hépatites virales b et c: actualités scientifiques · hepatitis b disease progression 1. cdc. hbv...
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Hépatites virales B et C: actualitésscientifiques
Dakar, 11.05.2016
Gilles Wandeler, MD MSc
Burden of HIV and viral hepatitis
Mortality in annualdeath rate
Matthews et al. J Clin Virol 14
Burden of HIV and viral hepatitis
Burden of HIV and viral hepatitis
Numbers are in millions of individuals
HIV accelerates liver injury caused by HBV infectionLiver mortality is 18x higher in HIV/HBV vs. HBV
Plan
Numbers are in millions of individuals
• Dépistage• Fibrose hépatique• Réponse au TDF• Nouveaux TX et
cure
• Guidelines OMS• DAA et santé
publique
HBV in the general population
Schweitzer et al. Lancet 2015
HBV prevalence among HIV-infectedpopulations
Stabinski et al. JAIDS 2015
49 studies from 16 countries (2005-13)
Median HIV/HBV-coinfection prevalence: Overall: 7.8% (range: 0%-28.4%)West Africa: 11.5%Southern Africa: 5.4%East Africa: 4.1%
HBV infection in the IeDEA network
IeDEA-Southern Africa (n=2,000)IeDEA-West Africa (n=2,000)
HBsAg+: 13%
HBsAg+: 9%
HBsAg+: 15%
HBsAg+: 19%
HBsAg+: 13%
Ongoing studies in HIV cohorts and key populations:
- HBV and HCV virology
- Liver fibrosis assessment
HBsAg+: 11%
Det. DNA: 66%
Geno: A1: 49%, E: 49%
HBsAg+: 8%
Det. DNA: 76%
Geno: A1: 70%, E: 23%
Implementation: HBV screening uptake
HBsAg screening uptake in Africa: results fromchart review of 3,000 patients starting ART
Coffie et al. abstract 565, CROI 2016
HBsAg screening uptake in Africa: results fromchart review of 3,000 patients starting ART
Coffie et al. abstract 565, CROI 2016
Central andSouth America: 9 sites7 countries
Africa:36 sites18 countries
Asia:10 sites7 countries
Screening and management of HIV/HBV-coinfection: urgent need for programmatic data!
(To be presented at AIDS 2016, Durban)
HBV screening guidelines
HBeAg(+) HBeAg(-) / anti-HBe(+)
ALT
HBV DNA
Minimal CH Moderate to severe CH Moderate to severe CHRemission
Cirrhosis
Immunotolerant
phase
Immuno-active
phase
Inactive phase
Low replication Reactivation phase
Cirrhosis
109-1012 IU/mL >2000-<109 IU/mL <2000 IU/mL >2000 IU/mL
Inactive cirrhosis
Treatment indicated Treatment indicated
HBsAg
Occult infection
EASL Clinical Practice Guidelines, J Hepatol 2012
HBV natural history
Specificities of HBV in Africa: natural history and transmission
50-90% 5% Chronic infection
Hepatitis B Disease Progression
1. CDC. HBV FAQs for health professionals. 2. Torresi J, et al. Gastroenterology. 2000;118(2 suppl 1):S83-S103. 3. Fattovich G, et al. Hepatology. 1995;21:77-82. 4. Seaberg EC, et al. Clin Transpl. 1998:17-37.
Acute Infection
ChronicInfection
Cirrhosis Death
30% of chronically infected
individuals[2]
23% of patients decompensate within 5 yrs of developing cirrhosis[3]
Liver Cancer (HCC)
Chronic hepatitis B is the 6th leading cause of liver transplantation in the US[4]
Liver Transplantation
Liver Failure(Decompensation)
HBV DNA and immune response = engine
ALT/Histological Activity Index (inflammation) = train speed
Fibrosis stage = distance from canyon
Multivariate analysis of factors associated with significant liver fibrosis
n/N OR (95% CI) p
Antigen HBs Negative
Positive
36/733
7/74
1
2.6 (1.0 – 6.4)
0.04
Alcohol use, (AUDIT-c score) <4
≥4 – 6
≥6
25/536
11/237
7/34
1
0.3 (0.1 – 2.5)
4.6 (1.8 – 11.4)
<10-2
HIV/HBV and HBV therapy
HBV-monoinfection HIV/HBV-coinfection
WHO HIV guidelines 2015
EASL guidelines J Hepatol 2012
WHO HBV guidelines 2015
Anti-HBV drugs
Nucleosides
Nucleotides
TDF*
ADV
ETV*
LAM* FTC*
Genetic barrier
TBV
*Anti-HIV activity
PegIFN
HBV treatment: tenofovir for all?
