Hepatitis C virusG Dusheiko

Royal Free Hospital London

London 11 June 2015

Disclosures

• Grants

– AbbVie, Bristol-Myers Squibb, Gilead Sciences,

GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Vertex

• Advisory Boards or Safety Monitoring Boards

– AbbVie, Bristol-Myers Squibb, Gilead Sciences,

GlaxoSmithKline, Janssen, Merck Sharp & Dohme,

Zymogenetics, Novira

• Speaker

– Abbott, AbbVie, Boehringer Ingelheim, Bristol-Myers

Squibb, Gilead Sciences, GlaxoSmithKline, Janssen,

Merck Sharp & Dohme

Isolation of a cDNA clone derived from a blood-borne

non-A, non-B viral hepatitis

Choo QL et al. Science 1989;244:359–62

The HCV discovery team

In 2000, Alter and Houghton were honoured with

the Lasker Award for Clinical Medical Research

The immediate fruits of discovery

• Blood tests to protect the blood supply

• Reduced transmission of hepatitis C

• Established that HCV was a major cause of hepatocellular carcinoma

• More sensitive diagnostics for HCV antibodies and RNA were

developed

• Means of monitoring response to treatment (HCV RNA)

• Discerned highly conserved sequence motifs

• HCV encoded its own unique protease, replicase, helicase and polymerase

enzymes (38)

• Identification of several potential drug targets: active drug target drug

discovery programmes

Colombo M. Lancet 1989;2:1006–8. Choo QL. Proc Natl Acad Sci USA 1991;88:2451–5. Dodd RY. Int J Hematol 2004;80:301–5

Global HCV viraemic infections:

prevalence and total infected

• Around 9 million people in Europe are chronically

infected with HCV (>185 million people worldwide)

Gower E, et al. J Hepatol 2014;61:S45–S57;

Messina J, et al. Hepatology 2015:61;77–87

Total Infected

(Viraemic)

200K-650K

650K-1.9M

0-200K

1.9M-3.5M

3.5M-9.2M

Prevalence

(Viraemic)

0.0%-0.6%

0.6%-0.8%

0.8%-1.3%

1.3%-2.9%

2.9%-7.8%

Global HCV genotype prevalence and

distribution

Gower E, et al. J Hepatol 2014;61:S45–S57;

Messina J, et al. Hepatology 2015:61;77–87 GBD: global burden of disease; GT: genotype

GT 1(46%)

GT 2(13%)

GT 3(22%)

GT 4(13%)

GT 5(1%)

GT 6(5%)

• GT 4: 13% (~15 million) of global HCV infected population

Risk of disease progression is linked to

fibrosis stage

• Cirrhotic patients who achieve SVR have a significant reduction in likelihood to develop HCC, but are still at higher risk than F2–3 patients– Achieving SVR doesn’t prevent HCC in patients who are already cirrhotic

Moorman AC, et al. AASLD 2014; Oral #174 DAA: direct-acting antiviral agent; LTx: liver transplant

1,1 1,7

5,2

1

4,6

11,3

6

10,8

23,1

3,8

11,9

28,6

0

5

10

15

20

25

30

35

F2 F3 F4

% o

f p

atie

nts

with

o

utc

om

e

LTx

HCC

Death

Decompensation

n=810 n=461 n=364

P<0.0001

P<0.0001

P<0.0001

74.6% 55.4% 47.2%Achieved SVR

CHeCS: Chronic Hepatitis Cohort Study –

clinical outcomes after baseline biopsy (prior to the availability of new DAAs)

MM08

Fibrosis progression occurs early

after infection

• FIB-4 scores doubled in the first 4 years after infection and more than 18% developed cirrhosis within 10 years after infection – need to treat early

Butt AA, et al. JAMA Intern Med 2015;175:178–85

ERCHIVES: Electronically Retrieved Cohort of HCV Infected

Veterans; FIB-4: fibrosis-4

Analysis of 610,514 people (half were HCV positive) in the ERCHIVES database 2002–2012

Time to development of cirrhosis

Pers

on

s w

ith

ou

t cir

rhosis

, % 100

80

90

70

60

50

6 80 2 4 10

HCV +ve

HCV -ve

2.5

2.0

1.5

1.0

Mea

n F

IB-4

score

Time to progression of liver fibrosis

0.5

0

1 2 3 4 5 6 7 8 9 10 11

Year

HCV -

HCV +ve

HCV -ve

MM07

0

10

20

30

40

50

60

70

80

90

100GT-3 Other

• Steatosis may be responsible for accelerated fibrosis progression and lower SVR1

