Management of HBV Infection

1
Management of HBV Infection
2
28 year old woman with no significant PMH is
referred for evaluation of HBsAg positivity She
is fit and healthy and asymptomatic She was born
in Korea and her family moved to the UK when she
was 5 yo She works in advertising, is single, and
has no children. She is sexually active with one
male partner and does not use barrier
contraception. She drinks approximately 15
units of alcohol/ week Non smoker She also
denies a history of blood transfusion or
intravenous-drug use. Her mother was diagnosed
with hepatitis B and HCC 8 months ago. She has no
siblings
3
OE No stigmata of CLD Abdomen soft,
non-distended, non-tender, liver edge smooth,
liver span 8 cm by percussion, no splenomegaly
Bloods HBsAg positive HIV negativeHepatitis
C virus (HCV) antibody (Ab) negativeHepatitis A
virus (HAV) IgG/IgM negative ALT 38 U/L (10-50
U/L) FBC NormalAST 26 U/L (10-40 U/L) UE
NormalALP 114 U/L (30-140 U/L) INR
NormalBili 17 ?mol/L (10-23)
4

• Which of the following blood tests would provide
  the most useful information
• to characterize the status of chronic hepatitis
  B and guide recommendations
• regarding antiviral therapy?
• HBeAg, HBsAb, and hepatitis B core antibody
  (HBcAb)
• HBeAg, HBeAb, and HBV genotype
• HBeAg, HBeAb, and HBV DNA viral load
• HBeAg, HBV DNA, and sequencing for YMDD mutation

5

• Which of the following blood tests would provide
  the most useful information
• to characterize the status of chronic hepatitis
  B and guide recommendations
• regarding antiviral therapy?
• HBeAg, HBsAb, and hepatitis B core antibody
  (HBcAb)
• HBeAg, HBeAb, and HBV genotype
• HBeAg, HBeAb, and HBV DNA viral load
• HBeAg, HBV DNA, and sequencing for YMDD mutation

6
HBV DNA

• HBV DNA load is measured by polymerase chain
  reaction (PCR)
• This can be qualitative or quantitative
• In a prospective cohort study of gt3500 patients
  with chronic hepatitis B,
• serum HBV DNA level was shown to be a powerful
  predictor
• progression to cirrhosis
• HBV DNA levels tend to be higher in
  HBeAg-positive patients
• compared with HBeAg-negative patients.

7
Cumulative Incidence of Liver CirrhosisREVEAL
HBV Study
37.1
1.0 x 106 n627 1.0-9.9x105 n344 1.0-9.9x104
n649 300-9.9x103 n1210 lt300 n944
n3,774
23.0
Cumulative incidence of liver cirrhosis
.2
.1
10.0
6.3
5.2
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Year of follow-up
P value for log-rank test, lt0.001
Uchenna H. I, et al. Gastroenterology 2006
130678-686
8
High Serum HBV DNA Levels are Associated with
Increased Risk of HCC Mortality
HBV DNA Negative
HBV DNA Low lt 105 copies/mL RR 1.7 (0.5-5.7)
HBV DNA High gt 105 copies/mL RR 11.2 (3.6-35.0)
p lt 0.001 across viral categories
Chen G, et al. J Hepatology 2005 42 (suppl
2)477A. Chen G, et al. Hepatology 2005 40
(suppl 1)594A.
9
Genotype

• There are 8 genotypes of hepatitis B (A through
  H)
• The clinical utility of HBV genotype has not yet
  been clearly
• defined.
• Although it is not routine, it may be reasonable
  to document
• HBV genotype prior to commencing antiviral
  therapy as in
• future HBV genotype may assumea more pivotal
  role in the
• management of hepatitis B.

10
The Emerging Role of HBV Genotypes

• Clear association with
• Precore/core promoter mutations
• Rates of HBeAg clearance
• Development of HBeAg-neg Chronic Hepatitis B
• Possible association with
• Liver disease activity
• Progression to cirrhosis
• Risk of HCC
• Response to IFN and nucleoti(si)de analogs

11
HBV Genotypes
F
D
A
A
B
C
D
C
Bj
D
D
C
D
D
Ba
E
F
F
A
Fung Lok, Hepatology 200440790-2
12
Further Blood results
AST 35 U/L HBsAg positiveALT 40 U/L HAV
IgG/IgM negative bilirubin 20 mmol/L HCV Ab
negative ALP 121 mg/d Hepatitis D virus (HDV)
IgM negativeHIV negative HBeAg
negativeHBeAb positiveHBV DNA 25,000
IU/mLHBV genotype B
13

