easl panel debate april 13 2019 final · greece y y hong!kong! y y hungary! y y iceland! y y...
TRANSCRIPT
PRO: Tes)ng for HCV Resistance-‐Associated Variants (RAVs) in Pa)ents A;er
DAA Failure and Impact on Subsequent Drug Selec)on
EASL 2019 Vienna
Ira M. Jacobson, M.D. Professor of Medicine Director of Hepatology NYU Langone Health
Disclosures
• Consul(ng: Abbvie, Assembly, BMS, Gilead, Janssen, Novo Nordisk, Siemens, Springbank
• Research Funding: Assembly, BMS, Enanta, Genfit, Gilead, Janssen
PRO: Tes)ng for HCV Resistance-‐Associated Variants (RAVs) in Pa)ents A;er
DAA Failure and Impact on Subsequent Drug Selec)on
This is a more complicated ques(on than it might seem to be… It depends on what regimens you can subsequently select from!
First genera(on regimens Low resistance barrier… Vulnerable to RASs
Second genera(on regimens High resistance barrier… Can overcome RASs
SIM+SOF LDV/SOF DCV+SOF PTV/r/EBR+DSV EBR/GZR
SOF/VEL GLE/PIB SOF/VEL/VOX
Countries With Approval for EPC & VSV* Country EPC VSV
Austria Y Y
Australia Y Y
Belgium Y Y
Bulgaria Y Y
Canada Y Y
Croa(a Y Y
Cyprus Y Y
Czech Republic Y Y
Denmark Y Y
Dominican Republic Y Y
Estonia Y Y
Finland Y Y
France Y Y
Country EPC VSV Germany Y Y
Greece Y Y
Hong Kong Y Y
Hungary Y Y
Iceland Y Y
Ireland Y Y
Israel Y Y
Italy Y Y
Kuwait Y Y
Latvia Y Y
Lebanon Y Y
Liechtenstein Y Y
Lithuania Y Y
Luxembourg Y Y
Malta Y Y
Country EPC VSV
Netherlands Y Y
New Zealand Y Y
Norway Y Y
Poland Y Y
Portugal Y Y
Romania Y Y
Slovakia Y Y
Slovenia Y Y
Spain Y Y
Sweden Y Y
Switzerland Y Y
UAE Y Y
United Kingdom Y Y
United States Y Y
* EPC = SOF/VEL * VSV = SOF/VEL/VOX Courtesy of Dr. Anand Chokkalingam, Gilead Sciences
Countries With Approval for EPC* Only Country EPC VSV
Albania Y
Argen(na Y
Bosnia Y
Brazil Y
Chile Y
China Y
Columbia Y
Costa Rica Y
Ethiopia Y
Georgia Y
India Y
Japan Y
Jordan Y
Country EPC VSV
Kosovo Y
Malaysia Y
Mexico Y
Montenegro Y
Pakistan Y
Panama Y
Peru Y
Saudia Arabia Y
Serbia Y
Singapore Y
Thailand Y
Taiwan Y
Uganda Y
Country EPC VSV
Ukraine Y
Uruguay Y
Uzbekistan Y
Vietnam Y
* EPC = SOF/VEL
* VSV = SOF/VEL/VOX
Courtesy of Dr. Anand Chokkalingam, Gilead Sciences
Neither EPC nor VSV* Approved
Country Algeria
Afghanistan
Andorra
Angola
An(gua & Barbuda
Armenia
Azerbaijan
The Bahamas
Bahrain
Bangladesh
Barbados
Belarus
Belize
Country Benin
Bhutan
Bolivia
Borneo
Bosnia & Herzegovina
Botswana
Brunei
Burkina Faso
Burundi
Cape Verde
Cambodia
Cameroon
Central African Republic
Country Chad
Comoros
Republic of Congo
Cuba
Djibou(
Dominica
Ecuador
Egypt
El Salvador
Equatorial Guinea
Eritrea
Eswa(ni
Fiji
Country Gabon
The Gambia
Ghana
Grenada
Guatemala
Guinea
Guinea-‐Bissau
Guyana
Hai(
Honduras
Indonesia
Republic of Ireland
Iran
* EPC = SOF/VEL; VSV = SOF/VEL/VOX † Does not reflect availability of licensed generics
Country Iraq
Israel
Ivory Coast
Jamaica
Kazakhstan
Kenya
Kiriba(
Kyrgyzstan
Laos
Lesotho
Liberia
Libya
Madagascar
Country Malawi
Maldives
Mali
Marshall Islands
Mauritania
Mauri(us
Federated States of Micronesia
Monaco
Mongolia
Morocco
Mozambique
Myanmar
Namibia
Neither EPC nor VSV* Approved Country Nauru
Nepal
Nicaragua
Niger
Nigeria
North Korea
North Macedonia
Oman
Palau
Papua New Guinea
Philippines
Qatar
South Africa
South Korea
