Update on Chronic Hepatitis B

Dr Nasir Khokhar MD FACP FACG
Professor of Medicine and
Director, Division of
Gastroenterology
Shifa International Hospital
Islamabad Pakistan
Strategies for Optimal HBV
Screening, Diagnosis, and
Treatment

Diagnosing HBV Infection and
Identifying Clinical Status

clinicaloptions.com/hep
HBV Core Curriculum 2008: Treatment and Management
Burden of Chronic HBV Disease
 ~ 400 million people worldwide living with chronic HBV
infection[1]
– Yearly, ~ 500,000 people die of HBV-related cirrhosis and HCC
– Up to two thirds are unaware of their infection[2]
 To reduce disease complications, need to
– Identify infected individuals
– Assess disease status and need for treatment and other
monitoring
– Optimize treatment outcomes: issues of who, when, and how to
treat
1. Sorrell MF, et al. Ann Intern Med. 2009;150:104-110. 2. Lin SY, et al. Hepatology. 2007;46:1034-1040.
3. CDC. MMWR. 2007;56:446-448.

Global Distribution of HBV
Centers for Disease Control and Prevention. CDC Health Information for International Travel 2010.
Prevalence of HBsAg
High ≥ 8%
Intermediate 2% to 7%
Low < 2%

Impact of Immigration
HBsAg Prevalence[2]
≥ 8% (high)
2% to 7% (intermediate)
< 2% (low)
Immigration Numbers by Continent: 2000-2009[1]
~ 3.6 million Asians
~ 875,000
South Americans
~ 804,000
Africans
~ 1.3
million
Europeans
1. US Department of Homeland Security. Yearbook of Immigration Statistics: 2009. 2. Weinbaum CM, et al.
MMWR Recomm Rep. 2008;57(RR-8):1-20.

 4 overlapping open
reading frames
 Reverse transcriptase/
DNA polymerase domain
overlaps with surface
gene
 100 times more infective
than HIV
 Found in blood and body
fluids
MMWR. 2003;52:1-33. Ott MJ and Aruda M. J Pediatr Health Care. 1999;13:211-
216. Ribeiro RM, et al. Microbes and Infection. 2002;4:829-835.
1622
EcoRI
3221, 1
(+)
(-)
polymerase
Hepatitis B Virus (HBV)

Transmission Routes and Endemicity
 Most primary HBV infections in highly endemic countries occur
during infancy or early childhood[1]
– Vertical transmission (from infected mother via perinatal exposure)
or horizontal transmission
 Most primary HBV infections in low prevalence countries occur
during adolescence/young adulthood[1]
– Transmission routes: unsafe sex practices or injection drug use
 ~ 21 million HBV infections worldwide in 2000 attributable to
unsafe injection administration in healthcare settings[2]
1. Shepard CW, et al. Epidemiol Rev. 2006;28:112-125. 2. Hauri AM, et al. Int J STD AIDS. 2004;15:7-16.

HBeAg and the Risk of HCC
Yang et al. N Engl J Med. 2002;347:168-174.
 11,893 Taiwanese men; 92,359 person-years (PYs) follow-up
 111 cases of HCC diagnosed during follow-up
– Incidence highest among individual HBeAg- and
HBs Ag+
39.1
324.3
1169.4
0
200
400
600
800
1000
1200
1400
HBsAg(-)
HBeAg(-)
HBsAg(+)
HBeAg(-)
HBsAg(+)
HBeAg(+)
IncidenceofHCC,
Cases/100,000PYs
P < .001
P < .001

Risk of HCC and Cirrhosis According
to Baseline HBV DNA
HBV DNA (copies/mL)
HCC(%perYr)[1]
1. Chen CJ, et al. JAMA. 2006;295:65-73. 2. Iloeje UH, et al. Gastroenterology. 2006;130:678-686.
< 300
300-9999
10,000-99,999
100,000-999,999
≥ 1 million
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
Cirrhosis(%perYr)[2]
HBV DNA (copies/mL)
< 300
300-9999
10,000-99,999
100,000-999,999
≥ 1 million
3.0
2.5
2.0
1.5
1.0
0.5
0

Yim HJ, et al. Hepatology. 2006;43:S173-S181.
. Chronic active
inflammation
Mild hepatitis
and minimal
fibrosis
Minimal
inflammation
and fibrosis
Active
inflammation
HBeAg
Anti-HBeAg
HBV DNA
ALT activity
Classic Concept of HBV Infection in the1980s
Phases of Chronic HBV Infection

Phase Immune
Tolerant
Immune
Clearance
Inactive
Carrier State
Reactivation
Liver
Minimal
inflammation
and fibrosis
Chronic active
inflammation
Mild hepatitis
and minimal
fibrosis
Active
inflammation
Yim HJ, et al. Hepatology. 2006;43:S173-S181.
Optimal treatment times
Anti-HBeAg
HBV DNA
ALT activity
Current Understanding of HBV Infection
4 Phases of Chronic HBV Infection
HBeAg

HBV Disease Progression
1. Torresi J, et al. Gastroenterology. 2000;118:S83. 2. Fattovich G, et al. Hepatology. 1995;21:77.
3. Perrillo RP, et al. Hepatology. 2001;33:424.
Chronic
Infection
Cirrhosis
Death
5%–10%1
Liver
Failure
30%[1]
23% in 5 yr2
Liver
Cancer
(HCC)
Chronic HBV is the 6th
leading indication for liver
transplantation in the
United States:[3] ~5%
Liver
Transplantation
Acute flare
6% in 5 yr[2]

