12/12/2014
Five Nations Conference on HIV and Hepatitis
in partnership with
Professor Jean-Michel Pawlotsky Hôpital Henri Mondor, Paris, France
Treatment of HCV in Monoinfected Patients
Prof. Jean-Michel Pawlotsky, MD, PhD
National Reference Center for Viral Hepatitis B, C and delta Department of Virology & INSERM U955 Henri Mondor Hospital University of Paris-Est Créteil, France
1 12/12/2014
I
New HCV Drugs
HCV Lifecycle
(Pawlotsky JM, Antivir Ther 2012;17:1109-17)
2 12/12/2014
HCV Lifecycle
Inhibition of polyprotein processing
(Pawlotsky JM, Antivir Ther 2012;17:1109-17)
HCV Lifecycle
Inhibition of HCV replication
(Pawlotsky JM, Antivir Ther 2012;17:1109-17)
3 12/12/2014
HCV Lifecycle
Inhibition of HCV assembly and release
Inhibition of HCV replication
(Pawlotsky JM, Antivir Ther 2012;17:1109-17)
NS3/4A Protease Inhibitors
(Raney et al., J Biol Chem 2010:285:22725-31)
4 12/12/2014
NS3/4A Protease Inhibitors
1st -wave, 1 st -generation 2nd -wave, 1 st -generation 2nd -generation Telaprevir (Janssen) Simeprevir (Janssen) Grazoprevir (Merck) Boceprevir (Merck) Paritaprevir/r (Abbvie) ACH-2684 (Achillion) Asunaprevir (BMS, Japan) Sovaprevir (Achillion) Narrow genotypic activity Vedroprevir (Gilead) Pangenotypic (~) Low barrier to resistance Vaniprevir (Merck, Japan) Higher barrier to resistance
All genotypes except 3 Low barrier to resistance
Protease Inhibitor Resistance
(HCV DRAG, Forum for Collaborative HIV Research, April 2014)
5 12/12/2014
Nucleoside/Nucleotide Analogue Inhibitors of HCV RdRp
Catalytic Site
(Kindly provided by Dr F. Penin)
Nucleoside/Nucleotide Analogue Inhibitors of HCV RdRp
Nucleotide analogues Sofosbuvir (Gilead) MK-3682 (Merck) ACH-3422 (Achillion) AL-335 (Janssen)
Pangenotypic High barrier to resistance
6 12/12/2014
Non-Nucleoside Inhibitors (NNI)
Thumb I BMS-791325 Palm I Dasabuvir
A
B C D
Thumb II GS-9669
Palm II
(Adapted from Dr F. Penin)
Non-Nucleoside Inhibitors (NNI)
Thumb-1 inhibitors Thumb-2 inhibitors Palm-1 inhibitors Beclabuvir (BMS) GS-9669 (Gilead) Dasabuvir (Abbvie)
Genotype 1 ~only Genotype 1 ~only Genotype 1 ~only Low barrier to resistance Low barrier to resistance Low barrier to resistance
7 12/12/2014
HCV NNI Resistance Mutations
95 142 96 Thumb Fingers A 495 C 451 282 499 411 176 423 448 496 419 414 316 482 B 365 201 DPalm
(courtesy of Isabel Najera, Roche)
NS5A Protein
Required for HCV RNA NS5A Dimer replication Domain III Domain II Required for HCV viral Domain I particle assembly Cytosol
ER membrane May be involved in the
ER lumen release of HCV particles
8 12/12/2014
NS5A Inhibitors
1st -generation 2nd -generation Daclatasvir (BMS) Elbasvir (Merck) Ledipasvir (Gilead) ACH-3102 (Achillion) Ombitasvir (Abbvie) GS-5816 (Gilead)
Genotypes 1 and 4, other Pangenotypic genotypes variable Slightly higher barrier Low barrier to resistance to resistance
