Division of GastroenterologyDuke University Medical Center

Hepatitis C Update

Andrew Muir, MD Director of Hepatology

U.S.A. 4 M

SOUTH

AMERICA

10 M

AFRICA 32 M

EAST MEDITERRANEAN

20M

SOUTH EAST ASIA30 M

AUSTRALIA0.2 M

SOURCE, WHO 1999

WEST EUROPE

9 M

FAR EAST ASIA60 M

HCV170 Million Carriers Worldwide, 3-4 MM new cases/year

Hepatitis C

• NHANES– 15 079 participants 1999 and 2002

• Results– HCV antibody + 1.6% (95% CI, 1.3% to 1.9%),

4.1 million (CI, 3.4-4.9 million)

– Chronic infection 1.3%

3.2 million (CI, 2.7-3.9 million)

Armstrong GL. Ann Intern Med 2006

HCV in the USA

1.6

4.3

9.4

13.6

0

5

10

15

20

US Age 40-49 Blacks 40-49 Black men 40-49

Pre

vale

nce

, %

Armstrong GL, Ann Intern Med 2006; 144: 705-714

Pre

vale

nce,

%

Overlapping international epidemics

40 million170 million

10 million

HIV HCV

HIV/HCV - USA

• United States• 30% of patients who are

HIV-infected are co-infected with HCV

• HIV– 2003 – approximately 1

million persons in the US with HIV/AIDS

Staples CT. Clin Infect Dis 1999

HCV + HIV

Transmission

• Drug use• Transfusion/blood products• Organ transplantation

Transmission

• Sexual– < 5% heterosexual monogamous couples

• No recommendations for condom use

– increased with multiple partners– ??? increased if HIV co-infection ???

• Vertical (mother to child)– HCV alone: 2-5%– HIV/HCV: 25%

• No treatment given teratogenic meds

Mast EE. J Infect Dis 2005Veronese L. Antimicrob Agents Chemother 2000

Transmission

• Transmission to patients– New York endoscopy center– Oklahoma pain clinic– Nebraska oncology treatment

center– Las Vegas ambulatory surgical

center 2008– Laurinburg, NC cardiology clinic

2008– Miami FL, Murfreesboro TN

VAMC 2009

MMWR 2001, 2008

CLOSED

Diagnostic approach

Acute Hepatitis C

Chronic Hepatitis 85 %

Cirrhosis 20 %

Di Bisceglie, Hepatology, 2000

Natural History

Faster progression•older age at infection•alcohol•HIV infection•post-transplant

20-3

0 ye

ars

20-5

0 ye

ars

Diagnosis

• Antibody tests– 3 generations

– ELISA

– positive 8-10 weeks

• HCV RNA– PCR or branched DNA

– documents viremia

– response to treatment

HCV Genotypes

• Genotype 1– Most common in USA

– > 90% for African Americans

– Requires 48 weeks of treatment

– Lowest response rates

• Genotype 2 and 3– Less common in USA

– 24 weeks of treatment

– Higher response rates

1

63

45

2

Simmonds P, Journal of Hepatology, 1999

Generally advisable

• If impacts management

Should not be mandatory

Aids in decision making process

Prognosis – cirrhosis?

Don’t be fooled by normal liver enzymes

Liver Biopsy

Stage 2-3

Stage 4

Stage 0Stage 0

Stage 0 = no fibrosisStage 1 = portal fibrosisStage 2 = portal with septaStage 3 = bridging fibrosisStage 4 = cirrhosis (nodules)

Alternatives to liver biopsy

FibroSURE® • α2-macroglobulin• haptoglobin• apolipoprotein A1• bilirubin• γ-glutamyl transpeptidase [GGT]

FIBROSpect II® • hyaluronic acid• TIMP-1• alpha-2 macroglobulin

Fibroscan

Role of liver biopsy

• HCV mono-infected– Establish degree of fibrosis– Consider watchful waiting if early fibrosis