HBV ACUTE /CHRONIC
HEPATITIS B
CIRRHOSIS
ESLD
HEPATOCELLULAR
CARCINOMA
20−30 years
Cirrhosis HCCNormal Cirrhosis
Chronic hepatitis B – consequences
Liver disease progression over time
Liver damage = the result of attempts, usually unsuccessful, to clear infected
hepatocytes as part of the immunoclearance stage of disease

Clinical Significance of
Viral Replication
Worsening histology,
including cirrhosis
HCC
Elevated ALT
Viral replication

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.
Lok AS, et al. Hepatology. 2007;45:507-539.
Marker
Acute
HBV
Acute HBV
Recovery
Chronic HBV Disease
Inactive HBeAg
Carrier StateHBeAg
Positive
HBeAg
Negative
HBsAg

(may clear)
  
Anti-HBs 
Anti-HBc IgM 
Anti-HBc     
HBeAg  
Anti-HBe

(in some cases)
 
Serologic Markers of HBV Infection

Surrogate Clinical Markers for
Hepatitis B Outcomes
Prevention
of Death,
Cirrhosis,
and HCC
Liver histology Serum HBV DNA
ALTSeroconversion

Chu CJ, et al. Gastroenterology. 2003;125:444-451.
Chronic Hepatitis B Disease Types
 HBeAg positive
– Also known as “wild type”
– Antibody to HBeAg negative
– HBV DNA > 20,000 IU/mL (> 105 copies/mL)
 HBeAg negative
– Also known as “precore mutant”
– Antibody to HBeAg positive
– HBV DNA > 2000 IU/mL (> 104 copies/mL)

Differentiating HBeAg-Negative Chronic
HBV from Inactive Carrier State
HBeAg-Negative Disease Inactive
Carrier
HBsAg positive  
Anti-HBe positive  
Anti-HBc positive  
HBV DNA > 104-5 copies/mL* < 103 copies/mL
ALT Elevated† Normal

Role of ALT in Assessment of
HBV Patients
 ALT > 20 IU/L associated with increased risk for
liver disease-related death[1]
 Patients with mildly elevated ALT (> 1 to 2 x ULN)
may be at increased risk of developing
complications or fibrosis progression[2,3]
 Up to 24% of patients with normal ALT have stage
2-4 fibrosis by biopsy[4,5]
1. Kim HC, et al. BMJ. 2004;328:983-986. 2. Yuen MF, et al. Gut. 2005;54:1610-1614. 3. Lai M, et al.
J Hepatol. 2007;47:760-767. 4. Lai M, et al. Hepatology. 2005;42(suppl 1):720A. 5. Alberti A, et al.
Ann Intern Med. 2002;137:961-964. 6. Kim WR, et al. Hepatology. 2008;47:1363-1370.

Histology
 Liver biopsy
– Establishes disease baseline before initiation of therapy
– Helps to exclude other causes of liver disease
– More sensitive and accurate than ALT
– Limitations
– Invasive procedure
– Sampling error
– Interobserver variability

Initial Evaluation

Initial Evaluation of Patients With
Chronic HBV Infection
 Medical history and physical examination
– Family history of HBV infection and liver cancer
 Consider liver biopsy to grade and stage possible liver disease
 Laboratory tests to assess liver disease
– CBC with platelets, hepatic panel, prothrombin time
 Serology
– HBeAg/anti-HBe
– HBsAg/anti-HBs
 Virology
– HBV DNA (PCR based)
 Test for viral coinfection (HIV, HCV, ± HDV)

What Is a “Normal” ALT Level?
 9221 first-time potential blood donors
 74% suitable donors after exclusion of anemia, seizure, sexual, and
other risk
– 57% determined to be at “low risk” for liver disease
– Negative viral serology
– BMI < 25
 Updated healthy ALT ranges determined from the group of low-risk
individuals
– Males: 30 IU/L
– Females: 19 IU/L
Prati D, et al. Ann Intern Med. 2002;137:1-10.

Brunetto MR, et al. J Hepatol. 2002;36:263-270.
Significance of ALT Fluctuation
 A single normal ALT level does not always indicate a
patient is immune tolerant
 64.1% of 164 HBsAg-positive/HBeAg-negative patients
followed for 1 yr had recurrent flares
 ALT should be monitored over time

 1387 asymptomatic HBsAg-positive patients with ≥ 1-yr follow-up
 21% of HBeAg-negative patients with PNALT and HBV DNA
< 5 log copies/mL had HAI ≥ 3 and/or fibrosis stage ≥ 2
Kumar M, et al. Gastroenterology. 2008;134:1376-1384.
*≥ 3 ALT values in the previous 1 yr prior to baseline liver biopsy that were all ≤ 40 IU/L and
remained so until the start of treatment or the last follow-up.
60.3
39.735.3
13.8
0
20
40
60
80
100
HBV DNA ≥ 5 log copies/mL Histologic Fibrosis Stage ≥ 2
HBeAg positive
HBeAg negative
Patients(%)
Patients With Normal ALT
May Have Significant Fibrosis

Advanced Fibrosis in Patients With
Normal/Near-Normal ALT
 Mean stage of fibrosis similar between patients with normal and
elevated ALT
– Elevated ALT: 2.0 – Normal ALT: 1.7
Goebel T, et al. AASLD 2008. Abstract 973.
Patients With Normal ALT
24
42
26
0
20
40
60
80
100
Cirrhosis Fibrosis Inflammation
Patients(%)

Favorable Outcomes in Patients With
High HBV DNA, Normal ALT
 240 HBeAg-positive individuals (male 130, female 110);
mean age: 27.6 yrs
 Mean follow-up: 10.5 yrs (range: 3-20)
 Spontaneous HBeAg seroconversion in 85% between the
ages of 20 and 39 yrs
 Reactivation of hepatitis after HBeAg seroconversion in
2.2% per yr
 Progression to cirrhosis in 5.4% after 10 yrs
 HCC: none
Chu CM, et al. Am J Med. 2004;116:829-834.

