Transcript Optimal Management of HBV: A Partnership Between Primary

Expert Perspectives on
Hepatitis B Virus and the
Infected Patient
HBV Virology
Hepatitis B Virus
Key Points
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DNA virus
Reverse transcriptase
Multiple genotypes
Human genome integration
Cellular dormant form with replicative potential
Generally not curable after development of chronic infection
– Clearance of HBsAg is rare even with treatment
cccDNA
– Stable intermediate
– Template for viral protein production
Organization of the
HBV Genome
Reprinted from Hunt CM, et al, Hepatology, 2000;31:1037, reprinted with permission of Wiley-Liss, Inc,
a subsidiary of John Wiley & Sons, Inc.
HBV Replication
cccDNA Formation and
mRNA Transcription
Viral
Entry
Uncoating
Nuclear
import
cccDNA
Repair
Transcription
5’
5’
3’
3’
2.4/2.1 kb RNA
3.5 kb RNA
Nassal M, et al. J Viral Hepat. 1996;3:217. Ganem D, et al. Fields Virology. 4th ed. Philadelphia: Lippincott-Raven
Publishers; 2000:2923.
Courtesy of Nezam H. Afdhal, MD.
HBV Replication
Translation and
Capsid Assembly
Viral
Entry
Uncoating
Positive
strand
synthesis
Nuclear
import
Removal of
pregenome
cccDNA
Repair
Transcription
5’
5’
3’
3.5 kb RNA
3’
2.4/2.1 kb RNA
Translation
Negative
strand
synthesis
Encapsulation
Nassal M, et al. J Viral Hepat. 1996;3:217. Ganem D, et al. Fields Virology. 4th ed. Philadelphia: Lippincott-Raven
Publishers; 2000:2923.
Courtesy of Nezam H. Afdhal, MD.
HBV Replication – Replenishment or Release
Export
Viral
Entry
Uncoating
Assembly
& budding
ER
Positive
strand
synthesis
HBsAg
Nuclear
import
Removal
of pregenome
cccDNA
Repair
Transcription
5’
5’
3’
3’ 2.4/2.1 kb RNA
3.5 kb RNA
Negative
strand
synthesis
Translation Encapsulation
Nassal M, et al. J Viral Hepat. 1996;3:217. Ganem D, et al. Fields Virology. 4th ed. Philadelphia: Lippincott-Raven
Publishers; 2000:2923.
Courtesy of Nezam H. Afdhal, MD.
Clinical Significance of
Viral Replication
Viral replication
Elevated ALT
Worsening
histology,
including cirrhosis
HCC
Goals of Suppression of Viral Replication
Virologic
response
Histologic
improvement
Reduction in
– HBV DNA
– cccDNA
Prevention
of death,
cirrhosis,
and HCC
Serologic
response
– HBeAg loss
– HBeAg seroconversion
– HBsAg loss and seroconversion
Biochemical
improvement
Diagnostic Testing
Who Should Be Screened?
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Patients engaged in high-risk sexual behaviors (men who have
sex with men, sexual contacts of HBV-infected persons)
Injection drug users
Immigrants, refugees, or adoptees/orphans from areas of high
endemicity
Immunocompromised patients
Dialysis patients
Household members of known HBV carriers
Persons exposed occupationally
Inmates in long-term correctional facilities or residents in
institutions for the developmentally disabled
Pregnant women
Individuals infected with HCV or HIV
CDC. Epidemiology & Prevention of Vaccine-Preventable Diseases. “The Pink Book.” 8th ed, 2005.
Lok ASF, et al. Hepatology. 2001;34:1225.
HBV Serologic and Molecular Tests
