liver disease in chinese- perspective from a practising...
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George KK LauMBBS (HK), MRCP(UK), FHKCP, FHKAM (GI), MD(HK), FRCP (Edin, Lond)
Liver Disease In Chinese-Perspective from a practisingHepatologist
Chairman, Humanity and Health Medical Group, Hong Kong SAR, ChinaConsultant in Gastroenterology & Hepatology, Humanity and Health Medical Centre, Hong Kong SAR, China
Director, Beijing 302-Hong Kong Humanity and Health Hepatitis C Diagnosis and Treatment Center, Beijing, ChinaCo-director, Institute of Translational Hepatology, 302 Hospital, Beijing, China
HEP DART 2017, Kona, Hawaii
Hong Kong-mainland China
Beijing – Hong Kong close collaboration
Beijing 302-Hong Kong Humanity and Health Hepatitis C Diagnosis and Treatment Centre
Beijing Team
Institute of Translational Hepatology, 302 Hospital, Beijing, China
National Scientific and Technological Progress Second Class Award-2015
HBV reactivation after DAAs treatment
Hepatitis due to HBV reactivation in HBsAg+ CHC Chinese treated with pan-oral DAAs
Female 46 yrsHCV GT1bFS 5HBsAg + HBeAg -
SOF-LDVETV
Patient ID: 2493
VIEKIRA PAK
ETVPatient ID: 2419
Male 52 yrsHCV GT1bFS 17HBsAg + HBeAg -
SOF-LDV Patient ID: 2222
Female 52 yrsHCV GT1bFS 6HBsAg + HBeAg -
Wang C et al. Clin Gastroentrol Hepatol 2017;15: 132-136
US FDA Box warning for HBV reactivation after DAAs therapy for CHC
Time to HBV reactivation was significantly shorter with DAAs
DAAs-based:Mean time: 8 weeksp<0.01 for the comparison
IFN-based: Mean time:42 weeks
Chen et al, APASL (Oral presentation) Shanghai 2017
Outline
Disease Burden
CHC-Science meet Public Health
CHB-a “cure”?
Disease burden
Increasing Deaths Due To Chronic Liver Disease In China
46% 45%37%
23%
7%
26%
10%6%
0%
13%
25%
38%
50%
Liver cancer Cirrhosis
HBV HCV Alcohol Other
Causes of Death from CLD China, 2010
0
55000
110000
165000
220000
1990 1995 2000 2005 2010 2013
Liver cancer-HBV Cirrhosis-HBVLiver Cancer-HCV Cirrhosis-HCV
Causes of CLD deaths, China
54%46%
19% 21%18% 22%
8% 11%
0%
15%
30%
45%
60%
Liver cancer Cirrhosis
HBV HCV Alcohol Other
Causes of Death from CLD China, 2013
Global Burden of Disease Study 2013 Collaborators, and others.Lancet 2015; 386Cowie et al. AASLD, 2013
Birth Dose Vaccination Is Effective In Prevention Of MTCT In China
Fan R, et al. Lancet Infectious Disease 2016;16:1103-1105Cui FQ et al, Emerging Infectious Diseases 2017; 23
Reported HCV Cases Increased In China
Duan ZP et al. J Clin Gastroenterol 2014;48:679–686
Prevalence of NAFLD And Obesity, T2DM And MS Among NAFLD
Younossi et al, Hepatology. 2016 Jul;64(1):73-84. doi: 10.1002/hep.28431. Epub 2016 Feb 22
NAFLD Obesity
T2DM MS
T2DM: Type 2 Diabetes; MS: Metabolic Syndrome
Prevalence of NASH Increased In The Past 10 Years In China
Ji D, et al. Unpublished data
HCV therapy: science meets public health
Adapted from Falade-Nwulia et al. Ann Intern Med. 2017;166:637-648.
