Chronic Hepatitis B In Low and Middle Income Countries

1
Chronic Hepatitis B In Low and Middle Income
Countries

• Regina B. Osih MD, MPH
• August 28, 2008
• rosih_at_rhru.co.za

2
Overview

• Epidemiology
• Pathogenesis and natural history of Hepatitis B
  acute infection
• Serologic markers
• Chronic Hepatitis B in all its forms
• Interaction with HIV
• Treatment options and guidelines

3
The epidemic

• 7th most common cause of infectious
  disease-related mortality in 2000
• 2 billion people estimated to have been infected
• 4 million acute cases per year
• 360 million are chronic carriers
• 25 develop chronic hepatitis cirrhosis and HCC
• 75 of carriers are Asian
• Hepatitis B is responsible for 60-80 of primary
  liver cancers
• 1 million deaths annually

Source World health organization
4
The epidemic
Source centers for disease control
5
Diversity of the epidemic

• Two very different scenarios

Slide courtesy of clinical care options Mast EE,
et al. MMWR Recomm Rep. 2006551-33.Custer B,
et al. J Clin Gastroenterol. 200438(10
suppl)S158-S168.
6
Transmission in Developing Countries

• Perinatal transmission the highest
• Baby born to an HBeAg positive mother has 90
  chance of being infected
• 25 of these infants will die of Hepatitis
  B-related disease
• China, Senegal and Thailand
• high infant rate and increasing in childhood
• Panama, Papua New Guinea, Greenland
• high childhood infection rates

World Health Organization http//www.who.int/csr/d
isease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf
7
What about South Africa?

• Survey of mine workers (1989)
• Overall prevalence of HBsAg 9.9 ranging from
  5.5 to 14
• Rural KZN
• 81 of women and 86 of men had at least one
  marker of infection
• 4.4 and 7.1 were chronic carriers
• Johannesburg
• 47 of HIV positive patients had some evidence of
  Hepatitis B
• Laboratory screening for HIV vaccine trials
• 106 of 2387 participants were excluded for HBsAg
  positivity
• Overall estimates for chronic HBV are 10 in
  rural areas and 1 in urban settings

Stevens, W et al PLoS ONE. 2008 Apr
303(4)e2043. Dusheiko et al Am J Epidemiology
1989129138-45 Abdool-Karim et al. Am J Public
health 1989 79(7)893-894 C Firhaber et al.
South African Medical Journal Vol. 98 (7) 2008
pp. 541-544
8
Natural History of Hepatitis B

• Variable presentation
• Different manifestations dependent on age, immune
  status and stage of disease
• Acute infection
• Incubation phase 6-24 weeks
• Nausea, malaise, vomiting, diarrhea, sometimes
  jaundice
• Asymptomatic infection
• Very common, most chronic carriers have no
  history of hepatitis
• lt10 of children and 30-50 of adults have
  icteric disease

World Health Organization http//www.who.int/csr/d
isease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf
9
Natural History of Hepatitis B

• Acute hepatitis
• Insidious onset of generalized malaise
• Striking elevations of ALT (up to 100x ULN)
• Icteric phase starts 10 days later
• Large viral dose shorter incubation period and
  more likely to develop icterus
• lt1 of acute cases are fulminant (more likely in
  the elderly)
• 90 are transient, 10 become chronic

World Health Organization http//www.who.int/csr/d
isease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf
10
Outcomes of acute infection
11
Interpretation of serological markers
Resolved infection, false-positive, low-level
chronic, resolving acute infection
Source centers for disease control and
prevention division of hepatitis www.cdc.gov/hepa
titis
12
Pathogenesis

• Chronic hepatitis gt cirrhosis gt hepatocellular
  carcinoma
• HBV not directly carcinogenic
• HBV causes chronic liver damage
• Inflammatory host responses
• Regeneration
• No viral oncogene, insertional mutagenesis, viral
  activation of cellular oncogene has been
  demonstrated

World Health Organization http//www.who.int/csr/d
isease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf
13
Life Cycle of HBV in the Hepatocyte
Subviralparticles
InfectiousHBV virion
Viral polymeraseconverts pre-genomic RNAto
partially ds DNA
ER
Cytoplasm
PartiallydsDNA
HBeAg
Minus strand DNA
Encapsulated pregenomic mRNA
HBsAg
HBcAg
cccDNA
mRNA
Precore/core
Nucleus
Hepatocyte
Slide courtesy of clinical care options Adapted
from Lai CL, et al. J Med Virol. 200061367-373.
14
HBV-Triggered Immune Response
Antigen-presenting cell
HBV
MHCclass II
HBVantigens
CD4T cell
HBVpeptides
HBV DNA
MHCclass I
Down-regulationsof viralreplication
CD8T cell
Infected hepatocyte
HBV RNA
TNF-aInterferon-gamma
HBV peptides
CD8T cell
HBV cores
HBsAg
MHCclass I
Slide courtesy of clinical care options Ganem D,
et al. N Engl J Med. 20043501118-1129.
15
Definitions