• Which statement is false regarding this patient's
  hepatitis B status?
• She is an inactive carrier of hepatitis B
• She is not in the immune-tolerant phase
• She likely has a mutation in the precore or core
  promoter region
• of the HBV genome
• HBeAg positivity is associated with a better
  prognosis than
• HBeAg negativity

14

• Which statement is false regarding this patient's
  hepatitis B status?
• She is an inactive carrier of hepatitis B
• She is not in the immune-tolerant phase
• She likely has a mutation in the precore or core
  promoter region
• of the HBV genome
• HBeAg positivity is associated with a better
  prognosis than
• HBeAg negativity

15
Viral fluctuation patterns are different in
different stages of the disease
16
Serologic Markers of Hepatitis B HBV Status

• HBsAg positive gt 6 months Chronic hepatitis B
• Anti-HBs positive Immunity to HBV infection
  (vaccination or clearance of infection)
• Anti-HBc IgG positive Prior exposure to HBV
• Anti-HBc IgM positive Acute HBV infection or
  reactivation of HBV
• HBeAg positive Active viral replication
• HBeAg negative Pre-core/core promoter mutation
  or non-replicative HBV infection
• Anti-HBe positive HBeAg seroconversion or
  precore/core promoter mutation

17
Which of the following statements is true
regarding lifestyle modifications and prevention
of spread of infection in this patient? A)The
amount of alcohol that this patient consumes is
insufficient to have an adverse impact on
disease course B) Her sexual partner is at high
risk for acquiring HBV infection, and
therefore should be started on hepatitis B immune
globulin (HBIG) C) The patient should receive a
2-dose series of vaccinations for hepatitis
A D) The risk for sexual transmission of
hepatitis B is considerably less than that
for hepatitis C
18
Which of the following statements is true
regarding lifestyle modifications and prevention
of spread of infection in this patient? A)The
amount of alcohol that this patient consumes is
insufficient to have an adverse impact on
disease course B) Her sexual partner is at high
risk for acquiring HBV infection, and
therefore should be started on hepatitis B immune
globulin (HBIG) C) The patient should receive a
2-dose series of vaccinations for hepatitis
A D) The risk for sexual transmission of
hepatitis B is considerably less than that
for hepatitis C
19
Lifestyle Modifications

• The patient should be informed of the potential
  modes of transmission,
• including sexual transmission, blood exposure,
  and vertical transmission.
• Close contacts should be tested for HBV and
  should be vaccinated if not
• immune.
• Patients with HBV infection should be vaccinated
  for hepatitis A if not
• already immune.
• Abstinence from alcohol is advisable as there is
  no clear safe limit for alcohol
• use and they should be advised to avoid
  hepatotoxic medications.
• Risk factors for the acquisition of other
  viruses, including HCV and HIV,
• should also be addressed.

20

• Considering this patient's clinical status and
  laboratory studies,
• what is the most appropriate next step in
  management?
• A) Start lamivudine 100 mg once daily
• B) Start one of the "second-generation" oral
  antiviral medications, such as
• adefovir 10 mg od, entecavir 0.5 mg od, or
  telbivudine 600 mg daily
• C) Obtain a liver biopsy
• D) Observation readdress initiation of treatment
  if serum ALT increases

21

• Considering this patient's clinical status and
  laboratory studies,
• what is the most appropriate next step in
  management?
• A) Start lamivudine 100 mg once daily
• B) Start one of the "second-generation" oral
  antiviral medications, such as
• adefovir 10 mg od, entecavir 0.5 mg od, or
  telbivudine 600 mg daily
• C) Obtain a liver biopsy
• D) Observation readdress initiation of treatment
  if serum ALT increases

22
Role of Liver Biopsy

• Serum ALT and HBV DNA level are generally, good
  surrogate markers of
• disease activity.
• BUT patients may have normal serum ALT in the
  setting of marked
• inflammation and/or fibrosis on liver biopsy.
• HBV DNA levels generally correlate well with the
  degree of disease
• activity. However, HBV DNA levels fluctuate, and
  a higher viral
• load does not always predict advanced disease.
• Conversely, patients with a lower (yet still
  elevated) viral load may still
• have advanced liver disease, including cirrhosis.