EASL. J Hepatol 2012
EASL. J Hepatol 2012
HBV virological response to tenofovir
De Vries et al. Gastroenterology 2010
N=641
N=102
Gordon et al. Hepatology 2013
HBV-monoinfection HIV/HBV-coinfection
TDF for HIV/HBV-coinfection in Africa
Stockdale et al. Clin Inf Dis 2015
Regression of liver fibrosis with TDF
Marcellin et al. Lancet 2013
27 - GILEAD CONFIDENTIAL AND PROPRIETARY DRAFT. FOR INTERNAL USE ONLY. NOT FOR DISTRIBUTION OR PROMOTION.27 - GILEAD CONFIDENTIAL AND PROPRIETARY DRAFT. FOR INTERNAL USE ONLY. NOT FOR DISTRIBUTION OR PROMOTION.
TAF delivers high potency of TDF while minimizing off-target renal and bone side effects
*HIV target cells include lymphocytes and other PMBCs, as well as macrophages.1. Lee W et. Antimicr Agents Chemo 2005;49(5):1898-1906. 2. Birkus G et al. Antimicr Agents Chemo 2007;51(2):543-550. 3. Babusis D, et al. Mol Pharm 2013;10(2):459-66. 4. Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63:449-5. 5. Sax P, et al. JAIDS 2014. 2014 Sep 1;67(1):52-8. 6. Sax P, et al. Lancet 2015 Apr 15 [Epub ahead of print].
HIV TARGET CELL
AMIDATE
ESTER
--
DIANION
GI TRACT
Tenofovir alafenamide
(TAF)
Tenofovir disoproxil
fumarate (TDF)
Tenofovir (TFV) Parent
Nucleotide
T1/2 = 90 min
T1/2 = 0.41 min
PLASMA
TAF25 mg
TDF 300 mg
TFV
TFV
TFV
TFV
HIV
E/C/F/TAF at IAS – Vancouver, July 2015
ConfidentialSlide 28
Treatment Naïve Adults
Truvada Switch
Renal Impairment Switch
Treatment Naïve Adolescents
Studies 292-0104/0111
(N=1,733)E/C/F/TAF vs. STRIBILD
Study 292-0109
(N=1,436)E/C/F/TAF vs. 3rd Agent + Truvada
Study 292-0112
(N=242)E/C/F/TAF, eGFR 30-68 mL/min
Study 292-0106
(N=50)E/C/F/TAF, 12-17 yo
Patient Population Clinical Study
HIV/HBV Co-infectionStudy 292-1249
(N=72)E/C/F/TAF
Study 292-0119
(N=135)E/C/F/TAF + DRV 800mg vs SBR
Phase 3
Regimen Simplification
Phase 3b
J. Gallant (poster)
TAF in HIV/HBV Co-infection
48 Weeks: Favorable safety, HIV/HBV suppression, and liver endpoints
% o
f su
bje
cts
48Wk 0
Study 292-1249 (N=72)HIV <50 c/mL, HBV DNA <9 log10
Switch to E/C/F/TAF
ConfidentialSlide 29
% %
%
%
% %
Gallant et al. IAS 2015
TAF in global HIV treatment scale-up
ConfidentialSlide 33
35 million HIV+
• TAF licensed to WHO Medicines Patent Pool (July 2014)
• 6 generic manufacturers to distribute TAF in 112 countries (September 2014)
40
20
10
30
0
30 million HIV+in developing countries
12 million HIV+on ARVs
7 million HIV+on TDF
2014
35 million HIV+
30 million HIV+in developing countries
21 million HIV+on ARVs1
16 million HIV+on TDF or TAF2
2020
1WHO projection2Gilead projection
• Adherence
– life long for NRTI
• Toxicity with pegylated-IFN
– low (<20%) efficacy, genotype A best
• Cost
– very few countries in high prevalence regions have reimbursement policies
• Drug resistance
– Rare with tenofovir but common with lamivudine
– In China, > 3 x 106 lamivudine resistant cases
• HBsAg-positivity on treatment
Current treatment is inadequate
Two approved classes of drugs are inadequate: low HBsAg loss
253
6 85 6 8
0
20
40
60
80
100
1.0 Yr 1.5-2.0 Yrs
3.0-4.0 Yrs
Pe
rce
nta
ge
with
HB
sA
gL
oss
HBeAg positive
Entecaivr
Tenofovir
PEG-IFN
0 0 04
7 9
0
20
40
60
80
100
1.0 Yr 1.5-2.0 Yrs 3.0-4.0 Yrs
HBeAg negative
< < N
(No head-to-head trials. Different populations and trial designs.Extended Treatment With Nucleos(t)ide Analogues vs. 1 Yr Peginterferon Treatment)
Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Buster EH, et al. Gastroenterology. 2008;135;459-467. Gish R, et al. Gastroenterology. 2007;133:1437-1444. Heathcote J. AASLD 2008. Abstract 158. Heathcote J, et al. AASLD 2009. Abstract 483. Janssen HL, et al. Lancet. 2005;365:123-129.
