Learning Objectives (HBV) VIRAL HEPATITIS: UPDATE ON HEPATITIS B AND HEPATITIS C Josh Levitsky, MD Assistant Professor of Medicine Northwestern Memorial Hospital Feinberg School of Medicine

Schematic Representation of HBV DNA polymerase

Inner protein core (HBcAg)

HBV DNA Outer lipid envelope containing HB surface antigen


Differentiate

the various stages of HBV infection
Review diagnostic tests
Discuss treatment  Choice

of agents  Treatment endpoints and long-term data  Resistance

Spectrum of Disease Acute HBV infection

90–95% neonatal infection 50% childhood infection

15–40%

Liver failure

5–10% adult infection ~2%

Fulminant hepatic failure HBsAg

Chronic HBV infection

Cirrhosis

Decompensated cirrhosis

Liver Cancer

Transplant/ Death

HBeAg

1

Natural History of Chronic HBV Infection 500

REPLICATIVE PHASE

NON-REPLICATIVE PHASE


Demographic

400

ALT HBV DNA

Risk Factors for Development of Liver Cancer    

→ seroconversion 300

HBeAg(+)

Anti-HBe(+)




200

←reactivation 100

factors

Male gender Age >45 years Ethnicity (Asian) Perinatal transmission: sAg carrier: 0.4%/yr Acquired later in life: 105 copies/mL

ALT

Management

+ + +/-

+ + + +

≤ 2 x ULN > 2 x ULN > 2 x ULN ≤ 2 x ULN Cirrhosis

+/-

-

Cirrhosis

Follow Treat Treat Follow Treat Comp: Treat Decomp: Refer for Liver Tx

Lamivudine* Entecavir

Phase 3 Emtricitabine*
Telbivudine
Clevudine**


Phase 2






Nucleotide analogues




Adefovir dipivoxil




Tenofovir*





Cytokines





Elvucitabine Valtorcitabine Amdoxovir Racivir LB80380 Alamifovir Pradefovir

Interferon alfa Peginterferon alfa-2a

*Currently approved for HIV **Phase 3 in South Korea Lok et al. Hepatology. 2004;39:857-861.

2

HBV DNA Levels Over Time

Treatment Endpoints in Chronic Hepatitis B

12

HBeAg Seroconversion

HBeAg Loss

Undetectable Serum HBV DNA

Treatment Endpoints

Normal ALT

Histological Improvement

Mean HBV DNA (log10 cp/mL)

On-treatment

Follow-up

10

PEGASYS® + placebo HBeAg serocon EOT = 27%; EOF = 32%

-1.95

8

-2.61 -2.39

6

-4.48*

PEGASYS® + lamivudine

-5.81

HBeAg serocon EOT = 24%; EOF = 27%

4 -7.18

lamivudine HBeAg serocon EOT = 20%; EOF = 19%

2 0

6

12 18 24 30 36 42 48 54 60 66 72

* all numbers shown are log10 reduction from baseline

HBeAg Seroconversion Increases With Duration of LAM Therapy

Lau et al AASLD 2004

Cumulative Lamivudine Genotypic Resistance Rates

80 60 40%

40

29% 22%

20 0

1

2

3

YMDD mutation detectable, %

HBeAg Seroconversion, %

100 100

70

75

53 42

50

24

25

0 0

Baseline

Duration of Therapy, years n= Leung et al. Hepatology. 2001:33;1527-1532.

58

54

1

2

(n = 335)

(n = 93)

3

4

(n = 58)

(n = 58)

Year

51 Lai et al. Clin Infect Dis. 2003;36:687.

3

HBeAg Seroconversion Rates Increase With Prolonged Adefovir

Adefovir Resistance 50

100

By Wk 48 (n = 171)

By Wk 96 (n = 85)

By Wk 144 (n = 65)

45 40

Patients, %

80

rtN236T and/or rtA181V mutations

M M + VR M + VR + ALT

35

29

30

60 46%

53%

25

46%

20

40

13

15

23% 20

18 16

33%

11

10

6

14%

5

3 0

0

0

3

2

0

0

HBeAg HBeAg Loss Seroconversion Kaplan-Meier estimates of time to confirmed event

11

10 8

Year 1

a.

Year 2

Year 3

Year 4

Year 5

Cumulative probabilities calculated by Life-Table analysis

Marcellin et al. EASL 2005. Abstract 73. Borroto-Esoda K., EASL 2006, Abstract 483

Entecavir for HBeAg-Positive Patients: Up to 96 Weeks

Managing Resistance





Response in nucleoside-naive patients receiving up to 96 weeks entecavir 

Cumulative HBV DNA suppression < 300 copies/mL during 96 weeks
Entecavir, 80% – Lamivudine, 39%

Continue the existing drug




Switch to a new drug(s)










Cumulative HBeAg seroconversion during 96 weeks
Entecavir, 31% – Lamivudine, 26%

No evidence of entecavir resistance through Week 96


Add a new drug(s)




Better than no treatment in some patients? Risk of disease reactivation and worsening Risk of liver enzyme flare during transition Consider risk of cross-resistance May be more effective Consider risk of cross-resistance

Gish et al. AASLD 2005. Abstract 181.

4

Hepatitis C Genome Learning Objectives (HCV)

Specific HCV enzymes HCV Polyprotein E1

C


Virology

E2

p7

NS2

NS3

NS4A

NS4B

NS5A

NS5B


Epidemiology
Transmission
Natural

History
Management ?

Newer drugs NS3 Protease domain

NS3 Helicase domain

NS3 Bifunctional protease / helicase

NS5B RNARNA-dependent RNA polymerase

© 2002 JG McHutchison, DUMC

HCV: Virology

HCV: Epidemiology


Genotype


~

distribution in the U.S.

 Genotype

1a/b 2  Genotype 3  Genotype 4-6  Mixed genotypes  Genotype

~75% ~10% ~10% ~