NS5A Inhibitor Resistance
(HCV DRAG, Forum for Collaborative HIV Research, April 2014)
9 12/12/2014
II
Treatment of Chronic Hepatitis C in 2014
DAAs Approved in 2014
Sofosbuvir Simeprevir Daclatasvir
Nucleotide Protease NS5A All genotypes Gen 1, 4 Gen 1, 3, 4, 5, 6
10 12/12/2014
Options in 2014
• IFN-based regimens • Sofosbuvir + Peg-IFN α + ribavirin (all genotypes) • Simeprevir + Peg-IFN α + ribavirin (genotypes 1, 4) • Daclatasvir + Peg-IFN α + ribavirin (genotypes 1, 3, 4-6)
• IFN-free regimens • Sofosbuvir + ribavirin (genotypes 2, 3) • Sofosbuvir + simeprevir (genotypes 1, 4) • Sofosbuvir + daclatasvir (genotypes 1, 3, 4-6)
11 12/12/2014
EASL Recommendations for Genotypes 1 and 4
IFN-based regimens
PEG-IFN + RBV + sofosbuvir [12 weeks]
PEG-IFN + RBV + simeprevir [12 weeks + RGT 12/36]
PEG-IFN + RBV + daclatasvir [12 weeks + RGT 12]
All-oral regimens
Sofosbuvir + simeprevir (±RBV) [12 weeks]
Sofosbuvir + daclatasvir (±RBV) [12–24 weeks]
(EASL Recommendations on Treatment of Hepatitis C 2014. http://files.easl.eu/easl-recommendations-on-treatment-of- hepatitis-C.pdf. Accessed July 2014)
EASL Recommendations for Genotype 2
IFN-based regimens
PEG-IFN + RBV + sofosbuvir [12 weeks]
All-oral regimens
Sofosbuvir + RBV [12-16/20 weeks]
(EASL Recommendations on Treatment of Hepatitis C 2014. http://files.easl.eu/easl-recommendations-on-treatment-of- hepatitis-C.pdf. Accessed July 2014)
12 12/12/2014
EASL Recommendations for Genotype 3
IFN-based regimens
PEG-IFN + RBV + sofosbuvir [12 weeks]
All-oral regimens
Sofosbuvir + RBV [24weeks]
Sofosbuvir + daclatasvir (±RBV) [12–24 weeks]
(EASL Recommendations on Treatment of Hepatitis C 2014. http://files.easl.eu/easl-recommendations-on-treatment-of- hepatitis-C.pdf. Accessed July 2014)
EASL Recommendations for Genotypes 5 and 6
IFN-based regimens
PEG-IFN + RBV + sofosbuvir [12 weeks]
All-oral regimens
Sofosbuvir + daclatasvir (±RBV) [12–24 weeks]
(EASL Recommendations on Treatment of Hepatitis C 2014. http://files.easl.eu/easl-recommendations-on-treatment-of- hepatitis-C.pdf. Accessed July 2014)
13 12/12/2014
P + R + Simeprevir-QUEST-1/2 Phase III, Treatment-naive, genotype 1
100 90 84% 85% 80
70
60 58%
50
40
SVR24 rate (%) rate SVR24 30
20
10 N=84 N=165 N=267 0 1a Q80K 1a no Q80K 1b
*Q80K prevalence in the US : GT 1a, 32.5%; GT 1b, 0.1% (Jacobson et al., Lancet 2014;384:403-13; Manns et al., Lancet 2014;384:414-26)
P + R + Sofosbuvir-NEUTRINO Phase III, 12 weeks, Gen 1-4-5-6, Treatment-naive 96% 100% 100 90% 89% 90
80
70
60
50
40
SVR12 rate (%) rate SVR12 30
20
10 N=327 N=292 N=28 N=7 0 TOTAL Genotype 1 Genotype 4 Genotype 5, 6 (89%) (9%) (2%) (Lawitz et al., N Engl J Med 2013;368:1878-87)
14 12/12/2014
Sofosbuvir + Simeprevir ± RBV COSMOS Cohort 2- Gen 1, Naive and NR, F3-F4
