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中国乙肝/丙肝抗病毒治疗临床 贾继东 首都医科大学附属北京友谊医院 北京, 201459

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中国乙肝/丙肝抗病毒治疗临床

贾继东 首都医科大学附属北京友谊医院

北京, 2014年5月9日

提纲

•现状

•挑战

•机遇

中国乙肝防治现状

1. Successful vaccination program since 1992 2. Protect equal right for education and

employment (2010) 3. Amend reimbursement list (2010) 4. Update and promote clinical guidelines(2010) 5. National Major Research Project (2008-) 6. Long-term follow-up system: CR-HepB (2012) 7. LIFT Project-Liver Center of Excellence (2013)

Routine infant HBV

vaccination, vaccine & service should be

paid

1st Jan 1992 1st Jan 2002

HBV vaccine

integrated into EPI, service fee (~1 US$)

should be paid

1st Jun 2005

HBV vaccine

fully integrated

into EPI for free

中国乙肝免疫预防策略发展历程

HBV vaccine

catch- up for

children under 15

years

Technical guideline for HBV

vaccine in adults

Courtesy of Professor Hui Zhuang

中国人群中HBsAg流行率下降 (1979,1992 and 2006)

0,00

2,00

4,00

6,00

8,00

10,00

12,001~

4

5~9

10~1

4

15~1

9

20~2

4

25~2

9

30~3

4

35~3

9

40~4

4

45~4

9

50~5

4

55~4

9

HBsA

g (%

)

Age Group (year)

1979

1992

2006

1.Qu Z. An epidemiological study on the distribution of HBsAg and anti-HBs in China. Chine Journal of Microbiogy Immunology. 1986; Suppl(20-40). 2.Dai ZC, G.M. Q. Seroepidemiological Survey in Chinese population (part one), 1992–1995. Beijing. Sci Tech Exp. 1996: 39-59. 3.Liang X, Bi S, Yang W, Wang L, Cui G, Cui F, et al. Epidemiological serosurvey of hepatitis B in China--declining HBV prevalence due to hepatitis B vaccination. Vaccine. 2009; 27(47): 6550-7.

1~4 0.96% 5~14 2.42% 15~59 8.57%

中国乙肝防治指南的更新和推广(2011)

7

中国乙肝指南和国际指南的比较

Guidelines Updated Recommendations for treatment-naïve CHB patients

APASL1 2012

ETV or TDF are the preferred NUCs for NUC-naïve CHB patients. LAM, ADV and LdT may only be used…if more potent drugs with a high barrier to resistance are not available or appropriate.

EASL2 2012 ETV and TDF are potent HBV inhibitors with a high barrier to resistance. Thus, they can be confidently used as first-line monotherapies.

AASLD3 2009 Treatment may be initiated with any of the seven approved antiviral medications, but peg-IFN-, TDF or ETV are preferred.

China4 2010 If possible, drugs with high potency and low resistance should be chosen for NUC-naïve patients.

1.Lok ASF & McMahon BJ. AASLD practice guidelines. Chronic hepatitis B: Update 2009. Hepatology, 2009 ,50(3):1-36. 2. Chinese Journal of Clinical Hepatology 2011, 27 (1): 1-16. 3. Liaw YF, et al. Hepatol Int , 2012 , 6(3):531-61.

4. EASL Clinical Practice Guidelines: J Hepatol 2012 , 57: 167-85.

8

中国大陆发表的乙肝临床试验英文论文

51

102

119

0

20

40

60

80

100

120

140

2000-2004 2005-2009 2010-2014

Pape

rs

9

国家重大专项资助的4个大型临床研究( RCT )

LdT (EFFORT study)

PEG- IFN (EXCEL study)

Lam (EXPLORE

study)

N=1594

ETV (DRAGON study)

EFFORT 研究方案

Treatment-naïve CHB

LDT

LDT I-B: W24 HBV DNA <300 copies/mL

LDT montherapy

I-A: w24 if HBV DNA ≥300 copies/mL Add ADV

0 w 24 W52 w12 W104

Add ADV if viral breakthorugh

optimization

SOC

LdT(EFFORT)

Sun J, et al. Hepatology 2014; 59:1283-92.

