HBV - ncsgna

Hepatitis B State of the Art

Joanna Ready, M.D. SGNA September, 2013

Magnitude of HBV Infection(s) • World wide: 2 billion persons infected — 350 million cases of chronic HBV — 15-40% progress to cirrhosis/HCC

• US: 1.25 million persons with chronic HBV — In Asian Americans: 7-16% carrier rate

HBV is a life long, dynamic disease • Changes over time • Risk of end stage liver disease and cancer increases with ongoing inflammation and viremia in adults • Fibrosis can be reversible • Drugs can decrease fibrosis progression • HBV can be controlled but not cured • Reactivation can occur even in those who have lost HBsAg Slide 3

Who should be tested for HBV? • • • • •

Blood and organs donors Hemodialysis patients Pregnant women Infants of HBsAg + mothers Behavioural contacts: — Household and sexual contacts — HIV+, MSM, IDU

• Individuals from countries where prevalence is ≥2% • Patients receiving immunosuppressive therapy • Abnormal ALT of unknown cause CDC 2008 Slide 4

Geographic Distribution of Chronic HBV Infection

Country

HBsAg+ (%)

China

5.3-122

South Korea

2.6-5.12

India

2.4-4.72

Taiwan

10-13.82

Vietnam

5.7-102

Japan

4.4-133

Africa

5-192

Russia

1.4-82

US/Europe

0.3-122

HBsAg 8: 2–8:

HBV-DNA

ALT HBeAg +ve chronic hepatitis

Inactive (carrier) state*

*Previously considered to be ‘healthy carriers’

HBeAg –ve active chronic hepatitis

Slide 12

HBV Control the goal • Inflammatory: normalize serum ALT, biopsy

• Virologic: decrease HBV DNA • Immune: seroconversion — HBeAg to HBeAb — HBsAg to HBsAb

• HBV never “cured” but controlled

Slide 13

Who should be considered for treatment? Immune tolerance

Immune clearance

HBeAg+ve

<

Immune control

><

Immune escape

HBeAg–ve

>

HBV-DNA

ALT

treat

treat HBeAg +ve chronic hepatitis

Inactive (carrier) state

HBeAg –ve/+ve active chronic hepatitis Slide 14

Overview of Algorithm Used to Determine Need for Treatment of HBV HBeAg Positive HBV DNA >20,000 IU/mL

HBeAg Negative HBV DNA >2,000 IU/mL ALT Level

Elevated ALT

Normal ALT

Monitor ALT Q3mos for 1y Treat

Consider Liver Biopsy If >40yrs

Significant fibrosis or inflammation Lok AS et al Hepatology, 2009 Slide 15

Approved HBV treatments 2013 • Interferon alfa-2b – 1991 • Lamivudine – 1998 • Adefovir – 2002 • Entecavir – 2005 • Peginterferon alfa-2a – 2005 • Telbivudine – 2006 • Tenofovir - 2008 For HIV: — Emtricitabine — Tenofovir + emtricitabine (single pill co-formulation) Slide 16

Therapeutic endpoints over time Improved Improved Anti-HBs+ survival histology Loss of Anti-HBe+ HBsAg Loss of HBeAg Loss of HBV DNA

TIME Slide 17

Treatment Goals in CHB: Remission Differences between the two strategies

On-therapy Off-therapy sustained maintained response response = Low viremia

= Low viremia

ALT normalization

ALT normalization

Continued need for

Immune control,

antiviral drugs

no antiviral drugs Slide 18

HBV Nucs: Nonresponse, Suboptimal Response, and Virologic Breakthrough

Change in HBV DNA (log10 IU/mL)

1.0

Antiviral Drug Primary nonresponse

0

Virologic breakthrough

-1.0 Suboptimal response

-2.0 -3.0

Nadir

-4.0 0

6

1 log 12

18

Months Lok AS, et al. Hepatology. 2007;45:507-539. Slide 19

HBeAg Seroconversion Rates Over Time in HBeAg-Positive Patients

HBeAg Seroconversion (%)

Not head-to-head trials; different patient populations and trial designs 100

Extended Treatment With Nucleos(t)ide Analogues* vs Limited Duration (1 Yr) Peginterferon Treatment

80

Entecavir Tenofovir Peginterferon

60 39

40 20

31 21

22 22-27

26 29-32

35 26

0 1.0 Yr

1.5-2.0 Yrs

3.0-4.0 Yrs

*With sustained undetectable HBV DNA. Chang TT, et al. J Viral Hepat. 2009;16:784-789. Chang TT, et al. AASLD 2006. Abstract 109. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Buster EH, et al. Gastroenterology. 2008;135;459-467. Heathcote J, et al. AASLD 2008. Abstract 158. Heathcote J, et al. AASLD 2009. Abstract 483. Janssen HL, et al. Lancet. 2005;365;123-129. Slide 20

HBsAg Loss Over Time in HBeAgPositive Patients Not head-to-head trials; different patient populations and trial designs

HBsAg Loss (%)

100

Extended Treatment With Nucleos(t)ide Analogues* vs 1 Yr Peginterferon Treatment

80

Entecavir Tenofovir Peginterferon

60

40 20 2

3

5

5

6

0 1.0 Yr

8

6

1.5-2.0 Yrs

8

NA 3.0-4.0 Yrs

*With sustained undetectable HBV DNA. Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Buster EH, et al. Gastroenterology. 2008;135;459-467. Gish R, et al. Gastroenterology. 2007;133:1437-1444. Heathcote J. AASLD 2008. Abstract 158. Heathcote J, et al. AASLD 2009. Abstract 483. Janssen HL, et al. Lancet. 2005;365:123-129. Slide 21

Undetectable HBV DNA Over Time in HBeAg-Negative Patients Not head-to-head trials; different patient populations and trial designs

Undetectable HBV DNA (%)

Extended Treatment With Nucleos(t)ide Analogues vs 1 Yr Peginterferon Treatment 100

90

96

93

80

100*

91

87 Entecavir Tenofovir Peginterferon

63

60 40 20

15 NA

0

*Single center study.