Lai CL, et al. N Engl J Med. 2006;354:1011-1020. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Marcellin P, et al. AASLD 2008. Abstract 146. Shouval D, et al. J Hepatol. 2009;50:289-295. Marcellin P, et al. AASLD 2009. Abstract 481. Brunetto M, et al. EASL 2008. Abstract.
Therapy
HB
V D
NA
ch
an
ge
fro
m b
as
eli
ne
(lo
g 1
0c
/mL
)
0.0
-1.0
-2.0
-3.0
-4.0
+1.0
Time
New treatment concepts for a functional cure of HBV infection
HBsAg
HBVDNA
cccDNA
SERUM
LIVER
The main differences between HIV, HBV and HCV
H
HBV1,2
Host cell
cccDNA
Host DNA
Integrated DNA
Nucleus
H
HIV1
Host cell
Host DNA
Proviral DNA
Nucleus
H
HCV1,3
Host cell
Host DNA
Nucleus
HCV RNA
Life-long suppression of viral replication
Definitive viral clearanceand SVR
Long-term suppression of viral replication
Adapted from 1. Sorriano V, et al. J Antimicrob Chemother 2008;62:1-4. 2. Locarnini S and Zoulim F. Antiviral Therapy 2010;15 (suppl 3):3-14. 3. Sarrazin C and Zeuzem S. Gastroenterology 2010;138:447-462.
HBV cure
Durantel et al. J Hepatol 2016
New HBV antiviral drug classes
Durantel et al. J Hepatol 2016
What May a HBV Curative Regimen Look Like?
cccDNAinhibitor
Anti-HBVNucleos(t)ide
Agent to prevent viral spread, cccDNA re-amplification
Agents to activate antiviral immunity orrelieve repression of the system
Selective agent to deplete or perturb cccDNA
Immuneactivator
+
+
HBV antigen inhibition
Agents to inhibit other components in the HBV life cycle [entry or cell-spread, capsid, HBX, HBsAg]
+
Adapted from S. Locarnini
http://www.who.int/hepatitis/publications/hepatitis-c-guidelines-2016
Pre-clinical
Phase I
Phase II
Phase III
FDA approval
DAA combinationsNuc-Polymerase inhibitors
Non-Nuc-Polymerase inhibitors
NS3/4A protease inhibitors
Others
NS5A-inhibitor inhibitors
Vedroprevir(Gilead)MS-5172
(MSD)
Simeprevir(Janssen)
Boceprevir(MSD)
Telaprevir(Vertex)
Sovaprevir(Achillion)
Danoprevir(Roche)
Faldaprevir(BMS)
ABT-450(AbbVie)
Asunaprevir(BMS)
ACH-3102 (Achillion)
GSK-2336805(GlaxoSmithKline
MK-8742(MSD)
PPI-688(Presidio)
ABT-333(AbbVie)
BI-207127(Boehr.Ingl.)Ledipasvir
(Gilead)
ABT-267(AbbVie)
Daclatasvir(BMS)
Tegobuvir(Gilead)
ABT-072(AbbVie)
BMS-791325(BMS)
TMC-647055(Janssen)
Mericitabine(Roche)
Sofosbuvir(Gilead)
VX-135(Vertex)
SofosbuvirSimeprevir
SofosbuvirLedipasvirABT-450r/
ABT-267/ABT-333
FaldaprevirBI-207127)
Miravirsen miR-122(Santaris)
DaclatasvirVX-125
AsunaprevirDaclatsivir
SimeprevirTMC-647055
DaclatasvirSimeprevir
Contexte: la révolutiondu TX anti-HCV
Curing HCV: population level impact
Individual level cure rate Population level cure rate (if no increase in treatment uptake)
Pop
ula
tio
n S
VR
(%
)
PEG-IFN +RBV
DAA combinations
Ind
ivid
ual
SV
R (
%)
Thomas DL. Lancet 2010;376:1441‒2.
Concerted efforts will be needed to improve HCV diagnosis and treatment rates
6
5
4
3
2
1
00 20 40 60 80 100
Diagnosis rate (%)
Tre
atm
en
t ra
te (
%)
France
Germany
Austria
England
Spain
Czech Republic
Egypt
Turkey
Brazil
Portugal
Belgium
Switzerland
Denmark
Canada
Australia
Sweden
• Note: size of bubble depicts viraemic HCV prevalence.Dore GJ, et al. J Viral Hepat 2014;21(Suppl 1):1–4.
Merci pour votre attention
Abstracts CROI disponibles à l’adresse
http://www.croiconference.org
Abstracts EASL disponibles à l’adresse
http://ilc-congress.eu/ilc-2016-barcelona
Consulter le site NATAP pour les les présentations oraleshttp://www.natap.org