharmacoeconomic Review Report:Tenofovir Alafenamide(Vemlidy):(Gilead Sciences Canada,Inc.)[EB/OL].2018,Apr.https://www.ncbi.nlm.nih.gov/books/NBK532825/. URL [本文引用:1]

Chronic hepatitis B virus infection

2018

... 慢性乙型肝炎(Chronic hepatitis B,CHB)是由乙型肝炎病毒(Hepatitis B Virus,HBV)感染引起慢性传染性疾病,在全球范围内对人类健康造成严重的威胁.据估计,2016年全球慢性乙型肝炎病毒感染率为3.5%,2.57亿人患有慢性感染^[1].最近的研究显示,病毒性肝炎已成为全球第七大发病和死亡原因,每年死亡145万人,超过艾滋病、疟疾和结核病^[2],由HBV引起的如肝硬化、肝细胞癌等并发症是CHB致死的主要原因^[3],仅在2015年,就有68万人死于乙肝病毒相关的肝硬化和肝癌^[4].CHB的治疗费用也给患者造成沉重的经济负担,有研究^[5]表明,由CHB导致各类肝脏疾病的治疗费用人均20 818元/年,占家庭年均收入的87.3%,占个人年均收入的261.8%. ...

Global HBV burden:guesstimates and facts

2018

乙型肝炎病毒感染的自然病程

2006

Global hepatitis report 2017

2017

α干扰素治疗慢性乙型肝炎的经济效益

2006

慢性乙型肝炎防治指南(2015年更新版)

2015

... CHB的治疗目标是最大限度地长期抑制HBV复制,减轻肝细胞炎性坏死及肝纤维化,延缓和减少肝功能衰竭、肝硬化失代偿、肝细胞癌及其他并发症的发生,从而改善生活质量和延长生存时间,抗病毒是治疗HBV的主要手段^[6].替诺福韦艾拉酚胺(tenofovir alafenamide,TAF)是一种口服生物利用度有限的核苷酸类似物,可抑制HBV和人类免疫缺陷病毒1型(human immunodeficiency Virus-1,HIV-1)的逆转录,是美国食品药物管理局(FDA)最近批准的一种用于治疗HBV感染的新药,与替诺福韦酯(tenofovir disoproxil fumarate,TDF)均为抗HBV一线用药^[7].TAF和TDF同为替诺福韦(tenofovir,TFV)的前体药物,它们在细胞内具有相同的活性代谢物二磷酸替诺福韦(tenofovir diphosphate,TFV-DP),TAF在血浆中比TDF更稳定,向靶细胞(HBV感染的肝细胞和HIV感染的淋巴样细胞)提供更高水平的TFV-DP.在治疗活性剂量下,TAF与TDF比较,循环中的TFV水平降低约90%,因此TAF对肾功能和骨密度的不良影响较少^[8]. ...

Update on prevention,diagnosis,and treatment of chronic hepatitis B:AASLD 2018 hepatitis B guidance

2018

Tenofovir alafenamide fumarate:a new tenofovir prodrug for the treatment of chronic hepatitis B infection

2017

马尔科夫模型及其在药品经济预测中的应用

2005

... Markov模型的基本原理是利用某一变量的现在状态和动向,去预测该变量未来的状态及其动向的一种分析手段.由于其具有的马尔科夫性(无后效性),对历史数据需求不多,预测方法具有很多优点 ,因此在现代统计学中占有重要的地位^[9].参考RUGGERI等^[10]的研究,使用TreeAgePro2011软件构建Markov模型.由于TAF和TDF在治疗HBV感染时发生耐药的概率极低^[11],同时国内肝移植较少且非常规治疗,故构建模型时未考虑耐药及肝移植两个状态,最终模型包含CHB 、HBeAg 血清学转换( HBeAg 阳性患者独有)、代偿性肝硬化(compensated cirrhosis,CC) 、失代偿性肝硬化(decompensated cirrhosis,DC)、肝癌(hepatocellular carcinoma,HCC)与死亡等6个状态,其中死亡为吸收态.各状态转换关系见图1. ...