50
60
70
80
90
100
1a 1b 2 3 4 5 6
SVR
12(%
)
Genotype
Efficacy from Clinical trials
Heterogeneity between groups: p = 0.933Overall (I^2 = 88.805%, p = 0.000);
Ji
Tapper
Subtotal (I^2 = 84.429%, p = 0.000)
12
Terrault
Crespo
Backus
BackusTerrault
Ji
Subtotal (I^2 = 92.631%, p = 0.000)
Kowdley
Crespo
8
Author
2016
2016
2016
2016
2016
20162016
2016
2017
2016
Year
37
1432
271
32
1223
2475881
153
622
335
SVR12
37
1521
305
34
1333
2615971
156
634
349
Total
0.948 (0.929, 0.964)
1.000 (0.905, 1.000)
0.941 (0.928, 0.953)
0.945 (0.927, 0.962)
0.889 (0.848, 0.922)
0.941 (0.803, 0.993)
0.917 (0.901, 0.932)
0.946 (0.937, 0.955)0.907 (0.887, 0.925)
0.981 (0.945, 0.996)
0.952 (0.901, 0.986)
0.981 (0.967, 0.990)
0.960 (0.934, 0.978)
ES (95% CI)
0.948 (0.929, 0.964)
1.000 (0.905, 1.000)
0.941 (0.928, 0.953)
0.945 (0.927, 0.962)
0.889 (0.848, 0.922)
0.941 (0.803, 0.993)
0.917 (0.901, 0.932)
0.946 (0.937, 0.955)0.907 (0.887, 0.925)
0.981 (0.945, 0.996)
0.952 (0.901, 0.986)
0.981 (0.967, 0.990)
0.960 (0.934, 0.978)
ES (95% CI)
.5 .65 .85 1Proportion (%)
SVR12 rate (ITT)
Effectiveness from real-world studies
F Li…G Lau, APASL 2017, Oral presentation
Lack of diagnosisRequirement for viral load assessment
and genotypingTreatment delivery
Lau G. Lancet Gastroenterol Hepatol. 2017
PR 48• Not covered by health insurance in most
parts of China, and even in some areas where it is covered, patients still need to be hospitalized to get reimbursement.
• Out-of-pocket cost- ranges from US$ 2,500 to 10,000.
14%
30%
12,40%
0,60%
43%
Outpatient insurance coverage for anti-HCV treatment
Government employee programGovernment public program, urbanGovernment public program, ruralOther types of health insurance
Zhou et al. Hepatology, Medicine and Policy. 2016: 1:7
Drug company-driven initiatives such as tiered pricing and voluntary licensing have demonstrated insufficient benefit, and act as a barrier to universal access to essential medications compared with unfettered generic drug competition.
http://www.thebody.com/content/75438/generic-drug-registration-licensing-anda-trip-to-g.html
Swathi Iyengar, WHO, 2016
HCV RNA <15 IU/ml, n/n (%)
SOF + LDV + RBV 12 weeks (n = 63, LC)
SOF + LDV + RBV 8 weeks (n = 65, CHC)
SOF + LDV 8 weeks(n = 64, CHC) p value*
During treatmentWeek 1 10/61(16.4) 33/64 (51.6) 32/63 (50.8) 0.932Week 2 28/61 (45.9) 46/64 (71.9) 44/63 (69.8) 0.801Week 3 49/61 (80.3) 60/64 (93.8) 59/63 (93.7) 1.000Week 4 58/61 (95.1) 64/64 (100) 63/63 (100) naWeek 8 na 63/63 (100) 63/63 (100) naWeek 12 61/61 (100) na na naAfter treatmentWeek 4 61/63 (96.8) 63/65 (96.9) 62/64 (96.9) 1.000Week 8 61/63 (96.8) 63/65 (96.9) 62/64 (96.9) 1.000Week 12 (SVR 12, ITT) 61/63 (96.8) 63/65 (96.9) 62/64 (96.9) 0.989On-treatment virologic breakthrough, n 0 0 0 naRelapse after therapy, n 0 0 1 naWithdrew consent, n 2 2 1 naLost to follow-up, n 2 1 1 naCHC, chronic hepatitis C; HCV, hepatitis C virus; ITT, intention-to-treat analysis; LC, liver cirrhosis; LDV, ledipasvir; n.a., not applicable; RBV, ribavirin; SOF, sofosbuvir; SVR,sustained virologic response.
Zeng et al, Journal of Hepatology 2017
Ledipasvir-sofosbuvir (Hepcinat LP) approved by Gilead Sciences earlier in 2015 and produced by Indian Natco Pharma Limited was used.
