The prevalence of CHB varies widely across EMEA (Europe, Middle East &

North Africa)

http://www.cdc.gov/ncidod/diseases/hepatitis/slides/hepb

≥8% High2–8% Intermediate

< >HBeAg +ve HBeAg -ve/ anti-HBe +ve

ALT

HBV-DNA

Normal/

mild CH

Moderate/severe CH Moderate/severe CHNormal/mild CH

Cirrhosis

Inactive-carrier state HBeAg –ve

CHB

HBeAg +ve

CHB

Immune

tolerance

Immune

clearance

Immune control Reactivation

phase

Cirrhosis

109–1010 cp/mL107–108 cp/mL

105 cp/mL

Inactive cirrhosis

Fattowich, J Hepatol 2003; 39: S50-S58

Adapted from: Fattovich, et al. Gastroenterology. 2004;127:S35-50. Torresi, et al. Gastroenterology. 2000;118:S83-103 Fattovich, et

al. Hepatology. 1995;21:77-82. Perrillo, et al. Hepatology. 2001;33:424-32

Chronic Infection

Cirrhosis

Liver Failure

Liver Cancer (HCC)

Death30%

23% in 5 yr

Liver Transplantation

Acute

flare

10–15% in 5 yr

5–10%

25–40% lifetime risk for death due to HCC or liver failure

25–40% lifetime risk for death due to HCC or liver failure

Natural progression of CHB

Who should be treated?

Adapted from Lok A. Clin Gastroenterol Hepatol. 2004;2(10):839–48.

Benefits Risks

Treatmentconsiderations

Severity of liver

disease/likelihood

of disease progression

to cirrhosis and

liver cancer

Probability of treatment

response

Adverse effects

Drug resistance

Age of patient

Gender

Co-morbidities

Viral load

HBeAg status

ALT

Previous treatment

HBV genotype

Liver histology

Goals of Therapy: 2 Distinct Patient

Populations

HBeAg positive (wild type)•HBeAg loss ± seroconversion•Suppression of HBV DNA•ALT normalization

HBeAg negative (precore and core promoter

mutants)•HBeAg seroconversion not an endpoint•Suppression of HBV DNA •ALT normalization

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

Current Guideline Recommendations

for First-line Therapy

• Peginterferon alfa-2a– Exceptions: pregnancy, chemotherapy prophylaxis,

decompensated cirrhosis, acute infection

• Entecavir• Tenofovir

EASL. J Hepatol. 2009;50:227-242. Liaw YF, et al. Hepatol Int. 2008;2:263-283. Lok AS, et al. Hepatology.

2009;50:661-662.

AASLD Guideline Recommendations

for Duration of NA Treatment

“32. Duration of nucleoside analogue treatment

a. HBeAg-positive chronic hepatitis B—Treatment should be

continued until the patient has achieved HBeAg seroconversion and

undetectable serum HBV DNA and completed at least 6 mos of

additional treatment after appearance of anti-HBe. (I)

● Close monitoring for relapse is needed after withdrawal of

treatment. (I)

b. HBeAg-negative chronic hepatitis B—Treatment should be

continued until the patient has achieved HBsAg clearance. (I)”

Lok AS, et al. Hepatology. 2009;50:661-662.

Impact of HBV treatment

• Decrease in the rate of decompensation• Decrease in liver transplantation• Absence of good data demonstrating an effect

on liver cancer occurrence in the context of

HBV (recent KCE report)

HBV vaccination: recommendations

• Universal in babies• « Rescue » in children and teenagers• People at risk:

– Newborns from carriers – Health professionals– Contacts, chronic liver disease, stay in

endemic countries…

[http://afssaps.sante.fr/htm/10/hepatite/vhb04.pdf]

Hepatitis C virus: The major causative

agent of viral non-A, non-B hepatitisA ‘blind’ recombinant immunoscreening approach, of general application to studies of infectious diseases, was used to clone and identify the genome of the previously uncharacterized non-A, non-B hepatitis (NANB) virus. This agent is a positive-stranded RNA virus that appears to be distantly related to the flaviviridae family. Data obtained using this assay indicate that this agent, termed the hepatitis C virus (HCV), is the major cause of post-transfusion, community-acquired and cryptogenic, NANB.