Economic analysis and budget impact of tenofovir and entecavir in the first-line treatment of hepatitis B virus in italy

2017

No Resistance to Tenofovir Alafenamide Detected Through 96 Weeks of Treatment in Patients with Chronic Hepatitis B

2018

Hepatitis B virus DNA levels and outcomes in chronic hepatitis B

2009

... 1.2.1 研究对象检索PubMed英文数据库,检索范围“Title/Abstract”,检索词“Chronic hepatitis B、tenofovir alafenamide、tenofovir disoproxil fumarate、randomized controlled trial”及其对应的MeSH词.检索时间为建库至今.由于HBV DNA水平已被确定为与慢性乙型肝炎患者肝并发症有关的重要指标^[12],因此排除HBV DNA报道不足、不良事件发生率报道不全的文献,最终选择样本量较大,且治疗周期长的1篇文献,作为本次研究的数据来源^[13].该文献是基于两项(GS-US-320-0110和GS-US-320-0108)大规模的、正在进行的、随机、双盲的国际III期试验,旨在比较TAF和TDF在治疗中的疗效和安全性.试验共计纳入门诊患者1 298例,服用TAF患者866例,服用TDF患者432例,每日分别服用TAF25 mg和TDF300 mg,随访时间2年.第96周时,HBeAg阳性患者病毒抑制率差异无统计学意义(P=0.47)、HBeAg阴性患者病毒抑制率差异无统计学意义(P=0.84).患者数据基线见表1.模型将模拟患者的终身治疗,根据2018年中国统计年鉴数据显示,我国居民平均预期寿命为76.34岁,纳入研究的患者平均年龄40岁,因此设置模型循环40个周期,每个周期代表1年. ...

96 weeks treatment of tenofovir alafenamide vs.tenofovir disoproxil fumarate for hepatitis B virus infection

2018

The impact of chronic hepatitis B on quality of life:a multinational study of utilities from infected and uninfected persons

2008

... 1.2.2 健康效用值健康效用值作为衡量疾病治疗效果的指标,其数值介于0(死亡)到1(完全健康)之间.本研究健康效用值参考LEVY等^[14]的研究,结果见表2. ...

Natural history of liver cirrhosis in south China based on a large cohort study in one center:a follow-up study for up to 5 years in 920 patients

2012

慢性乙型肝炎自然史的研究

2001

25946例行肝穿刺检查肝病病例的临床病理、流行病学及转归的研究

2008

慢性乙型肝炎并发肝硬化的转归研究

2007

药物经济学评价Markov模型中转移概率计算的探讨

2017

... 1.2.3 状态转移概率本研究各状态间转移概率来源于临床研究[13,15-18],提取数据,根据公式r=-[ln(1-P₁)]/t₁和P₂=1-exp(-rt₂),其中r为瞬时发生率,P₁为一段观察时限下发生某事件的概率,P₂为一个循环周期下的转移概率,t₁为观察的时限长度,t₂为单个循环周期的时间^[19].计算结果见表3. ...

中国12个地区乙型肝炎相关疾病住院患者经济负担调查

2017

... 1.2.4 治疗成本因TDF已在国内上市多年,且存在通过一致性评价的仿制药物,故本研究最终选择进口药物作为治疗药物.以2018年重庆市药品挂网价格为准,确定富马酸替诺福韦二吡呋辛酯片(TDF,韦瑞德,Gilead Sciences,Inc,0.3g/p,H20171313)每天治疗成本为人民币10.98元;富马酸丙酚替诺福韦片(TAF,韦立德,Gilead Sciences International Ltd,25 mg/p,H20180060)每天治疗成本为人民币39.33元,根据患者每日服用量确定药品治疗费用.参考文献确定CHB各状态下产生的治疗费用^[20],治疗费用=直接费用+间接费用+隐形费用,成本和效用值年贴现率设置为5%^[21].治疗过程中有13例(2%)接受TAF治疗和4例(1%)接受TDF治疗的患者因不良事件而停止治疗,比例均较低.两种治疗均耐受良好,大多数患者仅发生轻度至中度的不良反应.不良反应集中表现为头痛TAF98例(11.3%)TDF43例(10%);鼻咽炎TAF105例(12.1%)TDF44例(10.2%);上呼吸道感染、鼻咽炎TAF105例(12.1%)TDF45例(10.4%).因此由治疗引发的不良反应治疗费用及效用值降低未计算在内,结果见表4. ...