• Chronic Hepatitis B
• Chronic necro-inflammatory disease of the liver
  caused by persistent infection with hepatitis B
• Can be HBeAg positive or HBeAg negative
• Diagnostic criteria
• HBsAg gt6 months
• Serum HBV DNA gt20,000 IU (less in HBeAg-)
• Persistent or intermittent elevation of ALT/AST
• Liver biopsy showing chronic hepatitis with
  moderate or severe necro-inflammation

Lok AS, et al. Hepatology. 200745507-539.
16
Definitions

• Inactive HBsAg carrier state
• Persistent HBV infection in the liver without
  ongoing, significant necro-inflammatory disease
• Diagnostic critieria
• HBsAg gt6 months
• HBeAg-, anti-HBe
• Serum HBV DNA lt2000 IU
• Persistently normal ALT levels
• Liver biopsy confirms absence of significant
  hepatitis

Lok AS, et al. Hepatology. 200745507-539.
17
Definitions

• Resolved Hepatitis B
• Previous HBV infection without further virologic,
  biochemical or histological evidence of active
  virus infection or disease
• Diagnostic critieria
• Previous known history of acute or chronic
  hepatitis B (anti-HBc anti-HBs)
• HBsAg -
• Undetectable serum HBV DNA
• Normal ALT levels

Lok AS, et al. Hepatology. 200745507-539.
18
Definitions

• Acute exacerbation or flare of Hepatitis B
• Intermittent elevations of aminotransferase
  activity to gt 10x ULN and
• gt 2x baseline value
• Reactivation of Hepatitis B
• Reappearance of active necro-inflammatory disease
  of the liver in a person known to have inactive
  HBsAg carrier state or resolved hepatitis B
• HBeAg clearance
• Loss of HBeAg in a person who was previously
  HBeAg positive
• HBeAg seroconversion
• Loss of HBeAg and detection of anti-HBe in a
  person who was previously HBeAg positive and
  anti-HBe negative
• HBeAg reversion
• Reappearance of HBeAg in aperson who was
  previously HBeAg negative and anti-HBe positive

Lok AS, et al. Hepatology. 200745507-539.
19
4 Phases of Chronic HBV Infection

• Immune-tolerance phase
• HBeAg positive high HBV DNA (2 x 108-11 IU/mL)
  normal ALT
• HBeAg positive chronic hepatitis (immune
  clearance)
• Intermediate to high HBV DNA (200,000 - 2 x 109
  IU/mL) high or fluctuating ALT active
  inflammation on liver biopsy
• Inactive HBsAg carrier (low replication phase)
• HBeAg negative low HBV DNA (lt 2000 IU/mL)
  normal ALT
• HBsAg may become undetectable
• HBeAg-negative chronic hepatitis (reactivation
  phase)
• Intermediate to high HBV DNA (200,000 - 2 x 109
  IU/mL) high or fluctuating ALT active
  inflammation on liver biopsy

Slide courtesy of clincal care options Lok AS, et
al. Hepatology. 200745507-539. Pungpapong S,
et al. Mayo Clin Proc. 200782967-975.
20
Phases of Chronic HBV Infection
Slide courtesy of Clinical Care Options A. S. F.
Lok, MD.
21
Natural history of chronic infection

• Majority of carriers eventually loose HBeAg and
  develop anti-Hbe
• In SSA, seroconversion happens near puberty
• Rate of clearance is 8-12 per year
• Lower in carriers in the immune-tolerant phase
• Lower in immunocompromised patients
• Clearance may follow exacerbation of hepatitis
  with elevated ALT
• Older age, higher ALT, HBV genotype B associated
  with higher rate of spontaneous clearance

Lok AS, et al. Hepatology. 200745507-539.
22
Natural history of chronic infection
Chronic Hepatitis B (All HBsAg )
HBeAg - Anti-HBeAg
HBeAg
8-12 per yr
10-30
67-80
4-20
Inactive carrier Undetectable DNA No inflammation
Elevated ALT Detectable HBV DNA

• Lifelong follow-up of patients
• 0.5 of HBsAg carriers clear yearly
• Clearing HBeAg associated with increased survival
  and decreased risk of hepatic decompensation