• HIV-HCV co-infection– Establish fibrosis

• Hepatocellular carcinoma screening if advanced fibrosis

– Rule out hepatotoxicity from HAART– Watchful waiting less clear of a role given faster natural

history

Treatment

HCV treatment 2009

• Peginterferon alfa– Self-administered subcutaneous injection– Weekly

• Ribavirin– Capsule – Twice daily

HCV Treatment – PEG-IFN + ribavirin

56

46

76

5442

82

0

20

40

60

80

100

Peg 2a Peg 2b

All patients

Genotype 1

Genotype 2/3

SV

R,

%

Manns Lancet 2001Fried NEJM 2002

IDEAL study

• Peg 2a vs Peg 2b• Dose Peg 2b

– Standard 1.5 mcg/kg

– Low dose 1.0 mcg/kg

• Funded by Schering (maker of Peg 2b)

• 118 sites• 3070 patients

40.9 39.8 38

0

10

20

30

40

50

60

70

80

90

100

Peg 2a Peg 2b 1.5 Peg 2b 1.0

SVR

McHutchison JG NEJM 2009

Racial & Ethnic groups

Muir et al. N Engl J Med. 2004 Rodriguez-Torres M et al. N Engl J Med. 2009

SV

R, %

HIV/HCV treatment trialsPeg-IFN alfa + ribavirin

SV

R, %

Laguno M, AIDS 2004

Chung RT NEJM 2004

Torriani FJ NEJM 2004

Carrat F, JAMA 2004

Laguno M, AIDS 2004

Chung RT NEJM 2004

Torriani FJ NEJM 2004

Carrat F, JAMA 2004

Baseline Comparisons

RIBAVIC APRICOT ACTG 5071 Spain

No. patients 206 289 67 52

GT 1/4 52% 61% 78% 63%

Cirrhosis 38% 16% 10% 30%

African Am. NS 11% 33% NS

Median CD4 482 530 474 560

On HAART 83% 84% 86% 88%

HIV RNA (-) 67% 60% 60% 46%

RBV dose 800 800 600-1000 800-1200

Factors? No Yes Yes Yes

Treatment milestones for genotype 1

Baseline viral load

Week 12 HCV RNA

Week 24 HCV RNA

< 2 log reduction HCV RNA

> 2 log reduction HCV RNA

HCV RNA negative

HCV RNA positive

Factors Predictive of Response

Genotype 2 or 3 Absence fibrosis Low viral load Younger age Female Weight Non-African American

McHutchison JG. NEJM 1998Poynard T. Lancet. 1998 Manns MP. Lancet 2001

Prediction of response

• IDEAL trial

IDEAL on-treatment prediction of SVR

Low-Dose Peginterferon

Alfa-2b + Ribavirin

Standard-Dose Peginterferon

Alfa-2b + Ribavirin

PeginterferonAlfa-2a + Ribavirin

Weeks to first undetectable HCV RNA level

2 38/42 (90.5) 43/45 (95.6) 37/44 (84.1)

4 33/41 (80.5) 64/72 (88.9) 62/83 (74.7)

12 234/292 (80.1) 227/300 (75.7) 250/355 (70.4)

24 77/157 (49.0) 68/156 (43.6) 72/203 (35.5)

McHutchison JG NEJM 2009

Prediction of treatment response

• IDEAL study participants• Optional genetic component at enrollment• 3070 patients• 1604 IDEAL participants + 67 participants from Muir et al.,

2004– Excluded if inadequate specimen, noncompliance

• 1137 samples analyzed• Genome wide association study

Ge et al. Nature 2009

Prediction of treatment response

1 3 5 7 9 11 13 15 17 19 21 X M2 4 6 8 10 12 14 16 18 20 22 Y

-log 1

0(P

)

0.0

15.0

30.0

-log 1

0(P

)

0.0

15.0

30.0

-log 1

0(P

)

0.0

15.0

30.0

Chromosome 19 ideogram

0 M 10 M 20 M 30 M 40 M 50 M 60 M

39,623 K 39,666 K 39,708 K 39,750 K 39,793 K 39,835K

PAK4 SYCN IL28B IL29 LRFN1NCCRP1 AC011445.6IL28A GMFG

IL28B IL28AAC011445.6

39,711 K 39,721 K 39,732 K 39,743 K 39,753 K 39,764K

rs12979860P=1.37×10-28

1 3 5 7 9 11 13 15 17 19 21 X M2 4 6 8 10 12 14 16 18 20 22 Y

-log 1

0(P

)

