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Service de Gastroentérologie et d'Hépatologie et Service d'Immunologie et Allergie

CHUV - Université de Lausanne

Séminaire de formation continue CHUV, Lausanne, 29 novembre 2012

Darius Moradpour et Cyril André

Darius.Moradpour@chuv.ch Cyril.Andre@chuv.ch

  180-200 million chronically infected individuals worldwide

  1% of the population in Switzerland   > 50% are unaware of their infection   Most common cause of chronic hepatitis,

liver cirrhosis and HCC in the West   Most common indication to liver

transplantation   Peak of disease burden expected ~2020

Significance of Hepatitis C

Gravitz L. Nature 2011;474:S2-S4. Edlin BR. Nature 2011;474:S18-S19.

www.nature.com/nature/outlook/hepatitis-c

US response to HIV and viral hepatitis epidemics The coming problem

Smith BD et al. MMWR Recomm Rep 2012;61(RR-4):1-32.

  Persons born between 1945 and 1965 account for ¾ of all HCV infections in the US

  Additional target population for HCV screening

  Grading

  Staging

  Recognition of cofactors

  Prediction of treatment outcome

Chronic Hepatitis C Role of Liver Biopsy

treatment indication

2

Definition of Virological Response Patterns

SVR

Relapse

PR

2 log drop

NR

"Nonresponse"

Swiss Association for the Study of the Liver. SMW 2012;142:w13516. Schaefer M et al. Ann Intern Med 2012;157:94-103.

n = 181

Nonstructural Protein 3-4A

Brass V et al. PNAS 2008;105:14545-14550.

  Multiple functions in the viral life cycle (polyprotein processing, replication, assembly)

  Dynamic structural organization

  Role in the pathogenesis of hepatitis C

The Swiss Army Knife of Hepatitis C Virus

Morikawa K et al. J Viral Hepat 2011;18:305-315.

Reesink HW et al. Gastroenterology 2006;131:997-1002.

7

6

5

4

3

2

1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Study time (in days)

Med

ian

HC

V R

NA

(L

og10

IU/m

L)

Placebo VX-950 450 mg q8h VX-950 750 mg q8h VX-950 1250 mg q12h

•  Mean 4.4 log decline •  4/8 HCV RNA <30 IU/ml

HCV NS3-4A Protease Inhibitors

McHutchison JG et al. N Engl J Med 2009;360:1827-1838. Hézode C et al. N Engl J Med 2009;360:1839-1850.

Kwo PY et al. Lancet 2010;376:705-716.

3

ADVANCE

Jacobson IM et al. N Engl J Med 2011;364:2405-2416.

0

20

40

60

80

100

SVR eRVR RVR

68% 66%

9% 8%

58%

69%

44%

75%

T12PR T8PR PR48 (control)

Telaprevir-based triple therapy (n = 1088 tx-naïve, 21% F3/F4)

Viro

logi

cal r

espo

nse

(%)

57%

SPRINT-2

Poordad F et al. N Engl J Med 2011;364:1195-1206.

0

20

40

60

80

100

68% 67%

40%

23%

53%

SV

R (%

)

42%

Boceprevir-based triple therapy (n = 938 + 159 tx-naïve, 9% F3/F4)

PR+BPR44 PR+BPR24(+PR20) PR48 (control)

Cohort 1 (non-black)

Cohort 2 (black)

REALIZE

Zeuzem S et al. N Engl J Med 2011;364:2417-2428.

0

20

40

60

80

100

Prior null-response

Prior partial response

Prior relapse

83% 88%

24%

54%

15%

59%

33%

5%

29%

T12PR48 PR4 + T12PR44 PR48 (control)

SV

R (%

)

Telaprevir-based triple therapy (n = 622 tx-experienced)

Foster GR et al. J Hepatol 2011;54 Suppl 1:S3.

0

20

40

60

80

100

Prior null-response

33%

5%

29%

SV

R (%

)

< 1

15%

54%

≥ 1 Log decrease

at wk 4 (LI)

F0-2

39%

14%

41%

F3 F4 Fibrosis stage

Zeuzem S et al. N Engl J Med 2011;364:2417-2428.

SVR in prior null-responders by HCV RNA reduction after 4-wk

PR lead-in and fibrosis stage

REALIZE

RESPOND-2

0

20

40

60

80

100

75%

Prior null-response

Prior partial response

Prior relapse

69%

29%

40%

7%

52%

PR4 + BPR44 PR4+BPR32±PR12 PR48 (control)

Bacon BR et al. N Engl J Med 2011;364:1207-1217.

SV

R (%

)

Boceprevir-based triple therapy (n = 403 tx-experienced)

Cacoub P et al. J Hepatol 2012;56:455-463.