10-20
Reactivation HBeAg chronic hepatitis
Lok AS, et al. Hepatology. 200745507-539.
23
HBeAg negative chronic hepatitis

• Results from moderate or high level replication
  and reactivation in a patient who has cleared
  HBeAg
• Usually due to HBV variants in the pre-core or
  core promoter region with resulting inability to
  produce HBeAg
• Lower serum HBV DNA (mio)
• Patients are older and have more advanced liver
  disease
• 29-38 have cirrhosis at the time of presentation
• Represents later stage in natural course of
  Hepatitis B infection

Lok AS, et al. Hepatology. 200745507-539.
24
More on HBeAg negative chronichepatitis

• The incidence of liver cirrhosis
• Twice as high in HBeAg negative compared with
  HBeAg positive chronic hepatitis B patients.
• 5-year cumulative risk of developing
  hepatocellular carcinoma
• 17 in East Asia
• 10 in Western Europe and the U.S.
• 5-year rate of liver-related death
• 14 in East Asia
• 15 in Europe.

Fattovich G et al. J Hepatol. 2008
Feb48(2)335-52.
25
HBeAg-Negative Chronic Hepatitis B

• Most common in genotypes B, C, and D
• Asia and Southern Europe
• Not typically acquired as de novo infection
• Pre-core and basal core promoter mutants emerge
  during immune clearance phase
• 2 main patterns
• Persistently increased ALT, intermediate to high
  HBV DNA levels
• 30 to 40 of patients
• High HBV DNA levels before ALT increases
• Erratic ALT increases, low or negative HBV DNA
• 45 to 60 of patients
• Sustained spontaneous remission is uncommon (6
  to 15) and long-term prognosis is poorer
  compared with HBeAg-positive patients

Keeffe EB, et al. Clin Gastroenterol Hepatol.
20064936-962.
26
Risk factors for progression
27
Distribution of Hepatitis B Genotypes
Source clinical care options
28
Impact of HBV Genotype on Disease Progression

• Genotype C
• More frequently associated with severe liver
  disease and HCC than with genotype B
• Genotype B
• Associated with seroconversion from HBeAg to
  anti-HBe at younger age than with genotype C
• Genotypes A and B
• Higher rates of antiviral response and HBeAg
  loss following peginterferon alfa-2b than with
  genotypes D and C, respectively

Slide courtesy of Clincal Care Options Keeffe EB,
et al. Clin Gastroenterol Hepatol. 20064936-962.
29
Hepatitis B and HIV co-infection

• Liver disease leading cause of morbidity and
  mortality in HIV positive
• 6-13 of HIV positive patients also have chronic
  Hepatitis B
• Approximately 4 million cases
• Higher in places where both are endemic
• 65 of HIV in USA have evidence of HBV

Soriano et al. AIDS 200821(12)1399-410 Lok AS,
et al. Hepatology. 200745507-539.
30
Hepatitis and HIV interaction

• Increased HBV carriage rates
• Higher levels of HBV DNA
• More rapid decline in anti-HBsAg
• Lower rates of spontaneous HBeAg seroconversions
• Faster progression to cirrhosis
• HCC develops at younger age and is more
  aggressive
• Liver-related mortality
• MACS 8-fold increase rates of liver-related
  mortality
• EUROSIDA 3.6-fold increase
• Low CD4 counts

Soriano et al. AIDS 200821(12)1399-410 Lok AS,
et al. Hepatology. 200745507-539.
31
Hepatitis B and HIV

• Loss of CD4
• reactivation in previously healthy carriers
• rapidly progressive fibrosing cholestatic
  hepatitis
• Hepatitis flares during IRIS
• Other co-morbidities can cause ALT elevation
  (CMV, MAI)
• Occult HBV
• High levels of HBV DNA and inflammation
• Negative HBsAg but Anti-HBc positive
• HERS study high rates of occult HBV in HIV
  positive women1

Lok AS, et al. Hepatology. 200745507-539 1.Taylo
r L et al.. XVII International AIDS Conference,
Mexico City, abstract THAB0204, 2008.
32
What do we need toknow to manage Hepatitis B?