HBV DNA Testing
 Indicates chronic hepatitis when still positive 6 months
after diagnosis of acute HBV infection
– Can differentiate chronic, inactive carrier (< 2000 IU/mL) vs
resolved HBV infection (undetectable)
 Change in HBV DNA level used to monitor response to
therapy
 Increasing HBV DNA level during antiviral therapy
indicates emergence of resistant variants
 HBV DNA level correlates with disease progression
Adapted from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106.

Impact of HBV Genotype on Disease
Progression
 Genotype C (Asia)
– More frequently associated with
severe liver disease and HCC than
genotype B
 Genotype B
– Associated with seroconversion
from HBeAg to anti-HBe at younger
age than genotype C
 Genotypes A and B
– Higher rates of antiviral response
and HBeAg loss following pegIFN alfa
than genotypes D and C, respectively
HBV Genotyping
Line Probe Assay
Marker line
Conj. control
Amp. control
Genotype A
Genotype B
Genotype C
Genotype D
Genotype E
Genotype F
Genotype G
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16

Can HBV Infection Be Cured?
 HBV is not curable with current therapy (none targets
cccDNA intra-hepatocyte) but it is controllable
 HBsAg seroconversion is the ultimate form of viral control

Primary Goal of Hepatitis B Therapy:
Preventing Cirrhosis, HCC, and Death
 Prolonged viral suppression is associated with
– Reduction in necroinflammation, fibrosis, and cirrhosis
– Reduction in decompensation/reactivation
– Reduction in rates of HCC
– Reduction in mortality
Durable Suppression
of HBV Replication
Impact of viral suppression on liver disease outcomes

Benefits
Risks
Patient’s age
and preference,
costs
Likelihood of
 Adverse outcome
 Long-lasting response
Adverse effects
Drug resistance
Likelihood of adverse clinical outcome without treatment
Activity and stage of liver disease at presentation
Risk of cirrhosis/HCC in the next 10-20 yrs
Likelihood of long-term benefit with treatment
HBV: Who Should Be Treated?

Interferon alfa-2b
Lamivudine
Adefovir
Peginterferon alfa-2a
Telbivudine
Tenofovir
1990 1998 2002 2005 2006 2008
Entecavir
HBV Treatment Landscape

Decision to treat
IFN
(PegIFN alfa-2a)
Nucleos(t)ide
analogues
The First Branch Point in Choosing
What to Treat With

Advantages and Disadvantages of
Interferon
Pro Con
Finite course of therapy Subcutaneous administration
No resistance Adverse effects
Higher rate of HBeAg loss in
1 year vs oral drugs
HBeAg loss “catches up” with
> 1 year oral drugs;
prolonged IFN use not feasible
Potential for HBsAg clearance
with short duration therapy
HBsAg clearance also occurs
with oral agents

 Favorable predictors of response
– Genotype A or B > C or D
– Low HBV DNA
– High ALT
 Specific patient demographics
– Generally young people
– Young woman wanting future pregnancy
– Absence of comorbidities
 Patient preference
 Concomitant HCV infection
When to Consider PegIFN

Interferon
-alfa
Antiviral action
Immunomodulatory
action
T helper cell
Natural killer
cell
Cytotoxic T cell
Reduction in viral load
Destruction of infected cells
Induction of antiviral state
through gene activation
prevents infection of new
cells
Tipping the balance of immune control
in CHB through IFN therapy
Effects translate into a response that is sustained post-treatment

Treatment of
HBeAg-Positive Patients

Keeffe EB, et al. DDW 2008. SP198. Keeffe EB, et al. Clin Gastroenterol Hepatol.
2006;4:936-962.
HBeAg positive
HBV DNA
< 20,000 IU/mL
HBV DNA
≥ 20,000 IU/mL
ALT normal ALT elevated
 No treatment
 Monitor every 6-12
months
 Monitor ALT every 3-12
months (immune tolerant)
 Consider biopsy, if age is
> 35-40 years and treat if
significant disease
 Treat to HBeAg
seroconversion
 ETV, TDF,
and pegIFN are
first-line options
HBV Patients With Compensated
Disease: HBeAg Positive

Adapted from Lok AS, et al. Hepatology. 2007;45:507-539. Heathcote EJ, et
al. AASLD 2007. Abstract LB6.
*By PCR based assay (LLD ~ 50 IU/mL) except for some LAM studies.
40-44
21
67
25
69
PatientsWithUndetectable
HBVDNA(%)
60
0-16
Not head-to-head trials; different patient populations and trial designs
76
Virologic Response in HBeAg+ Patients
(Undetectable* HBV DNA at Wk 48-52)
100
80
60
40
20
0
LAM ADV ETV LdT TDF Peg-
IFN
Peg-
IFN +
LAM
PLB

27*
*Response 6 months after stopping treatment.
Adapted from Lok AS, et al. Hepatology. 2007;45:507-539. Heathcote EJ, et
al. AASLD 2007. Abstract LB6.
Virologic Response in HBeAg+ Patients
(HBeAg Seroconversion at Wk 48-52)
PatientsAchieving
HBeAgSeroconversion(%)
100
80
60
40
20
0
IFN
Peg-
IFN +
LAM
PLB
16-21
12
21
32*
4-6
27 24
22 21