• An analysis of 14 studies from 1997 to 2004, steatosis was reported in 73% (501/685) of patients with GT-3 HCV and in 50% (1468/2932) of patients with non-GT-3 HCV infection1

HCV GT-3 is more commonly associatedwith steatosis than other genotypes1

Pre

vale

nce

of

ste

ato

sis

(%)

Figure adapted from 1. Asselah T, et al. Gut 2006;55:123. 2. Hourigan LF, et al. Hepatology 1999;29:1215–9. 3. Rubbia-Brandt L, et al. J Hepatol 2000;33:106–15. 4. Adinolfi LE, et al. Hepatology 2001;33:1358–64. 5. Westin J, et al. J Hepatol 2002;37:837–42. 6. Poynard T, et al. Hepatology

2003;38:75–85. 7. Castéra L, et al. Gut 2003;52:288–92. 8. Asselah T, et al. Gut 2003;52:1638–43. 9. Rubbia-Brandt L, et al. Gut 2004;53:406–12.

Hourigan19992

Rubbia-Brandt20003

Adinolfi20014

Westin20025

Poynard20036

Castera20037

Asselah20038

Rubbia-Brandt20049

HCV GT-3 patients are at a higher risk for late-stage liver disease events and death

Hazard ratio

0 0,5 1 1,5 2

HCC

Liver-relatedhospitalisation

Decompensatedcirrhosis

Cirrhosis GT-1

GT-2

GT-3

Other

Observational cohort study of 28,769 patients with HCV from the VA CCR, which compiled electronic medical records data from 1999 to the present.CCR, HCV clinical registry; VA, Veterans Affairs.

Adapted from McCombs J, et al. JAMA Intern Med 2014;174:204–12.

B cell homeostasis in chronic hepatitis C virus–related mixed cryoglobulinemia is maintained through naïve B cell apoptosis

Holtz et al, Hepatology Volume 56 pages 1602-1610, 14 OCT 2012

B cell numbers paradoxically reduced in HCV-infected patients with MC HCV patients

Increased sensitivity of naıve B cells to apoptosis: reduction in size of naıve B cell

subset.

Faster progression with age even when

controlling for alcohol and other co-morbidities

Kirk D, et al. Ann Intern Med 2013;158:658–66

Liver fibrosis and age among HIV/HCV co-infected patients

and HCV mono-infected patients

30 35 40 50 6055

Age (years)

6

8

10

12

14

Pre

dic

ted f

ibro

sis

sco

re (

KP

a)

9.2 years

45

HIV/HCV

HCV

Splenorenal shunt Large varices

Hoofnagle et al. NEJM 1986; 315:1575–8

Pilot study of 10 patients receiving alpha-interferon for up to 12 months

Serial determinations of alanine aminotransferase (ALT) levels in two patients

(no. 3 and 4) with chronic non-A, non-B hepatitis who were treated for one year with

two courses of recombinant human alpha interferon

The doses of alpha interferon, 1 to 5 million units (MU) daily, every other day (qod),

or three times weekly (tiw), are indicated above the stippled areas

Treatment of NANBH with interferon alpha

1950 1960 1990 2000 2010 2020

10

20

30

40

70

80

50

60

90

% r

esp

onse

100

1998 IFN

48 weeks1998 IFN

24 weeks

1998

IFN + RBV

48 weeks

2001–2004

PegIFN + RBV

2011

PegIFN +

RBV+ DAA

1957:

Discovery

of IFN

1989:

Discovery

of HCV

1991: FDA

approves

injectable

IFN

2001:FDA

approves

PegIFN

2011:FDA

approves

First

DAA’s

2013:FDA

approves

SOF

2009

IL28

Hepatitis C: the evolution of the treatment landscape

Adapted from Cornberg M et al. In: Hepatology A Clinical Textbook; 2013. Flying Publisher

2013

SOF+ RBV

±PegIFN

Translation and polyprotein processing

NS3/4protease inhibitors

HCV Life Cycle and Targets for Direct-Acting Antivirals (DAAs)

Receptor binding and endocytosis Transport

and release

Virion assembly

RNA replication

Fusion and uncoating

(+) RNA

Membranous web

NS5B polymeraseinhibitors

Nucleos(t)ideNon-nucleoside

NS5A inhibitors

replication and assembly

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Treatment Options 2015

Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir (± RBV)

Sofosbuvir + Simeprevir (± RBV)