Moldova
Country Russia
Rwanda
Saint Kies & Nevis
Saint Lucia
Saint Vincent & the Grenadines
Samoa
Sao Tome & Principe
Senegal
Seychelles
Sierra Leone
Solomon Islands
Somalia
South Sudan
Sri Lanka
Sudan
Country Suriname
Syria
Tajikistan
East Timor
Togo
Tonga
Trinidad & Tobago
Tunisia
Turkmenistan
Tuvala
United Arab Emirates
Tanzania
Vanuatu
Venezuela
Yemen
Zambia
Zimbabwe
* EPC = SOF/VEL; VSV = SOF/VEL/VOX † Does not reflect availability of licensed generics
GLE/PIB is Also Not Yet Available Everywhere
Regulatory filings submieed: 71
Regulatory approvals received: 59 Product available on market: 42
Abbvie Booth EASL 2019
Background on Resistance
HCVguidelines.org 2018
AASLD/IDSA Guidance: HCV Resistance Primer
Ac)vity of Pibrentasvir Against NS5A RASs
Ng TI et al, An(microb Agents Chemother. 2017 Apr 24;61(5). pii: e02558-‐16.
Analysis of GT3 Complex RASs in Vitro
Smith D et al, Hepatology, First published: 09 February 2018, DOI: (10.1002/hep.29837)
Most pa)ents who Fail Ini)al DAA Regimens DO Have RASs A;er Virologic Failure...
And They are Durable
Dietz J et al, EASL 2019.
Persistence of RASs in GLE/PIB Failures: GT3
Dietz J et al, EASL 2019
How Might Baseline RASs Impact on Management Decisions?
More “advanced”
regimen (Higher resistance
barrier)
Longer dura(on
Addi(on of ribavirin
• Approved? • Guideline
recommended? • Improvise?
Guidelines and Appoval Language do not Always Reflect the Impact of Baseline RASs on Treatment Outcomes and
What Might be Done to Minimize Failure
Impact of Baseline RASs on SVR With LDV/SOF: A Comprehensive Anaysis of Treatment Outcomes
Sarrazin C et al, Gastroenterology, 2016;151:501-‐512.
Treatment naïve GT1
ENDURANCE-‐3: Glecaprevir/Pibrentasvir 8 vs 12 Wks vs Daclatasvir/Sofosbuvir in
GT3 HCV Without Cirrhosis
Zeuzem S et al, N Engl J Med 2018;378:354-‐69
Relapse 3 BT 1
Relapse 1 BT 0
Relapse 5 BT 1
Another Example of a RAS With Impact That Might be Obscured in a Large Data Set
ENDURANCE-‐3: Baseline RASs and SVR12 in GT3
Zeuzem S et al, N Engl J Med 2018;378:354-‐69 (Supplemental Appendix p 22)
*“Insufficient evidence to recommend tes(ng for RASs or extension of therapy in the sevng of A30K at this (me, but the effect of the A30K muta(on should con(nue to be explored in real world cohorts” -‐ AASLD/IDSA Sept 2017
All had A30K at BL; A30K + Y93H at relapse
*
First genera(on regimens Low resistance barrier… Vulnerable to RASs
Second genera(on regimens High resistance barrier… Can overcome RASs
SIM+SOF LDV/SOF DCV+SOF PTV/r/EBR+DSV EBR/GZR
SOF/VEL GLE/PIB SOF/VEL/VOX
PRO: Tes)ng for HCV Resistance-‐Associated Variants (RAVs) in Pa)ents A;er
DAA Failure and Impact on Subsequent Drug Selec)on
LDV/SOF 24 Weeks for LDV/SOF Failures
Lawitz E, et al, EASL 2015. Vienna
Wk 0 Wk 12 Wk 36 Wk 24
LDV/SOF + RBV SVR12 SOF failures (n=51)
LDV/SOF SVR12 LDV/SOF failures (n=41)
LDV/SOF + RBV SVR12 SOF failures (advanced liver disease)
98% SVR121
22
68 80
100 74
46 60
0
20
40
60
80
100
No Yes 8 wks 12 wks No Yes
15/22 14/19 24/30 5/11 11/11 18/30
Cirrhosis Prior Treatment Duration
Baseline NS5A RAVs
♦ All 11 pa(ents without NS5A RAVs received 8 weeks of prior treatment
SV
R12
(%)
No Yes No Yes No Yes
LDV/SOF 24 Weeks for LDV/SOF Failures
Lawitz E, et al. EASL 2015, Vienna.
