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What’s new in HCV and HBV 2019 (and beyond)

St Gallen 5/12/2019

Thanks to Jane Collier and Ellie Barnes

NIHR Biomedical Research Centre, Oxford MRC STOP-HCV programme

Wellcome Trust ….and all the patients

Shared issues in viral hepatitis

Virus persistence mechanisms Host immune mechanisms

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HCV is not going away Messina et al Hepatology 2015 Data from 1200 papers since hep C was discovered.

• WHO data 2017: HCV Prevalence -approximately 75 million RNA +

• New infections fuel the global epidemic 1.7 million new infections in 2015

Changes in HCV prevalence 2016-17

Personal communication: data 2017-2018 also dismal

Hill AM J Virus Erad. 2017 Jul 1;3(3):117-123

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Genotypes and sub-genotypes

• HCV has an error-prone RNA-dependent RNA polymerase.

• The mutation rate is very high: 2.5 mutations per genome replication1.

• There are 7 genotypes, G1 to G7, which differ by 30-35%2.

• Within these genotypes, there are 67+ subtypes that differ by up to 20%2.

1 Ribeiro et al, (2012). Quantifying the diversification of Hepatitis C Virus (HCV) during primary infection: estimates of the in vivo mutation rate. PLoS Pathogens doi: 10.1371/journal.ppat.1002881 2 Smith, Bukh, Kuiken, Muerhoff, Rice, Stapleton and Simmonds (2014). Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment Web resource. Hepatology 59:318-327

G4

G3

G1

G6

G2 G7

G5

SNPs in the Interferon lambda 3 locus uncover a new cytokine - Interferon lambda 4

Laidlaw and Dustin, 2014

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GWAS results: HLA and IFNL4 regions impact on the evolution of HCV

virus proteins

human chromosomes

IFNL3/4 MHC

Ansari et al Nat Genetics 2017

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Acute disease

Usually

asymptomatic

Persistent

infection

>80%

Progressive

disease

mild disease

Resolved

infection

<20%

E. coli expression of influenza hemagglutinin DR1 tetramer HCV Clinical Course

T Cell Immunity vs HCV - the evidence

• HLA association studies and GWAS (Class I and Class II HLA

with clearance) (Neumann C, et al. Hepatology 2006;Duggal et al, Ann Int

Med 2013 )

• Chimpanzee CD4+ and CD8+ T cell depletion experiments (Shoukry N J Ex Med 2003)

• Association of breadth and magnitude of T cell response with

viral clearance (Lauer et al Gastro 2004)

• IFN- HCV specific CD8+ T cell responses are temporally

correlated with reduced viremia after infection (Lechner F J Exp Med

2000; Thimme et al J Exp Med 2001)

• Prophylactic vaccine data (Adeno/DNA) in a chimp challenge

model. (Folgori et al Nat med 2008)

• BUT…NO ONE CORRELATE OF PROTECTION

(BIG,BROAD,SUSTAINED, FUNCTIONAL etc)

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Development of T cell vaccine for HCV

Barnes et al Science Tr Med 2012; Swadling et al Science Tr Med 2014

Generation of HCV-specific T cell responses

Same vector as used for Ebola vaccine

Measure IFN gamma

Secreting T cells (like T-spot TB)

Development of T cell vaccine for HCV

Barnes et al Science Tr Med 2012; Swadling et al Science Tr Med 2014

Generation of HCV-specific T cell responses

Same vector as used for Ebola vaccine

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No overall benefit seen from this vaccine…..

No overall benefit seen from this vaccine…..

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Vaccine induces strong T cell help (like spontaneous clearance) but DAA therapy does not restore immunity

Hartnell et al in review 2019

Hepatitis C therapy pipeline 2013/14

Phase I

Phase II

Phase III

Phase IV

NS5A inhibitors

Protease inhibitors

ABT072

(Abbott)

ABT333

(Abbott)

MK3291

(Merck)

ACH-2684

(Achillon)

ACH-2928

(Achillon)

ACH-3102

(Achillon)

AZD-7295

(AstraZeneca)

IDX719

(Idenix) PPI-461

(Presidio) PPI-688

(Presidio)

ITX-5061

Entry Inhibitor

(iTherX) Telaprevir/VX-222

(Vertex)

ABT-450

(Abbott/Enanta)

ACH-1625

(Achillion) ALS-2200

(Alios/Vertex)

ANA598

(Anadys/Genentech)

BI 207127

(Boehringer)

BIT225

(Biotron)

BMS-650032

(BMS)

BMS-791325

(BMS)

