HBV
Curbside consultation and case discussion in special
populations
Brenda Appolo PAC, MHS
University of Pennsylvania, Perelman School of Medicine
HBV: Special Populations
•
•
•
•
•
•
•
•
Pregnancy
HBV and Risk of Reactivation
HBV and HIV co-infection
Decompensated cirrhosis
Hepatitis D
HBV and HCV co-infection
Resistant HBV
HBV in Liver Transplant Recipients
Clinical Profiles of
Chronic HBV Infection
Immune
Tolerant
Inactive HBsAg
HBeAg (+) CHB
Carrier
HBeAg (-)
CHB (Precore
Mutant)
HBsAg
+
+
+
+
HBeAg
+
+
–
–
Anti-HBe
–
–
+
+
Normal

Normal

ALT
HBV DNA
Histology
>20,000 IU/mL
<200 IU/mL
>20,000 IU/mL
(>105 copies/mL) (>105 copies/mL) (<103 copies/mL)
Normal/Mild
Active
HBeAg, hepatitis B e antigen.
*Expert opinions vary as to this value
Adapted from Hoofnagle JH et al. Hepatology. 2007;45:1056-1075.
Normal
>2,000 IU/mL
(>104* copies/mL)
Active
.
Therapeutic Endpoints
Anti-HBs+ Improved
Improved
survival
histology Loss of
HBsAg
Anti-HBe+
Loss of
HBeAg
Loss of
HBV DNA
= HBeAg seroconversion
TIME
Approved Therapies
for Chronic HBV
First-Line Therapy
Peginterferon alfa-2a
PEGASYS®
Roche Laboratories
2005
Tenofovir
VIREAD®
Gilead Sciences
2008
BARACLUDE™
Bristol-Myers Squibb
2005
Adefovir dipivoxil
HEPSERA™
Gilead Sciences
2002
Telbivudine
TYZEKA™
Idenix and
Novartis
2006
EPIVIR-HBV®
GlaxoSmithKline
1998
Entecavir
Second-Line Therapy
Third-Line Therapy
Lamivudine
\.
Case #1
• 33 F presents for initial HBV consultation
• Moved from Belgium with husband 8 yrs ago to
US; she was born in China
• 21 wks pregnant with first child; no complications
• Meds: Prenatals; never treated for HBV in past
• Exam: unremarkable for stigmata of liver disease
• Labs
•
•
•
•
•
CBC wnl
ALT 19; AST 16; T bil 0.9; AlkPhos 189; Albumin
INR 1.0
HBV s Ag +; HBV e Ag +; HBV e Ab neg
HBV > 170,000,000 iu/ml
Case #1
• What other history is pertinent
• FHx: Mother HBV +; Sister HBV ?; Father HBV ?; Maternal Uncle
HBV + / HCC
• Husband HBV per patient “negative”
• What other labs / imaging at this point?
• What is risk of vertical transmission to baby?
• Should we treat mom?
• Why? Why not?
• What should we advise mom and OB/neonatology
colleagues if anything?