in Serum
Category
Test
Significance
Viral antigens
HBsAg*
Acute or chronic infection;
infectivity
HBeAg
Acute or chronic infection;
infectivity
Viral antibodies
Anti-HBc*
Anti-HBe
Anti-HBs*
Marker of infection
Low infectivity
Marker of immunity
Molecular tests
HBV DNA
Acute or chronic infection;
infectivity
*Test recommended for initial screening
2nd-Phase Testing
in HBsAg+ Patients
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HBeAg
– Positive, indicates active HBV replication
– Negative
 If HBV DNA negative, suggests HBV replication is
suppressed
 If HBV DNA positive, most likely has precore mutation
Anti-HBe
HBV DNA quantification
– Quantitative level correlates with level of HBV replication
Anti-HDV
– Detects coinfection with delta agent
Ranges of HBV DNA Assays
103
Each lab must validate the
assay in-house and
determine their own
performance characteristics,
which may vary from lab
to lab
3 x 104 105
Roche (PCR)
AMPLICOR Monitor v2.0
COBAS Monitor v2.0
TaqMan HBV ASR (PCR)
1000–40,000,000
200–200,000
170–640,000,000
Bayer (bDNA)
VERSANT HBV 1.0
VERSANT HBV 3.0
700,000–5,000,000,000
2000–100,000,000
Digene II (Hybrid Capture)
Ultrasensitive
Standard
0
Courtesy of Robert G. Gish, MD.
4700–57,000,000
142,000–1,700,000,000
2
4
6
8
HBV DNA Concentration in Log10 Copies/mL
?
Diagnostic Tests
Screening for HCC–New AASLD Practice Guidelines
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At-risk hepatitis B carriers
– Asian males ≥40 years
– Asian females ≥50 years
– All cirrhotic HBV carriers
– Family history of HCC
– Africans older than age 20 years
– Those with high HBV DNA concentrations and
ongoing hepatic inflammation remain at risk for HCC
Ultrasound scanning of liver every 6–12 months
Bruix J, et al. Hepatology. 2005;42:1208.
Diagnostic Tests
Liver Biopsy—Pros
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Excludes other diseases
Guides decisions on initiation of treatment
– See US Algorithm guidelines*
Predicts prognosis
– Grade and stage
Utilizes change from baseline as marker for treatment
response
– Nucleoside/nucleotide analogs FDA-approved for
histologic improvement
*Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;4:936.
Diagnostic Tests
Liver Biopsy—Cons
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Risks and patient reluctance
Not required by AASLD guidelines as a factor in
deciding to treat1,2
HBV DNA/serology/ALT could dictate treatment
Cancer risk may be independent of cirrhosis
1. Lok ASF, et al. Hepatology. 2001;34:1225. 2. Lok ASF, et al. Hepatology. 2004;39:857.
Natural History
Natural History of HBV Infection
Early
childhood
>95%
HBeAgchronic
hepatitis B
Immune
tolerance
Cirrhosis
Adulthood
<5%
HBeAg+
chronic
hepatitis B
Inactive
carrier
Chen DS, et al. J Gastroenterol Hepatol. 1993:8:470. Seeff L, et al. N Engl J Med. 1987;316:965.
Courtesy of W. Ray Kim, MD.
Phases of Chronic HBV Infection
Immune
Tolerant
Phase
HBeAg
Positive
CHB
Inactive
HBsAg
Carrier
HBeAg
Negative
CHB*
HBsAg
+
+
+
+
HBeAg
+
+
–
–
Anti-HBe
–
–
+
+
Normal