100% 100 94% 93% 93% 93% 90
80
70
60
50
40
SVR12 rate (%) rate SVR12 30
20
10 N=80 N=27 N=14 N=24 N=15 0 All patients SOF+SIM+RBV SOF+SIM SOF+SIM+RBV SOF+SIM
12 weeks 24 weeks (Lawitz et al., Lancet 2014; epub ahead of print)
Sofosbuvir + Simeprevir ± RBV TARGET 2.0- Genotype 1, Real-life, US
Without RBV With RBV
100% 90% 92% 93% 87% 89% 89% 87% 86% 86% 85% 83% 84% 82% 85% 80%
60%
40% Adjusted Adjusted SVR4 20%
0% Overall Cirrhosis No cirrhosisGenotype 1a Genotype 1b Naïve Experienced
(Jensen et al., AASLD 2014)
15 12/12/2014
Sofosbuvir + Daclatasvir ± RBV Treatment-naive and PI failures, Genotype 1 24 Weeks 12 Weeks 24 Weeks Treatment Naïve Treatment Naïve PI Failures 100% 100% 100% 95% 100% 95% 100
90
80
70
60
50
40
SVR12 rate (%) rate SVR12 30
20
10 N=14 N=15 N=41 N=41 N=21 N=20 0 SOF + DCV SOF + DCV SOF + DCV SOF + DCV SOF + DCV SOF + DCV + RBV + RBV + RBV (Sulkowski et al., N Engl J Med 2014;370:211-21 )
III
Treatment of Chronic Hepatitis C in 2015 and After
16 12/12/2014
IFN-Free Combination Options
Option 1 Option 2 Option 3
Protease NS5A Protease 2nd -gen inhibitor inhibitor inhibitor protease inhibitor
Nucleotide NS5A analogue inhibitor 2nd -gen NS5A inhibitor
Non- Non-nucleoside ± ribavirin nucleoside inhibitor inhibitor
± ribavirin ± ribavirin
(Pawlotsky JM, Gastroenterology 2014;146:1176-92)
IFN-Free Combination Options
Option 1 Option 2 Option 3
Protease NS5A Protease 2nd -gen inhibitor inhibitor inhibitor protease inhibitor
Nucleotide NS5A analogue inhibitor 2nd -gen NS5A Gilead inhibitor
Non- Non-nucleoside ± ribavirin nucleoside inhibitor inhibitor
± ribavirin ± ribavirin
(Pawlotsky JM, Gastroenterology 2014;146:1176-92)
17 12/12/2014
IFN-Free Combination Options
Option 1 Option 2 Option 3
Protease NS5A Protease 2nd -gen inhibitor inhibitor inhibitor protease Abbvie inhibitor Nucleotide NS5A analogue inhibitor 2nd -gen NS5A Gilead inhibitor
Non- Non-nucleosideBMS ± ribavirin nucleoside inhibitor inhibitor
± ribavirin ± ribavirin
(Pawlotsky JM, Gastroenterology 2014;146:1176-92)
IFN-Free Combination Options
Option 1 Option 2 Option 3
Protease NS5A Protease 2nd -gen inhibitor inhibitor inhibitor protease Abbvie inhibitor Nucleotide NS5A analogue inhibitor 2nd -gen NS5A Gilead Merckinhibitor
Non- Non-nucleosideBMS ± ribavirin nucleoside inhibitor inhibitor
± ribavirin ± ribavirin
(Pawlotsky JM, Gastroenterology 2014;146:1176-92)
18 12/12/2014
IFN-Free Combination Options
Option 1 Option 2 Option 3
Protease NS5A Protease 2nd -gen inhibitor inhibitor inhibitor protease Abbvie inhibitor Nucleotide NS5A analogue inhibitor 2nd -gen NS5A Gilead ?Merckinhibitor Non- Non-nucleosideBMS ± ribavirin nucleoside inhibitor Merckinhibitor
± ribavirin ± ribavirin
(Pawlotsky JM, Gastroenterology 2014;146:1176-92)
IFN-Free Combination Options