Sofosbuvir + Daclatasvir (± RBV)

Ombitasvir/Paritaprevir/Ritonavir (± RBV)

PegIFNa + RBV + sofosbuvir

PegIFNa + RBV + simeprevir

Sofosbuvir + RBV

Sofosbuvir/Ledipasvir (± RBV)

IFN-free regimens

IFN-containing regimens

GT

1

1, 4

All

4

1, 4

2, 3

1, 4, 5, 6

All

EASL HCV guidelines 2015

Effect of NS5a inhibitor on membranous web biogenesis

Wild type versus Y93H

Berger et al Gastroenterology epub 2014

Major categories of response rates with DAA therapy 2015

0

10

20

30

40

50

60

70

80

90

100

95-100% 90-95% 85-90% Less than 85%

sofosbuvir simeprevir daclatasvir

Non cirrhotic, 1b

Duration RBV

Cirrhosis CPA, 1a/b Cirrhosis CPB,C G3, TE, CP C

Duration RBV, NS5a?

Third DAA, pan

genotypic

RBV

Earlier treatmentThird DAA, pan

genotypic

Earlier treatment

sofosbuvir ledipasvirombitavir, paritaprevir/r dasabuvir

HCV treatment landscape – 2015

Webster D, Klenerman P Dusheiko G The Lancet online February 14 GT: genotype; IFN: interferon; RBV: ribavirin

Protease¥, NS5B# and NS5A* inhibitors

Ombitasvir *Paritaprevir¥

Ritonavir ¥

Dasabuvir#

± RBV

Asunaprevir¥

Daclatasvir*Beclabuvir#

± RBV

Sofosbuvir#

Ledipasvir*± RBV

Jul–Dec Jan–Jun Jan–Jun Jul–Dec Jan–JunJul–Dec Jan–Jun Jul–Dec

Telaprevir¥

Boceprevir¥

Triple therapy

Sofosbuvir#

Sofosbuvir#

Daclatasvir*(GT 4)

2011 2012 2013 2014 2015

IFN

-fre

eW

ith

IFN

an

d R

BV

Simeprevir¥

(GT 1, 4)

Sofosbuvir#

+ RBV

2016-2017

GS5816*

Elbasvir*+ MK3682 #

Sofosbuvir#

GS-5816*

Grazoprevir¥

Elbasvir*

Jul–Dec

Sofosbuvir# + Daclatasvir* Sofosbuvir# + Simeprevir¥Sofosbuvir# + Ledipasvir*

± RBV

HCV cure decreases mortality from both

hepatic and non-hepatic diseases

23,820 adults in Taiwan; 1095 anti-HCV positive,

69.4% with detectable HCV RNA

Lee MH, et al. J Infect Dis 2012;206:469–77

20

18

16

14

12

10

8

6

4

2

0

20

18

16

14

12

10

8

6

4

2

00 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20

Follow-up (years) Follow-up (years)

Cu

mu

lati

ve m

ort

ali

ty (

%)

Cu

mu

lati

ve m

ort

ali

ty (

%)

Hepatic diseases Extrahepatic diseases

HCV seropositive, HCV RNA detectable

HCV seropositive, HCV RNA undetectable

HCV seronegative

12.8%

1.6%0.7%

19.8%

12.2%

11.0%

p<0.001 for comparison among three groups

p<0.001 for HCV RNA detectable vs undetectable

p<0.001 for comparison among three groups

p=0.002 for HCV RNA detectable

vs undetectable

Drug resistance in hepatitis C is here to stay?

• Forestall resistance

• Treat with the optimal regimen

• Treat resistance with the right drugs• New second generation protease and NS5A inhibitors

• Need to survive to obtain these agents

C-EDGE treatment-naive study: 12-week regimen of GZR/EBR in G1/4/6 patients

Zeuzem S, et al. EASL 2015, Vienna. #G07

NS3 RAVsRAV status in pts with BL sequence % (n/m)

SVR12All pts

% (n/N)

SVR12 NS3 RAVs≤5-fold

potency loss

SVR12NS3 RAVs

>5-fold potency loss

G1a RAVs

BL NS3 RAVs 57 (86/151) 97 (83/86) 97 (83/86) 0 (0/0)

No BL NS3 RAVs 43 (65/151) 89 (58/65) — —

G1b RAVs

BL NS3 RAVs 19 (25/129) 96 (24/25) 96 (21/22) 100 (3/3)

No BL NS3 RAVs 81 (104/129) 100 (104/104) — —

NS5A RAVsRAV status in pts with BL sequence % (n/N)

