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Hepatitis C‘ An Update’

Alnoor RamjiGastroenterology & HepatologyClinical Associate ProfessorDivision of GastroenterologyUniversity Of British ColumbiaSt. Paul’s Hospital Siteramji_a@hotmail.comFax: 604-689-2004

Company Name Relationship

Abbvie Investigator, consultant

BI Investigator, Consultant

BMS Investigator, Consultant,

Gilead Sci. Inc Investigator, Consultant, Speaker

Hoffman LaRoche Investigator, Consultant, SpeakerNursing Support

Janssen (J. & J.) Investigator, Consultant, Speaker

Novartis Investigator

Merck & Co. Investigator, Consultant, SpeakerNursing Support

Vertex Pharmaceuticals Investigator, Consultant, Speaker

Disclosures

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Disclosure of Commercial Support

• This program has NOT received financial support.• This program has NOT received in-kind support.

• Potential for conflict(s) of interest:– As prior slide, nil else.

Mitigating Potential Bias

• The presentation was reviewed by an external reviewer forany biases.

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Objectives

• Epidemiology and natural history

• Screening

• Treatment options

• Treatment outcomes

• Fibrosis evaluation

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Estimated 170 Million Persons WithHCV Infection Worldwide

• 3-4 million newly infected each yr worldwide

World Health Organization 2008. Available at: http://www.who.int/ith/es/index.html. Accessed October 28, 2009.

> 10%2.5%-10%

1%-2.50%Prevalence of infection

NA

1a, 1b2a, 2b,

3a

1a, 1b2a, 2b, 2c,

3a

4

5a

1b

1b,61b,

3a

1b,3a

3b

4

Fang et al. Clin Liver Dis. 1997.

HCV Infection:Worldwide Genotype Distribution

1a, 1b,2b, 3a

2a

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9

HCC: hepatocellular carcinoma.1. Remis RS. Final Report. Public Health Agency of Canada. 2007. Available from: http://www.phac-aspc.gc.ca/sti-its-surv-epi/model/pdf/model07-eng.pdf.

Canadian Burden of HCV

Modeled Non-exclusive Burden of HCV and Sequelae in Canada1

HCC: hepatocellular carcinoma.1. Remis RS. Final Report. Public Health Agency of Canada. 2007. Available from: http://www.phac-aspc.gc.ca/sti-its-surv-epi/model/pdf/model07-eng.pdf.

10HIV: human immunodeficiency virus1. Ly et al. Ann Intern Med. 2012;156:271-278

Importance of Screeningand Treating HCV

HCV-related mortality exceeds mortality from HCV1

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111. Seeff LB. Hepatology 2002;36(Suppl 1):S35-46; 2. Sherman et al. Curr Oncol. 2011;18:228-40; 3. Consensus recommendations of the Steering Committee.

Natural History of HCVHCV exposureHCV exposure

Chronic infectionChronic infection

Cirrhosis20-30 yrs following infection

Cirrhosis20-30 yrs following infection

Liver failure or decompensationLiver failure or decompensation Hepatocellular carcinoma3Hepatocellular carcinoma3

Acute infectionAcute infection60-75% are asymptomatic60-75% are asymptomatic

50-85% of patients50-85% of patients

>20% of patients3>20% of patients3

1-4% ofpatients/yr

1-4% ofpatients/yr

Liver transplant, deathLiver transplant, death

4% ofpatients/yr3

4% ofpatients/yr3

Progression To Cirrhosis

Progression to cirrhosis: based on inflammation of initial biopsy.

Yano. Hepatology 1996

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• 312 patients with initially compensated cirrhosis of viral aetiology

Cirrhotic patients at risk of seriousmorbidity

Benvegnù L, et al. Gut 2013; 53: 744‒9

Patients at riskHCC 312 311 310 303 297 268 226 189 153 129 94 65 45 27 11 5Variceal bleeding 312 312 312 309 301 269 237 190 163 131 97 71 44 29 13 7Ascites 312 311 312 305 296 259 223 181 152 125 93 60 48 30 15 9Encephalopathy 312 312 312 309 300 270 235 192 161 127 95 65 43 30 13 7

Cum

ulat

ive

risk

(%)

Years of follow-up

HCCVariceal bleedingAscitesPortal-systemic encephalopathy

50

40

30

20

10

00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

14*Other modes of transmission include sexual, occupational, nosocomial and vertical transmission.IDU: injection drug use.1. Remis RS. Final Report. Public Health Agency of Canada. 2007. Available from: http://www.phac-aspc.gc.ca/sti-its-surv-epi/model/pdf/model07-eng.pdf.

HCV PrevalenceAccording to Exposure

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15CDC: Centers for Disease Control and Prevention1. Hepatitis C: Proposed Expansion of Testing Recommendations, 2012. Available from:http://www.cdc.gov/nchhstp/newsroom/docs/HCV-TestingFactSheetNoEmbargo508.pdf;2. Centers for Disease Control and Prevention. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6104a1.htm?s_cid=rr6104a1_w.

CDC Recommendations(August 2012)

*** In Canada : CLF suggests 1945-1975

→ One-time testing during a yearly checkup or as a part of insuranceblood work

In the US, >75% of adults with chronic hepatitis C are baby boomers

• 73.4% of HCV-related deaths were in persons 45-64 years of age

Screening of those born between 1945-19651,2

Virological tests to confirmHCV infection

• Anti-HCV• HCV-RNA• HCV genotype

Bloodwork• CBC• Liver enzyme & function tests:

• ALT, AST, GGT, alkaline phosphatase,bilirubin, INR (or PT), albumin

• Normal ALT is not a contraindication totreatment (⅓ have normal test results)2

• Creatinine

16ALT : alanine aminotransferase; AST : aspartate transaminase; CBC: complete blood count; GGT: gamma-glutamyl transferase; HAV: hepatitis A virus; HAV-AB: hepatitis A antibody; HB: hepatitisB; HBsAG: hepatitis B surface antigen; HBsAb: hepatitis B surface antibody; HIV: human immunodeficiency virus; INR: International normalized ratio; PT: Prothrombin time1. Myers et al. Can Gastroenterol. 2012;26(6):359-75; 2. Pinette et al. Public Health Agency of Canada. Available from: http://www.phac-aspc.gc.ca/hepc/pubs/pdf/hepc_guide-eng.pdf.