104-week Outcomes OPTIMIZE N = 300

MONO N = 299 P Value

Median reduction of HBV DNA, log10 copies/mL -6.3 -6.1 0.009

ALT Normalization, n (%) 234 (80.7) 232 (79.2) NS

HBeAg Seroconversion, n (%) 71 (23.7) 66 (22.1) NS

HBsAg Clearance, n (%) 2 (0.7) 2 (0.7) NS

Virological Breakthrough, n (%) 18 (6.0) 91 (30.4) <0.001

Genotypic Resistance, n (%) 8* (2.7) 77 ** (25.8) <0.001

EFFORT 研究结果

Sun J, et al. Hepatology 2014; 59:1283-92.

12

REALM 研究中国方案

• Inclusion criteria for present cohort: – Enrolled at one of the 50 Chinese study sites of REALM study – NUC−naïve

ADV, adefovir; LdT, telbivudine; LVD, lamivudine; oSOC, other standard of care

Dosing

Baseline Wk 48 Wk 144 Wk 96

ETV (0.5 mg, once daily) Randomized

1:1

Wk 192 Wk 240

oSOC (= LVD, ADV, or LdT)

REALM study

Hou JL, et al. APASL 2014. Abstract 245

13

REALM 中国 研究病人流程图 (240 周)

*Patients with decompensated liver disease or HCV co-infection were excluded from efficacy analyses. †Remained on study but discontinued their randomized assigned regimen and were offered alternative anti-HBV therapy at discretion of investigator. oSOC: other standard of care (ADV, LVD, LdT)

Randomized N=3546

ETV n=1773

oSOC n=1773

Treated n= 1766

Efficacy population* n=1724

Treated n=1760

Efficacy population* n=1720

Never treated n=13

Never treated n=7

Discontinued from originally prescribed

therapy† n=199

Discontinued from originally prescribed

therapy† n=123

Discontinued from study n=175

Discontinued from study n=109

Hou JL, et al. APASL 2014. Abstract 245

14

69 79 83 85 85

36

49 56

62 67

0102030405060708090

100

48 96 144 192 240

REALM 中国研究病毒学效果

oSOC

ETV

1151 1672

589 1635

1288 1623

774 1567

1327 1597

849 1529

1319 1544

902 1460

HB

V D

NA

<50

IU/m

L (%

)

Week

1238 1457

899 1347

Non-completer = missing analysis

oSOC: other standard of care (ADV, LVD, LdT) Hou JL, et al. APASL 2014. Abstract 245

15

中国 EVOLVE 研究 6 个大区, 63 个中心, ~200 名研究者, 3435 例病人

• A 2-year Prospective and Observational Study

• To Evaluate the Effectiveness of Nucleos(t)ide Analogs (NUC) Therapy Among CHB Patients Naive to NUC in Real World Practice at Hospitals in Tier 2 Cities in China

• Started from December 2012 • Enrollments: as of end of March

2014, totally 3,431 patients have been enrolled, the target number is 3,435.

http://www.clinicaltrials.gov/ct2/show/study/NCT01726439

16

建立中国乙肝随访与临床科研平台 China Registry- Hepatitis B(CR-HepB)

• Up to Jan 15, 2014,24205 cases inputted,follow-up times 105502

鲲鹏计划

•肝病诊疗管理规范白皮书发布( 2013)

中国治疗乙肝所面临的挑战

• High disease burden • Accessibility & affordability to

treatment • Insufficient reimbursement for rural

residents • Inadequate therapy-First line therapy

not first

估计HBV感染和病人数量(2010)

Classification Proportion (%)