Option 1 Option 2 Option 3
Protease NS5A Protease 2nd -gen inhibitor inhibitor inhibitor protease Abbvie inhibitor Nucleotide NS5A analogue inhibitor 2nd -gen NS5A Gilead ?Merckinhibitor Non- Non-nucleosideBMS ± ribavirin nucleoside inhibitor Merckinhibitor
± ribavirin ± ribavirin Janssen
(Pawlotsky JM, Gastroenterology 2014;146:1176-92)
19 12/12/2014
IFN-Free Combination Options
Option 1 Option 2 Option 3
Protease NS5A Protease 2nd -gen inhibitor inhibitor inhibitor protease inhibitor
Nucleotide NS5A analogue inhibitor 2nd -gen NS5A inhibitor
Non- Non-nucleoside ± ribavirin nucleoside inhibitor inhibitor
± ribavirin ± ribavirin
(Pawlotsky JM, Gastroenterology 2014;146:1176-92)
Sofosbuvir/Ledipasvir FDC ± RBV ION-1-Phase III, Gen 1, Rx-naive, 16% cirrhosis
99% 98% 99% 100 97%
90
80
70
60
50
40
SVR12 rate (%) rate SVR12 30
20
10 N=214 N=217 N=217 N=217 0 SOF/LDV SOF/LDV+RBV SOF/LDV SOF/LDV+RBV 12 weeks 24 weeks
(Afdhal et al., N Engl J Med 2014;370:1889-98)
20 12/12/2014
Sofosbuvir/Ledipasvir FDC ± RBV ION-3-Phase III, Gen 1, Rx-naïve
95% 100 94% 93% 90
80
70
60
50
40
SVR12 rate (%) rate SVR12 30
20
10 N=215 N=216 N=216 0 SOF/LDV SOF/LDV+RBV SOF/LDV 8 weeks 8 weeks 12 weeks
(Kowdley et al., N Engl J Med 2014;370:1879-88)
Sofosbuvir/Ledipasvir FDC ± RBV ION-2-Phase III, Gen 1, Rx-experienced, 20% cirrhosis
99% 99% 100 94% 96% 90
80
70
60
50
40
SVR12 rate (%) rate SVR12 30
20
10 N=109 N=111 N=109 N=111 0 SOF/LDV SOF/LDV+RBV SOF/LDV SOF/LDV+RBV 12 weeks 24 weeks
(Afdhal et al., N Engl J Med 2014;370:1483-93)
21 12/12/2014
Sofosbuvir/Ledipasvir FDC ± RBV Integrated analysis of 513 patients with compensated cirrhosis
Treatment-naïve Treatment-experienced
98% 100% 100% 100 96% 97% 96% 98% 90% 90
80
70
60
50
40
SVR12 rate (%) rate SVR12 30
20
10
0 12 wk 12 wk 24 wk 24 wk 12 wk 12 wk 24 wk 24 wk No RBV +RBV No RBV +RBV No RBV +RBV No RBV +RBV (Bourlière et al., AASLD 2014)
Sofosbuvir/Ledipasvir FDC ± RBV SIRIUS- Genotype 1, cirrhosis, PI failures
96% 97% 100
80
60
40 SVR12 rate (%) rate SVR12 20
N=77 N=77 0 LDV/SOF + RBV LDV/SOF 12 Weeks 24 Weeks
(Bourlière et al., AASLD 2014)
22 12/12/2014
Sofosbuvir/Ledipasvir FDC + RBV SOLAR-1- Genotype 1, decompensated cirrhosis
LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks
89% 89% 86% 90% 100 87% 87%
80
60
40 SVR12 rate (%) rate SVR12 20
N=52 N=/47 N=30N=27 N=22 N=20 0 Overall CPT B CPT C
(Flamm et al., AASLD 2014)
Sofosbuvir/Ledipasvir FDC + RBV SOLAR-1- Genotype 1, post-transplant HCV recurrence
LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks
96%98% 96% 96% 100 85% 83% 80 67% 60% 60
40 SVR12 (%) SVR12 20
N=55 N=56 N=26 N=25 N=26 N=18 N=5 N=3 0 F0–F3 CPT A CPT B CPT C
(Reddy et al., AASLD 2014)
23 12/12/2014
IFN-Free Combination Options
Option 1 Option 2 Option 3
