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HCV resistance
- From A Virological Perspective
- Dr. rer. nat. Frank Wiesmann
PZB Aachen AREVIR-Meeting - Cologne 05.05.2017 t = 25 min
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HCV resistance - From A Virological Perspective Dr. rer. nat. - - PowerPoint PPT Presentation
HCV resistance - From A Virological Perspective Dr. rer. nat. - - PowerPoint PPT Presentation
HCV resistance - From A Virological Perspective Dr. rer. nat. Frank Wiesmann PZB Aachen AREVIR-Meeting - Cologne 05.05.2017 t = 25 min www.pzb.de Disclosures Within the last 5 years I received sponsoring by the following companies Abbvie,
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- Natural Resistance – Overcoming HCV diversity
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www.pzb.de HCV: Up to 40% diversity between genotypes Up to 30% diversity between subtypes
Margeridon-Thermet et al. 2010
a) HCV and Genetic Diversity
HCV-specific RNA-dependant polymerase
El-Shamy A, Hotta H.,World Journal of Gastroenterology 2014; 20(24): 7555-7569
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a) Global Distribution of HCV Genotypes
World Health Organization, 2009
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Adapted Christoph Neuman-Haefelin, 25. Jahrestagung der Paul-Ehrlich Gesellschaft, 06.10.16
IFN-free therapy
a) Milestones in HCV Treatment
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- Different genotypes,
different virological response
Nelson D, et al. EASL 2013
a) Natural Resistance – HCV Genotypes
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Viekirax+Dasabuvir
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- Genotype/subtype-dependant differences in
response to therapy
⇒An accurate genotyping/subtyping is crucial
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Advantages of genotyping by sequencing (NS5A and NS5B)
- Ability to detect subtypes of all genotypes
- Ability to predict HCV reinfection with same genotypes
- Ability to re-analyze RAS if necessary
Genotyping/Resistance Analysis
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- Detection of primary drug-specific resistance
mutations
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RF in EC50 3 2 2 3 2 50 8965 2 3 41383 1472
58 155 800 0,5 1675 66740 32 30 261 Krishnan P. et al., EASL 2014, #P1230
b) Resistance-associated Baseline Mutations Genotype 1A
Total Prevalence: NS3 <1% NS5A 10,2% NS5B 5,4%
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www.pzb.de Krishnan P. et al., EASL 2014, #P1230
RF in EC50 0,4 0,9 0,8 0,4 77 229 5 11 316N+556G = 38 (10%) No NS3 mutations In this study
Total Prevalence: NS5A 30,8% NS5B 40%
b) Resistance-associated Baseline Mutations Genotype 1B
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- Is there a need for HCV resistance interpretation
before initiation of DAA-therapies?
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www.pzb.de Krishnan P. et al., EASL 2014, #P1230
SVR in Patients with Genotype 1 Infection with and without Baseline-Mutations (Abbvie 3D) Genotype 1a+b Genotype 1a
Only 1 Genotype 1b Patient (without Baselinemutations) did not reach SVR
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N=1765
Resistance-associated Baseline Mutations Genotype 1 treated with (SOF/LDV)
Zeuzem S. et al., Journal of Hepatology 2017, #P1230
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- What do the guidelines say?
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EASL Guidelines 2016
Gt DAA combination Setting Best possible treatment with NS5A RAS knowledge Best possible treatment without NS5A knowledge
1a Sofosbuvir/Ledipasvir Therapy-experienced but DAA-naive 12 weeks 12 weeks + RBV 1a Grazoprevir/Elbasvir naive&experienced 12 weeks 16 weeks + RBV (>800.000 IU/ml] 1a Sofosbuvir/Daclatasvir Therapy-experienced but DAA-naive 12 weeks 12 weeks + RBV 3 Sofosbuvir/Velpatasvir compensated cirrhosis 12 weeks (no Y93H) 12 weeks + RBV
www.easl.eu
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- How long do Resistance-Associated Variants
persist under/after therapy?