Estimated in 2010(million)

Seroclearance 6.91 6.43

HBV Carrier 59.23 55.08

Chronic Hepatitis B 32.44 30.17 Cirrhosis 1.04 0.97

HCC 0.38 0.35

Total 100.00 93.00

Courtesy of Dr FQ Cui

10,0009,0008,0007,0006,0005,0004,0003,0002,0001,000

0

每例

患者

花费

(US

$)

慢性

乙肝

代偿

性肝

硬化

失代

偿性

肝硬

肝细

胞癌

家庭

年收

人均

GD

P

慢性

乙肝

代偿

性肝

硬化

失代

偿性

肝硬

肝细

胞癌

家庭

年收

人均

GD

P

北京 广州

Hu M & Chen W. value in health, 2009

直接医疗费用

直接非医疗费用

间接经济负担

北京和广州慢性乙肝相关疾病经济负担及经济指数

1636

2722

4611

6615

14522065

4290

6054

7314*

9145*

~8000 ~8000

4

10,0009,0008,0007,0006,0005,0004,0003,0002,0001,000

0

每例

患者

花费

(US

$)

慢性

乙肝

代偿

性肝

硬化

失代

偿性

肝硬

肝细

胞癌

家庭

年收

人均

GD

P

慢性

乙肝

代偿

性肝

硬化

失代

偿性

肝硬

肝细

胞癌

家庭

年收

人均

GD

P

北京 广州

Hu M & Chen W. value in health, 2009

直接医疗费用直接医疗费用

直接非医疗费用

间接经济负担间接经济负担

北京和广州慢性乙肝相关疾病经济负担及经济指数

1636

2722

4611

6615

14522065

4290

6054

7314*

9145*

~8000 ~8000

4

Direct medical cost Direct nonmedical cost Indirect cost

CH

B

Com

cirr

D

ec c

irr

HC

C

Fam

ily

inco

me/

yr

Per c

apita

G

DP

CH

B

Com

cirr

D

ec c

irr

HC

C

Fam

ily

inco

me/

yr

Per c

apita

G

DP

Beijing Guangzhou

Cos

t per

cas

e/yr

Study on knowledge of 452 patients with CHB from 6 cities of China, Chinese Society of Hepatology & Chinese Society of Infectious Diseases, 2004

接受抗病毒治疗的比例

No, 81%

Yes, 19%

0

未接受抗病毒治疗的原因

%

Cost Side effect Not recomm Other drugs

Data from 115 physicians active in treatment of CHB, China Medical Tribune, 2005.

10

20

30

40

50

60

70

80 76.8

15.2

4.8 3.2

中国抗乙肝核苷(酸)类似物应用情况

JL Hou, et al. Journal of Viral Hepatitis, 2010,17:10-17. Treatment survey for 2, 500 chronic hepatitis B patients in 12 first and second tier cities in 2008.

Chronic hepatitis B patients: 20 ~ 30 million cases Antiviral treatment:1,850,000 cases TCM and others:550, 000 cases

Others 50,000 cases TCM

500,000 CASES

Adefovir dipivoxil 350,000 cases

Lamivudine 500,000 cases

Entecavir 300,000 cases

Interferon (Peg-IFN,IFN) 300,000 cases

Telbivudine 100,000 cases

Domestic Adefovir dipivoxil products(2)

150,000 cases each

抗病毒药物市场预测

25

Patients on treatment (Million)

中国慢性丙肝现状

1. Declining prevalence of HCV infection 2. Release & promote clinical guidelines 3. Amend reimbursement list 4. National Major Research Project

1992 和 2006抗-HCV流行率变化

1992

2006

4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0

0 10 20 30 40 50 60

Ant

i-HC

V (%

)

age(yr)