Normal

HBV DNA
>105
copies/mL
>105
copies/mL
<105
copies/mL
>104†
copies/mL
Histology
Normal/mild
Active
Inactive
Active
ALT
*Precore mutant
†Expert opinions vary as to this value
Lai CL, et al. Lancet. 2003:362:2089. Lok AS, et al. Gastroenterology. 2001;120:1828.
HBeAg Negative Patients
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HBeAg positive patients may develop
antibodies (anti-HBe)
When HBeAg is lost, 2 possible scenarios
– Inactive carrier (normal ALT, low or negative
HBV DNA level)
– Precore mutant chronic HBV (moderate
to high HBV DNA, elevated ALT)
Inactive Carriers
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HBeAg negative, normal ALT, low/negative
HBV DNA
“Healthy carriers” = oxymoron
All patients who are HBsAg positive need
ongoing monitoring as part of management
– Monitor for increased ALT or HBV DNA
every 6 months
– Monitor for HCC in at-risk groups
Sherman M. Semin Liver Dis. 2005;25:143.
Spontaneous Viral Clearance at 10 Years
100
HBeAg clearance
(up to 80%)
Patients (%)
80
60
40
HBsAg clearance
(5%)
20
0
1
2
3
4
5
Years
Lok ASF, et al. Hepatology. 2001;34:1225.
6
7
8
9
10
HBV Disease Progression
Liver
cancer (HCC)
5%–10%1
6% in 5 years2
Chronic
infection
30%1
Cirrhosis
Liver
transplantation
23% in 5 years2
Acute flare
Liver failure
1. Torresi J, et al. Gastroenterology. 2000;118:S83. 2. Fattovich G, et al. Hepatology. 1995;21:77.
Death
Patients Surviving (%)
Actuarial Survival in HBV-Related Liver Disease
Historical Studies
100
80
Cirrhosis1
(n = 130)
60
55%
40
Decompensated cirrhosis2
(n = 21)
20
14%
0
0
1
2
3
4
5
Years
1. Weissberg JI, et al. Ann Intern Med. 1984;101:613. 2. De Jongh FE, et al. Gastroenterology. 1992;103:1630.
Survival with Compensated Cirrhosis
Patients Surviving (%)
HBeAg Positive vs Negative
HBeAg negative (n = 34)
97%
100
80
72%
HBeAg positive (n = 43)
60
40
20
0
0
1
2
3
4
5
Years
Reprinted from Gastroenterology, 103, De Jongh FE, et al, 1630, copyright 1992, with permission
from the American Gastroenterological Association.
Cumulative Incidence (%)
HBe Antigen Status and Risk of HCC
12
HBsAg+, HBeAg+
(RR = 60.2)
10
8
6
4
HBsAg+, HBeAg–
(RR = 9.6)
2
HBsAg–, HBeAg–
0
0
1
2
3
4
5
Year
6
7
8
9
10
RR = relative risk
Yang H-I, et al. N Engl J Med. 2002;347:168. Copyright 2002, Massachusetts Medical Society.
All rights reserved.
Age- and Race-Specific HBV Mortality
Death Rate (/100,000)
6
Other
5
4
3
2
Black/African American
1
White
0
<25
25–34
35–44
45–54
55–64
65–74
75+
Age (Years)
CDC. Underlying Cause of Death. 1994–1998.
Compressed Mortality File (CMF) compiled from CMF 1968-1988, Series 10, No. 2A 2000, CMF 1989–
1998, Series 20, No. 2E 2003, and CMF 1999–2001, Series 20, No. 2G 2004 pm. CDC WONDER On-line
Database.
HBV Vaccination
Effect on HCC Incidence and Mortality*
Incidence
0.8
0.70
0.57
0.6
0.36
0.4
0.2
0
1981–86
1986–90
1990–94
*Nationwide vaccination in Taiwan, implemented 7/84
Chang M-H, et al. N Engl J Med. 1997;336:1855.
Mortality
1
Per 100,000 Children
(6–14 Years)
Per 100,000 Children
(6–14 Years)
1
0.80
0.8
0.58
0.6
0.34
0.4
0.2
0
1981–86
1986–90
1990–94
HBV DNA Level Predicts Morbidity
and Mortality
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Elevated HBV DNA level
– Strong predictor of cirrhosis regardless of ALT
level1 or HBeAg status2
– Associated with increased mortality from chronic
liver disease and HCC3
Incidence of cirrhosis increases with HBV DNA level in
dose-dependent manner4
Incidence of HCC risk in people with normal ALT levels
increases with HBV DNA level in dose-dependent
manner5
Abstracts from 40th EASL; April 13-17, 2005: 1. Iloeje UH, et al. Abstract 497. 2. Chen G, et al. Abstract
476. 3. Chen G, et al. Abstract 477. 4. Iloeje UH, et al. Abstract 496. 5. Iloeje UH, et al. Abstract 495.
Risk Evaluation of Viral Load Elevation and