Chang TT, et al. J Gastro Hepatol. 2004;19:1276-1282. Lok AS et al. Gastroenterol. 2003;125:1714-1722. Chang TT, et al. N Engl J Med.
2006;354:1001-1010. Chang TT, et al. Hepatology. 2006;44(suppl 1):229A. Marcellin P, et al. N Engl J Med. 2003;348:808-816.
Marcellin P, et al. Hepatology. 2006;44(suppl 1):548A. Lai CL, et al, Hepatology. 2005;42(suppl 1):748A.
Lai CL, et al. Hepatology. 2006;44(suppl 1):222A. Han S, et al. AASLD 2007. A938.
*(ETV-022 + ETV-901) 16% additional to 31% HBeAg seroconversion in ETV-022 (Year 2).
HBeAg Seroconversion During
Continued Treatment
5047
40
29
22
0
20
40
60
LAM ADV
ETV LdT
1 2 3 4 5
Years of Therapy
Patients(%)
80
100
47*
37
31
21
0
20
40
60
80
100
48
12
0
20
40
60
80
100
23
29
1 2 3 4 5
Years of Therapy
0
20
40
60
80
100

Treatment of
HBeAg-Negative Patients

HBeAg negative
HBV DNA
< 2000 IU/mL
HBV DNA
≥ 2000 IU/mL
ALT
normal
ALT
elevated
 No treatment
 Monitor every
6-12 months
 Monitor ALT and
HBV DNA, or
 Consider biopsy,
since ALT often
fluctuates and treat if
significant disease
 Treat long term
 ETV, TDF,
or PegIFN are
first-line options
Keeffe EB, et al. DDW 2008. Abstract 198.
HBV Patients With Compensated
Disease: HBeAg Negative

IFN
Peg-
IFN +
LAM*By PCR based assay (LLD ~ 50 IU/mL) except for some LAM studies.
~ 70
51
90
63
8788
Adapted from Lok AS, et al. Hepatology 2007;45:507-539. Marcellin P, et al. AASLD
2007. Abstract LB2.
93
Virologic Response in HBeAg- Patients
(Undetectable* HBV DNA at Wk 48-52)
PatientsWithUndetectable
HBVDNA(%)
100
80
60
40
20
0

Tolerability and Safety: Nucleos(t)ide
Analogues vs Peginterferon
Nucleos(t)ide Analogues
 Safe at all stages of disease,
including decompensated
cirrhosis
 Safe in immunocompromised
populations
– Selected drugs probably safe in
pregnancy
 Reported toxicities are rare
Peginterferon
 Contraindications
– Decompensated cirrhosis
– Pregnancy
– Significant cardiopulmonary
disease
– Uncontrolled seizures,
psychiatric disease
– Autoimmune diseases
 Not recommended
– Cirrhosis
 Adverse effects common
Lok AS, et al. Hepatology. 2007;45:507-539. Lok AS, et al. Hepatology. 2009;50:661-662.

Treatment End Point

Treatment Endpoints in Chronic
Hepatitis B
Potential Treatment Endpoints in Chronic Hepatitis B
Treatment
Endpoints
Normal ALT
Histological
Improvement
Undetectable
Serum
HBV DNA
HBeAg
Seroconversion
HBeAg Loss
cccDNA
Clearance
HBsAg
Clearance

End Points of Therapy
Two Distinct Patient Populations
 HBeAg+ (wild-type)
– HBeAg response/seroconversion a potential endpoint-?
 HBeAg-/anti-HBe+/HBV DNA+
(precore mutant)
– HBeAg seroconversion not an endpoint
– High relapse rate and long-term therapy the rule

HBsAg clearance –
closest outcome to cure
 HBsAg seroconversion
– Natural course of resolved infection
– Closest we can get to a „clinical cure‟ of HBV
– cccDNA = reservoir for reactivation
– Reactivation: in patients with immunosuppression
– eg BMT, chemotherapy
– Organ transplant

What is so special about HBsAg?

HBsAg is found free in serum in
various forms
 Present in lipid envelope of virus
 Various forms in serum
 Defective particles exceed virions by a factor
of 103–105

Replication of HBV – the stealth
virus
cccDNA acts as a viral reservoir allowing re-activation
LHBs
SHBs
mRNA X
mRNA
SHBs/MHBs
mRNA LHBs
mRNA Core/Pol
cccDNA
AAA
pgRNA 3.5kb
Core protein
Polymerase
negative
strand
positive strand
AAA
AAA

Measuring cccDNA
 cccDNA can be measured in liver biopsy samples
 Can we measure it without a biopsy?

Is serum HBsAg an indicator of
cccDNA?
 cccDNA acts as transcription template
 Serum HBsAg levels reflect cccDNA (A) and intrahepatic HBV DNA (B)
 Non-invasive marker of infected cells
A B
Chan et al. Clin Gastro Hepatol 2007
HBsAgatbaseline
HBsAgatbaseline
Log (cccDNA) at baseline Log (intrahepatic HBV DNA) at baseline
A

Steps along the way to cure are used to
monitor response
 Markers of response to therapy used in clinical trials
HBsAg clearance – the closest outcome to cure
Marcellin et al. EASL 2008; Perrillo et al. Hepatology 2006
Fattovich et al. Am J Gastroenterol 1998
HBV DNA
suppression
HBeAg
seroconversion
HBsAg
clearance
Time

HBsAg – Anti-HBs seroconversion:
The hallmark of recovery from CHB
HBsAg clearance: the gold standard
of immune control of HBV infection
Go for gold – not only at the Olympic games!