PRO: Tes)ng for HCV Resistance-‐Associated Variants (RAVs) in Pa)ents A;er
DAA Failure and Impact on Subsequent Drug Selec)on
First genera(on regimens Low resistance barrier… Vulnerable to RASs
Second genera(on regimens High resistance barrier… Can overcome RASs
SIM+SOF LDV/SOF DCV+SOF PTV/r/EBR+DSV EBR/GZR
SOF/VEL GLE/PIB SOF/VEL/VOX
Impact of Baseline RASs on SVR in ASTRAL-‐3 (Pivotal GT3 Study)
Foster GR, et al. N Engl J Med 2015 Dec 31;373(27):2608-‐17
SOF/VEL ± RBV for GT3 Pa)ents With Cirrhosis RBV Helps Overcome RASs
n SVR Relapse
SOF/VEL 101 91% 5%
SOF/VEL+RBV 103 96% 2%
Esteban R et al, Gastroenterology 2018;155:1120-‐27
Overall results
96 99
0
20
40
60
80
100
SOF/VEL SOF/VEL+RBV
No RASs
84 96
0
20
40
60
80
100
SOF/VEL SOF/VEL+RBV
RASs
SOF/VEL + RBV 24 Weeks for DAA Failures
Gane EJ et al, Hepatology 2017;66:1083-‐89
• Numbers with RAS small • Related to short dura)on of prior therapy
VF: BL L31M
*
*
“Resistance Guided” Retreatment of NS5A Failures Focus on SOF/VEL
Di Maio VC et al, EASL 2019 THU-‐133
PRO: Tes)ng for HCV Resistance-‐Associated Variants (RAVs) in Pa)ents A;er
DAA Failure and Impact on Subsequent Drug Selec)on
First genera(on regimens Low resistance barrier… Vulnerable to RASs
Second genera(on regimens High resistance barrier… Can overcome RASs
SIM+SOF LDV/SOF DCV+SOF PTV/r/EBR+DSV EBR/GZR
SOF/VEL GLE/PIB SOF/VEL/VOX
MAGELLAN-‐1, Part 2: Impact of RASs on Efficacy of GLE/PIB in GT1 DAA Nonresponders
Pilot-‐Ma(as T et al, EASL 2017 poster SAT-‐204; Poordad F et al, 2018
Efficacy of GLE/PIB in GT1 Pa)ents who Failed Prior Treatment With NS5A-‐Inhibitor Plus SOF Regimens
Sulkowski M, et al. AASLD 2018, San Francisco, USA. #226
Efficacy of GLE/PIB in GT1 Pa)ents who Failed Prior Treatment With NS5A-‐Inhibitor Plus SOF Regimens
Sulkowski M, et al. AASLD 2018, San Francisco, USA. #226
Arm Prior Tx Days since exp Response NS3 RAS NS5A RAS
Baseline Failure Baseline Failure No Cirr. GLE/ PIB 12 weeks
LDV/SOF 470 Breakthrough None R155W+A156G Q30N+Y93H M28T+Q30N+Y93H
No Cirr. GLE/ PIB 12 weeks
LDV/SOF 711 Breakthrough None A156V (21%) Q30R+L31M Q30R+L31M+H58D
No Cirr. GLE/ PIB 16 weeks
LDV/SOF 210 Breakthrough None A156V (90%)
A156V+D168E (10%) Q30R+L31M+H58D Q30R+L31M+H58D
Cirr. GLE/PIB + RBV 12 weeks
LDV/SOF 425 Breakthrough None A156V M28T+Q30R (28%)
Q30R (14%) M28T+Q30R+H58D
Cirr. GLE/PIB + RBV 12 weeks
LDV/SOF 580 Breakthrough None R155W+A156G Q30H+L31M+Y93H Q30H+L31M+Y93H
Cirr. GLE/PIB + RBV 12 weeks
LDV/SOF 684 Breakthrough None None L31M L31M+P32-‐del
Arm Prior Tx & days
since exp Response
NS3 RAS NS5A RAS
Baseline Failure Baseline Failure
No Cirr. GLE/PIB 12 weeks LDV/SOF (936) Relapse None None Y93N L31M+Y93N
No Cirr. GLE/PIB 12 weeks VEL/SOF (284) Relapse None None Q30H+Y93H Q30H+L31V+Y93H (60%) Q30N+Y93H (40%)
No Cirr. GLE/PIB 12 weeks LDV/SOF (788) Relapse None S122G* None None
No Cirr. GLE/PIB 12 weeks LDV/SOF (861) Relapse R155k R155K Q30E Q30E+H58D
No Cirr. GLE/PIB 16 weeks DCV/SOF (180) Relapse None A156T (3%) M28V+Q30R+L31V M28A+Q30R+L31V
No Cirr. GLE/PIB 16 weeks LDV/SOF (958) Relapse None None M28T+Q30R M28S+Q30R
Cirr. GLE/PIB 16 weeks LDV/SOF (912) Relapse None A156V (4%) Y93N H58D+Y93N
No cirr. GLE/PIB 12 weeks LDV/SOF (325) Reinfec\on None None None None
• Lots of complex BL RAS paeerns in the virologic failures • Several breakthroughs (unusual) • Just coincidence??? • Might you prefer GLE/PIB/SOF+RBV with complex RAS paeerns?