Associated Liver Disease/Cancer (REVEAL)
HBV Study, Taiwan
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Prospective, multicenter, observational cohort study
3851 HBsAg positive patients with adequate sample for
baseline1 HBV DNA
– 3653 patients seronegative for anti-HCV were included in
study and followed for HCC1 and cirrhosis2
– HCC detected by health exam or through Taiwan national
cancer registry for January 1, 1991 through June 30, 20041
– Patients were evaluated for cirrhosis via ultrasound every
6-12 months for a mean of 11 years through June 30, 20042
1. Chen CJ, et al. JAMA. 2006;295:65.
2. Iloeje UH, et al. Gastroenterology. 2006;130:678.
Persistent HBV Viral Load Elevation Is
Associated with Greatest Risk of HCC
REVEAL Study
289 study participants, last follow-up serum samples not available
Serum level of HBV DNA (copies/mL)
Cohort Entry Examination
<104
104–105
104–105
104–105
105
105
105
Follow-Up Examination
Not tested
<104
104–105
105
<104
104–105
105
*Adjustment for gender, age, cigarette smoking, and alcohol consumption.
Chen CJ, et al. JAMA. 2006;295:65. Reprinted with permission.
Multivariate-Adjusted HR*
(95% CI)
1.0 (referent)
1.6 (0.7–3.9)
0.5 (0.1–3.6)
3.5 (1.4–9.2)
3.8 (1.7–8.4)
7.3 (3.5–15.3)
10.1 (6.3–16.2)
Cumulative Incidence of HCC (%)
16
Baseline HBV DNA Level and
Cumulative Incidence of HCC
Entire Cohort
14
14.89
12.17
12
N = 3653, 13-year follow-up
10
8
6
3.57
4
0
1.37
1.3
2
<300
300–<104
1IU = ~5 copies/mL
Chen C-J, et al. JAMA. 2006;295:65.
104–<105
105–<106
HBV DNA (Copies/mL)
≥106
Baseline HBV DNA Level and Cumulative
Incidence of HCC
Cumulative Incidence of HCC (%)
Subgroup of Noncirrhotic HBeAg– Patients with Normal ALT
16
13.50
14
12
N = 2925
10
7.96
8
6
4
2
0
3.15
0.89
0.74
<300
300–<104
Chen C-J, et al. JAMA. 2006;295:65.
104–<105
105–<106
HBV DNA (Copies/mL)
≥106
Baseline HBV DNA Level and Relative
Risk of Cirrhosis
Relative Risk
Adjusted for gender, age, smoking, alcohol consumption
10
9
8
7
6
5
4
3
2
1
0
9.8
N = 3582, 11-year follow-up
5.9
2.5
1
<300
1.4
300–9.9x103
1.0–9.9x104
1.0–9.9x105
HBV DNA (Copies/mL)
Iloeje UH, et al, Gastroenterology. 2006;130:678.
≥106
HBV Genotypes
Global Distribution of the 8
HBV Genotypes
A
G
A, B, C, D, G
D
B, C
D
A, D, E
H, F
F
A, B, C, D
Arauz-Ruiz P, et al. J Gen Virol. 2002;83:2059.
Bell SJ, et al. J Clin Virol. 2005;32:122.
Kidd-Ljunggren K, et al. J Gen Virol. 2002;83:1267.
US Prevalence of HBV Genotypes
Prevalence (%)
100
80
N = 694
60
40
35
31
22%
20
10
0.4
0.6
1
E
F
G
0
A
B
C
D
HBV Genotype
Chu C-J, et al. Gastroenterology. 2003;125:444.
HBV Genotypes
Role in Pathogenesis
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May affect rate of chronicity (A > D)
Relationship to precore mutation (GA1896) (B, C, D > A)
– T1896—A stabilizes the stem-loop structure in genotype B, ~ C, D
– Genotype A has C1896 favoring wild-type G base pairing
Association with HBeAg seroconversion
– Earlier seroconversion (B > C)
– More likely to be sustained
Relationship to antiviral response1,2
– IFN response: genotype A > D, B > C
– HBeAg negative: A > D/E
– Transplant outcome: A better than D (n = 22)
1. Enomoto M, et al. Clin Lab. 2006;52:43. 2. Devarbhavi HC, et al. Liver Transpl. 2002;8:550.
Association Between HBV Genotype and
Disease Severity
Western Patients1
Frequency of Liver-Related Death
Incidence of Advanced Fibrosis
(F3/F4)
P = .02
40
40
P = .034
33
P = .002
30
N = 258
21
20
10
Patients (%)
Patients (%)
Asian Patients2
30
N = 585
20
13
10
5
1
0
0
A
D
F
B
C
1. Sanchez-Tapias JM, et al. Gastroenterology. 2002;123:1848. 2. Sumi H, et al. Hepatology. 2003;37:19.
Whom to Treat
Candidacy for Anti-HBV Treatment
Principle
In general, a patient with chronic HBV is a
treatment candidate if there is evidence of
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Liver disease (abnormal ALT)