Filibuvir

(Pfizer)

GS 9190

(Gilead)

GS-9256

(Gilead)

IDX184

(Idenix)

MK-5172

(Merck)

GS-938

(Gilead)

RG7128

(Gilead/Genentech) RG7227

(InterMune/Genentech)

Vaniprevir

(Merck)

VX-222

(Vertex)

VX-759

(Vertex)

Faldaprevir

(Boehringer)

asuneprevir

(BMS)

Sofosbuvir

(Gilead)

Simeprevir

(Medivir/Tibotec)

Boceprevir

(Merck) Telaprevir

(Vertex)

RG7128/RG7227

(Genentech)

GS-7977/TMC435

(Gilead/Tibotec)

GS-9256/GS-9190

(Gilead)

Boceprevir/Mericitabine

(Merck/Genentech)

BMS-790052/TMC435

(BMS/Tibotec)

BMS-790052/GS-7977

(BMS/Gilead)

BI 201335/BI 207127

(Boehringer)

ABT-450/ABT-333

(Abbot/Enanta)

ABT-450/ABT-267

(Abbot/Enanta)

ABT-450/ABT-072

(Abbot/Enanta)

ABT-450/ABT-267 and/or ABT-333

(Abbot/Enanta)

BMS-790052/BMS-650032

(BMS)

TMC435/TMC647055

(Medivir/Tibotec)

DAA combinations

Polymerase inhibitors

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NS5A inhibitors Protease inhibitors Polymerase

inhibitors

Sofosbuvir

Ledipasvir

(Gilead)

GT1, 4, 5, 6

Sofosbuvir

Velpatisvir

(Gilead)

GT3

Granzoprevir/

Elbasvir/ (Merck)

GT1,4

Daclatasvir

Sofosbuvir

(BMS &Gilead)

GT1,3

Approved

Phase II

Phase III

The pipe line is “resolved”

Glecapravir

Pibrentasavir

(AbbVie)

Pan-GT

Sofosbuvir

Velpatisvir

Voxilaprevir

(Gilead)

Pan-GT

Pan-GT

SVR rates now 95%

Role of resistance testing • Role of resistance reported partially in phase-3 studies

• Patients with base line resistance usually still respond to therapy

– Q80T mutation in gt 1a infection linked to resistance to Simeprevir

• Resistance testing will be required in treatment failures

– whilst PI RAV revert to wild type, NS5A RAV persist for years….implications for retreatment strategies.

• So far little resistance reported in treatment failures in phase-III studies

– but in the real world difficult to treat, adherence and prescription mistakes, means potentially more likely…

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HCV Genotype

3a

3b

3g

3i

Presence ofRAS

Non−RAS

RAS

A30

K

L31M

Y93

H

Daclatasvir Velpatasvir Elbasvir Pibrentasvir

A30

K +

L31

M

A30

K +

Y93

H

A30

K +

L31

M +

Y93

H

A30

K +

L31

M

A30

K +

Y93

H

A30

K +

L31

M +

Y93

H

A30

K +

L31

M

A30

K +

Y93

H

A30

K +

L31

M +

Y93

H

A30

K +

L31

M

A30

K +

Y93

H

A30

K +

L31

M +

Y93

H

100

102

104

106

108

1010

1012

Substitutions

Me

an

EC

50 F

old−

Ch

an

ge

(L

og

Sca

le)

Identified “rare subtypes” ? Resistant to new DAAs

Resistance analysis of genotype 3 hepatitis C virus

indicates subtypes inherently resistant to

nonstructural protein 5A inhibitors

Hepatology, Volume: 69, Issue: 5, Pages: 1861-1872,

First published: 09 February 2018, DOI: (10.1002/hep.29837)

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Wei, L. et al. Sofosbuvir–velpatasvir for treatment of chronic hepatitis C virus infection in Asia: a single-arm, open-label, phase 3 trial. Lancet Gastroenterol. Hepatol. (2019)

Slides from AASLD 2018 : Safety and Efficacy of Sofosbuvir/Velpatasvir in Genotype 1-6 HCV-Infected Patients in China: Results From a Phase 3 Clinical Trial

Rare subtypes show drug resistance in real life

Retreatment options…if the drugs don’t work

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Case 60yr old man – cirrhotic and complications

• 2009 – Hepatitis C antibody positive; HCV RNA negative

• 2012 – Hepatitis C RNA positive; genotype 3 – Still intermittent IVDU

• 2013 – Seen liver clinic – Panic attacks, anxiety, methadone 20mls, mirtazapine 30mg – Clinically cirrhotic (large spleen on ultrasound and low platelets) – Felt not tolerate interferon therapy

