Recent Advance of Chronic Hepatitis

B Treatment

Lukman Hakim Zain

Divisi Gastroenterologi Dan Hepatologi
Departemen Ilmu Penyakit Dalam
FK USU/RSUP Adam Malik Medan
HBV Virology
 Partially ds DNA genome, 42nm
 4 genes – HBsAg, HBcAg, HBV Pol/RT, X protein
 Serologic marker of HBV infection: HBsAg
 Serologic markers of HBV replication:
HBeAg, HBV DNA, HBV Polymerase
 HBV Genotypes and Subtypes
Genotype Subtype Areas of prominence
A adw2, ayw1 NW Europe, USA, Central
Africa
B adw2, ayw1 Taiwan, Japan, Indonesia, China,
Vietnam
C adw2, adrq+, adrq-, ayr E Asia, Taiwan, Korea, China,
Japan, Vietnam
D ayw2, ayw3 Mediterranean area, India

E ayw4 W Africa

F adw4q, adw2, ayw4 Central and S America

G adw2 France, USA

•B associated with less active disease, slower progression, and lower incidence
of HCC than C
•A and B respond better to IFN than C and D
 Modes of Transmission

Perinatal/vertical Child-to-child
transmission
Hepatitis B

Unsafe injections
Sexual contact and transfusions

HBV is transmitted via contact with blood or body fluids in

the same way as HIV. However, HBV is
50–100 times more infectious than HIV
WHO Fact Sheet 2000
 Treatment Options for CHB
α- IFN /
Pegylated IFN
Immunomodulatory action Antigen presenting
cell

T helper cell

B cell
Cytotoxic T cell
Antiviral action
Natural killer cell

Nucleoside/
nucleotide
Antiviral action
analogues
 Goals of Antiviral Treatment of CHB

 Sustained suppression of HBV replication

  serum HBV DNA to <105 copies/ml
– HBeAg to anti-HBe seroconversion
– HBsAg to anti-HBs seroconversion
 Remission of liver disease
– Normalization of serum ALT levels
  necroinflammation in liver
 Improvement in clinical outcome
  risks of developing cirrhosis, liver failure and HCC
  survival
Mechanism of Action of Antiviral Drugs

Infectious
HBV virion Antiviral drugs Infectious
HBV virion

HBsAg
DNA pol envelopes
Partially double- RT
stranded DNA
(-)-DNA

Encapsidated
A(n) pregenomic
cccDNA mRNA mRNA

Lai et al., J Med Virol 2000

 Evolution of Approved HBV Therapy Over
Time

Peginterferon alfa-2a

Lamivudine Entecavir Tenofovir

1990
1990 1998
1998 2002 2005
2005 2006 2008
2008

Interferon alfa-2b Adefovir Telbivudine

 Recommendations for Treatment Initiation
in HBeAg-Positive Patients
AASLD 2007[1] US Algorithm 2008[2] EASL 2009[3]
HBV DNA, IU/mL > 20,000 > 20,000 ≥ 2,000
ALT, x ULN* >2 >1 >1
Moderate/severe necroinflammation
Disease stage/grade
and/or significant fibrosis
ADV,† ETV, ETV, TDF, ETV, TDF,
First-line therapy
pegIFN pegIFN pegIFN
 Criteria for HBV DNA, ALT and disease stage/grade must all be met
– If not, guidelines recommend monitoring and consideration of treatment based on individual’s age, health
status, and stage of infection/disease

1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-
1341. 3. EASL HBV Guidelines. J Hepatology. 2009;50:227-242.
 Recommendations for Treatment
Initiation in HBeAg-Negative Patients
AASLD 2007[1] US Algorithm 2008[2] EASL 2009[3]
HBV DNA, IU/mL > 20,000‡ > 2000 ≥ 2000
ALT, x ULN* 1 to > 2 >1 >1
Moderate/severe necroinflammation
Disease stage/grade
and/or significant fibrosis
ADV,† ETV, ETV, TDF, ETV, TDF,
First-line therapy
pegIFN pegIFN pegIFN
 Criteria for HBV DNA, ALT and disease stage/grade must all be met
– If not, guidelines recommend monitoring and consideration of treatment based on
individual’s age, health status, and stage of infection/disease

1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. 3. EASL HBV
Guidelines. Journal of Hepatology. 2009;50:227-242.
Special Populations That Should Also Be
Considered for HBV Treatment
Regardless of HBV DNA and ALT levels
• Patients with rapid deterioration of liver function
• Patients with compensated cirrhosis
If DNA > 2,000 IU/mL, regardless of ALT
• Patients with decompensated cirrhosis (IFN
contraindicated)
• Recurrent HBV infection post liver transplantation
• HBV carriers undergoing immunosuppressive or
cytotoxic chemotherapy
Factors Associated With Choosing
Nucleos(t)ides as Initial Therapy
Favorable predictors of response
High ALT
Low HBV DNA (baseline and on treatment)
Specific patient demographics
Older people
Patient preference
Concomitant HIV infection
No HCV coinfection
 Selecting Between Recommended First Line
Nucleos(t)ide and Interferon Therapy
Nucleos(t)ides Interferon-Based Therapy
Feature Pro Con Pro Con
Long term/
Administration Oral Finite duration Subcutaneous
indefinite
Low durable rates
Antiviral activity High
DNA suppression
Very low
Resistance No
resistance†
Rare renal tox with
Adverse events Minimal Substantial*
nucleotide
HBeAg loss and HBeAg loss  Higher rates vs HBeAg loss ≠ HBV
Lower rates vs IFN
clearance over time nucles(t)ides DNA suppression
HBsAg loss and Higher and earlier High rates (select Low rates in general
Low rates
clearance events† populations) patient groups
May induce HIV
Other Anti HIV (TDF) resistance Anti HCV/HDV
(TDF/ETV)
Factors Driving Selection of Initial
Nucleos(t)ide

