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HCV eradication with direct acting antivirals (DAAs)?
Emilie Estrabaud
Service d’Hépatologie et INSERM UMR1149, AP-HP Hôpital Beaujon, Paris, France.
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HCV eradication with direct acting antivirals (DAAs)?
HCV replication
HCV genome and DAAs targets
NS3 inhibitors
NS5A inhibitors
NS5B inhibitors
Take home messages
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HCV viral cycle
Asselah et al. Liver Int. 2015;35 S1:56-64.
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CapsidRNA
Polymerase
MetalloproteaseSerine protease
RNA helicase
EnvelopeGlycoproteins
E1C E2
Nonstructural proteinsStructural proteins5’NTR 3’NTR
NS1 NS2 NS3 NS4A NS4B
Cofactors
NS5A NS5B
Protease Inhibitors
TelaprevirBoceprevirSimeprevirFaldaprevirAsunaprevir
NS5A Inhibitors
DaclatasvirLedipasvirABT-267GS-5816
Polymerase Inhibitors
Nucs Non-Nucs Sofosbuvir ABT-333VX-135 Deleobuvir
Direct acting antivirals
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Direct Acting Antivirals: 2015
Asselah et al. Liver Int. 2015;35 S1:56-64.
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Genetic barrier for HCV direct acting antivirals
Low
High
Nucleos(t)ideAnalog Inhibitors
1 st generation ProteaseInhibitors
NS5 AInhibitors
n Non Nucleos(t)ide Analog Inhibitors
:
2 st generation ProteaseInhibitors
1 mutation= low cost to fitness
1 mutation= high cost to fitness, 2-3 additional mutations to increase fitness
Halfon et al. J Hepatol 2011. Vol 55(1):192-206.
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HCV protease inhibitors (PI)
Inhibit NS3/NS4A serine protease responsible for the processing of the polyprotein
1st generation 1st generation, 2nd wave 2nd generation
Resistance barrier
low low high
Genotype activity 1: 1 a< 1b All except 3 all
Drug drug interaction
Important Less Less
Drugs BoceprevirTelaprevir
Simeprevir (Janssen)Faldaprevir (BI)
Paritaprevir (ABT-450)/r (AbbVie)
Vedroprevir (Gilead)Vaniprevir (Merck)
Sovaprevir (Achillion)Asunaprevir (BMS)
MK-5172ACH-2684
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Self cleavage
Insertion of the carboxy-terminal tail
Repositioning of helicase domain
NS3/NS4A structure
Bartenschlager et al. Nature Reviews Microbiology 2013 11, 482–496
Inactive Active
Lipid Bilayer
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How inhibitors interact with NS3/NS4A
Bartenschlager et al. Nature Reviews Microbiology 2013 11, 482–496
Residues from the catalytic triad:D81H57 S139
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NS3/4A Protease Inhibitors
V36M
T54S
V55A
Q80R/K
R155K/T/Q
A156S
A156T/V
D168A/E/G/H/T/Y
V170A/T
Telaprevir
Boceprevir
Narlaprevir
Danoprevir
Simeprevir
BI201335
Vaniprevir
Asunaprivir
ABT-450
GS-9451
Problem of Cross-Resistance to protease inhibitors
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HCV NS5A inhibitors
Inihibit NS5A, whose funtion is not fully understood. Inhibition of pre-initiation complex Inhibition of assembly Degradation of NS5A?
1st generation 2nd generationResistance barrier
low intermediate
Genotype activity 1 à 4 all all
Drugs Ombitasvir (ABT-267)
PPI-461PPI-668
DaclatasvirLedipasvir
Elbasvir (MK-8742)ACH-3102GS-5816
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Berger et al. Gastro 2014. Vol 147 (5): 1094-1105.
HCV NS5A inhibitors
Lipid Bilayer
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Interaction of daclatasvir with NS5A
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NS5A/inhibitor cannot be incorpoated in replication compexs (RCs). NS5A is therefore shuttled at the surface of lipid droplets
The inhibition of NS5A limits the formation of replication complex
Targett-Adams et al. J Virol. 2011 Jul;85(13):6353-68
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Inhibition of NS5A activity by Daclatasvir
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NS5A inhibitors require a rigid core structure for potent activity. End groups of ACH-3102 were optimized to retain activity against
resistant variants
Rigid Core
Daclatasvir
ACH-3102
Structural changes to optimize against resistance
Structural changes to optimize against resistance
Optimization of NS5A inhibitors structures against resistance variants
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HCV NS5B inhibitors
Inihibit NS5B polymerase. Two kind of inhibitors:
● Nucleot(s)ides analogues: inhibit competively by binding to the catalytic site of NS5B.
● Non- nucleot(s)ides inhibitors: allosteric inhibition of the binding site of NS5B
Nucleos(t)ide analogues
Non-nucleoside inhibitors
Resistance barrier high low
Genotype activity all G1 (1b > 1a)
Drugs SofosbuvirACH-3422
BMS-791325 (BMS)Dasabuvir (ABT-333)
(AbbVie)ABT-072 (AbbVie)
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Bartenschlager et al. Nature Reviews Microbiology 2013 11, 482–496
HCV NS5B crystal structure
Interaction with viral RNA
Lipid Bilayer
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Bartenschlager R et al. Nat Rev Microbiol 2013;11:482-496.Scheel TK and Rice CM. Nat Med 2013;19:837-849.
Nucleos(t)ide inhibitors (NI)- Mericitabine- Sofosbuvir
Non-nucleoside inhibitors (NNI) = allosteric inhibitors
A Thumb Ie.g. deleobuvir
B Thumb IIe.g. lomibuvir, filibuvir
C Palm Ie.g. ABT333, setrobuvir
D E Palm IIe.g. nesbuvir, tegobuvir
HCV NS5B inhibitors
Palm
FingerThumb
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Nucleotide /Nucleoside analogs
Sofosbuvir : Nucleotide
Mericitabine : Nucleoside
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SVR12
SOF/LDV8 sem.
Re-traitementSOF/LDV + RBV
24 sem.
Post-traitement
NS5A : L31M (25,5 %)NS5B : no mutations
NS5A : Q30L (3,47 %) L31M (94,38 %)L31V (4,67 %) Y93H (98,19 %)
NS5B : 282T (8,00 %)
NS5A : Q30L (4,5 %)L31M (> 99 %)Y93H (96,74 %)
NS5B : S282T (91,24 %)
0
2
4
6
7
Post-traitement
HC
V R
NA
(lo
g10
UI/m
l)
5
3
Lawitz E ,US, AASLD 2013, Abs. 215/1844.
Re-treatment of patients who relapsed after 8 weeks of sofosbuvir + ledipasvir
Patient from LONESTAR study
< 25 UI/ml detectable< 25 UI/ml un-detectable
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Take home messages
Knowledge of HCV replication crucial for the development of DAAs
Importance of genetic barrier
Cross-resistance to protease inhibitorsNS5A functions are not fully understood, however
blocking NS5A inhibit HCV replication
The combination of DAAs decreases the risks of resistance
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PI, 1st Generation
PI, 2nd Generation
NS5A Inhibitors 1st Generation
NS5A Inhibitors 2nd Generation
NS5BNucleosideInhibitors
NS5B Non-Nucleoside
Inhibitors
Efficacy
Resistance Profile
Pangenotypic Efficacy
Adverseevents
Drug-drug interactions
Good profile Average profile Least favorable profile
Schinazi R et al. Liver International 2013
General Characteristics of Direct-Acting Antivirals