• Given we have HBsAg
• Anti-HBc
• HBeAg
• Anti-HBeAg
• Serum delta antibodies
• HBV DNA
• In HIV fibrosis at lower ALT, less inflammation
• Additionally, it would be nice to have
• Liver biopsy/ fibroscan/ fibrotest
• But most importantly
• History, physical exam, risk factors for
  progression

33
Treatment

• Aims
• Achieve sustained suppression of viral
  replication
• Remission of liver disease
• ALT normalization
• HBeAg seroconversion
• Improvement of liver histology

Soriano et al. AIDS 200821(12)1399-410 Lok AS,
et al. Hepatology. 200745507-539.
34
Who should be treated?
Adapted from Mandell, Douglas Bennett,
Principles and Practice of Infectious disease 6th
Edition
35
Algorithm in HIV positive
HBV DNA gt2000
HBV DNA lt2000
ALT elevated
ALT Normal
Mild fibrosis
Significant fibrosis
No Treatment
Treatment

• Soriano et al. AIDS 200821(12)1399-410

36

• Treatment should be offered in patients who meet
  the following criteria, regardless of CD4 count
• hepatitis B e antigen positive
• raised ALT (more than twice upper limit of
  normal)
• evidence of fibrosis on biopsy or on appropriate
  imaging
• hepatitis B viral load gt10 000 copies/ml.
• The ART regimen should include tenofovir (TDF)
  and lamivudine (3TC) or emtricitabine (FTC).

37
Interferon a 2b

• Interferon a 2b
• Antiviral, anti-proliferative, immunomodulatory
  and anti-fibrotic
• Mechanism?
• Pegylated better side-effect profile
• Cost and SE are prohibitive
• Shorter duration of treatment in HBeAg positive,
  12 months in HBeAg negative
• Duration of HBeAg clearance 80 at 4-8 y

38
Nucleoside Analogues

• Reverse transcription step in lifecycle
• Inhibition of the viral DNA polymerase by chain
  termination
• Lamivudine
• HBeAg seroconversion rates 16-18 compared to 6
  control
• Cannot eliminate cccDNA- durability?
• Treat seroconverters for one year
• Continue for longer if no seroconversion but HBV
  suppressed
• Histological benefit
• Further chance of seroconversion
• If HBV not suppressed - no benefit
• Resistance is a major issue 80 at 5 years

39
Treatment options
Lok AS, et al. Hepatology. 200745507-539.
40
Tenofovir

• Indicated in treatment-naïve HBeAg/- compensated
  liver disease
• Not evaluated in decompensated disease
• Treatment-experienced or LAM-associated mutations
  not well represented in the study
• Reviewed Studies 907 and 903 for Hepatitis B
  outcomes (n5/6)

AUGUST 15, 2008!
Dore et al. JID 2004189 (1 April) 1185
41
Resistance
Nash K et al. Lancet ID 20088444-48
42
Combination treatment

• High rates of resistance, including multidrug
  resistant HB
• Should we learn from HIV and TB?
• Resistance longer to develop- difficult to assess
  outcomes
• Less efficient replication less liver disease?
• Breakthrough replication causes liver disease
• Patients with low-level replication progress
• Lamivudine and adefovir are dissimilar and
  synergistic in vitro
• 44 monotherapy vs 19 combination had
  breakthrough1

Nash K et al. Lancet ID 20088444-48 1. Sung et
al. J Hepatol 200848728-35
43
CombinationTreatment

• Several studies in treatment-experienced patients
  show superior outcome
• Use add-on approach
• Naïve patients
• Lack of evidence
• Short term studies no superiority (Virologic
  response)
• Interferon and lamivudine
• Nucleoside/nucleotide analogues
• Used post-transplantation
• In HIV coinfection

Nash K et al. Lancet ID 20088444-48
44
And in HIV co-infection?

• If HIV treatment not indicated
• Avoid HIV active drugs
• HAART despite high CD4
• If HIV treatment warranted
• Two NA active against Hepatitis B
• High rates of LAM resistance
• No evidence of efficacy of FTC as monotherapy
• Do not withdraw 3TC or TDF when switching to
  another regimen
• Potentially fatal flares may occur

Jain et al J viral Hepat 2007 14176-82 Bani-Sadr
et al. Clin Infect Dis 2004391062-64
45
Other approaches prevention
46
Other Approaches

• Detection of positive mothers
• Vaccination of infants (/- HBIG if born to
  positive mother)
• Vaccination of susceptible individuals
• Health care workers
• Other exposed
• Screening of all HBsAg adults gt20 years for HCC
  (SSA)
• AFP and US
• Vaccinate against Hep A
• Avoid other liver injuries

47
Summary

• Huge PREVENTABLE problem
• Vaccination program will decrease incidence
• For infected patients
• Accurate interpretation of serology
• Anti-Hbc positive only
• Occult HBV (DNA only, no serology)
• Always ask for HBeAg as this is the major
  determinant of disease and outcomes
• Treatment with combination therapy
• Careful with HIV treatment changes

48
Post-test question

• How many times did I mention HBeAg?
• Questions?