*Defined as < 2 log reduction in serum HBV DNA after 6 months of therapy.
Adapted from Lok AS, et al. Hepatology. 2007;45:507-539.
LogHBVDNA
0.0
-1.0
-2.0
-3.0
-4.0
+1.0
1 log
Antiviral Drug
Mutant
Primary nonresponse*
Secondary
treatment
failure
Time
2 log
Antiviral Treatment Failure in HBV

HBV Resistance Mutations
845 a.a.
Terminal
protein
Spacer Pol/RT RNaseH
A B C ED
YMDDGVGLSPFLLA
I(G) II(F)
Allen MI, et al. Hepatology. 1998;27:1670-1677. Qi X, et al. J Hepatol. 2004;40(suppl 1):20-21.
Tenney D, et al. Antimicrob Agents Chemother. 2004;48:3498-3507. Tyzeka [package insert]. Lai CL, et
al. Gastroenterology. 2005;129:528-536. Schildgen O, et al. N Engl J Med. 2006;354:1807-1812.
Locarnini S. 2006 IDRW. Abstract P2.
rtL80V/I rtM204V/I/SLAM resistance rtV173L
rtL180M
rtA181T/V rtN236T
rtl233V ?
ADV resistance
rtM204V/I
rtS202G/C rtM250I/VrtT184S/A/I/L
ETV resistance rtL180M
rtM204ILdT resistance rtL80V/I rtL180M
TDF resistance rtA194T rtM204V
rtL180M

Emergence of Resistance During
Antiviral Therapy
Fung SK, et al. Antivir Ther. 2004;9:1013-1026.
Locarnini S, et al. Antivir Ther. 2004;9:679-693.
Time
Wild-type virus
Naturally occurring viral variants
Drug-resistant mutant virus
Factors contributing to resistance include
those related to the drug, the patient, and
the virus
Treatment
begins
HBVReplication

Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.
PatientsWithDisease
Progression(%)
Wild type (n = 221)
YMDDm (n = 209)
Time After Randomization (Months)
0
5
10
15
20
25
0 6 12 18 24 30 36
Placebo (n = 215)
5
13
21
LAM Resistance Associated With Faster
Progression of Liver Disease

n =
HBV DNA at Month 6 of LAM Predicts
Later Risk of Resistance
N = 159 HBeAg-positive patients
Median follow-up: 29.6 months
Yuen ME, et al. Hepatology. 2001;34:785-791.
PatientsWithResistance(%)
8
13
32
64
0
20
40
60
80
100
≤ 2 ≤ 3 ≤ 4 > 4
PatientsWith
YMDDVariants(%)
HBV DNA at 6 Months (log10 copies/mL)
12 23 41 118

ADV
(N236T/A181V)[1]
IncidenceofResistanceCumulative Incidence
HBV Antiviral Resistance
1. Qi, et al. EASL 2004, Abstract 57. 2. Lai, et al. Clin Infect Dis. 2003;36:687.
3. Tenney DJ, et al. AASLD 2004 Abstract 184.
LAM (M204V/I)[2]
ETV (WT / LAM
refractory)[3]
70%
0
10
20
30
40
50
60
70
80
Year 1 Year 2 Year 3 Year 4
3.9%0% / 6%
LAM
ETV ADV

Elevated HBVDNA
=
Increased resistance

Current Recommendations on
Antiviral Resistance Testing
Lok ASF, et al. Hepatology. 2007;46:254-265.
 2007 HBV Drug Resistance Working Group
– If a rise in serum HBV DNA (≥ 1.0 log10 IU/mL) above nadir
(virologic breakthrough) occurs, assess drug compliance
– Consider evaluation for genotypic resistance
– Tests for antiviral-resistance mutations should be performed
to
– Confirm genotypic resistance (≥ 1.0 log10 IU/mL increase in HBV DNA
from nadir)
– Determine the pattern of mutations (ie, cross-resistance)

Potential Role of
Combination Therapy

Any Present Role for Combination
Therapy as Initial Treatment?
 No combination therapy has convincingly shown increased short-term efficacy
as initial treatment
– L-dT + LAM vs L-dT vs LAM[1]
– LAM + ADV vs LAM[2]
– FTC + ADV vs ADV[3]
– TDF + FTC vs TDF[4]
 Currently available drugs have excellent resistance profile
 Studies to establish any advantage of combination therapy require
– Large number of patients
– Long duration
– Shorter-term endpoints than resistance
1. Lai CL, et al. Gastroenterology. 2005;129:528-36. 2. Sung JJ, et al. J Hepatol. 2008;48:728-735.
3. Hui CK, et al. J Hepatol. 2008;48:714-720. 4. Berg T, et al. 2008 EASL. Abstract 76.

Potential Populations in Which to
Consider Combination Therapy
 Cirrhotics
– Risk of hepatitis flare with emergence of resistance is high
 HIV/HBV coinfection
– ETV monotherapy no longer optimal with recent data on HIV susceptibility and
genotypic resistance
– Risk of resistance with any monotherapy in HIV/HBV coinfection
 Suboptimal response to an initial drug
– Especially if high-level viremia on potent drug
 Established resistance to antiviral medication(s)
– Lessons learned from ADV switch vs add-on in patients with LAM resistance
Jacobson IM. J Hepatol. 2008;48:687-691.

Predictors of Long-term
Virologic Success

Early, Profound Suppression Leads to
Greater Sustained Response
HBV DNA at Week 24HBV DNA at Week 12
1. Farci P, et al. EASL 2005 Abstract 484. 2. Zeuzem S. EASL 2006. Abstract 51.
PatientsPCRNegative
atFollow-up(%)
0
20
40
60
80
100
PegIFN alfa-2a
at Week 72[1]
HBeAg Negative
< 400
c/mL
≥ 400
c/mL
n =
61
31
70 106
LdT at Week 52[2]
HBeAg Positive
< QL ≥ QL
95
33
255203
LAM
at Week 52[2]
HBeAg Positive
< QL ≥ QL
84
20
146 317