0.0

15.0

30.0

-log 1

0(P

)

0.0

15.0

30.0

-log 1

0(P

)

0.0

15.0

30.0

Chromosome 19 ideogram

0 M 10 M 20 M 30 M 40 M 50 M 60 M

39,623 K 39,666 K 39,708 K 39,750 K 39,793 K 39,835K

PAK4 SYCN IL28B IL29 LRFN1NCCRP1 AC011445.6IL28A GMFG

IL28B IL28AAC011445.6

39,711 K 39,721 K 39,732 K 39,743 K 39,753 K 39,764K

rs12979860P=1.37×10-28

Ge et al. Nature 2009

Prediction of treatment response

Ge et al. Nature 2009

Prediction of treatment response

Ge et al. Nature 2009

Previously treated patients

• Relapse– Negative end of treatment but then positive

• Nonresponder– Never HCV RNA negative

• Retreat these patients?– Low response rates

– Maintenance therapy trials negative

– Can you improve treatment from previous course?• Compliance?• Alcohol?• Inappropriate dose reductions?

– Consider HCV trials of new agents

Ghany MG, Hepatology 2009

New therapies

• Protease inhibitors– FDA approval 2011?

• Polymerase inhibitors– Phase 2 trials in progress

• Alternatives to interferon alfa• No alternative therapies with FDA approval

expected soon

Boceprevir

• Protease inhibitor• SPRINT-1• Phase 2, RCT study• GT 1 patients

– Control group

– Lead in with PEG/RBV 38

75

56

0

10

20

30

40

50

60

70

80

90

100

Control 52 weeks 28 weeks

SVR rates in SPRINT-1

Kwo P, EASL 2009

Telaprevir

• Protease inhibitor

• Phase 2, RCT study

• 260 GT 1patients– Control group– Intervention groups

• Telaprevir only during 1st 12 weeks

• T12/PR12

• T12/PR24

• T12/PR48

• Issues– Rash– Mutations– Anemia

41 35

6167

0

10

20

30

40

50

60

70

80

90

100

PR T12PR12 T12PR24 T12PR48

SVR rates in PROVE 1

McHutchison JG, NEJM 2009

Telaprevir – prior relapsers

• PROVE3• 4 arms

– T12PR24– T24PR48– T24P24 (no RBV)– Control (PEG/RBV)

6976

42

20

0

20

40

60

80

100

T12PR24 T24PR48 T24P24 Control

SVR rates in PROVE3, %SVR rates in PROVE3, %

Manns MP, EASL 2009Manns MP, EASL 2009

Telaprevir – prior nonresponders

• PROVE3• 4 arms

– T12PR24– T24PR48– T24P24 (no RBV)– Control (PEG/RBV)

39 38

10 9

0

20

40

60

80

100

T12PR24 T24PR48 T24P24 Control

SVR rates in PROVE3, %SVR rates in PROVE3, %

Manns MP, EASL 2009Manns MP, EASL 2009

Complementary and alternative therapies

• Milk thistle (Silybum marianum) from the aster family

• Active extract is silymarin, found in the fruit– Anti-oxidant properties

• Used in Europe for jaundice since the 16th century

• Not anti-viral• Studies in progress

Complementary and alternative therapies

• Hepatotoxic herbal remedies– Chaparral leaf germander– Jin bu huan– Kava kombucha mushroom– Margosa oil– Mistletoe– Pennyroyal– Pyrrolizidine alkaloids– Traditional Chinese herbs

Verma S. Clin Gastro Hep 2007

Recommendations for all patients

• Consideration of treatment• Avoid alcohol• Vaccination for Hep A and Hep B if no prior

exposure• Cirrhosis

– Pneumococcal vaccination– Upper endoscopy to r/o varices– Hepatocellular carcinoma screening

Alcohol & HCV

• No safe level of alcohol• Interventions typically aimed if abuse• Duke NIH study

– Wider range of alcohol use– Individual and group therapy

Resouces

• American College of Physicians– pier.acponline.org

• American Liver Foundation– www.liverfoundation.org

• Centers for Disease Control– www.cdc.gov

• NIDDK– digestive.niddk.nih.gov

• Veterans Affairs HCV program– www.hepatitis.va.gov

Take home message