200.100
17.425.000
- 2.000.000 4.000.000 6.000.000 8.000.000
10.000.000 12.000.000 14.000.000 16.000.000 18.000.000 20.000.000
Treated with DAAs Estimated number of HCVpatients
Only 1% of the patients were treated with DAAs by Sept 2016
WHO. Global report on access to hepatitis C treatment. Focus on overcoming barriers. 2016.Messina et al. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology 2015;61:77-87
Approved Pan-oral DAAs for HCV in China, 2017: Still Expensive
3D Viekirax®
Paritaprevir 75 mg/Ritonavir 50 mg + Ombitasvir 12.5 mg+Exviera®
Dasabuvir 250mg
12 weeks ¥ 58968 CNY(USD ~9000)
Daklinza® + Sunvepra®
Daclatasvir 60mg +
Asunaprevir 100mg
24 weeks ¥ 57800 CNY(USD~8700)
Sovaldi®
Sofosbuvir 400mg
12 weeks ¥ 58,980 CNY(USD ~9000)
Comparison between HnH and TARGET in patients treated with Harvoni
8 week p value 12 week p valueHnH Target HnH Targetn=43 n=305 n=182 n=971
Sex, Male, N (%) 25 (58) 134 (44) 0.08 97 (53) 570 (59) 0.13Age, yr median (range) 49 (22-75) 58 (18-84) 0.003* 52 (20-83) 60 (21-87) <0.001*Genotype <0.001 <0.0011a 0 (0) 197 (65) 1 (0.5) 646 (67)1b 37 (86) 97 (32) 155 (85) 270 (28)Other 6 (14) 11 (4) 26 (14) 55 (6)
HCV RNA Log10 IU/mL, median (range) 6.6 (1.4-7.6) 6.0 (0-7) 0.009* 6.5 (1.4-7.7) 6.3 (0-8) <0.001*HCV RNA >=6 million IU/mL N (%) 13 (30) 13 (4) <0.001 67 (37) 177 (18) <0.001Albumin g/dl, median (range) 4.1 (2.9-5.6) 4.1 (2.6-5.1) 0.35* 3.9 (1.6-5.1) 4.1 (1.3-6.9) 0.005*Albumin>=3.5 g/dl N (%) 39 (91) 267 (88) 0.56 134 (74) 730 (75) 0.77T Bilirubin mg/dl, median (range) 0.8 (0.2-2.3) 0.5 (0.1-2.3) 0.58 0.9 (0.1-13.7) 0.6 (0.1-7.0) <0.001*T Bilirubin <=1.2 mg/dl N (%) 34 (79) 288 (94) <0.001* 131 (72) 773 (80) 0.015Platelets, median (range) 143 (53-381) 228 (62-581) <0.001* 124 (18-359) 186 (6-647) <0.001*Cirrhosis 12 (33) 3 (1) <0.001 88 (52) 259 (27) <0.001IL28bC/C 23 (56) - 120 (72) -C/T 18 (44) - 46 (27) -T/T 0 (0) - 1 (0.6) -
ITT SVR12 rate, % (95%CI)95.3 (87.2-
99.4) 88.8 (85.3-92.3) 0.19 98.3 (95.2-99.6)90.7 (88.9-
92.5) <0.001* significance test by two-sample t-test was done to compare the difference between mean
BL, D2, D4, wk 1,2,4,8 and 12
1 Division of Gastroenterology & Hepatology, Humanity & Health Medical Centre, Hong Kong, Hong Kong SAR, China.2 Second Liver Cirrhosis Diagnosis and Treatment Center, 302 Hospital, Beijing, 100039, China. 3 Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France.4 Institute of Infectious Disease, 302 Hospital, Beijing, 100039, China.5 State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China6 Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China.7 Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine and Veterans Affairs Medical Center, Atlanta, GA, 30322, USA8 Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM 87545, USA9 Department of Mathematics, North Carolina State University, Raleigh, NC 27695, USA
Lau G. Lancet Gastroenterol Hepatol. 2016