Safety

Efficacy
(potency)

Barrier to
resistance
(durability)
Efficacy (Potency)
 Undetectable* HBV DNA in HBV Patients After
1 Year of Treatment
Not head-to-head trials; different patient populations and trial designs
HBeAg Positive HBeAg Negative
100 100
91
Undetectable* HBV DNA (%)

90 88
80 76 80
67
60 60-73
60 60
51-63
40-44
40 40

20 13-21 20

0 0
LAM ADV ETV LdT TDF LAM ADV ETV LdT TDF
*By PCR-based assay (LLD ~ 50 IU/mL) except for some LAM studies.

Lok A, et al. Hepatology. 2007;45:507-539. EASL HBV Guidelines. Journal of Hepatology. 2009;50:227-242 .
 HBeAg Loss/Seroconversion in HBeAg-Positive
Patients After 1 Year of Treatment
Not head-to-head trials; different patient populations and trial designs
HBeAg Loss/Seroconversion

HBeAg Loss HBeAg Seroconversion

100 100

80 80
(%)

60 60

40 32 40
24 22 26 23
22 21 21
20 20 12-18
NR
0 0
LAM ADV ETV LdT TDF LAM ADV ETV LdT TDF

Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Marcellin P, et al. N Engl J Med. 2003;348:808-816 Chang TT, et al. N Engl J
Med. 2006;354:1001-1010. Lai CL, et al. N Engl J Med. 2007;357:2576-2588. Marcellin P, et al. N Engl J Med. 2008;359:2442-
2455.
 Resistance and
Treatment Durability
 Cumulative Rates of Resistance With Oral
Agents in Nucleos(t)ide-Naive Patients

LAM ADV ETV LdT TDF

100

80 70
67
Patients (%)

60 49
40 38
29
24
18
20 17 11
4 3 0.5
0 0.2 0 0 1.2 1.2 1.2 1.2
0
1 2 3 4 5 6
Year
 Summary of Potency and Genetic
Barrier to Resistance
LAM and LdT
Potent agents with low genetic barriers and high rates of resistance
ADV
Less potent agent with low pharmacologic barrier with intermediate
rate of resistance
ETV
Potent agent with high pharmacologic and genetic barriers and low
rates of resistance
TDF
Potent agent with high pharmacologic and low rates of resistance,
genetic barrier not yet defined
 Proposed Special Populations for
Combination Therapy
Cirrhosis (especially decompensated)
High risk of hepatitis flare with emergence of resistance
HIV/HBV coinfection
Drugs with dual antiviral activity must be used in combination
to prevent drug resistance
Preexisting resistance
Rates of infection with resistant virus low but increasing

No data showing benefit of combination therapy vs. monotherapy with newer more
potent agents in treatment naïve patients
 Summary of FDA Approved Oral HBV
Treatments
Oral Antiviral Pharmacologic Genetic Adverse Events‡
Drug Potency* Barrier Barrier†
LAM + + 1 --
ADV ++ + 1 Nephrotoxicity (≤1% per year)
ETV ++++ ++++ 3 --
LdT ++ ++ 1 Myalgia, myositis, neuropathy,
cardiac arrhythmia (rare)
TDF ++++ ++++ ? Nephrotoxicity§
*Approximate and relative.
†
Number of mutations needed for primary antiviral drug resistance.
‡
Only includes reported adverse events that may differ in historical incidence associated with
LAM and, therefore, potentially affecting selection vs other agents. Pancreatitis has been
reported as a class effect and all agents have to be dose adjusted for renal insufficiency.
§
From HIV databases
Summary: Selecting the Best Nucleos(t)ide
for Initial Therapy
• Use nucleos(t)ides as monotherapy with
•Highest antiviral potency and genetic barrier to resistance
•Low incidence of resistance over time
•Rapid and sustained to maximize cumulative benefit
•LAM/LdT/ADV not generally recommended as first-line therapy
• Combination therapy may be considered in patients where
avoiding resistance is especially important
•Currently no data supporting this approach vs newer
monotherapies
• Consider individual patient characteristics in relation to safety
•Comorbidities (ie, compromised renal function)
•Coinfections (ie, anti-HIV activity of agents)
•Conception planning
Selecting an Interferon-Based Initial HBV
Treatment
Factors Associated With Choosing
Interferon for Initial Therapy
Favorable predictors of response
Genotype A or B > C or D
Low HBV DNA (baseline and on treatment)
High ALT (baseline)
Specific patient demographics
Younger people
Young woman wanting future pregnancy

Patient preference
No coinfection with HIV
Concomitant HCV infection
PegIFN Treatment-Associated Adverse
Effects
Patients should be carefully monitored for adverse events
Most common adverse events: flu-like symptoms (fever, chills, headache,
malaise, and myalgia) as well as psychological impairment
Incidence/Severity
Increase in

Depression
Fatigue
Anxiety
Flu-like
symptoms
0 1 2 3 4
Months
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.
 Summary of PegIFN alfa-2a
as Initial Therapy

•Advantages: finite duration of treatment, durable

response in a subset of responding patients; lack of viral
resistance development
•Disadvantages: administered by subcutaneous
injections; associated with significant toxicities in most
patients
•HBeAg and HBsAg seroconversion rates, tolerability, and
likelihood of response to treatment vs nucleos(t)ides all
play a role decision
THANK YOU

THE END!