easl panel debate april 13 2019 final · greece y y hong!kong! y y hungary! y y iceland! y y...

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



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

*

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.

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

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


LDV/SOF 580 Breakthrough None R155W+A156G Q30H+L31M+Y93H Q30H+L31M+Y93H


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

easl panel debate april 13 2019 final · greece y y hong!kong! y y hungary! y y iceland! y y...

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