• Sofosbuvir (SOF, NS5B inhibitor) 400 mg/ledipasvir (LDV, NS5A inhibitor) 90 mg once daily• Daclatasvir (DCV, NS5A inhibitor) 60 mg once daily• Simeprevir (SMV, a protease/ NS3/4 inhibitor) 150 mg once daily• Asunaprevir (ASV, a protease/ NS3/4 inhibitor) 100 mg twice daily
Day 0 3521 1052
GT-1bNon-
cirrhotic Chinese
N=26
Group 1: SOF+LDV+ASV N=12
Group 2: SOF+DCV+SMV N=6
Follow up
Follow up
Follow up
Group 1: SOF+LDV+ASV N=6
Group 2: SOF+DCV+SMV N=6
Group 3: SOF+DCV+ASVN=6
Patie
nt ra
ndom
ly a
ssig
ned
Group 3: SOF+DCV+ASVN=8
Plasma HCV RNA < 500 IU/ml by Day 2
Lau G. Lancet Gastroenterol Hepatol. 2016
0
10
20
30
40
50
60
70
80
90
100
Day 2 Day 4 Day 7 Week 2 Week 3 Fu_Week 4 Fu_Week 12
16,7
83,3
100 100 100 100 100
33,3 33,3
66,7
0 0
33,3
83,3
SVR
12(%
)
SOF+LDV+ASV(Group 1)SOF+DCV+SMV(Group 2)SOF+DCV+ASV(Group 3)
1/6
100 100 100 100 100 100 100
2/60/6 0/6
2/65/6 2/6
4/66/6 5/6
6/66/6 6/6
6/66/6 6/6
6/66/6 6/6
6/66/6
% p
atie
nts w
ith H
CV R
NA
< LL
OQ
(IT
T)
Lau G. Lancet Gastroenterol Hepatol. 2016
Duration(weeks) Treatment-naive cirrhosis
Sustainedvirological
response (n [%])Sofosbuvir and odalasvir (PROXY) 6 Yes No 12 (100%)Ledipasvir, sofosbuvir, GS-9669 (SYNERGY) 6 Yes No 19(95%)Ledipasvir, sofosbuvir, GS-9451 (SYNERGY) 6 Yes No 19(95%)Sofosbuvir, ledipasvir, ribavirin (ELECTRON) 6 Yes No 17(68%)Sofosbuvir, velpatasvir, voxilaprevir (formerly GS-9857; LEPTON) 6 Yes No 14(93%)
Grazoprevir, elbasvir, sofosbuvir (C-SWIFT) 6 Yes No 26 (87%)Daclatasvir, asunaprevir, beclabuvir, sofosbuvir(FOURward) 6 Yes No 8 (57%)
Sofosbuvir, velpatasvir, voxilaprevir (LEPTON) 6 No Yes 20 (67%)Ledipasvir, sofosbuvir, GS-9451 (SYNERGY) 6 No Yes (48%) 20 (80%)Grazoprevir, elbasvir, sofosbuvir (C-SWIFT) 6 Yes Yes 16 (80%)Sofosbuvir, velpatasvir, voxilaprevir (LEPTON) 6 Yes Yes 13 (87%)Ledipasvir, sofosbuvir, GS-9451 (SYNERGY) 6 Yes Yes (40%) 18 (72%)Ledipasvir, sofosbuvir, GS-9451 (SYNERGY) 4 Yes No 10 (40%)Ledipasvir, sofosbuvir, GS-9451, GS-9669 (SYNERGY) 4 Yes No 5 (20%)Grazoprevir, elbasvir, sofosbuvir (C-SWIFT) 4 Yes No 10 (32%)Sofosbuvir, velpatasvir, voxilaprevir (LEPTON) 4 Yes No 4 (27%)Daclatasvir, asunaprevir, beclabuvir, sofosbuvir(FOURward) 4 Yes No 4 (29%)
Sofosbuvir, ledipasvir, asunaprevir (SODAPI) 3 Yes (50%) No 6 (100%)Sofosbuvir, ledipasvir, asunaprevir (SODAPI) 3 Yes (67%) No 6 (100%)Sofosbuvir, ledipasvir, asunaprevir (SODAPI) 3 Yes (83%) No 6 (100%)
Emmanuel B, …, Lau G. Lancet Gastroenterol Hepatol. 2017
SYNERGY study:SOF + LDV + GS9451 ± GS9669 for 4 weeks
Virological response based on baseline RAV
Kohli A, et al. Ann Intern Med. 2015;163:899-907
0
10
20
30
40
50
60
70
80
90
100
Absence of any NS3, NS5A, orNS5B RAV
Presence of ≥1 NS3, NS5A, or NS5B RAV
SVR1
2 (%
)
0
10
20
30
40
50
60
70
80
90
100
Absence of NS3, NS5A, or NS5BRAV with >20-fold resistance
Presence of NS3, NS5A, or NS5BRAV with >20-fold resistance
SVR1
2 (%
)
11/29
4/21
15/40
0/10
P = 0.35 P = 0.022
Resistant Associated Variants (RAVs) with drug resistance have emerged both in vitro and in clinical trials, leading guidance to recommend resistance testing in patients in whom treatment has failed and in selected regimens at baseline.