68
LdT
PCRUndetectable
atWeek104(%)
61
40
20
88
78
63
20
73
60
28
7
60
25
5
82
0
10
20
30
40
50
60
70
80
90
100
< QL QL-3 3-4 > 4 < QL QL-3 3-4 > 4
LAM
HBeAg Positive HBeAg Negative
HBV DNA at Week 24 (log10 copies/mL)
DiBisceglie A, et al. AASLD 2006. Abstract 112.
GLOBE: Week 24 HBV DNA Predicts
Week 104 Undetectable HBV DNA

HBeAgSeroconversion
atWeek104(%)
HBV DNA at Week 24 (log10 copies/mL)
39
46
19
6
0
20
40
100
< QL QL-3 3-4 > 4
HBeAg Positive:
Combined Treatment Groups (LAM + LdT)
DiBisceglie A, et al. AASLD 2006. Abstract 112.
80
60
GLOBE: Week 24 HBV DNA Predicts
Week 104 HBeAg Seroconversion

Early Suppression of HBVDNA
=
Increased sustained response
Increased seroconversion

 2007 AASLD guidelines[1]
– IFN (preferably pegIFN alfa-2a)
– Monitor HBV DNA levels every 12-24 weeks during
treatment
– Monitor HBV DNA levels every 12 weeks during the
first 24 weeks of posttreatment
– Nucleos(t)ide analogues
– Monitor HBV DNA levels every 12-24 weeks
1. Lok AS, et al. Hepatology. 2007;45:507-539.
2. Lok, AS, et al. Hepatology. 2007;46:254-265.
On-Treatment HBV Monitoring
Recommendations

Prevention and Monitoring of
Resistance
Prevention
Avoid unnecessary treatment
Initiate potent antiviral that has low rate of drug resistance or use combination
therapy
Switch to alternative therapy in patients with primary nonresponse
Monitoring
Test for serum HBV DNA (PCR) every 3-6 mos during tx
Check for medication compliance in patients with virologic breakthrough
Confirm antiviral resistance with genotypic testing
Lok AS, et al. Hepatology. 2009;50:661-662. Chronic Hepatitis B: Update 2009, Lok ASF, McMahon
BJ, www.aasld.org. Copyright@2009. American Association for the Study of Liver Diseases.
Reproduced with permission of the American Association for the Study of Liver Diseases.

The Road Map Concept

Management Roadmap According to
Week 12 Virologic Response
Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.
Week 12
Assess for primary nonresponse
Primary response
HBV DNA 1 log10 IU/mL drop
Primary treatment failure
HBV DNA < 1 log10 IU/mL drop
Continue
Start treatment
If nonadherent,
counsel
If adherent,
add a more
potent drug

Management Roadmap According to
Week 24 Virologic Response
Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.
Patients with primary response
Week 24
Assess early predictors of efficacy
Complete response
HBV DNA negative by PCR
Partial response
HBV DNA
60 to < 2000 IU/mL
Continue therapy;
monitor every 6 months
Inadequate response
HBV DNA ≥ 2000 IU/mL
Add a more potent drug;
monitor every 3 months

Outcome of hepatitis viral infection and
liver disease
•
Immune system Virus
Antiviral treatment is aimed at changing the
“pathogenic equilibrium” into a “non pathogenic one”

Treatment of Special Populations

Reactivation of chronic hepatitis B
 Seen as early as 1991
 Occurs most frequently with immunosuppression and
chemotherapy
 Can range to subclinical enzyme elevation to fatal
hepatitis
 General physicians and other subspecialists are not aware
of risk with prescribing agents
 Patients should be tested for HBsAg status and placed on
antiviral therapy if positive
Khokhar et al.. Chemotherapy 2009; 55: 69-75

Reactivation of Hepatitis B:
Chemotherapy or Immunoprophylaxis
 Alkylators
– Cyclophosphamide
– Ifosfamide
– Chlorambucil
– Carboplatin, cisplatin
 Antimetabolites
– Cytarabine
– Fluorouracil
– Gemcitabine
– Mercaptopurine
– Methotrexate
– Thioguanine
 Corticosteroids
– Prednisone/dexamethasone, etc
 Antitumor antibiotics
– Anthracyclines
– Bleomycin
– Mitomycin
– Actinomycin
 Immunotherapy
– Rituximab (anti-CD20)
– Alemtuzumab (anti-CD52)
– Infliximab (anti-TNF)
 Plant alkaloids
– Vincristine
– Vinblastine
 Others
Lalazar G, et al. Br J Haematol. 2007;136:699-712.

Reactivation of HBV With Rituximab
Administration
 Retrospective analysis of patients who received
1 course of rituximab at single center: 2005-2007
 180 of 258 patients (70%) treated with rituximab tested
for HBV
– Vaccinated: 46%
– Negative: 39%
– Anti-HBc/anti-HBs positive: 11%
– HBV DNA positive: < 1%
Metzler F, et al. AASLD 2008. Abstract 848.

Reactivation of Hepatitis B:
EASL Management Guidelines
 Screen for HBsAg and anti-HBc prior to chemotherapy or
immunosuppressive therapy
 HBV vaccination in seronegative patients
 HBsAg-positive individuals
– Prophylactic oral therapy continuing 12 mos after cessation of therapy
– ETV or TDF in most patients, particularly with high HBV DNA
– LAM may be possible for patients with low HBV DNA, low risk of resistance
 HBsAg-negative, anti-HBc positive, undetectable HBV DNA
patients
– Monitor ALT and HBV DNA
– Treat with oral therapy upon HBV reactivation before ALT elevation
EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol. In press.

