Hepatitis C virus G Dusheiko Royal Free Hospital London London 11 - - PowerPoint PPT Presentation

Hepatitis C virus

G 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

5 10 15 20 25 30 35

F2 F3 F4

% of patients with

• utcome

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 Persons without cirrhosis, % 100 80 90 70 60 50 6 8 2 4 10 HCV +ve HCV -ve 2.5 2.0 1.5 1.0 Mean FIB-4 score Time to progression of liver fibrosis 0.5 1 2 3 4 5 6 7 8 9 10 11 Year

HCV -

HCV +ve HCV -ve

MM07

10 20 30 40 50 60 70 80 90 100 GT-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 associated with steatosis than other genotypes1

Prevalence of steatosis (%)

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. Hourigan 19992 Rubbia-Brandt 20003 Adinolfi 20014 Westin 20025 Poynard 20036 Castera 20037 Asselah 20038 Rubbia-Brandt 20049

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

Hazard ratio

0,5 1 1,5 2 HCC Liver-related hospitalisation Decompensated cirrhosis 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 60 55

Age (years)

6 8 10 12 14

Predicted fibrosis score (KPa)

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),

• r 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 % response 100

1998 IFN 48 weeks 1998 IFN 24 weeks 1998 IFN + RBV 48 weeks 2001–2004 PegIFN + RBV 2011 PegIFN + RBV+ DAA

1957: Discovery

• f IFN

1989: Discovery

• f 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 NS3/4 protease 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 polymerase inhibitors Nucleos(t)ide Non-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

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 treatment Third DAA, pan genotypic Earlier treatment sofosbuvir ledipasvir

• mbitavir, 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–Jun Jul–Dec Jan–Jun Jul–Dec

Telaprevir¥ Boceprevir¥

Sofosbuvir#

Sofosbuvir#

Daclatasvir* (GT 4)

2011 2012 2013 2014 2015

IFN-free With IFN and RBV 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 20 18 16 14 12 10 8 6 4 2 2 4 6 8 10 12 14 16 18 20 2 4 6 8 10 12 14 16 18 20

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

Cumulative mortality (%) Cumulative mortality (%)

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 RAVs

RAV status in pts with BL sequence % (n/m) SVR12 All pts % (n/N) SVR12 NS3 RAVs ≤5-fold potency loss SVR12 NS3 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 RAVs

RAV status in pts with BL sequence % (n/N) SVR12 All pts % (n/N) SVR12 NS5A RAVs ≤5-fold potency loss SVR12 NS5A 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.

2,3 4,7 32,6 46,5 7 20 40 60 80 100

1 43 14 43 9 11 20 43 n N 2 43 3 43 3 targets NS3 + NS5A NS5A + NS5B NS5A NS5B

GT1a-infected patients with TEVs, %

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

68 80 100 74 46 60 20 40 60 80 100 Cirrhosis Prior treatment duration Baseline NS5A RAVs SVR12 (%) No Yes No Yes 8-wk 12-wk 15/ 22 14/ 19 24/ 30 5/ 11 11/ 11 18/ 30 100 80 33 20 40 60 80 100 Q30R or M28T L31M Y93H/N 100 69 50 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 d double or triple r 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

a b MK-8408 GS-5816 MK-8742 Ledipasvir Daclatasvir 100 200 300 400 500 1a_H77 M28T Q30E Q30K Q30H Q30R L31V L31M Y93C Y93H Y93N

Fold Shift (vs. WT) NS5A Signature RAVs

MK-8408 GS-5816 MK-8742 Ledipasvir Daclatasvir c

Treatment choices in f future: will w we h have to stratify fy 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