Niebel M et al. Lancet Gastroenterol Hepatol. 2017; 2.
NS3 protease sequences
NS5A sequences
NS5B polymerase sequences
Chen GF et al, APASL 2017, Oral presentation
3 logreduction
Current price(96729)
2 logreduction
1 logreduction
172,2
17,11,77 0,24
020406080
100120140160180200
Price per bottle
Cost savings (US$ Billion)
130
172193
225
0
50
100
150
200
250
40% 67% 80% 100%Proportion of patients who can achieve HCV
RNA<500 IU/mL by day 2
Cost savings (US$ Billion)
Even the price could be reduced by 3 log to US$96 per bottle, the government could stillsave US$240 million using Response-Guided Therapy.
Ceiling prices restrict market negotiations by setting maximum prices purchasers can pay for drugs
Reference prices use local or international price comparisons of drugs classified in a group as therapeutically similar to determine a single or maximum price for all drugs in that group
Profit limits control how much profit a drug manufacturer may earn per product or within a specified period of time.
John E. Dicken. An Overview of Approaches to Negotiate Drug Prices Used by Other Countries and U.S. Private Payers and Federal Programs. Thursday, January 11, 2007
A MUST: Strong recommendation by WHO
WHO. Guidelines for the screening, care and treatment of persons with hepatitis C infection.2014Duan et al. J Clin Gastroenterol. 2014; 48: 8
What is the real burden of HCV
Bland–Altman bias plot of differences(A) Compared with the Abbott RealTime assay in plasma
(B) Xpert HCV Viral Load assay for HCV RNA detection in finger-stick capillary whole-blood samples compared with the Abbott RealTime assay in plasma
Grebely et al, Lancet Gastroenterol Hepatol 2017; 2: 514–20
• Major barriers– Lack of diagnosis– Requirement for viral load assessment and genotyping– Treatment delivery
Strategy Point-to-care Short treatment duration Government efforts to negotiate with better price
Lau G. Lancet Gastroenterol Hepatol. 20
Therapies For Chronic Hepatitis B
Conventional/Peg-IFN α-2a: • Sustained off-therapy
response (immune control)• Low HBV DNA level (<2000 IU/ml)
and Normal ALT level• Finite therapy Relapse
Sustained Remission (<20%)
Chronic Hepatitis B
Nucleos(t)ide analogues (NUCs):• Maintained on-treatment response (viral control)• Undetectable HBV DNA level and Normal ALT• Lifelong or indefinite
There are 30 approved registration for generic Tenofovir in China
TenofovirBrand Name Viread Ke Lao Er Bei Xin
Packaging
Company GSK Aahui Biochem Bio-Pharmaceutical Co., Ltd. Brilliant
Dosage form Tablets Tablets Dispersible Tablets
Price / month US$ 74 US$ 64 US$ 74
TenofovirBrand Name Qing Zhong Fu Gan Ding
Packaging
Company Chitai Tianqing Fujian Consunter Pharmaceutical
Dosage form Tablets Capsules
Price / month US$ 70 US$ 67
EntecavirBrandName Baraclude Leiyide Run Zhong Tian Ding
Packaging
Company BMS Dawnrays Pharmaceutical Chiatai Tianqing Chiatai Tianqing
Dosageform Tablets Dispersible tablets Dispersible Tablets Tablets
Price /month US$ 105 ~ 150 US$ 83 US$ 48 ~ 60 US$ 52
EntecavirBrandName Gan Ze Wei Li Qing En Gan Ding Bei Shuang Ding
Packag-ing
Company Chiatai Tianqing Qingfeng Pharmaceutical Fujian ConsunterPharmaceutical
Aahui Biochem Bio-Pharmaceutical Co., Ltd.