• 2015 – Seen in Drug and Alcohol Service by Community Hepatitis Nurse – Last injected heroin 6 weeks ago, anxiety. Hearing voices when used crack

cocaine, occ cannabis – No alcohol 6 months; previous 4-6 cans strong lager/day – Olanzapine. Methadone 30mg, mirtazapine – Clinically cirrhotic

• 2016

– Community Clinical Nurse specialist managed to get to secondary care for treatment

– Hepatitis C RNA 326255 IU/ml

– August- started Sofosbuvir + Ribavirin orally + Pegylated interferon (Dosette box)

– October – HCV RNA undetected

– November - week 10 low mood but tolerating

– End of treatment ( week 12) –undetectable hepatitis C

– Ultrasound- 4cm hepatocellular carcinoma

• 2017

– January – Hepatocellular carcinoma resected

– March - 3 months post HCV RNA positive (relapse)

– September – 16 weeks of glecaprevir/pibrentasvir (3 tablets /day)

– Methadone 25mg/mirtazapine/Olanazipne

– Week 4 viral load dropped from 3,701,609 to 68

• 2018

– January completed 4 month DAA therapy and HCV RNA negative

– CT no recurrent Hepatocellular carcinoma

– Bilirubin 5; Albumin 35; INR 1.1 ; Platelets123

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• 2016

– Community Clinical Nurse specialist managed to get to secondary care for treatment

– Hepatitis C RNA 326255 IU/ml

– August- started Sofosbuvir + Ribavirin orally + Pegylated interferon (Dosette box)

– October – HCV RNA undetected

– November - week 10 low mood but tolerating

– End of treatment ( week 12) –undetectable hepatitis C

– Ultrasound- 4cm hepatocellular carcinoma

• 2017

– January – Hepatocellular carcinoma resected

– March - 3 months post HCV RNA positive (relapse)

– September – 16 weeks of glecaprevir/pibrentasvir (3 tablets /day)

– Methadone 25mg/mirtazapine/Olanazipne

– Week 4 viral load dropped from 3,701,609 to 68

• 2018

– January completed 4 month DAA therapy and HCV RNA negative

– CT no recurrent Hepatocellular carcinoma

– Bilirubin 5; Albumin 35; INR 1.1 ; Platelets123

Conclusions

Rapid emergence of highly effective IFN-free therapies

Sickest patients

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Conclusions

Rapid emergence of highly effective IFN-free therapies

Sickest patients

Patients with less advanced fibrosis

General availability

Conclusions

Rapid emergence of highly effective IFN-free therapies

Sickest patients

Patients with less advanced fibrosis

Emerging availability

Undiagnosed Awaiting ascertainment

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• 257 million people have chronic HBV infection (WHO report, April 2017) • In 2015, 887 000 deaths – mostly from complications (liver cirrhosis and HCC) • Endemic in Sub-Sharan Africa and East Asia

Chronic HBV

Chronic HBV infection – cccDNA (Persistently infected Hepatocytes)

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Chronic HBV – Exhaustion of HBV specific T-cell

Reference: T cell exhaustion. E John Wherry. Nature Immunology 12, 492–499 (2011) doi:10.1038/ni.2035

Nucleoside/nucleotide analogues in the treatment of chronic hepatitis B

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Strategies to overcome chronic HBV infection

• Direct Chronic HBV infection

1. Entry inhibitors

2. cccDNA

3. siRNA – targetting viral transcripts

4. Capsid assembly modulators

5. Inhibitors of HBs release

• Restoration of Immune response

Restore Innate immunity

1. TLR agonists

2. Specific antiviral cytokine delivery

Restore Adaptive immunity

1. Therapeutic vaccines

2. Inhibitors of negative checkpoint modulators

3. Autologous transfer of engineered HBV-specific T cells

1

2

3 4

5

Aims of Immunotherapy

Vaccines (multiple antigens)

Immuno-modulators

Immunotherapy

Reference: PD-1/PD-L1 pathway and T-cell exhaustion in chronic hepatitis virus infection. Journal of Viral Hepatitis, 2010, 17, 453–458. T. Watanabe, A. Bertoletti & T. A. Tanoto.

Overcome the inhibitory mechanisms impairing the T cell function

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Awaiting progress…

Shared issues in viral hepatitis

Virus persistence mechanisms Host immune mechanisms

Antivirals

C

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Shared issues in viral hepatitis

Virus persistence mechanisms Host immune mechanisms

Antivirals

B

RT Other targets