BORDERNETwork
Training on
Hepatitis B
Dr. med. Wolfgang Güthoff /
Alexander Leffers, M.A.
www.bordernet.eu
www.aidshilfe-potsdam.de
This presentation arises from the
BORDERNETwork project which
has received funding from the
European Union, in the framework
of the Health Program, and cofunding
of
the
Ministry
of
Environment,
Health
and
Consumer
Protection
of
the
Federal State of Brandenburg. The
sole responsibility of any use that may
be made of the information lies with the
authors (SPI, AIDS-Hilfe Potsdam e.V.)
Table of Contents
Epidemiology
Genotypes
Natural Course
Diagnostic
Therapy
Treatment
Viral Hepatitis
Virus
Transmission
Clinical outcome
Hep. A
RNA
fecal-oral
never chronic
Hep. B
DNA
parenteral
5-10% chronic
Hep. C
RNA
parenteral
50 - 80% chronic
Hep. D
RNA
parenteral
as super infection
90% chronic
Hep. E
RNA
fecal-oral
never chronic
Viral Hepatitis B
Country
HBsAg+
(%)
China
5,3 - 12
(2)
South Korea
2,6 - 5,1
(2)
India
2,4 - 4,7
(2)
Taiwan
10 - 13,8 (2)
Vietnam
5,7 - 10
(2)
Japan
4,4 - 13
(3)
Africa
5 - 19
(2)
Russia
1,4 - 8
(2)
US / Europe
0,3 - 12
(2)
HBV:
 DNA-Virus
 worldwide ca. 350 - 400
Millions with chronic infection
Incubation period:
 2 - 6 months
Transmission ways:
 blood contact
 sexual intercourse
 vertical transmission
Distribution of Chronic HBV Infection
> 8 % High
2 - 8 % Intermediate
< 2 % Low
1. WHO. Hepatitis B. 2002.
2. Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl): p. 158.
3. WHO/WPRO data.
Epidemiology of HBV (WP7 Countries)
Country
No. Of Persons with Reported no of Prevalence Incidence 2006-08,
HBV/HIV Co
chronic HBV estimated persons with
rate
cases per 100.000 infection estimated
chronic HBV
Bulgaria
no data
no data
Estonia
no data:
no data
no data
9,9
no data
3,5
(NIHD: 2,16 in 2009
/ 1,72 in 2010)
1,2
1,1
no data
Germany
Poland
492.300
1.400.000
1.276 in 2009
0,6
3,7
no data
~10.000
Romania
1.200.000 – 1.300.000
~ 20.000
5,6
5,1
Slovakia
32.474
no data
0,6
2,1
~10.000 / 2.400
reported
no data
Ukraine
no data
no data
no data
no data
no data
BORDERNETwork Questionnaire for Cooperation Partners;
http://ecdc.europa.eu/en/publications/Publications/101012_TER_HepBandC_survey.pdf
http://ecdc.europa.eu/en/publications/Publications/TER_100914_Hep_B_C%20_EU_ neighbourhood.pdf
OECD Health Data 2010; WHO Europe (2010). Health at a Glance Europe 2010
Distribution of HBV Genotypes
Ae,
Bj, C,
D, F
B, A/Bj
H
B, C,
A, D,
G
A
G
D
D
F, H
B, C
A, D
B3
E
H, F2
A, a
B, C, D
HBV Genotypes
Genotype
Region
Comments
A
Northern America,
Northern Europe
India
Africa
•
•
•
More sensitive to pegIFN
ALT more frequently
More rapid 3TC resistance
B
Asia
•
•
More benign
More sensitive to pegIFN
C
Asia
•
More severe disease, HCC
D
Southern Europe
Middle East and India
•
•
Less response to pegIFN
Pre-core mutations higher
E
F
G
H
West- and South Africa
Central- and South America
USA and Europe
Central America and California
•
Unknown
Natural History of Hepatitis B
Asymptomatic Carrier
Resolution
Acute Hepatitis B
Fulminant Hepatitis
HBsAg Positive
> 6 Month
Chronic HBeAg
negative VBH
Chronic Hepatitis
Zirrhosis
HCC
Chronic HBeAg
positive VBH
Clinical Outcome of Chronic HBV Infection
Acute
Hepatitis B
____________
Chronic
Hepatitis B
____________
Liver Cirrhosis
____________
Liver Cancer
HCC
____________
Acute liver
infection is
subclinical in
about 70%
Development of
chronic
liver
disease in 5 –
95%
5-year rate of
progression from
chronic Hepatitis
to cirrhosis is 1020%
Increasing risk for
HCC in patients
with cirrhosis and
with high
HBVDNA levels
Virus B Hepatitis and HCC
Chen CJ et al. JAMA 2006; 295: p. 65 – 73.