QL Choo, et al. Chiron Corporation, Emeryville California, USA - 1990

Hepatitis C Virus

• Single stranded, positive sense, RNA– Flaviviridae family– Spherical, enveloped

• Great genetic diversity– Six genotypes: 1 through 6– Multiple subtypes: a, b, c, etc– Viral sequences can be used to track a common

source of infection

~ 50 nm

U.S.A. 4 M

SOUTH

AMERICA

10 M

AFRICA

32 M

EAST

MEDITERRANEAN20M

SOUTH EAST ASIA30 M

AUSTRALIA

0.2 M

SOURCE, WHO 1999

WEST

EUROPE 9 M

FAR EAST ASIA60 M

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

3% of World Population

HCV: A Global Health Problem

CANADA 300,000

Detection• Infection: Infection: Infection: Infection: HCV Ab, PCR (quantitative) if HCV Ab, PCR (quantitative) if HCV Ab, PCR (quantitative) if HCV Ab, PCR (quantitative) if

HCV Ab +HCV Ab +HCV Ab +HCV Ab +

• Hepatitis: Hepatitis: Hepatitis: Hepatitis: serum transaminasesserum transaminasesserum transaminasesserum transaminases

FIBROTIC PROGRESSION

10 20 30 40 500

Mild

Moderate

Severe fibrosis

Cirrhosis- mild

Cirrhosis - severe

HCC20-33%

15-33%

Years

adapted from Afdhal, Sem Liver Disease, 2004

Natural History

Stable

75% to 95%

HCC or Decompensation

1% to 3%/yr

Stable 97% to 99%/yr

Resolved

15%

Acute HCV

Cirrhosis

5% to 25%

Chronic HCV

85%

Thomas DL, et al. Clin Liver Dis. 2005;9:383-398 Strader DB, et al. Eur J Gastroenterol Hepatol. 1996;8:324-328. Seeff LB, et al.

Hepatology. 2002;36(suppl):S1-S2. Seeff LB, et al. Hepatology. 2002;36(suppl):S35-S46. Liang TJ, et al. Ann Intern Med.

2000;132:296-305. Fattovich G, et al. Gastroenterology. 1997;112:463-472.

Modes of HCV Transmission

• HCV can probably survive on environmental surfaces at room temperature for 16-72 hours

• Do not exchange blood– Razors, toothbrushes, nail clippers

• Sexual transmission rate is low– Condoms recommended for multiple sexual partners

• Not transmitted by casual contact (eg, hugging)

HCV Infection: High-Risk Populations in Which

Screening Is Indicated

• Injection drug use• Nasal inhalation of cocaine• Chronic renal failure on

dialysis

• Incarceration• Multiple sexual partners,

MSM, HIV positive

• Transplantation or transfusion of blood

products before 1992

• Occupational exposure to blood products

• Body piercing and possibly tattoo

• Children born to HCV-positive women

Centers for Disease Control and Prevention. April 10, 2007. Verucchi G, et al. Infection. 2004;32:33-46.

Large Population Underscreened and

HCV Patients Underdiagnosed

• Current screening practices fail to identify a large proportion of patients with chronic HCV infection[1]

– As few as 25% of patients are diagnosed

• Survey of 4000 primary care physicians[2]

– Only 59% of 1412 respondents asked all patients about HCV risk factors

• AASLD recommends that “as part of a comprehensive health evaluation, all persons should be screened for behaviors that

place them at high risk for HCV infection”[3]

• CDC recommends to screen all baby-boomerspatients born between 1945 and 1965.