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Who Should be Treated with Triple Therapy?   Treatment-naïve patients with CHC genotype 1

triple therapy new standard for most pts consider P + R lead-in in pts with favorable

baseline predictors or doubt re adherence   Previous relapsers or PR with CHC genotype 1

triple therapy new standard   Previous NR with CHC genotype 1

carefully consider retreatment with triple therapy vs. await quad or IFN-free regimens

consider P + R lead-in   Patients with genotypes other than 1

PEG-IFN-α + ribavirin Swiss Association for the Study of the Liver. SMW 2012;142:w13516.

  Telaprevir (TPV) Incivo®, 375-mg tablets 750 mg q8h, with a meal or a snack (20 g fat) AE: anemia, skin rashes, pruritus, GI, fatigue

Practical Use of TPV and BOC

  Boceprevir (BOC) Victrelis®, 200-mg capsules 800 mg q8h, with a meal or a snack AE: anemia, dysgeusia, fatigue

  Strong potential for drug-drug interactions! Cytochrome P450 3A4 (cf. package labels, www.hep-druginteractions.org, EpocratesTM, Leise MD et al. Hepatology 2011;54:1463-1469)

Practical Use of Telaprevir

Swiss Association for the Study of the Liver. SMW 2012;142:w13516.

Practical Use of Boceprevir

Swiss Association for the Study of the Liver. SMW 2012;142:w13516.

Setting New Goals in CHC Therapy   Interferon-free combinations

  High barrier to antiviral resistance

  Once daily oral therapy

  Pan-genotypic antiviral activity

  Reasonable safety and minimal drug-drug interactions

  Short duration (12 weeks?)

  SVR rates > 90%

Hepatitis C Virus Life Cycle

Moradpour D, Penin F and Rice CM. Nat Rev Microbiol 2007;5:453-463.

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Novel Antiviral Strategies

Entry inhibitors

RNA interference Antisense strategies

Antagomirs

IRES inhibitors

Protease inhibitors

Helicase inhibitors NS4B and NS5A inhib.

RdRp inhibitors

Host factors Assembly inhibitors

Immunotherapy Antifibrotic therapy

Vaccines

Preclinical

Phase I

Phase II

Phase III

Filed

Telaprevir

Boceprevir Alisporivir

SCY635

IDN6556

Vaniprevir

Danoprevir

Simeprevir

Faldaprevir

Asunaprevir (ASV)

VX985

MK5172

IDX320

GSK2336805

Daclatasvir (DCV)

BMS824393

AZD7259 Mericitabine (MCB)

Sofosbuvir (SOF)

Filibuvir TGV

BI207127

Faldaprevir BI207127

MCB DNV

ASV

The Hurricane of HCV Drug Development

GSK2336805

GS9620

ACH1625

GS9256

ABT450

ABT267

PPI461

IDX184

GS9669

PSI938 ABT333

Setrobuvir

GSK2485852

PEG-IFN-λ

NIM811

ITX5061

Clemizole

Narlaprevir

GS9451

ABT450r ABT333

VX222

GS5885

TGV

GS9451

Status 11/2012 (selection)

BMS986094

Erlotinib Mira- versen

Many others

DCV

Telaprevir

VX222

GS5885

IDX719

ABT267

DCV SOF

BMS791325

ASV DCV BMS791325

Daclatasvir + Asunaprevir

Log 1

0 HC

V R

NA

7

6

5

4

3

2

1

Week 0 1 2 3 4 6 8 10 12

* LOD

LOQ

LOD

LOQ

Log 1

0 HC

V R

NA

7

6

5

4

3

2

1

Week 0 1 2 3 4 6 8 10 12

Daclatasvir + Asunaprevir + P + R

Lok AS et al. N Engl J Med 2012;366:216-224. See also Chayama K et al. Hepatology 2012;55:742-748.

4/11 SVR (6 BT = gt 1a) 10/10 SVR

Aronsohn A and Jensen D. Hepatology 2012;56:1591-1592.

  Screen persons at risk (anti-HCV)   Liaise with expert center   Deliberate treatment indication crucial

(Treat the disease, not the infection!)   Triple therapy comprising TPV or

BOC increases SVR rates to ~70%, with shortened treatment duration in ~½

  Advances come at the expense of new adverse effects and increased cost

Key Points

Moradpour D and Hadengue A. RMS 2011;7:1667-1668. Swiss Association for the Study of the Liver. SMW 2012;142:w13516.

  Therapy has become (temporarily?) much more complex (patient education, adherence, treatment milestones, adverse effect management, DDIs, laboratory turnaround time, resistance)

  Emerging data in patients with high unmet need (HIV coinfection, LT recipients)

  Available resources are being stretched   The future looks bright!

Key Points

Moradpour D and Hadengue A. RMS 2011;7:1667-1668. Swiss Association for the Study of the Liver. SMW 2012;142:w13516.