• HBV Vaccination & HBIg IM w/in 12 hours of birth
– HBV vaccination: Birthday, 2m, 6m
– Confirm Ab at one year of age
HBV and Pregnancy
Treatment of CHB in Women
Considering Pregnancy
Options:
• Treat prior to pregnancy - finite treatment course
• Defer treatment until post-partum
– Main consideration is risk to mother in absence of
treatment
– May be deferring for years if planning >1 pregnancy
• Defer treatment until after first trimester
– 1st trimester is period of greatest risk for developing
fetus
– Reduction of viral load may reduce risk of
transmission to infant
Risk-Benefit Assessment
Treatment During Pregnancy
Possible Benefits
• Prevent disease
progression during
pregnancy
• Prevent flares in
association with abrupt
withdrawal of therapy
• Reduce risk of pre-term
labor 1, 2
• Prevent intrauterine
transmission
Possible Risks
• Adverse outcome
of pregnancy
1
Tse et al. J Hepatology 2005
2 Su et al. World J Gastroenterol 2004
Antiviral Medications and Pregnancy Risk
Drugs
FDA Category
Lamivudine
C
Telbivudine
B
Tenofovir
B
Entecavir
C
Adefovir
C
Interferon-alfa and pegylated
interferon-alfa
C
Pregnancy Categories – Drug Safety
Category
Definition
A
Controlled studies show no risk: adequate, well-controlled studies in
pregnant women failed to demonstrate risk to the fetus
B
No evidence of risk in humans: either animal findings show risk,
but human findings do not; or, if no adequate human studies
have been done, animal findings are negative
C
Risk cannot be ruled out: human studies are lacking, and animal
studies are either positive for foetal risk, or lacking as well. However,
potential benefits may justify the potential risk
D
Positive evidence of risk: investigational or post-marketing data show
risk to the fetus. Nevertheless, potential benefits may outweigh the
potential risk
X
Contraindicated in pregnancy: studies in animals or humans, or
investigational or post-marketing reports, have shown fetal risk
which clearly outweighs any possible benefit to the patient.
Antiretroviral Pregnancy Registry Data
Earliest Trimester of Exposure
Agents
1st trimester birth
defects / live births
2nd- 3rd trimester birth
defects / live births
Lamivudine
127/4088 (3.1%)
186/6635 (2.8%)
Adefovir
0/48
0/0
Telbivudine
0/9
0/9
Tenofovir
31/1370 (2.3%)
18/782 (2.3%)
Entecavir
1/42
0/2
http://www.apregistry.com – 1 January 1989 through 31 January 2012
Risk of Transmission to Infants (%)
Estimated Risk of Perinatal HBV
Transmission (without prevention)
Chronic HBV
infected mothers
90%
100
60
60
40
10-40%
20
20
0
80-90%
100
80
80
40
Acute hepatitis HBV
infected mothers
0
HBeAg
negative
HBeAg
positive
10%
Infected
Infected
during 1st during 3rd
trimester trimester
ITT analysis
50
P=0.003
46%
% Infant with HBV-DNA positive at age 1 yr
40
30
Lamivudine in Late
Pregnancy to Prevent
Perinatal Transmission
20%
20
• Double-blind, RCT in China
10
0
• N = 141
LAM
Placebo
Based on those tested
50
P=NS
40
10
0
• HBV-DNA >109 copies/ml
• LAM 100 mg/D vs placebo; from
GA 32 wk to 4 wk after delivery
• All received HBIG + HBV vaccine
30
20
• HBsAg+ pregnant women
15%
7%
LAM
• High drop-out rate
(LAM 13%, placebo 31%)
Placebo
Xu WM et al. J Viral Hepat 2009;16:94-103
% Infant with HBsAg+ at
age 7 months
Efficacy of Telbivudine in Late Pregnancy for Prevention of
Vertical HBV Transmission
50
P=0.002
• Open-labeled prospective study
40
30
• N = 141 (all Chinese)
20
10
0
8%
0%
• HBsAg+ pregnant women
• HBeAg+
LdT
Placebo
• HBV-DNA >109 copies/ml
• LdT 600 mg/D vs untreated
control
• from GA 20-32 wk to delivery
• All received HBIG+HBV vaccine
Han GR, et al. J Hepatol 2011;55:1215-21
Tenofovir for Prevention of HBV Vertical
Transmission
• Retrospective analysis
• 11 HBV infected mothers with HBeAg positive; median HBV-DNA 9
(7.7-9.4) log10 copies/ml
• TDF was started at the median GA of 29 (28-32) wk
• Maternal outcomes
–
–
–
–
HBV-DNA significantly reduced at delivery compared to BL
6/11 pt. had HBV-DNA < 6 log10 before delivery
No significant changes in serum creatinine
TDF was stopped soon after delivery in 8 pt; no ALT flare
• Infant outcomes
– All infants were HBsAg negative at 28-36 wk of age
– No congenital defect
– All infants received HBIG+HBV vaccine
Pan CQ, Mi LJ, Bunchorntavakul C, et al. Dig Dis Sci 2012;57:2423-9
Proposed Algorithm for HBV Management
During Pregnancy
Buchanan C, Tran TT. Clin Liver Dis 2010;14:495-504
Case #1 – wrap up
• Should we treat mom?