SVR12All pts

% (n/N)

SVR12 NS5A RAVs

≤5-fold potency loss

SVR12NS5A RAVs

>5-fold potency loss

G1a RAVs

BL NS5A RAVs 12 (19/154) 58 (11/19) 90 (9/10) 22 (2/9)

No BL NS5A RAVs 88 (135/154) 99 (133/135) — —

G1b RAVs

BL NS5A RAVs 14 (18/130) 94 (17/18) 100 (1/1) 94 (16/17)

No BL NS5A RAVs 86 (112/130) 100 (112/112) — —

All pts with VF had BL HCV RNA of >800,000 IU/mL

Treatment emergent variants at post-treatment Week 48 in GT1a-infected patients

Krishnan P, et al EASL-ILC 2015; Oral presentation O057.

* 3D without RBV for GT1b noncirrhotic patients, 3D+ RBV for GT1a and all cirrhotic patients, 12 week treatment duration for all except GT1a cirrhotic patients who receive 24 weeks.TEV = treatment-emergent variant.

2,34,7

32,6

46,5

7

0

20

40

60

80

100

143

1443

911

2043

nN

243

343

3 targets NS3 + NS5A NS5A + NS5B NS5A NS5B

GT1

a-in

fect

ed

pat

ien

ts w

ith

TEV

s, %

Post-treatment Week 48

Retreatment of patients who failed 8 or 12 weeks of LDV/SOF-based regimens with LDV/SOF for 24 weeks

Lawitz E, et al. EASL 2015, Vienna. #O005

Shorter therapies produce less-frequent treatment-emergent RAVs

More complex RAV pattern = less likely to achieve response

Retreatment with longer duration more likely to be successful with fewer NS5A RAVs or RAVS with smaller shifts in EC50

6880

100

74

46 60

0

20

40

60

80

100

Cirrhosis Priortreatmentduration

BaselineNS5A RAVs

SVR

12

(%

)

No Yes No Yes8-wk 12-wk

15/22

14/19

24/30

5/11

11/11

18/30

100 80

33

0

20

40

60

80

100

Q30R orM28T

L31M Y93H/N

100

69

50

0

20

40

60

80

100

None 1 ≥2

Number of NS5A RAV(s)

11/11

11/16

7/14

Type of single NS5A RAV

5/5

4/5

2/6

Potential new double or triple regimens:

• Grazoprevir (MK5172) Elbasvir (MK 8742) or MK8408 MK3682 (IDX21437)*

• ABT-493 ABT-530

• GS 9451 Ledispasvir Sofosbuvir, GS 9669*

• +GS 9857 GS-5816 ++

• Simeprevir JNJ-56914845 (GSK2336805)

• Sovaprevir (ACH-1625) ACH-3102 ACH-3422~ , sofosbuvir^

• Simeprevir

• TD 6460@

Lazerwith SE J Med Chem 57 95) 1893 2014 Yan Antimicrob Agents Chemother. 2014;58(2):647-53. *Zeuzem EASL 2015 G7 Gane EASL 2015 LB poster ^ Gane LB poster ~ Gane LB poster Assalah Astral @ Lawitz Poster

Protease inhibitor NS5A inhibitors NS5B Polymerase

MK-8408 activity vs Clinically Relevant GT1a RAVs

aFridell et al. (2010) AAC 54: 3641 bWong et al. (2013) AAC 57:6333 cCheng et al. (2013) EASL

ab

MK-8408

GS-5816

MK-8742LedipasvirDaclatasvir

0

100

200

300

400

500

1a_H77 M28T Q30E Q30K Q30H Q30R L31VL31M

Y93C Y93H

Y93N

Fold

Sh

ift

(vs.

WT)

NS5A Signature RAVs

MK-8408 GS-5816 MK-8742 Ledipasvir Daclatasvir

c

Treatment choices in future: will we have to stratify and select patients based on cost?

Author opinion

Severe disease

Minimal disease

NHS expanded access

F0–F1 patients

F2 patients

F3 patients

F4

GD30

Treatment: prioritisation strategy

• Population impact on:• Incident cases of chronic infection• Severe liver disease and morbidity

• In next 20 years

• Prioritise treatment to either: • People who inject drugs with mild fibrosis?• Persons with moderate or advanced fibrosis?

• Watershed moment in the epidemic

• But which approach to follow?

Innes H, et al. Gut. 2014. doi: 10.1136/gutjnl-2014-308166.[Epub ahead of print]

GD31