R E V E A L: 4.155 Patients with
chronic hepatitis B infection were
followed up over 11 years high HBVDNA concentration is associated
with increasing HCC risk
Diagnostic of HBV – Infection
Viral components
Viral surface
HBsAg
Antibodies
antiHBs
antiHBc IgM
core -
HBcAg
antiHBc
Viral core
antiHBc IgG
envelope -
HBVDNA
HBeAg
antiHBe
Immunologic Markers of HBV Infection
HBsAg
HBeAg
HBVDNA
Anti HBc
IgM
Anti HBc
IgG
Anti
HBe
Anti
HBs
ALAT
Acute Virus B
Hepatitis
+
+
+
+
Ø
Ø
Ø
Chronic HBeAg
pos. Hepatitis
+
+
+
Ø
+
Ø
Ø
Chronic HBeAg
neg. Hepatitis
+
Ø
+
Ø
+
+
Ø
Chronic HBeAg
neg. HBV
Infection (Carrier)
+
Ø
Low or
negative
Ø
+
+
Ø
normal
Occult Virus B
Hepatitis
Ø
Ø
+
Ø
+
+
+
normal
Hepatitis
Recovery
Ø
Ø
Ø
Ø
+
+
+
normal
Vaccination
Ø
Ø
Ø
Ø
Ø
Ø
+
normal
Who Should Be Tested for Hepatitis B?
 Blood- and organs donors
 Pregnant women
 Infants of HBsAg + mothers
 Household and sexual contacts with HBV infected persons
 MSM, IDU, HIV infected persons
 Individuals from countries where prevalence is ≥2%
 Patients receiving immunosuppressive therapy
 People with signs of liver disease and/or elevated liver
enzymes
Treatment of Chronic Hepatitis B
HBe positive Hepatitis
HBsAg positive
HBeAg positive
HBe negative Hepatitis
(YMDD – Mutation)
HBsAg positive
HBeAg negative
Decision for therapy depends on:
HBVDNA concentration (>2000 IU/ml)
liver biopsy with grading and staging
ALAT / ASAT increased
Patients with HBeAg negative chronic Hepatitis have more severe histological changes,
the incidence of cirrhosis appears to be twofold higher than HBeAg positive patients.
Two Different Treatment Strategies
Peg-Interferon:
 Induction of sustained virological
response with limited duration of
therapy (48 weeks)
Nukleos(t)idanalogues:
 Long term suppression of HBVreplication
 Improvement of histology
 Problem: Development of drug
resistance
 Elimination of HBV?
Development of Therapy in chronic VBH
(Interferon, Nukleosidanalogues, Nukleotidanalogues)
1992
alfa-Interferon
1999
Lamivudine (Zeffix)
2003
Adefovir (Hepsera)
2005
Peg-IFNa-2a (Pegasys)
2006
Entecavir (Baraclude)
2007
Telbivudine (Sebivo)
2008
Tenofovir (Viread)
Treatment of Chronic Hepatitis B
 Pegylated Interferon is given by injection once a week for 48 weeks.