• How long should therapy continue?
• Is she breastfeeding
• HCC surveillance?
Case #2
• 56 yr old F present to ED with new onset jaundice, malaise
• PMHx – CD20-positive diffuse large B-cell non-Hodgkin's
lymphoma; completed treatment 6 weeks prior (rituximab
+ CHOP)
• SHx – no alcohol, previous IVDU 20 yrs ago
• Meds: levothyroxine
• Exam: Scleral icterus; exam otherwise unremarkable
• Pretreatment labs
– Per patient LFTs normal
• ED Labs
– ALT 333; AST 235; T bil 5.4; AlkPhos 241; Albumin 3.0
Case #2
• What is your DDx?
• What patient history is most pertinent?
• Viral serologies
– HAV IgM negative; HAV total +
– HCV Ab +; HCV RNA negative
– HBV core Ab Total +; HBV IgM equivocal
– HBV s Ag +
– HBV DNA 545,000
HBV and Immunosuppressed
States : Chemotherapy and
Corticosteroids
Natural History of HBV Reactivation
During Chemotherapy
ChemoRx
and/or
steroids
Recovery of
neutropenia or
steroid
withdrawal
Death
Acute liver
failure
Chronic
hepatitis
Cirrhosis
ALT
Acute
hepatitis
HBV DNA
IMMUNE
SUPPRESSION
0
4
8
12
IMMUNE REBOUND
16
20
24
28
32
RECOVER
36
52
100
Weeks after
Exposure
Reactivation of Hepatitis B Infection Among Cancer
Patients
Large database from MD Anderson examined to determine HBV screening rates for patients
who received chemotherapy
87
17% patients
screened
70,737
new
patients
10,729
chemotherapy
1,787
screened
1/5 with HBV risk
screened
87
HBsAg-
HBsAg
1
HBsAg+
anti-HBc1,665
HBsAg and
anti-HBc
25
HBsAg+
anti-HBc+
123
HBsAganti-HBc+
35
anti-HBc
Hwang JP, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst. 172.
2
anti-HBc+
34
HBV
Reactivation
2% of screened
23% of positive
Results of Prophylaxis or Treatment of 34
Patients with Reactivation
Fisher’s Exact Test, p<0.05
71%
72%
22%
Chemotherapy
•
Reactivation
Conclusion: Persons at risk for HBV are not being adequately screened prior to
chemotherapy, resulting in preventable reactivation and mortality
Hwang JP, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst. 172.
Risk Factors of HBV Reactivation
Patient and HBV status
• Male, young age
• Level of HBV-DNA >20,000 IU/ml
• HBeAg positive
• Active liver disease
Level of immunosuppression
• Corticosteroids
• Chemotherapy regimens : Vinca-alkaloid, anthracycline
• Rituximab, infliximab
• Immune reconstitutional periods
• Bone marrow transplantation
Mindikoglu AL, Regev A, Schiff ER. Clin Gastroenterol Hepatol 2006;4:1076-81
Manzano-Alonso ML, Castellano-Tortajada G. World J Gastroenterol 2011;17:15-1537
Efficacy of Lamivudine Prophylaxis for
Chemotherapy-Induced HBV Reactivation
%
54%
•
31%
•
•
•
9.2%
Review of 10 RCTs &
prospective case series
Total N=173
LAM dose 100mg/D
AEs : LAM=placebo
8.7%
Kohrt HE, Ouyang DL, Keefe EB. Aliment Pharmacol Ther 2006;24:1003-16
HBV: Management of Patient Undergoing
Immunosuppressive Therapy
HBsAg negative
*Anti-HBs +
Anti-HBc -
Anti-HBs Anti-HBc -
Prior vaccination
with appropriate
immune response
HBV vaccination
is recommended
(double-dose ?)
