Transcript Management of HBV Infection

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
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: negative
Hepatitis C virus (HCV) antibody (Ab): negative
Hepatitis A virus (HAV) IgG/IgM: negative
ALT
AST
ALP
Bili
38 U/L (10-50 U/L)
FBC Normal
26 U/L (10-40 U/L)
U&E Normal
114 U/L (30-140 U/L) INR Normal
17 mol/L (10-23)
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?
A) HBeAg, HBsAb, and hepatitis B core antibody (HBcAb)
B) HBeAg, HBeAb, and HBV genotype
C) HBeAg, HBeAb, and HBV DNA viral load
D) HBeAg, HBV DNA, and sequencing for YMDD mutation
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?
A) HBeAg, HBsAb, and hepatitis B core antibody (HBcAb)
B) HBeAg, HBeAb, and HBV genotype
C) HBeAg, HBeAb, and HBV DNA viral load
D) HBeAg, HBV DNA, and sequencing for YMDD mutation
HBV DNA load is measured by polymerase chain reaction (PCR)
This can be qualitative or quantitative
In a prospective cohort study of >3500 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.
Cumulative incidence of liver
cirrhosis
.4
Baseline HBV DNA Level, copies/mL
37.1%
1.0 x 106 n=627
1.0-9.9x105 n=344
1.0-9.9x104 n=649
300-9.9x103 n=1210
<300 n=944
.3
n=3,774
23.0%
.2
.1
10.0%
6.3%
5.2%
0
0
1
2
3
4
5
6
7
8
Year of follow-up
Uchenna H. I, et al. Gastroenterology 2006; 130:678-686
9
10
11
12
13
P value for log-rank test, <0.001
Survival distribution function
100%
HBV DNA
Negative
96%
92%
HBV DNA Low
< 105 copies/mL
RR = 1.7 (0.5-5.7)
88%
84%
HBV DNA High
> 105 copies/mL
RR = 11.2 (3.6-35.0)
p < 0.001 across viral
categories
80%
0
1
2
3
4
5
6
7
Survival time (Years)
Chen G, et al. J Hepatology 2005; 42 (suppl 2):477A.
Chen G, et al. Hepatology 2005; 40 (suppl 1):594A.
8
9
10
11
12
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.
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
F
A
C
D
A
B
D
D
D
E
F
A
Fung & Lok, Hepatology 2004;40:790-2
D
C
C
D Ba
F
Bj
Further Blood results
AST 35 U/L
ALT 40 U/L
bilirubin 20 mmol/L
ALP 121 mg/d
HBsAg: positive
HAV IgG/IgM: negative
HCV Ab: negative
Hepatitis D virus (HDV) IgM: negative
HIV: negative
HBeAg: negative
HBeAb: positive
HBV DNA: 25,000 IU/mL
HBV genotype: B
Which statement is false regarding this patient's hepatitis B status?
A) She is an inactive carrier of hepatitis B
B) She is not in the immune-tolerant phase
C) She likely has a mutation in the precore or core promoter region
of the HBV genome
D) HBeAg positivity is associated with a better prognosis than
HBeAg negativity
Which statement is false regarding this patient's hepatitis B status?
A) She is an inactive carrier of hepatitis B
B) She is not in the immune-tolerant phase
C) She likely has a mutation in the precore or core promoter region
of the HBV genome
D) HBeAg positivity is associated with a better prognosis than
HBeAg negativity
HBeAg
Anti-HBe
HBV-DNA
ALT
immune immune
tolerance clearance
inactive
carrier
reactivation
HBsAg positive > 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
HBeAg seroconversion or precore/core promoter mutation
Anti-HBe positive
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
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
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.
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
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
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.
Cumulative incidence of liver
cirrhosis
.4
Baseline HBV DNA Level, copies/mL
37.1%
1.0 x 106 n=627
1.0-9.9x105 n=344
1.0-9.9x104 n=649
300-9.9x103 n=1210
<300 n=944
.3
n=3,774
23.0%
.2
.1
10.0%
6.3%
5.2%
0
0
1
2
3
4
5
6
7
8
Year of follow-up
Uchenna H. I, et al. Gastroenterology 2006; 130:678-686
9
10
11
12
13
P value for log-rank test, <0.001
Liver Biopsy showed Grade 1 inflammation and no fibrosis
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
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
Which of the following statements is true regarding HCC
screening in this patient?
A)HCC screening is not necessary because there is no fibrosis on
biopsy
B) HCC screening should be initiated because the patient's age
and sex place her at higher risk for HCC
C) Her ethnicity places her at higher risk for HCC than if she were
of African descent
D)Her family history of HCC increases her risk for HCC, and
therefore screening should be initiated
Which of the following statements is true regarding HCC
screening in this patient?
A)HCC screening is not necessary because there is no fibrosis on
biopsy
B) HCC screening should be initiated because the patient's age
and sex place her at higher risk for HCC
C) Her ethnicity places her at higher risk for HCC than if she were
of African descent
D) Her family history of HCC increases her risk for
HCC, and therefore screening should be initiated
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 < 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.
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 > 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 > 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.
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 > 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 > 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.
HBV reactivation is common among patients receiving
chemotherapy
haematological malignancy > 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.
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
All patients undergoing chemotherapy should be screened
for HBV Infection. (Flares have been seen with the use of
Immunomodulatory drugs such as infliximab/rituximab)
Consider Rx in hepatitis B cAb+ve 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
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.
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.
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
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
Extended LAM therapy in HBeAg(-) CHB:
The Italian experience (616 patients)
100
Virological response 1
89%
Virological Breakthrough2
80
% patients
63%
61%
60
48%
37%
40
20
52%
39%
11%
0
1 year
2 years
3 years
4 years
1 HBV DNA < 105 copies/mL
2 Re-appearance of HBV DNA > 105 copies/mL
Di Marco V for AISF Lamivudine Study Group, Hepatology. 2004; 40: 883-91
Which of the following is the most appropriate management strategy in
this patient?
A) Continue lamivudine and do not add an additional antiviral agent
unless serum ALT and HBV DNA level continue to increase
B) Continue lamivudine and add adefovir 10 mg once daily
C) Discontinue lamivudine and start adefovir 10 mg once daily
D) Begin entecavir 0.5 mg once daily
Which of the following is the most appropriate management strategy in
this patient?
A) Continue lamivudine and do not add an additional antiviral agent
unless serum ALT and HBV DNA level continue to increase
B) Continue lamivudine and add adefovir 10 mg once daily
C) Discontinue lamivudine and start adefovir 10 mg once daily
D) Begin entecavir 0.5 mg once daily
Rebound of serum
HBV DNA
>1 log10
cpm
Rise in serum
transaminases
Worsening of liver disease
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
Once Viral Resistance has developed
Add or Switch?
WT
v
LAM
ADV
LAM
LAM-R
ADV-R
Zoulim, Antiviral Research, 2004
Wild type
v
LAMIVUDINE
LAM-R
ADEFOVIR
ADV-R
Frequency ??
LAM + ADV -R
Zoulim, Antiviral Research, 2004
What are your recommendations for following this patient?
A)She should remain on antiviral therapy indefinitely
B) Serum ALT and HBV DNA levels should be followed every
3-6 months
C)Screening for HCC should continue indefinitely
D)All of the above are appropriate recommendations for
following this patient
What are your recommendations for following this patient?
A)She should remain on antiviral therapy indefinitely
B) Serum ALT and HBV DNA levels should be followed every
3-6 months
C)Screening for HCC should continue indefinitely
D)All of the above are appropriate
recommendations for following this patient