The drug can cause side effects such as flu-like symptoms and depression.
 Lamivudine with few side effects, but drug resistance
 Adefovir Dipivoxil (Hepsera) with few side effects, but low antiviral activity
 Entecavir (Baraclude) with few side effects, high antiviral activity
 Telbivudine (Tyzeka, Sebivo) with few side effects, but development of drug
resistance
 Tenofovir (Viread) with few side effects, approved August 2008 for adults
Characterization of Different
Nukleos(t)ide- Analogues
Nukleotide-Analogues
TDF
moderate
LdT
Lam
Low
Antiviral Potency
high
Nukleoside-Analogues
ADV
low
middle
Genetic Barrier
high
ETV
Aims of Therapy in Chronic Hepatitis B
 Reduce morbidity and mortality of HBV
infected persons
 Increase of survival
Treatment endpoints (1)
HBVDNA level
 complete and persistent suppression
is a reliable endpoint for clinical
progression of liver disease
Seroconversion - Treatment endpoints (2)
HBeAg positive chronic Hepatitis B
HBeAg negative chronic Hepatitis B
HBeAg positive
HBeAg negative
antiHBe positive
HBsAg positive
HBsAg negative
antiHBs positive
HBsAg positive
HBsAg negative
antiHBs positive
Treatment endpoints (3)
In all cases:
biochemical:
Sustained ALAT normalisation
histological:
Reduction of fibrosis stage or
absence of progression
Reduction of inflammatory
activity
Treatment endpoints (4)
HBsAg seroconversion to anti HBs
 complete eradication of HBV is impossible
 covalently closed circular HBVDNA (cccDNA)
persists in hepatocytes
 reactivation can occur in certain circumstances
(Rituximab)
Hepatitis B - Indication for Therapy
(Limited liver function: Prolonged prothrombin time (Quick-Test < 50%)
HBsAg-positive
Acute
hepatitis B?
NO
NO
HBV-DNA
> 2.000 IU/ml?
Chronic
hepatitis B?
Liver cirrhosis
NEW: ALT repeated
raised or histology
> A1/F1?
NO
NO
Extra hepatic manifestations
or risk of HCC
NO
No Therapy
Yes
HBV-DNA
positive?
Yes
No therapy;
Monitoring all
6 – 12 Months
Therapy
Limited liver
function?
Yes
NO
Yes
Yes
Yes
Cornberg et al. Z Gastroenterol 2011; 49: 871-930.
Yes
NO
Indication for
therapy
No therapy;
Monitoring all
6 – 12 Months
Treatment Algorithm for Chronic HBV
(PEG)-Interferon
alpha
Yes
Temporally limited therapy
with PEG-IFN (48 weeks)
NO
No liver cirrhosis
Liver cirrhosis
Nukleos(t)id-Analogue
with high genetic barrier
Nukleos(t)id-Analogue: Choice depends on:
Viral load, co-morbidity, former therapy
Virological response after 6 – 12 months?
After 6 months
HBV-DNA
< 200 IU/ml
Continue therapy
After 12 months
HBV-DNA negative
Check HBV-DNA
all
3 – 6 months
Cornberg et al. Z Gastroenterol 2011; 49: 871-930.
With high viral load it
can take longer, but
continuous
HBV-DNA decrease
without plateau is
important
If HBV-DNA
increases
> 1 log over nadir
No response
Therapy adherence?
Yes
Adjust therapy
Suggestions for adaptation of therapy in case of insufficient virological
response or development of resistance in nucleos(t)id-analogue-mono-therapy
Insufficient response to therapy / resistance
Options1
Lamivudine
 Change to Tenofovir (A)
 (Change to Entecavir)2
 Change to Tenofovir (B)
 Change to Entecavir (B)
 Change to Tenofovir (A)
 Change to Tenofovir (A)
 (Change to Entecavir)2
 Change to Entecavir, or
Adefovir3
Entecavir
Telbivudine
Tenofovir4
add Lamivudine, Telbivudine or Entecavir (C)
1
These suggestions are not proved in all cases through controlled studies.