23
Cumulative Incidence of Liver CirrhosisREVEAL
HBV Study
37.1
1.0 x 106 n627 1.0-9.9x105 n344 1.0-9.9x104
n649 300-9.9x103 n1210 lt300 n944
n3,774
23.0
Cumulative incidence of liver cirrhosis
.2
.1
10.0
6.3
5.2
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Year of follow-up
P value for log-rank test, lt0.001
Uchenna H. I, et al. Gastroenterology 2006
130678-686
24
Liver Biopsy showed Grade 1 inflammation and no
fibrosis
25
What is the most appropriate management strategy
at this time? A) Start lamivudine 100 mg once
daily B) Start adefovir 10 mg once daily C)
Start entecavir 0.5 mg once daily D)
Observation follow liver function tests every 3
months for 1 year
26
What is the most appropriate management strategy
at this time? A) Start lamivudine 100 mg once
daily B) Start adefovir 10 mg once daily C)
Start entecavir 0.5 mg once daily D)
Observation follow liver function tests
every 3 months for 1 year
27

• Which of the following statements is true
  regarding HCC screening in this patient?
• HCC screening is not necessary because there is
  no fibrosis on biopsy
• HCC screening should be initiated because the
  patient's age and sex place her at higher risk
  for HCC
• Her ethnicity places her at higher risk for HCC
  than if she were of African descent
• Her family history of HCC increases her risk for
  HCC, and therefore screening should be initiated

28

• Which of the following statements is true
  regarding HCC screening in this patient?
• HCC screening is not necessary because there is
  no fibrosis on biopsy
• HCC screening should be initiated because the
  patient's age and sex place her at higher risk
  for HCC
• Her ethnicity places her at higher risk for HCC
  than if she were of African descent
• Her family history of HCC increases her risk for
  HCC, and therefore screening should be initiated

29
Case Continued Two years later the patient is
seen by her GP with new complaints of fatigue and
cervical lymphadenopathy. Lymph node biopsy
reveals a diagnosis of non-Hodgkin's lymphoma.
Chemotherapy with rituximab and CHOP
(cyclophosphamide, doxorubicin, vincristine, and
prednisone) is planned. Serum ALT remains within
normal range and HBV DNA level at this time is lt
2000 IU/mL. The patient decides to undergo
chemotherapy at a hospital closer to family
members who live in another part of the country.
You discuss her case with the oncologist who will
be assuming her care.
30
What are your recommendations at this time? A)
Continue to follow serum aminotransferases and
HBV DNA levels at monthly intervals while
she is receiving chemotherapy. Begin antiviral
therapy if ALT level rises to gt 2 times
ULN. B) Continue to follow serum
aminotransferases and HBV DNA levels at
monthly intervals while she is receiving
chemotherapy. Start antiviral therapy if
her HBV DNA level rises gt 20,000 IU/mL even if
serum ALT remains normal. C) Start
lamivudine 100 mg once daily. Continue for at
least 3 months after completion of
chemotherapy. D) Given that the HBV load is
undetectable, her disease is classified as
inactive and she no longer needs regular
follow-up at all.
31
What are your recommendations at this time? A)
Continue to follow serum aminotransferases and
HBV DNA levels at monthly intervals while
she is receiving chemotherapy. Begin antiviral
therapy if ALT level rises to gt 2 times
ULN. B) Continue to follow serum
aminotransferases and HBV DNA levels at
monthly intervals while she is receiving
chemotherapy. Start antiviral therapy if
her HBV DNA level rises gt 20,000 IU/mL even if
serum ALT remains normal. C) Start
lamivudine 100 mg once daily. Continue for at
least 3 months after completion of
chemotherapy. D) Given that the HBV load is
undetectable,her disease is classified as
inactive and she no longer needs regular
follow-up at all.
32
Chemotherapy and HBV

• HBV reactivation is common among patients
  receiving
• chemotherapy
• haematological malignancy gt solid malignant
  tumors.
• 21 to 53 of patients who are HBsAg positive
  will have a
• flare with chemotherapy.
• HBsAg-positive patients are at the highest risk.

33
Chemotherapy and HBV

• BUT
• Patients with resolved HBV infection (ie,
  HBsAg-negative, HBcAb positive
• and HBsAb-positive) may have reactivation with
  immunosuppression.
• Worse if
• HBeAg-positivity
• High pretreatment HBV load
• Male sex
• Young age
• High pretreatment serum ALT
• The risk for hepatic decompensation is greatest
  during recovery from
• immunosuppression

34
Current Advice

• All patients undergoing chemotherapy should be
  screened
• for HBV Infection. (Flares have been seen with
  the use of
• Immunomodulatory drugs such as infliximab/rituxima
  b)
• Consider Rx in hepatitis B cAbve patients
• sAg positive patients should be started on
  lamivudine
• 3 weeks before treatment
• Patients should have Lamivudine for 3 months
  after the
• completion of chemotherapy