HBV replication (HBV DNA+)
Factors to Consider in Initiating
Anti-HBV Therapy?
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HBV DNA levels
ALT levels
HBeAg status
Cirrhosis vs no cirrhosis
Compensated vs decompensated
disease
Which Patients Should Be Treated?
AASLD Guidelines
HBV DNA
(Copies/mL)
ALT
Management
+
>105
≤2 x ULN
Follow
+
>105
>2 x ULN
Treat
–
>105
>2 x ULN
Treat
–
–
≤2 x ULN
Follow
+/–
>105
Cirrhosis
If compensated, treat;
if decompensated*, refer
for liver transplant
+/–
–
Cirrhosis
If compensated, observe;
if decompensated*, refer
for liver transplant
HBeAg
*Do not use IFN or PEG IFN if patient has decompensated cirrhosis. Specific treatment recommendations
will be discussed in an upcoming audioconference in this series.
Lok ASF, et al. Hepatology. 2004;39:857. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John
Wiley & Sons, Inc.
US Treatment Algorithm Update
HBeAg Positive Without Cirrhosis
HBeAg positive
HBV DNA
<105 copies/mL


No treatment
Monitor every 6–12 months
HBV DNA
≥105 copies/mL


Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936.
Courtesy of Emmet Keeffe, MD.
ALT normal
ALT elevated
Monitor every 3–12
months (immune
tolerant)
Consider biopsy, if
age >35–40 years;
treat if significant
disease
Treat
US Treatment Algorithm Update
HBeAg Negative Without Cirrhosis
HBeAg negative
HBV DNA
<104 copies/mL
HBV DNA
≥104 copies/mL
ALT normal


No treatment
Monitor every 6–12 months



Monitor ALT, or
Consider biopsy, since ALT
often fluctuates; treat if
significant disease
Long-term treatment
required
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936.
Courtesy of Emmet Keeffe, MD.
ALT elevated


Treat
Long-term
treatment
required
US Treatment Algorithm Update
Compensated Cirrhosis
HBV DNA
≥104 copies/mL
HBV DNA
(PCR)
HBV DNA
<104 copies/mL
May choose to treat or observe
Treat
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936.
Courtesy of Emmet Keeffe, MD.
US Treatment Algorithm Update
Decompensated Cirrhosis
HBV DNA
Detectable by PCR?
No


Observe
Wait list for transplant
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936.
Courtesy of Emmet Keeffe, MD.
Yes


Treat
Wait list for transplant
Monitoring for Patients Not Considered
for Treatment


Check ALT every 3–6 months
– If ALT is persistently elevated,
re-evaluate for treatment
HCC surveillance in relevant population
Lok ASF, et al. Hepatology. 2001;34:1225. Lok ASF, et al. Hepatology. 2004;39:857.
Challenges in Special Patient
Populations
Considerations for Special Populations
with HBV Infection

Pregnancy
– Mother needs treatment
– Prevention of vertical transmission
(neonatal infection)