Entecavir can be used, if presence of virus variants with resistance against Entecavir is excluded, and the application
of Tenofovir is not possible through other reasons.
3 Adefovir is no more recommended for the first line therapy. In case of therapy adaptation possible pre-treatment with
Lamivudine and existence of confirmed drug resistance have to be regarded.
4 So far for Tenofovir no resistances are demonstrated.
2
Strategy for prevention of HBV Reactivation
Patients, who will get a high dosage* immunosuppression
Measurement of HBsAg and anti-HBc
(if positive, also HBV-DNA for exclusion of occult HBV-infection)
HBsAg positive
HBsAg negative,
Anti-HBc positive**
HBsAg negative,
Anti-HBc negative
or occult HBV-infection
Control of HBV-DNA in
short terms
Vaccination (if antiHBs < 100 IU/l)
HBV-DNA positive
HBV-DNA negative
Therapy with a Nukleos(t)id-Analogue***
6 – 12 month after stopping immune suppressive therapy treatment finishing is possible,
if there is no further indication
*
The risk for Hepatitis-B-Reactivation depends on the degree of Immunosuppression
** Exception: Pre-emptive therapy should be done in bone marrow and stem cell transplantation
*** Choice of drug depends on: e.g. viral load, co morbidities
Patients who will receive or already receive
immunosuppressive or chemotherapy
 Up to 50% with HBV carrier status develop HBV reactivation
under immunosuppressive or chemotherapy
 Reactivations occur more frequently with regimens that contain
corticosteroids or rituximab
 Every NUC is possible,
 If the patient is expected to be treated for more than 6 month ETV or TDF should be preferred
How the therapy with nucleos(t)id-analogue
can be stopped?
HBeAg+
HBeAg-
Seroconversion
HBeAg-/anti-HBe+
No
seroconversion
End of therapy:
earliest 12 months
after Seroconversion
& HBV-DNA negative
Long-term therapy
Long-term therapy
End of therapy: anti-HBs-seroconversion
Cornberg et al. Z Gastroenterol 2011; 49: 871-930.
Hepatitis B and special Circumstances:
1. Acute and Fulminant Hepatitis B
 Fulminant hepatitis B is a life threatening event and may require liver
transplantation
 A treatment should be started:
• if the patient has a deep jaundice more than 4 weeks and
prolongation of INR
 First line: Tenofovir, Entecavir
 Second line: Lamivudine, Telbivudine
 Do not use Interferon and Adefovir
Hepatitis B and special Circumstances:
2. Patients with Liver Cirrhosis
Aim of therapy: Prevention of liver related complications and
liver cirrhosis
progression
 Treatment should not be based on elevated ALAT
 First line: Drugs with high viral potency and high genetic
barrier to HBV resistance, such as Entecavir and Tenofovir
 For settings were these drugs are not available, treatment
with Lamivudine or Adefovir is also possible,
 Close monitoring for treatment complications is necessary
Pregnant Women with Hepatitis B
 Pregnancy is no contraindication for treatment with NUC, but
Interferon is contraindicated
 An existing therapy with Lamivudine or Tenofovir can be continued
 A therapy with Adefovir or Entecavir should be changed
 It is also possible to start a treatment during pregnancy,
 It should be done, if there is a risk of liver de-compensation or a
high level of HBVDNA
 Treatment should be continued at least 6 month after delivery
Summary
liver cirrhosis
 Great advances in diagnosis and treatment of chronic
Hepatitis B in the last 15 years
 Morbidity and mortality of chronic Hepatitis B can be
reduced
• by increasing awareness,
• by commitment of drugs,
• by managing the therapy in a good clinical practice.