Protease NS5A Protease 2nd -gen inhibitor inhibitor inhibitor protease inhibitor
Nucleotide NS5A analogue inhibitor 2nd -gen NS5A inhibitor
Non- Non-nucleoside ± ribavirin nucleoside inhibitor inhibitor
± ribavirin ± ribavirin
(Pawlotsky JM, Gastroenterology 2014;146:1176-92)
Paritaprevir/r + Ombitasvir + Dasabuvir ± RBV Phase III, Genotype 1, Rx-naïve, No cirrhosis, 12 weeks
SAPPHIRE-I PEARL-IV PEARL-III 98% 99% 99% 100 96% 95% 97% 90% 90
80
70
60
50
40
SVR12 rate (%) rate SVR12 30
20
10 N=473N=322 N=151 N=100 N=205 N=210 N=209 0 All 1 1a 1b 1a 1a 1b 1b 3D+RBV 3D+RBV 3D+RBV 3D+RBV 3D 3D+RBV 3D
(Feld et al., N Engl J Med 2014;370:1594-603; Ferenci et al., N Engl J Med 2014;370:1983-92)
24 12/12/2014
Paritaprevir/r + Ombitasvir + Dasabuvir ± RBV Phase III, Genotype 1, Rx-experienced, No cirrhosis, 12 weeks
SAPPHIRE-II PEARL-II 100% 100 96% 96% 97% 97%
90
80
70
60
50
40
SVR12 rate (%) rate SVR12 30
20
10 N=297 N=173 N=123 N=88 N=91 0 All 1 1a 1b 1a 1b 3D+RBV 3D+RBV 3D+RBV 3D+RBV 3D (Zeuzem et al., N Engl J Med 2014;370:1604-14; Andreone et al., Gastroenterology 2014;147:359-65)
Paritaprevir/r + Ombitasvir + Dasabuvir ± RBV TURQUOISE-Phase III, Genotype 1, Rx-naïve and experienced, 12-24 weeks
95.9% 100 91.8% 90
80
70
60
50
40
SVR12 rate (%) rate SVR12 30
20
10 N=208 N=172 0 3D + RBV 3D + RBV 12 weeks 24 weeks
(Poordad et al., N Engl J Med 2014;370:1973-82)
25 12/12/2014
Paritaprevir/r + Ombitasvir + Dasabuvir + RBV CORAL-1-Phase II, Genotype 1, Post-transplant, 24 weeks
97.1% 100
90
80
70 NB: Phase I data
60 • 7-fold increase in tacrolimus half-life • 3-fold increase in cyclosporine half-life 50
40 => Dose adjustment needed SVR12 rate (%) rate SVR12 30
20
10 N=34 0 3D + RBV 24 weeks
(Mantry et al., AASLD 2014)
Daclatasvir + Asunaprevir + Beclabuvir± RBV UNITY 1/2- Phase III, Genotype 1, 12 weeks 98% 100 92% 93% 93% 87% 90 89%
80
70
60
50
40
SVR12 rate (%) rate SVR12 30
20
10 N=312 N=103 N=57 N=55 N=45 N=45 0 3DAA 3DAA 3DAA 3DAA+RBV 3DAA 3DAA+RBV Naive Experienced Treatment-naive Treatment-experienced Non Cirrhotics Cirrhotics (Muir et al., AASLD 2014; Poordad et al., AASLD 2014)
26 12/12/2014
IV
Remaining Issues
Remaining Issues
• Genotype 3 patients
• Ribavirin vs longer duration
• Drug-drug interactions (HIV patients, 3D regimens)
• Actual results in the real-life setting
• HCV resistance to DAAs in failing patients
• Implementation
27 12/12/2014
Conclusions
• HCV is the only curable chronic viral infection
• Greater understanding of the HCV lifecycle has provided a new toolbox of highly effective strategies • PEG-IFN-containing • PEG-IFN-free ++++
• Challenges remain in implementation
• Treatment recommendations will continue to evolve as more data becomes available
28 12/12/2014
Follow me on Twitter @JMPawlotsky
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