Patients receiving chemotherapy
– Prevent reactivation of hepatitis B,
which may be fatal
Lamivudine Treatment During Pregnancy to
Prevent Perinatal Transmission of HBV





8 highly viremic (HBV DNA ≥1.2 × 109 geq/mL) mothers treated with
lamivudine 150 mg/d in last month of pregnancy
Historical controls: 24 children born to untreated, highly viremic,
HBsAg positive mothers
All children had passive-active immunization at birth, then were
followed for 12 months
1 of 8 children (12.5%) in the lamivudine group still HBsAg and HBV
DNA positive at 12 months
– All others seroconverted to anti-HBs and maintained
seroprotection
– HBV DNA temporarily detected by PCR in 3 children
Control group: 7 of 25 children (28%) were infected perinatally
van Zonneveld M, et al. J Viral Hepat. 2003;10:294.
Preventing Perinatal Transmission



Screen all expectant mothers for HBV
Particularly if highly viremic, HBV-infected
pregnant women may transmit HBV to their
infants
Lamivudine treatment in last month of
pregnancy reduces risk of transmission
American College of Obstetricians and Gynecologists, “Hepatitis B Virus in Pregnancy.”
Available at: www.acog.org/publications/patient_education/bp093.cfm
Fatal Reactivation of HBV Infection in
Chemotherapy Patients
4 Chinese patients with lymphoma who were
carriers of HBV developed fulminant hepatitis
within 1 month after chemotherapy
– 1 initially HBeAg positive; 3 anti-HBe positive
– All initially had normal ALT levels
 Reactivation: jaundice; HBV DNA in serum; and
seroreversion from anti-HBe to HBeAg positivity
 All died within 3 weeks

Lau JYN, et al. Q J Med. 1989;73:911.
Lamivudine Prophylaxis Before
Chemotherapy for HBV Reactivation
Review of 9 prospective studies and 1 randomized trial
Rate of hepatitis*
Rate of HBV
reactivation†
Lamivudine
Prophylaxis
0%–20%
Placebo Controls
0%–24%
29%–56%
33%–67%
*ALT increased ≥3-fold over baseline and exceeded ULN, or absolute increase of ≥100 IU/mL over baseline
†HBV DNA increased ≥10-fold over baseline, or absolute increase ≥1000 x 106 geq/mL
Kohrt HE, et al. Aliment Pharmacol Ther. 2006;24:1003.
Preventing HBV Reactivation in
Chemotherapy Patients




Chemotherapy can reactivate HBV and allow
hepatocyte infection
Withdrawal of chemotherapy causes immunologic
rebound with resultant destruction of hepatocytes
– Massive liver necrosis; potentially fatal
Test patients for HBsAg before chemotherapy
If HBsAg positive, start antiviral therapy before
chemotherapy to prevent clinically significant
reactivation
Summary and Conclusions
Practical Implications for Patient
Management


It is critical to identify patients with chronic
hepatitis B by screening at-risk individuals
Once identified, they can
– Have family members screened and vaccinated
– Receive education about lifestyle modification
– Enroll in suitable follow-up programs
– Be considered for antiviral therapy
Newly Diagnosed Hepatitis B
New chronic hepatitis B
• Screen and vaccinate sexual contacts
and household members
• Counsel about alcohol use
• Determine activity
and severity of hepatitis
• ALT, HBeAg, HBV DNA
• Liver biopsy?
Initiate antiviral therapy
Refer to practice guidelines
• AASLD
• US Tx algorithm
Initiate regular scheduled follow-up
and monitoring
Summary and Conclusions

HBV infection is a worldwide epidemiologic and clinical
challenge

Screening at-risk individuals identifies those with HBV infection
– HBsAg, anti-HBe, anti-HBc

Pretreatment evaluation includes history, physical examination,
and additional diagnostic testing
– HBeAg, ALT, HBV DNA, liver biopsy?

Candidates for anti-HBV treatment include patients with active
liver disease and high levels of HBV replication