1. Kim WR. Hepatology. 2002;36:S30-S34. 2. Shehab TM, et al. J Viral Hepat. 2001;8:377-383. 3. Ghany MG, et al. Hepatology. 2009;49:1335-1374.

HCV therapy

• Goals: viral eradication

• Duration: limited in time depending on genotype

• Whom? : active hepatitis and/or fibrosiscompensated cirrhosis

- normal ALT? (15 to 20% progressive disease)

Standard Therapy for HCV

SVR naïve

patients (%)

No therapy

1989 1999 2002

Monotherapy

24 weeks

Combination therapy

48 weeks

16%

0%

41%

Combined data :Poynard et al (1998), McHutchison et al (1998), Zeuzem et al (2000), Fried et al (2002)

0

10

20

30

40

50

60

6%

Monotherapy

48 weeks

1995

PEG-IF

48 weeks

PEG-IF + RIBA

48 weeks

Genotype sp

39%

2000

54,56,61,76%

SVR Rates With BOC or TVR in

Genotype 1 Treatment-Naive

Patients

0

20

40

60

80

100

SV

R (

%)

PegIFN/RBV BOC or TVR +

PegIFN/RBV

38-44

63-75

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

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

NOT EXHAUSTIVE

2011 2012 2013 2014 2015

Wave 1: Triple (Launched) Wave 3: Oral Combinations,

IFN Free & QUAD

BOC

TVR

Evolving Landscape to "IFN-free" Therapies

EU Approval Timelines for Key DAAs with 1st indication

DCV + PR

TN 1b

TMC-435 +PR

TN, Relapsers

BI-201335 + PR

TN, TE

GS-7977+R (G2/3, G1?)

TN

GS-7977 +

GS-5885 ± R

TN

Wave 2: Triple

1st Market Approval

ASU +DCV ± PR

TN, TE, IFN intol/inel

DCV: daclatasvir; ASU: asunaprevir (BMS)

ABT-450/r/ABT-267 +

ABT-333 ± Rcirrhotics

Only molecules in phase 3 shown. Vaniprevir not included as ph3 is in Japanese patients. Alisporivir not included as on hold

Dates estimated by end of phase 3 (primary objective completion date) + approx. 1 year (clinicaltrials.gov)

NEUTRINO: SVR12 With Sofosbuvir + P/R

According to Genotype and Fibrosis Level

Lawitz E, et al. EASL 2013. Abstract 1411..

SV

R1

2 (

%)

92

80

100

80

60

40

20

0No

Cirrhosis

Cirrhosis

252/273 43/54

SVR12 According to

Fibrosis Level

SV

R1

2 (

%)

8996

100100

80

60

40

20

0GT 1 GT 4 GT 5,6

261/292 27/28 7/7

SVR12 According to

Genotype

n/N =

TURQUOISE II: Abbvie 3 DAAs + RBV in

Cirrhotic Pts by HCV Subtype

12 wks

24 wks 100 100

Naive Relapse

100 100 85.7 100 100 100

Partial

Response

Null

Response

GT1b

Poordad F, et al. EASL 2014. Abstract O163. Reproduced with permission.

SV

R1

2 (

%)

Naive Relapse Partial

Response

Null

Response

GT1a

59/

64

14/

15

52/

56

13/

13

11/

11

40/

50

10/

10

39/

42

� Virologic failure in 17/380 pts (4.5%); relapse more frequent with 12-wk vs 24-wk treatment (12 vs

1 pt), 7/12 relapsers by posttreatment Wk 12 were GT1a null responders

100

80

60

40

20

0

92.2 92.993.3 100 100 100

80.0

92.9100

80

60

40

20

0

22/

22

25/

25

18/

18

20/

20

6/7 14/

14

3/3 10/

10

Conclusions HCV

• It will be possible in a near future to cure all HCV patients

• Difficulties will be to diagnose all patients