Retreatment of GT1b DAA Failures With GLE/PIB 12 Weeks: RASs Don’t Marer…
Un)l You Look Hard Enough
P32 is a highly resistant variant Kurosaki M et al, EASL 2019
POLARIS-‐1: SOF/VEL/VOX 12 weeks in NS5A Inhibitor-‐Experienced GT1–6 Pa)ents
Placebo
SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC
0 4 8 12
1:1
Time (weeks)
SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC G2–6 (n=152) NS5A inhibitor-‐experienced
G1 (n=262) NS5A inhibitor-‐experienced
96
0
20
40
60
80
100
SVR1
2, %
253/263
6 relapses 1 on-‐tx failure
2 withdrew consent 1 LTFU
99 93
0
20
40
60
80
100
No Cirrhosis Cirrhosis
SVR1
2, %
140/142 113/121
1 withdrew consent 1 LTFU
6 relapses 1 on-‐tx failure
1 withdrew consent
Bourlière M, et al. N Engl J Med 2017
46% cirrhosis
Bourlière M, et al. N Engl J Med 2017;376:2134-‐46
POLARIS-‐1: No Impact of Baseline RASs
Resistance Analysis From POLARIS-‐1
Sarrazin C, et al. J Hepatology 2018;69:1221-‐1230
• All VF’s had cirrhosis • 27/29 GT3 w/Y93 had SVR
• 20/22 (91%) w/cirrhosis
SOF/VEL/VOX in 573 Veterans A;er DAA Failure
Belperio P et al, AASLD 2018, abstract 227; *From J Feld, AASLD 2018 Hepa((s Debrief
*
Baseline RASs in GT1 and GT3 Pa)ents Who Later Failed SOF/VEL/VOX
Dietz J et al, EASL 2019, THU-‐134
GT1 GT3
Retreatment of DAA failures: EASL Guidelines
*Daily weight-‐based RBV (1,000 mg or 1,200 mg in pa(ents <75 kg or ≥75 kg, respec(vely); start RBV at a dose of 600 mg daily and adjust dose depending on tolerance; †Pa(ents with NS5A RASs who failed twice to achieve SVR a�er a combina(on regimen including a PI and/or an NS5A inhibitor EASL CPG HCV. J Hepatol 2018;69:461–511.
Recommenda)ons
A�er failure of PEG-‐IFNα + RBV, SOF + PEG-‐IFNα/RBV or SOF + RBV • Retreat according to recommenda(ons for TE pa(ents, by HCV genotype A 1
HCV resistance tes(ng a�er failure of any DAA-‐based regimen (excluding regimens with SOF as the only DAA) is a useful guide to retreatment B 2
A�er failure of DAA (PI and/or NS5A inhibitor)-‐containing regimen • First-‐line retreatment
– SOF/VEL/VOX for 12 weeks (without cirrhosis/with compensated cirrhosis) – SOF/VEL + RBV* for 24 weeks (decompensated cirrhosis)
• Pa(ents with predictors of poor response, SOF + GLE/PIB for 12 weeks: – Advanced liver disease – Mul(ple courses of DAA-‐based treatment – Complex NS5A RAS profile
• Very difficult-‐to-‐cure pa(ents:† SOF/VEL/VOX + RBV or SOF + GLE/PIB + RBV for 12 weeks or for 16 or 24 weeks
A B B C
1 2 2 2
Grade of evidence Grade of recommenda)on
I agree! ☺
In the Fight Against Refractory HCV…
Don’t bury your head in the sand… Op(mize the chance of success for every pa(ent…Test for RASs