运用Markov模型对恩替卡韦治疗慢性乙型肝炎的成本效果分析

2010

中国药物经济学评价指南(2011版)

2011

... 1.2.5 评价指标本次研究将质量调整生命年(QALYs)做为评价指标,使用增量成本-效果比(ICER)作为2种药品的药物经济学评价标准.因国内目前尚无具体标准,故本次研究根据世界卫生组织建议,设定ICER<1倍人均GDP为极有成本-效果;1倍人均GDP<ICER<3倍人均GDP为有成本-效果;ICER>3倍人均GDP为不具有成本-效果^[22].本次研究选定2018年1倍人均GDP即64 644元为阈值标准,数据来源于中国统计年鉴. ...

Long-term clinical outcomes in cirrhotic chronic hepatitis B patients treated with tenofovir disoproxil fumarate for up to 5 years

2015

... 相关研究表明,TDF比较与其他核苷酸类似物具有更好的病毒学应答,不良反应少,耐药率低等优点^[23].2008年FDA批准TDF用于CHB治疗,2014年中国食品药品监督管理局批准TDF用于CHB患者抗病毒治疗^[24].TAF比较TDF具有更高的生物利用度,TAF25 mg与TDF300 mg的抗病毒作用无明显差异.MURAKAMI等^[25]的实验结果显示,TAF系孵育的肝细胞中 TFV-DP的浓度分别是TFV系和TDF系的120倍和5倍,说明TAF的抗病毒复制的活性最强.而正是由于起给药剂量远低于TDF,因此TAF对肾和骨骼的毒性较小,安全性较高^[26]. ...

替诺福韦酯治疗慢性HBV感染临床应用专家共识

2015

Implications of efficient hepatic delivery by tenofovir alafenamide(GS-7340) for hepatitis B virus therapy

2015

Improved bone safety of tenofovir alafenamide compared to tenofovir disoproxil fumarate over 2 years in patients with chronic HBV infection

2018

Pharmacoeconomic Review Report:Tenofovir Alafenamide(Vemlidy):(Gilead Sciences Canada,Inc.)

2018

... TAF作为近年国内唯一获准上市的抗HBV感染药物,且和TDF同为TFV的前体药物,国内目前尚无文献对两者进行比较.参考加拿大卫生部药品和技术局(Canadian Agency for Drugs and Technologies in Health,CADTH)的TAF药物经济学报告^[27],采用TAF治疗的患者(7 137美元·人^-1)比采用TDF治疗的患者(1 784美元·人^-1)每年治疗费用多出5 353美元·人^-1,报告结果提示TAF比较TDF并不具有成本效益.本研究采用增量成本-效果做为评价标准,从药物经济学的角度出发对TAF和TDF进行评价,结果提示现阶段TAF较TDF并不具有经济学效益,结果与CADTH一致. ...

项目	例数	平均年龄, 岁(范围)	平均HBV DNA, lg/ U·mL^-1(范围)	中位ALT (Q1,Q3)	HBeAg状态		已知肝硬化患者的患者	平均纤维化评分(范围)	纤维化评分≥0.75
					阳性	阴性
					TAF 25 mg	866				40(18~80)	7.0(1.8~9.9)	80(56,123)	569(65.7)	297(34.3)	65/636(10)	0.37(0.04~0.98)	76/846(9)
TDF 300 mg	432	41(18~72)	7.0(1.4~9.9)	80(53,130)	290(67.1)	142(32.9)	38/326(12)	0.37(0.03~0.99)	42/421(10)
总数		41(18~80)	7.0(1.4~9.9)	80(54,125)	859(66.2)	439(33.8)	103/962(11)	0.37(0.03~0.99)	118/1267(9)

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