superiority of roadmap strategy in hbeag positive chb...
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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%
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.
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
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
化
肝细
胞癌
家庭
年收
入
人均
GD
P
慢性
乙肝
代偿
性肝
硬化
失代
偿性
肝硬
化
肝细
胞癌
家庭
年收
入
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
化
肝细
胞癌
家庭
年收
入
人均
GD
P
慢性
乙肝
代偿
性肝
硬化
失代
偿性
肝硬
化
肝细
胞癌
家庭
年收
入
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
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.
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
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