Anti-HBs ±
Anti-HBc +
• Monitor HBV-DNA q 1-3 mo
during and until 6 mo after
immunosuppressive Rx
• Antiviral prophylaxis,
if HBV-DNA positive
*Anti-HBs+ is
considered when
titer ≥10 mIU/ml
Check anti-HBs at 1-2 mo
after vaccination
Adapted from Bunchorntavakul C, Reddy KR. Medical treatment of hepatobiliary diseases associated with ulcerative colitis. In:
Lichtenstein G. editor. Medical Therapy of Mucosal Ulcerative Colitis. Springer Publishing, New York, USA; 2012 [in press]
HBV: Management of Patient Undergoing
Immunosuppressive Therapy
HBsAg positive
HBV-DNA <2,000 IU/ml
Normal ALT
• Start antiviral prophylaxis before initiation of
immunosuppressive Rx and continue for 6 mo after
discontinuing all immunosuppressive Rx (12 mo for
rituximab)
• LAM can be used, if the anticipated Rx duration is
<12 months
HBV-DNA ≥2,000 IU/ml
Normal or elevated ALT
• HBV treatment
• Delay immunosuppressive
Rx until anti-HBV is initiated
and HBV DNA negative
• ETV or TDF is preferred, if longer duration of Rx is
anticipated
Adapted from Bunchorntavakul C, Reddy KR. Medical treatment of hepatobiliary diseases associated with
ulcerative colitis. Springer Publishing. [in press] and Lok ASF, McMahon BF. AASLD Practice guideline 2009
Case #3
49 yr old male presents with self reported history of Hepatitis A,B,C
His only complaint is fatigue; referred by area health clinic
Exam notable for temporal muscle wasting; trace icterus, + fluid wave
He has high risk behaviors including IV drug use, multiple sexual
partners; “alcohol was never my thing”
• Labs: T bil 2.1; AST 119; ALT 242; Albumin 3.0; AlkPhos 245; INR 1.3
• You have no medical records or labs otherwise
• You order “viral hepatitis panel”
•
•
•
•
• HCV Ab positive
• HBV s Ag positive
• HBV IgM negative
• Now what?
• What is the likely hood this patient actually has chronic, active HBV and
HCV
• What other co – infections should we screen for in ALL our patients?
HBV and HIV Co-infection
Prevalence of HBV-HIV co-infections by
Geography and Route of Infection
Thio CL. Hepatology 2009;49:S138-S145
Liver-Related Mortality
Liver-related mortality rate
(per 1,000 person-years)
• Multicenter prospective cohort study of
5293 men who had sex with men (in USA)
20
14.2
15
10
5
1.7
0
0
HIV-/HBV-
HIV+/HBV-
Thio CL, et al. Lancet 2002;360:1921-6
0.8
HIV-/HBV+
HIV+/HBV+
Influence of HIV on HBV
• Lower rates of clearance of HBeAg
• Increased serum HBV DNA viral load 1
• Reactivation of hepatitis in
asymptomatic carriers
• Increased liver injury
• Faster fibrosis cirrhosis and HCC
• Higher mortality and morbidity
(1) Perillo RP, Regenstein FG, et al. Chronic hepatitis B in asymptomatic homosexual men with antibody to the human immunodeficiency
virus. Ann Intern Med 1986:105:382-3
Influence of HBV on HIV
CONFLICTING DATA
• Increased rate of HIV progression to AIDS ? 1
• No change in progression ? 2
• Cohort studies suggest that HBV does not
appear to influence the progression of HIV.