35
Case Continued Despite your recommendation, she
was not treated with preemptive antiviral therapy
before initiation of chemotherapy. She was
successfully treated with 6 cycles of R-CHOP
(CHOP rituximab), and her non-Hodgkin's
lymphoma is thought to be in remission. Two
months after completion of chemotherapy,
laboratory studies revealed a rise in her serum
ALT and HBV DNA levels she was started on
lamivudine 100 mg once daily for presumed HBV
reactivation. Fortunately, her serum ALT
normalized and HBV viral load became undetectable
on lamivudine.
36
She has now been on lamivudine continuously for
more than 1 year. Her most recent laboratory
studies were as follows AST 85 ?ALT 132
?HBV DNA 400,000 IU/L A liver biopsy was
obtained and revealed grade 2 inflammation and
stage 2 fibrosis. No lymphoma was identified.
37
What is the most likely cause of the recent rise
in this patient's serum ALT and HBV DNA
load? A) Recurrent lymphoma with hepatic
infiltration B) Emergence of a
lamivudine-resistant strain of HBV C) Delayed
hepatotoxicity from the chemotherapy regimen D)
Hepatic failure from a paraneoplastic syndrome
38
What is the most likely cause of the recent rise
in this patient's serum ALT and HBV DNA
load? A) Recurrent lymphoma with hepatic
infiltration B) Emergence of a
lamivudine-resistant strain of HBV C) Delayed
hepatotoxicity from the chemotherapy regimen D)
Hepatic failure from a paraneoplastic syndrome
39
Virological Response to LAM (4 Years) Resistance
Exceeds Efficacy
Extended LAM therapy in HBeAg(-) CHBThe Italian
experience (616 patients)
Virological response 1
Virological Breakthrough2
100
89
80
63
61
60
52
48
patients
39
37
40
20
11
0
1 year
2 years
3 years
4 years
1 HBV DNA lt 105 copies/mL 2 Re-appearance of HBV
DNA gt 105 copies/mL
Di Marco V for AISF Lamivudine Study Group,
Hepatology. 2004 40 883-91
40

• Which of the following is the most appropriate
  management strategy in this patient?
• Continue lamivudine and do not add an additional
  antiviral agent unless serum ALT and HBV DNA
  level continue to increase
• Continue lamivudine and add adefovir 10 mg once
  daily
• Discontinue lamivudine and start adefovir 10 mg
  once daily
• Begin entecavir 0.5 mg once daily

41

• Which of the following is the most appropriate
  management strategy in this patient?
• Continue lamivudine and do not add an additional
  antiviral agent unless serum ALT and HBV DNA
  level continue to increase
• Continue lamivudine and add adefovir 10 mg once
  daily
• Discontinue lamivudine and start adefovir 10 mg
  once daily
• Begin entecavir 0.5 mg once daily

42
(No Transcript)
43
Rebound of serum HBV DNA
gt1 log10 cpm
44
Rise in serum transaminases
Worsening of liver disease
45
Extended LAM therapy in HBeAg(-) GHBThe Italian
experience (616 patients)

• Major clinical events under therapy
  
• (Hepatitic flares, decompensation,HCC,
• transplantation, death)
• Non-cirrhotics 6.5
• Cirrhosis Child. A 31
• Cirrhosis Child B-C 86

Di Marco V for AISF Lamivudine Study Group,
Hepatology. 2004 40 883-91
46
Once Viral Resistance has developed Add or
Switch?
47
Evolution of viral quasi-species during
sequential monotherapies
WT
v
LAM
ADV
LAM
LAM-R
ADV-R
Zoulim, Antiviral Research, 2004
48
Evolution of viral quasi-species with a de novo
combination therapy
Wild type
v
LAMIVUDINE
LAM-R
ADV-R
Zoulim, Antiviral Research, 2004
49

• What are your recommendations for following this
  patient?
• She should remain on antiviral therapy
  indefinitely
• Serum ALT and HBV DNA levels should be followed
  every 3-6 months
• Screening for HCC should continue indefinitely
• All of the above are appropriate recommendations
  for following this patient

50

• What are your recommendations for following this
  patient?
• She should remain on antiviral therapy
  indefinitely
• Serum ALT and HBV DNA levels should be followed
  every 3-6 months
• Screening for HCC should continue indefinitely
• All of the above are appropriate recommendations
  for following this patient

51
http//hepatologist.eu