Evaluation:

Laboratory Testing1,2

Abdominal ultrasound• Test for cirrhosis and exclude

hepatocellular carcinoma

Tests to rule out coinfections• Hepatitis A (HAV-Ab)• Hepatitis B (HBsAg, HBsAb)• HIV (Anti-HIV)

Tests to excludeother causes of liver disease

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Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting,April 27-28, 2011, Silver Spring, MD.

SV

R (%

)

IFN6 mos

PegIFN/ RBV12 mos

IFN12 mos

IFN/RBV12 mos

PegIFN12 mos

2001

1998

2011

StandardIFN

RBV

PegIFN

1991

DAAs

PegIFN/RBV/DAA

IFN/RBV6 mos

6

16

3442 39

55

70+

0

20

40

60

80

100

The Advancing Present

201490

PegIFN/RBV/DAAOr DAA+RBV

Impact of SVR on All-Cause Mortality byGenotype

• VA clinical case registry (N=16,864)• SVR associated with improved survival among HCV

genotypes 1, 2 and 3

Backus L, et al. 61st AASLD; Boston, MA; October 29-November 2, 2010; Abst. 213.

G: GenotypeHR: Hazard RatioCI: Confidence Interval

G1 HR(95% CI)

Pvalue

G2 HR(95% CI)

Pvalue

G3 HR(95% CI)

Pvalue

Unadjusted0.45

(0.39-0.52)<0.001

0.50(0.38-0.65)

<0.0010.30

(0.22-0.40)<0.001

Adjusted0.67

(0.56-0.79)<0.001 0.63

(0.45-0.86)0.004

0.45(0.32-0.65)

<0.001

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0

20

40

60

80

100

SV

R (%

)

PegIFN/RBVBOC or TVR +PegIFN/RBV

38-44

67-81

Poordad F, et al. N Engl J Med. 2011;364:1195-1206.Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

The Present: SVR Rates With Boceprevir orTelaprevir in Genotype 1 Treatment-Naive Patients

Triple Therapy for upto 48 Weeks

F0-2 F3-4

52-62

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Adverse Event Arm 1 (PR48); n=363 (%) Arm 2 (RGT); n=368 (%) Arm 3 (BOC/PR48); n=366 (%)

Fatigue 59 52 57

Headache 42 45 43

Nausea 40 46 42

Anemia 29 49 49

Dysgeusia 18 37 43

Chills 28 36 33

Pyrexia 32 33 30

Insomnia 32 31 32

Alopecia 27 20 28

Decreased Appetite 25 26 24

Pruritis 26 23 25

Neutropenia 21 25 25

Influenza Like Illness 25 23 22

Myalgia 26 21 24

Rash 22 24 23

Irritability 24 22 22

Depression 21 23 19

Diarrhea 19 19 23

Dry Skin 18 18 22

Dyspnea 16 18 22

Dizziness 15 21 17

Most Common Treatment-Related Adverse Events*

*Reported in >20% of patients in any treatment arm and listed by decreasing overall frequency

85% of patients havetreatment shortened to 24

weeks total

Virologic Outcomes

Jacobson I, et al. EASL 2013. Abstract 1425. Reproduced with permission.

18/31

n/N =

5/17

188/229

80

60

40

20

0

100

HC

V R

NA

Und

etec

tabl

e (%

)

No cirrhosis Cirrhosis

82

5358

29

SMV + P/R P/R

60/113

Virologic Response to Simeprevir (2nd gen. proteaseInh.) + PEG-INF + Ribavirin x 24 weeks Treatment:

Genotype 1

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Virologic Response to Sofosbuvir (Nuc. Inh.) + PEG-INF+ Ribavirin x 12 weeks Treatment: Genotype 1

Lawitz E, et al. EASL 2013. Abstract 1411. Reproduced with permission.S

VR12

(%)

9280

100

80

60

40

20

0No

CirrhosisCirrhosis

252/273 43/54

SVR According toFibrosis Level

SVR

12 (%

)

8996

100100

80

60

40

20

0GT 1 GT 4 GT 5,6

261/292 27/28 7/7

SVR According toGenotype

n/N =

0

20

40

60

80

100

SV

R (%

)

PegIFN/RBVX 24 wks

70-80%

97%

Poordad F, et al. N Engl J Med. 2011;364:1195-1206.Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

Virologic Response to PEG-INF + RBV vs. Sofosbuvir+ RBV (all-oral) in Genotype 2 and 3 Treatment-

Naive Patients

Geno 2SOF+RBVX 12 wks

92-94%

Geno 3SOF+RBVX 24 wks

Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5.Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

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Fibrosis is the key

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Hepatitis C: Summary

• HCV is common

• Screening for HCV is imperative– ‘baby-boomers’ and immigrants

• Viral eradication / cure in 70-90%

• Viral eradication has a mortality benefit

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Hepatitis C‘ An Update’

Alnoor RamjiGastroenterology & HepatologyClinical Associate ProfessorDivision of GastroenterologyUniversity Of British ColumbiaSt. Paul’s Hospital Siteramji_a@hotmail.comFax: 604-689-2004