(1) Eskild A, Magnus P, et al. Hepatitis B antibodies in HIV-infected homosexual men are associated with more rapid progression to AIDS.
Aids 1992:6:571-4
(2) Diamondsstone LS, Blakly SA, et al. Prognostic factors for all-cause mortality among hemophiliacs infected with human immunodeficiency
virus. Am J Epidemiol 1995:142:304-13
HBV and HIV Therapies
Wild-type
HBV
YMDD HBV
HIV
Activity
Interferon (IFN)
S
S
N
Lamivudine (LAM)
S
R
Y
Adefovir (ADV)
S
S
N*
Entecavir (ETV)
S (0.5mg)
S (1mg)
Y
Emtricitabine (FTC)
S
R
Y
Tenofovir (TDV)
S
S
S
R
Y
N†
Telbivudine (LdT)
* ADV at dose 10mg/D has negligible activity against HIV (activity against HIV started at dose
30mg/D)
†
LdT has no activity against HIV, but should not be used in HIV/HBV co-infection because risk of
selection of M204I mutation in YMDD motif of HIV
HBV-DNA ↑, ALT ↑
(Liver biopsy is considered in pt. with fluctuating or
mildly elevated ALT)
Not on HAART and treatment for both
HIV and HBV in planned
Start antiviral Rx that is active against both viruses
(combination Rx is preferred)
Lamivudine
or
Emtricitabine
+ Tenofovir
When HAART regimens are altered, drugs that are effective against HBV should not be
discontinued without substituting another drug that has activity against HBV
AASLD Practice Guideline 2009
Hepatitis D
Treatment of Hepatitis D:
Peginterferon Versus Adefovir
• RCT, 31 HDV patients
• HBV-DNA levels decreased at wk 48 and rebounded at week 72 in all
patients
P=0.02
Patients (%)
50
P=0.006
45
P=0.004
40
P=0.003
35
31
30
26
PEG-IFN + ADV
PEG-IFN
20
ADV
10
10
0
0
HDV-RNA negative
ALT normalization
Results at 72 weeks FU
Wedermayer H, et al. N Eng J Med 2011;364:322-31
HBV Decompensated
Cirrhosis
Lamivudine significantly reduced the
incidence of hepatic decompensation and
HCC
• Multicenter, DB-RCT in Asian populations, N=651
P=0.001
Liaw YF, et al. N Engl J Med 2004;351:1521-31
P=0.047
Entecavir and Tenofovir in Advanced Cirrhosis
% patients (at 48 weeks analysis)
• DB-RCT, N=112
• CTP and MELD scores improved in all groups
100
TDF 300 mg
FTC/TDF
ETV 0.5 or 1 mg
87.8
80
76
70.5
72.7
57
60
P=NS, across treatment groups
55
Tolerability failure = increased Cr ≥ 0.5
mg/dl from BL or serum phosphate <2
mg/dl x2 consecutive visit
40
20
6.7
9.1
4.4
0
HBV <400 cp/ml
ALT
normalization
Tolerability
failure
2.2 2.2
0
Drug-related
AEs
Liaw YF, et al. Hepatology 2011;53:62-72
Summary & Curbside Thoughts
• Prenatal HBV screening does not always lend way to linkage to care
• HBV monitoring during pregnancy and post pregnancy / life long
appropriate
• Hepatitis B core – check it!
• Chronic HBV infection (sAg+) and Chronic HCV infection (+RNA) rare -- treatment paradigm will change in era of HCV DAAs for HCV
• Delta screening – one time – for all; patients tend to have evidence of
advanced disease; low HBV DNA titers
• Always treat HBV in HBV s Ag and clinical or histological evidence of
cirrhosis
• Chronic HBV infection – a carcinogen!
– Yearly HCC surveillance at 40 for males; 50 for females
– Earlier age surveillance if FHx HCC or African
– If cirrhosis semi annual surveillance