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5/23/2014
1
Hepatitis C‘ An Update’
Alnoor RamjiGastroenterology & HepatologyClinical Associate ProfessorDivision of GastroenterologyUniversity Of British ColumbiaSt. Paul’s Hospital [email protected]: 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 [email protected]: 604-689-2004