DosageForm Capsules Dispersible tablets Capsules Dispersible Tablets
Price /Month US$ 56.76 US$ 64.28 US$ 28.28 US$ 30.17
There are 35 approved registration for generic Entecavir in China
Estimated number of diagnosed with HBV ontreatment in China
Global Hepatitis Report 2017. Geneva: World Health Organization; 2017.Cui Y, Jia JD. Journal of Gastroenterology and Hepatology 2013; 28
120 million CHB
patients
9% know their diagnosis
864,000 on treatment
8%on
treatment
Do we need an HBV cure?
Nayagam S, et al. Lancet Infect Dis 2016;16:1399-408
Impact on Total Cost of Global Eradication
CURE reduce total costs by >10% (> USD $5 Billion)
Non-invasive Method To Screen Liver Fibrosis In General Population: Example From China
Distribution of Liver Fibrosis In Chinese General Population (N= 174,314)
90,2 87,583,7
79,685,4
7,5 9,4 11,5 13,810,5
1,6 2,1 3,1 4,1 2,70,6 0,8 1,2 1,8 1,00,1 0,2 0,5 0,6 0,40,0
25,0
50,0
75,0
100,0
18-29 30-44 45-59 60-75 TotalAge group
F0F1 (<=7.3) F2 (7.3-9.7) F2F3 (9.7-12.4) F3F4 (12.4-17.5) F4 (>=17.5)
Usefulness of screening in general population
Advanced fibrosis with normal ALTAdvanced fibrosis with normal
ALT, HBsAg-N = 566 N=150
Male 408 (72.1) 124 (82.7)Age, years 52.5 (22-75) 52 (25-74)BMI>24 kg/m2 404 (71.4) 114 (76.0)
n=404 n=114Liver steatosis (UAP) 257.2 (187-400) 262.5 (216-377)Minimal (<240) 124 (30.7) 28 (24.6)Mild (240-264) 99 (24.5) 31 (27.2)Moderate (265-294) 86 (21.3) 22 (19.3)Severe (>=295) 95 (23.5) 33 (29)GGT>=50 84 (20.1) 25 (21.9)Impaired glucose (FBG>=6.1) 72 (17.8) 17 (14.9)Total Cholestrol>5.2 158 (39.1) 41 (36.0)HDL>1.42 119 (29.4) 31 (27.2)LDL<2.1 61 (15.1) 23 (20.2)Triglyceride>1.7 187 (46.3) 58 (50.9)HBsAg- 114 (28.2)+ 13 (3.2)Unknown 277 (68.6)
Continous variables are presented as median (range); Categorical variables are presented as number (percentage).
• Collaboration platform for professionals from mainland China, Taiwan, Hong Kong and Macau to research fatty liver disease• Targets to prevent and control the rapidly increased prevalence of fatty liver disease in the region•http://www.gc-flc.or
Greater China Fatty Liver Consortium (GC-FLC)
What we need in the near future?
Biological samples and paired biopsy specimenNext-generation functional genomics-
PNPLA3ProteinomicsLipid profilingmiRNA-miRNA-12213-carbon isotope
❖ Humanity & Health Medical Group, Hong Kong
❖ Vanessa Wu❖ Yudong Wang❖ Cheng Wang❖ Jing Chen❖ Catherine Lok❖ April Wong
❖ 302 Hospital, Beijing❖ Wang FS❖ Guofeng Chen❖ Zhang Zheng ❖ Qing Shao❖ Jin Li❖ Dong Ji❖ Bing Li❖ Jialiang Liu❖ Xiaxiao Niu❖ Shiying Ding
❖ Nanfang Hospital, Guangzhou❖ Jinlin Hou❖ Jian Sun❖ Zhang Xiao Yong
❖ Hôpital Pitié-Salpêtrière, Paris ❖ Yves Benhamou
❖ Hong Kong Molecular Pathology Diagnostic Centre
❖ Chris L.P. Wong❖ Stella T.Y. Tsang
❖ Los Alamos National Laboratory❖ Alan S. Perelson❖ Ruian Ke❖ Ruy M. Ribeiro
❖ Emory University❖ Raymond F. Schinazi❖ Leda Bassit❖ Hui-Mien Hsiao
❖ Patients
❖ ABL SA, Luxembourg❖ Chalom B. Sayada❖ Dimitri Gonzalez❖ Ronan Boulmé
Ethics Science Quality