Hepatitis B Management Guidelines:
Cirrhotics
HBV DNA
(copies/mL)
Management
< 104 Treat or follow
≥ 104 Treat
Keeffe et al. Clin Gastroenterol Hepatol. 2004;2:87-106.
HBV DNA Management
Undetectable Follow; waitlist for transplant
Detectable
Treat carefully with oral antiviral;
waitlist for transplant
Compensated
Decompensated

Management of Patients With
Compensated Cirrhosis
Preferred therapies
ETV or TDF
– NAs should be used; IFN can be associated with hepatitis flare
Treatment duration
Long-term treatment
– Can discontinue in HBeAg-positive patients with confirmed HBeAg
seroconversion and ≥ 6 mos consolidation therapy
– Can discontinue in HBeAg-negative patients with confirmed
HBsAg clearance
Treatment discontinuation requires close monitoring for flare or
relapse

Management of Patients With
Decompensated Cirrhosis
Preferred therapies
 (LAM or LdT) + (ADV or TDF); TDF or ETV monotherapy*
– Treatment should be coordinated with transplantation center
– IFNs should not be used in decompensated cirrhosis
Treatment duration
 Lifelong treatment recommended
*Clinical data documenting safety and efficacy of TDF or ETV monotherapy in
decompensated cirrhosis are lacking.

Hepatitis B and Pregnancy
Mother
 Worsening of hepatitis
before or during
pregnancy?
 Worsening of hepatitis
after delivery?
 Hepatitis B and other
disorders during
pregnancy
Infant
 Transmission of HBV?
 Teratogenicity of
drugs?
 Risk of fulminant
hepatic failure?
 Breast-feeding?

HBV Transmission: When Does It
Happen?
 In utero transmission
– Very rare (< 10%); associated with high HBV DNA levels[1]
 During amniocentesis
– Very rare; no transmission reported in 2 case series[2,3]
 At birth!
– HBeAg-positive mothers: 85%
– HBeAg-negative mothers: 31%[4]
1. Wang Z, et al. J Med Virol. 2003;71:360-366. 2. Alexander JM, et al. Infect Dis Obstet Gynecol.
1999;7:283-286. 3. Towers CV, et al. Am J Obstet Gynecol. 2001;184:1514-1518. 4. Beasley RP, et al.
Am J Epidemiol. 1977;105:94-98.

 No effect of cesarean section on incidence of
immunoprophylaxis failure[1]
 If immunoprophylaxis cannot be provided, elective
cesarean section might reduce mother-to-child-
transmission of HBV[2]
1. Wang J, et al. Chin Med J. 2002;115:1510-1512.
2. Yang J, et al. Virol J. 2008;5:100.
Mode of Delivery Has No Effect on
HBV Transmission

1. Linnemann CC, et al. Lancet. 1974;2:155.
2. Hill JB, et al. Obstet Gynecol. 2002;99:1049-1052.
3. Cornberg M, et al. J Viral Hepat. 2008;15:1-21.
4. Johnson MA, et al. Clin Pharmacokinet. 1999;36:41-66.
Breast-feeding and Risk of HBV
Transmission
 HBV can be detected in breast milk[1]
 Neonates that are correctly immunized may be breast-
fed[2,3]
 Caveat: nucleos(t)ide analogues can be detected in breast
milk[4]

Prevention of HBV Transmission by
Postnatal Vaccination
 Active plus passive immunization most effective[1]
 Role of maternal HBV DNA on transmision[2]
– HBV DNA < 150 pg/mL (1.1 x 107 IU/mL) = 0% transmission
– HBV DNA > 150 pg/mL = 32% transmission
No Vaccine Passive
Immunization
Passive + Active
Immunization
Infants without HBV, % 5 72 95
1. Ranger-Rogez S, et al. Expert Rev Ant Infect Ther. 2004;2:133-145.
2. del Canho R, et al. Vaccine. 1997;15:1624-1630.

Can Antiviral Treatment Reduce
Vertical HBV Transmission?
 No complete prevention of transmission, even in case of
successful LAM treatment[1]
 LAM given 1 month before delivery decreased HBV
transmission from 28.0% in untreated historical controls to
12.5% (OR: 2.9; 95% CI: 0.29-28.0)[2]
– All received standard prophylaxis
– High maternal viremia associated with vaccination failure
– No adverse events noted with LAM
1. Kazim SN, et al. Lancet. 2002;359;1488-1489.
2. van Zonneveld M, et al. J Viral Hepat. 2003;10:294-297.

Recommendations for HBV-Infected
Women Who Desire Pregnancy
 Women with mild liver disease, low viremia
– Pregnancy before treatment
 Women with moderate liver disease, no cirrhosis
– Treatment before pregnancy; if response, stop treatment before
pregnancy
 Women with advanced liver disease
– Treatment before and during pregnancy; continue treatment after delivery
 Women with mild liver disease, very high viremia
– Treatment in last trimester
Wedemeyer H, et al. Dtsch Med Wochenschr. 2007;132:1775-1782.
EASL Clinical Practice Guidelines. J Hepatol. In press.

HBV Recurrence After Liver
Transplantation
 Prospective NIH-HBV-OLT study (N = 191)
– US patients who received OLT for HBV at 15 centers between March
2001 and September 2007 prospectively followed
 Status at time of transplantation
– HBeAg positive: 29%
– HBV DNA > 5 log10 copies/mL: 38%
– On antiviral therapy: 74% (LAM monotherapy: 68%)
– Viral breakthrough prior to OLT: 19%
– Confirmed genetic resistance: 67%
Lok A, et al. AASLD 2008. Abstract 594.