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www.pzb.de Sarrazin C, et al. Gastroenterology 2007; 132:1767-77
- Resistant variants develop fast under monotherapy
- Resistant quasispecies are detectable for a long time after stop of treatment
c) HCV resistance develops fast under monotherapy
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Mono- vs Dual- vs Triple-DAA
< 0.0001 % < 0.0001 %
Frequency of resistant colonies
10X + 10x + 10X EC50 5X + 5x + 5X EC50
ABT-450 + ABT-267 + ABT-333 (106 cells)
0.0045% 0.0011% 0.0027%
Frequency of resistant colonies 10X + 10X EC50 (106 cells)
ABT-267 + ABT-333 ABT-450 + ABT-333 ABT-450 + ABT-267 >1% ~ 0.5% >1%
Frequency of resistant colonies 10X EC50 (105 cells)
ABT-333 ABT-267 ABT-450 < 0.0001 % < 0.0001 %
Frequency of resistant colonies
10X + 10x + 10X EC50 5X + 5x + 5X EC50
ABT-450 + ABT-267 + ABT-333 (106 cells)
0.0045% 0.0011% 0.0027%
Frequency of resistant colonies 10X + 10X EC50 (106 cells)
ABT-267 + ABT-333 ABT-450 + ABT-333 ABT-450 + ABT-267 >1% ~ 0.5% >1%
Frequency of resistant colonies 10X EC50 (105 cells)
ABT-333 ABT-267 ABT-450
1 active drug 2 active drugs 3 active drugs
Pilot-Matias et al. Poster 867, EASL 2012
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www.pzb.de Feld J., EASL 2014
Saphire-I: Resistenz-associated Variants At Time of Therapy Failure (3D+RBV)
62.5% with 3-class resistance
N=473
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Persistance of NS3 Resistance Mutations
- Loss of detectable resistance mutations in patients with resistant variants at
therapy failure (TVR + pegIFN/RBV)
V36M alone R155K alone V36M + R155K % 1a Therapy Failure 10 20 46 Median Months until loss 6 (4-9) 10 (9-13) 13 (10-13)
Probability Months after therapy failure R155K alone(n = 41) V36M alone (n = 22) V36M + R155K (n = 124) 0.2 0.4 0.6 0.8 1.0 2 4 6 8 10 12 14 16 18
- 1. Sullivan J, et al. EASL 2011. Abstract 8.
- 2. Liverton N. et al. EASL 2010.
*1 *2 *1
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www.pzb.de Wyles et al. et al. , EASL 2015, Abstract O059 >96 weeks=82%
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Therapy Transmission Resistant Virus After Months/Years
?
Persistance of resistant HCV
Still minor knowledge about transmission
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- Does a resistance test guide decisions in patients
with prior failure of DAA-based therapy?
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RASs
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www.pzb.de Lawitz et al. et al. , EASL 2015, Abstract O005
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Real-World Data (European Resistance Database)
Persons failing on DAA-therapy in clinical trials (N=310)
Vermehren J. et al., EASL 2016, Abst. PS103
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www.pzb.de Vermehren J. et al., EASL 2016, Abst. PS103
Real-World Data (European Resistance Database)
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- Future treatment options after DAA-failure
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Adapted Christoph Neuman-Haefelin, 25. Jahrestagung der Paul-Ehrlich Gesellschaft, 06.10.16
IFN-free therapy
2017/2018
- 8 weeks
- One-pill regimen / no RBV
- Price reduction
- Use in dialysis
- Therapies after
DAA failure
- pangenotypic
Milestones in HCV Treatment
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Treatment Options after DAA-failure
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Selection of most recent clinical trials
SOF/VEL/VOX
POLARIS-1[1] 12 wks for NS5A inhibitor experienced GT1-6 HCV PBO POLARIS-2[2] 8 wks for DAA-naive GT1-6 HCV SOF/VEL POLARIS-3[3] 8 wks for cirrhotic GT3 HCV SOF/VEL POLARIS-4[4] 12 wks for DAA-experienced (no NS5A inhibitors) GT1-6 HCV SOF/VEL GLE/PIB ENDURANCE-1[5] 8 or 12 wks for noncirrhotic pts with GT1 HCV GLE/PIB ENDURANCE-2[6] 12 wks for noncirrhotic pts with GT2 HCV PBO ENDURANCE-4[7] 12 wks for noncirrhotic pts with GT4-6 HCV None SURVEYOR-II/3[8] 12 or 16 wks for pts with GT3 HCV ± tx exp ± cirrhosis GLE/PIB EXPEDITION-IV[9] 12 wks for pts with GT1-6 HCV and stage 4/5 CKD None MK-3682/GZR/RZR C-CREST Part B[10] 8/12/16 wks ± RBV for GT1-3 HCV ± tx exp ± cirrhosis MK-3682/GZR/RZR C-CREST Part C[11] 16 wks + RBV for 8-wk MK-3682/GZR/(RZR or EBR) failures None C-SURGE[12] 16 or 24 wks ± RBV for GT1 HCV pts relapsing on DAAs MK-3682/GZR/RZR
Future treatment 8-16 weeks irrespective of genotype, disease status and therapy experience
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56% MAGELLAN-1, Part 2: Glecaprevir/Pibrentasvir Demonstrates Promising Activity in Patients With Genotype 1 or 4 HCV Infection Who Failed Previous DAA Therapy
Poordad F et al., EASL 2017, PS 156
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Voxilaprevir/Sofosbuvir/Velpatasvir
Sarrazin et al., EASL 2017, THU-248
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Grazoprevir/Uprifosbuvir/Ruzasvir
Wedemeyer et al., EASL 2017, PS-159
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Conclusion
- HCV Resistance occurs frequently but is rarely clinically significant
(SVR >90%)
- Patients with viral breakthrough or Relapse show in almost every case
development of viral resistance
- Drug-recycling is theoretically possible particularly in combination with
additional substances (RBV, IFN or other DAAs)
- Limited knowledge / often individual cases
- Resistance mutations detected after therapy failure disappear in
general after stop of therapy until wildtype-Variants dominate the viral
- population. This process can take months/years.
- Many additional pan-genotypic treatment options are expected to come
up in the following year for treatment of patients with prior DAA-failure
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