Chen YS,et al. Chin J Epidemiol 2011;32:888-91

北京

天津 山西

内蒙古

辽宁

吉林

黑龙江

江苏

浙江

安徽

福建

江西

山东

河南

湖北

湖南

广东 广西

海南

四川

贵州

云南

西藏自治区

重庆

陕西

甘肃 青海

新疆

台湾省

河北 宁夏

香港

上海

中国HCV 基因型分布(CCgenos)

35.10%

0

48.10%

13%3.90%

61.3%

5.4%

27.0%

5.4%0.9%

37.0%

4.3%13.0%

26.1%

19.6%

55.1%

5 1%

32.7%

3.1%4.1%

71.4%

1.6%

17.5%

6.3%3.2%

53.4%

3.5%

29.4%

8.9%

4.8%

National Wide

Rao H, et al. J Gastroenterol Hepatol. 2014;29:545-53.

Genotype 1 Genotype 1 mixed Genotype 2 Genotype 3 Genotype 6

TT

CC CT

IL28B Genotype (rs12979860)

中国人口IL28B 基因型分布

Rao H, et al. J Gastroenterol Hepatol. 2014;29:545-53.

11

16

18

0

2

4

6

8

10

12

14

16

18

20

2000-2004 2005-2009 2010-2014

中国发表的丙肝临床试验英文论文

31 31

中国大型HCV 临床队列和临床试验

十一五丙肝临床研究

十一五丙肝 延长研究

HCV natural history Follow-up =1200

Difficult to treat

CHC=800

TN=400

Relapsers=120

Nonresponders=80

Generic IFN=200

SVR 24W

Relapse pridictors

Novel diagnostic tech

Long-term outcomes

Efficacy predictors

N=2000

Courtesy of Prof L Wei

32 32

Peg-IFN-α-2a 180µg/wk +RBV 96 W

48 W 24W 96 W 12 W 0

f/u 24 W

PEGIFN

+RBV

120W

Treatment naive

cEVR

No-cEVR (stop if NVR )

Peg-IFN-α-2a 180µg/wk +RBV 72W

Peg-IFN-α-2a 180µg/wk +RBV 48W

F/u 24W

F/u 24W

N=438

randomization cEVR:HCV RNA<15 IU/ml at wk 12

难治性丙肝的个体化PEGIFN+RIB 治疗方案

Genotype 1b or HVL(HCV RNA≥4×10^5 IU/ml)

72 W

A

B

C

Courtesy of Prof L Wei

33 33

优化 PEFIFN+RIV 方案的 总体SVR 达到8.7% (初治)

PP Set =338 ITT set =427

78,7%

64,2%

9,70% 7,9%

0,0%

10,0%

20,0%

30,0%

40,0%

50,0%

60,0%

70,0%

80,0%

90,0%

100,0%

SVR Relapse SVR Relapse

Courtesy of Prof L Wei

中国丙肝治疗所面临的挑战

• High diseases burden • Accessibility & affordability to

treatment • High disease burden and Insufficient

reimbursement for rural residents

报告的丙肝病例数增加

42381 57282

75610 97826

114561

137147 158758

183310 201622

0

50000

100000

150000

200000

250000

2004 2005 2006 2007 2008 2009 2010 2011 2012

China CDC

扩大检出和治疗的人群才能有效控制丙肝疾病危害

Thomas DL. Nature Med 2013, 19:850-8

中国在乙肝和丙肝治疗中的机遇

• 高效抗乙肝病毒药物已在中国上市 (ETV and TDF)

• 抗丙肝小分子化合物在中国已开始临床试验

• 采用公共卫生策略来治疗乙肝将为大幅度降价提供了机会

• 目前通过公共卫生项目治疗HIV的TDF 谈判后价格仅 113

元/月 (而治疗乙肝需 1,470元/ 月)

• 通过医改建立治疗肝炎的公共卫生项目降为大幅度降价、从而

扩大治疗人群提供了良好的机会

WHO WPRO Informal Technical Meeting Manila, April 1-2, 2014

谢谢各位!