51
28 year old woman with no significant PMH is referred for evaluationof 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 yoShe 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/ weekNon smokerShe 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
BloodsHBsAg: positiveHIV: 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) U&E NormalALP 114 U/L (30-140 U/L) INR NormalBili 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.
Uchenna H. I, et al. Gastroenterology 2006; 130:678-686
Year of follow-up
Cu
mu
lati
ve in
cid
ence
of
liver
ci
rrh
osi
s
.2
.1
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0
.4
.3
Baseline HBV DNA Level, copies/mL
P value for log-rank test, <0.001
n=3,774
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
5.2%6.3%
10.0%
23.0%
37.1%
80%
84%
88%
92%
96%
100%
0 1 2 3 4 5 6 7 8 9 10 11 12
Survival time (Years)
Su
rviv
al d
istr
ibu
tion
fun
ctio
n
HBV DNA Negative
HBV DNA LowHBV DNA Low< 105 copies/mL copies/mL RR = 1.7 (0.5-5.7)RR = 1.7 (0.5-5.7)
HBV DNA HighHBV DNA High> 105 copies/mL copies/mL
RR = 11.2 (3.6-35.0)RR = 11.2 (3.6-35.0)
p < 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.
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 mutationsRates of HBeAg clearanceDevelopment of HBeAg-neg Chronic Hepatitis B
Possible association with:Liver disease activityProgression to cirrhosisRisk of HCCResponse to IFN and nucleoti(si)de analogs
AD
D
DD Ba
CC
Bj
F
D
E
AD
BC
F
F
Fung & Lok, Hepatology 2004;40:790-2
A
AST 35 U/L HBsAg: positiveALT 40 U/L HAV IgG/IgM: negative bilirubin 20 mmol/L HCV Ab: negativeALP 121 mg/d
Hepatitis D virus (HDV) IgM: negativeHIV: negativeHBeAg: negativeHBeAb: positiveHBV DNA: 25,000 IU/mLHBV genotype: B
Further Blood results
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
immunetolerance
immuneclearance
inactivecarrier
reactivation
HBeAgAnti-HBe
HBV-DNA
ALT
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
Anti-HBe positive HBeAg seroconversion or precore/core promoter mutation
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 diseaseactivity. 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.
Uchenna H. I, et al. Gastroenterology 2006; 130:678-686
Year of follow-up
Cu
mu
lati
ve in
cid
ence
of
liver
ci
rrh
osi
s
.2
.1
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0
.4
.3
Baseline HBV DNA Level, copies/mL
P value for log-rank test, <0.001
n=3,774
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
5.2%6.3%
10.0%
23.0%
37.1%
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
positiveand HBsAb-positive) may have reactivation with immunosuppression.
Worse if HBeAg-positivityHigh pretreatment HBV loadMale sexYoung ageHigh pretreatment serum ALT
The risk for hepatic decompensation is greatest during recovery from
immunosuppression
All patients undergoing chemotherapy should be screenedfor HBV Infection. (Flares have been seen with the use ofImmunomodulatory 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
% p
atie
nts
Di Marco V for AISF Lamivudine Study Group, Hepatology. 2004; 40: 883-91
1 HBV DNA < 105 copies/mL 2 Re-appearance of HBV DNA > 105 copies/mL
39%48%
63%
89%
61%
52%
37%
11%
0
20
40
60
80
100
1 year 2 years 3 years 4 years
Virological response 1 Virological Breakthrough2
Extended LAM therapy in HBeAg(-) CHB:The Italian experience (616 patients)
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
Worsening of liver disease
Rise in serum transaminases
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 developedAdd or Switch?
v
LAM ADV LAM
WT
LAM-R
ADV-R
Zoulim, Antiviral Research, 2004
v
Wild type
LAM-R
ADV-R
LAM + ADV -R
Frequency ??
LAMIVUDINE
ADEFOVIR
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