Management of Patients With HIV
Coinfection
1. Lok AS, et al. Hepatology. 2009;50:661-662. 2. DHHS Adults and Adolescents Guidelines. 2009.
 HBV/HIV-coinfected patients who require HBV therapy should be
treated[1]
Not on or Anticipating
Antiretroviral Therapy*
Planning Antiretroviral
Therapy
Already Receiving
Antiretroviral Therapy
 Treat with antiviral
therapy that is not active
vs HIV, such as pegIFN
or ADV 10 mg
 Although LdT does not
target HIV, it should not
be used in this
circumstance
 Treat with therapies that
are effective against both
viruses: TDF + (FTC or
LAM) preferred (plus ≥ 1
other anti-HIV agent)
 If regimen does not
include drug active
against HBV, may add
pegIFN or ADV
 If LAM resistance, add
TDF
*DHHS guidelines recommend that any HBV/HIV-coinfected patient in whom HBV treatment is indicated
should initiate a fully suppressive antiretroviral regimen containing 2 drugs with anti-HBV activity.[2]

Risk Factors Associated With HBV
Risk Factor Cases,* %
Multiple sex partners 38.3
Injection drug use 15.0
Surgery 11.7
Men who have sex with men 10.5
Sexual contact with hepatitis B patient 6.2
Percutaneous injury 4.3
Household contact of hepatitis B patient 2.3
Medical employee with blood contact 0.6
Blood transfusion 0.5
Hemodialysis 0.2
Unknown 58.0
Daniels D, et al. MMWR Surveill Summ. 2009;58(3):1-27.
*Percentage of cases calculated based on total number of cases for which any data for that exposure
type were reported. Percentages do not total 100% because multiple risk factors could be reported by
a single case.

HCC Screening
 AASLD guideline
– AFP and ultrasound q 6 months
 Other recommendations
– AFP L3%
– PIVKA-II
– MRI
Bruix et al. Hepatology. 2005;42:1208-1236
Sangiovanni et al. Hepatology. 2007;46:406A. [#375]

AASLD Guideline Recommendations
for HBV Screening
“1. The following groups should be tested for HBV infection (Grade I)”
 US-born persons not vaccinated as infants whose parents were born in regions with
high HBV endemicity
 Persons with chronically elevated aminotransferases
 Persons needing immunosuppressive therapy
 Men who have sex with men
 Persons with multiple sexual partners or history of sexually transmitted disease
 Inmates of correctional facilities
 Persons who have ever used injection drugs
 Dialysis patients
 HIV- or HCV-infected individuals
 Pregnant women
 Family members, household members, and sexual contacts of HBV-infected persons

for Screening
“1. . . . Testing for HBsAg and anti-HBs should be performed, and
seronegative persons should be vaccinated (Grade I)”
CDC. Hepatitis B FAQs for Health Professionals.
HBsAg Anti-HBs Total Anti-HBc IgM Anti-HBc
 Indicates that the
person is infected
 Indicates recovery
and immunity from
HBV infection
 Develops in a
person who has
been successfully
vaccinated against
hepatitis B
 Indicates previous
or ongoing
infection with HBV
in an undefined
time frame
 Appears at the
onset of symptoms
in acute hepatitis B
and persists for life
 Indicates recent
infection with HBV
(≤ 6 mos)
 This test is used to
distinguish acute
from chronic HBV
infection

HCC Surveillance: AASLD Practice
Guideline Recommendations
 Hepatitis B
– Cirrhosis regardless of age
– Asian males 40 yrs of age or older
– Asian females 50 yrs of age or older
– HCC in first-degree relative (start before 40 yrs of age)
– African older than 20 yrs of age
 Cirrhosis from other causes
Bruix J, et al. Hepatology. 2005;42:1208-1236.

for Counseling
Lok AS, McMahon BJ. Hepatology. 2009;50:661-662. Chronic Hepatitis B: Update 2009, Lok ASF,
McMahon BJ, www.aasld.org. Copyright@2009. American Association for the Study of Liver Diseases,
Reproduced with permission of the American Association for the Study of Liver Diseases.
Recommendations Regarding Prevention of Transmission of HBV to Others
Persons who are HBsAg positive should:
 Have sexual contacts vaccinated
 Use barrier protection during sexual intercourse if partner not vaccinated or naturally
immune
 Not share toothbrushes or razors
 Cover open cuts and scratches
 Clean blood spills with detergent or bleach
 Not donate blood, organs, or sperm
Children and adults who are HBsAg positive:
 Can participate in all activities including contact sports
 Should not be excluded from daycare or school participation and should not be isolated
from other children
 Can share food, utensils, or kiss others

Who Should Be Vaccinated for HBV?
CDC. Hepatitis B FAQs for Health Professionals.
Infants
 At birth
Children
 Who were not vaccinated as infants
At-Risk Adults
 Regions of intermediate/high endemicity
 Susceptible sex partners and household contacts of HBsAg-positive persons
 Persons seeking evaluation or treatment for an STD
 Persons with behavioral or occupational exposures
 Persons with end-stage renal disease, chronic liver disease, or HIV infection
 Residents/staff in certain settings with clients with known HBV risk factors

Summary and Conclusions

Take home messages
 Hepatitis B is common in our country.
 A normal ALT does not mean that everything is OK.
 Appropriate work up must be ensured before starting therapy.
 HBsAg clearance, HBeAg disappearance, development of Anti HBe
and disappearance of HBV DNA should be the goal.
 Potent and durable HBV DNA suppression may take years.
 Resistance to antivirals is common and should be monitored.
 Patients after seroconversion should be monitored periodically.
 Screening for HCC in all patients is recommended.

Take home messages (cont’d)
 Chemotherapy administration is associated with reactivation of
hepatitis B and should be monitored and managed.
 Perinatal transmission should be prevented by appropriate
vaccination and immune globulins to newborn.
 Low rate of HBV recurrence when antiviral therapy and HBIG
given together as prophylaxis after liver transplantation
 Liver fibrosis and cirrhosis developes in many patients with
chronic HBV infection and normal or moderately elevated ALT
levels.
 The goal in all patients should be undetectable HBV DNA

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