16

1 Yr

2 Yrs

3 Yrs

Lok AS, et al. Hepatology. 2009;50:661-662. Marcellin P, et al. AASLD 2008. Abstract 146. Marcellin P, et al. AASLD 2009. Abstract 481. Marcellin P, et al. Gastroenterology. 2009;136:2169-2179. Baqai S, et al. AASLD 2009. Abstract 476. Lai CL, et al. Hong Kong International Liver Congress 2006. Slide 22

HBsAg Loss Over Time in HBeAg-Negative Patients Not head-to-head trials; different patient populations and trial designs 100

Extended Treatment With Nucleos(t)ide Analogues* Vs 1 Yr Peginterferon Treatment

Patients (%)

80 Entecavir Tenofovir Peginterferon

60

40 20 0

1.2 X 109 during the last 4 weeks of pregnancy – 1 of 8 infants sAg positive at 1 year (12.5%) vs 28% of historical controls

—

Xu et al (2009): • Double-blind, placebo-controlled trial of lamivudine and immunoprophylaxis during the last 8 weeks of pregnancy vs HBIg and HBV vaccination alone – – – – –

151 women 18% of babies in arm A were sAg positive at 1 year 39% of babies in arm B were sAg positive at 1 year In large part due to a significant number of mothers/infants lost to follow-up For those with complete data: » At 1 year: 13% positive in arm A 31% in arm B no significant difference

• No study has reported increased adverse fetal events with lamivudine Slide 39

Pregnancy (cont) • Tenofovir — Class B drug — High genetic barrier to resistance

— No increased adverse fetal events

• Telbivudine — Similar results — Low genetic barrier to resistance

• No published studies using entecavir, adefovir, emtricitabine to prevent vertical transmission • Current CDC/AASLD guidelines have not made specific recommendations regarding the treatment of pregnant women with HBV

Slide 40

Pregnancy (cont) • Effect on successful delivery — Theoretical but not proven: • Increased bleeding/abruption • Gestational diabetes • LBW

• Pregnancy’s effect on HBV — Rare, usually eAg + mothers

• Effect of Rx on mother’s disease: — No change in disease progression — Stopping Rx after delivery: • ALT flare 12-25%; rarely clinically significant; responds to reinstitution of Rx – 12-17% of women will have a mild flare after deliver without withdrawal of drugs Slide 41

Pregnancy (cont) • When to begin treatment? — No data available • First/second trimester if mother has evidence of significant liver impairment/ongoing damage – High ALT and VL – Evidence of fibrosis  low platelet count; radiographic evidence

• Check VL at the end of the second trimester consider Rx for VL>106 (200,000IU/ml) OR history of prior children with chronic hepatitis B, regardless of the VL

• When to end treatment? — Again, no data available — Consider if in immunotolerant phase — Risk  hepatic decompensation Slide 42

Slide 43

Slide 44

Reactivation of HBV • High rate of reactivation in immunosuppressed patients — Chemotherapy — HIV after immune reconstitution — Post organ transplant — Biologic response modifiers: rituximab (antiCD20), TNF- inhibitors: GI, hematologists, rheumatologists, dermatologists

• Reactivation can occur in immunocompetent treated with steroids, BRMs Slide 45

Reactivation of HBV • Highest in HBV active disease — HBsAg and HBeAg pos, high HBV DNA — HBsAg and HBeAb pos, low HBV DNA

— HBsAg neg, anti-HBs neg, anti-HBc pos • “occult HBV”

— Deaths occur in all groups

• ALL patients undergoing chemotherapy must have tested HBsAg, HBsAb and HBcAb prior to treatment Slide 46

Screening for Liver Cancer: Lack of Consensus

• Optimal age for initiation of screening unknown1 — Patients ≥ 35 yrs are at much higher risk for HCC than those < 35 years2 — Asian males aged 40; females aged 50 — Sub-Saharan Africans > 20 — Cirrhosis, any age — Co-infection with HCV/HIV

Current AASLD guidelines

— ? ETOH • Among HBV-infected individuals, HCC can occur at any age, including childhood (genotype B?) • Up to 1/3 of patients with HCC have normal AFP

• AFP may be elevated in 1/3 of patients with cirrhosis without HCC 1. Lok AS, and McMahon BJ. Hepatology. 2001; 34:1225-1241. 2. Liaw YF, et al. Gastroenterology. 1986;90:263-267. Slide 47

HBV is a dynamic disease •

Diagnose

•

Initial evaluation includes education — Family and sexual contacts should be tested — counsel drugs to avoid- steroids, chemo, BRM

•

Monitor as status changes over time — ALT /HBV DNA may not remain normal over time especially in anti-HBe

•

•

Selection who to treat •

Individualize treatment decisions

•

Change if no/ poor response

Long term monitoring HCC, reactivation Slide 48

HBV: The importance of monitoring HBV is a dynamic disease!!! Require treatment 60%

40%

Require monitoring… • Inactive disease may not remain inactive • Liver damage may occur if HBV reactivates

HBV can be controlled but not cured Slide 49

Serology of HBV (addendum) Infection

ALT HBeAG AntiHBV DNA HBeAb IU.ml

histology

Immune tolerant

nl

Pos+

Neg-

High

normal

Chronic hepatitis HBeAg +

up

Pos+

Neg-

>20,000

Active

Inactive carrier

nl

Neg-

Pos+

2,000

active Slide 50