Yerevan APASL STC

Institute of Liver & Biliary Sciences HBV 4.10.15

Dedicated to Excellence in Patient Care,

Teaching & Research in Liver & Biliary Diseases
Hepatitis B:
Future of Hepatology
Treatment
Indications and
Therapeutic End-
Points

A Deemed to be University
Dr. S K Sarin
shivsarin@gmail.com
New Delhi, India

www.ilbs.in
 Basis of HBV Treatment

• Viremia - qHBV DNA

• Hepatic inflammatory activity - ALT
• Liver fibrosis - Biopsy/
Fibroscan/APRI
 GOALS AND END POINTS OF THERAPY IN CHRONIC HBV
INFECTION

GKK Lau

3.4.1 Global eradication of HBV infection by

vaccination, treatment and prevention of
transmission. [A1]
3.4.2 To improve quality of life, Survival of infected
by preventing progression to cirrhosis,
decompensated cirrhosis, ESLD, HCC and
death. [A1].
3.4.3 Ideal end-point in HBeAg +ve & negative is
sustained off-therapy HBsAg loss, with or
without seroconversion to anti-HBs.[A1].
3.4.GOALS AND END POINTS OF THERAPY

GKK Lau

3.4.4 Sustained off-therapy virological response in HBeAg

positive [with anti-HBe seroconversion] and
HBeAg-ve patients is a satisfactory end point [A1].

3.4.5 If sustained off-therapy response not achievable ,

then maintained virological remission
(undetectable HBV DNA) under antiviral therapy is
the next most desirable end point [A1].
 INDICATIONS OF THERAPY
HBeAg +ve APASL HBV Guidelines 2015

HBsAg +ve HBV DNA ALT Treatment

Patient (IU/mL)
Decompensated Detectable Any Treat immediately
Cirrhosis Histology not needed.
Consider LT if no
stabilization. [A1]
Compensated >2000 Any Treat. [A1]
Cirrhosis Assess fibrosis -
histology or noninvasive
Severe Detectable Elevated Treat immediately
reactivation of [B1]
chronic HBV
 Definitions
Three Phases of HBV Reactivation
Phas Diagnostic
Feature Comments
e Markers
1 Increase in Viral HBV DNA Rise of > 1 log10 IU/mL AASLD STC 2013,
 2Log DNA
Replication HBeAg In HBeAg negative >200,000 IU/ml if
baselne DNA
HBsAg Reverse seroconversion unknwn

2 Appearance of ALT Rise of > 3 times baseline

>5-10 ULN
Disease Activity Symptoms Indicative of more severe
Jaundice injury
3 Recovery HBV DNA Fall to baseline values
ALT Fall to baseline values
HBsAg May be cleared late

Hoofnagle JH, Hepatology 2009

Algorithm to differentiate b/w Reactivation of CHB
and Acute hepatitis B
 Short term outcome of flare
Hepatitis Flare Spontaneous
HBeAg seroclearance
3mo 12mo 18mo
No
ALT<5x ULN <2% 5% 8%
Yes
ALT
>5xULN 19% 50% 67%
5-10xULN 5% 45% 58%
>10xULN 25% 52% 70%
AFP
>100 ng/ml 31% 62% 72%
<100 ng/ml 4% 15% 19%
BHN
Yes 67%
No 16%
Acute hepatitis- like Episodes in patients
with chronic HBV infection

Acute on chronic hepatitis B: Hepatitis B flares

• Spontaneous flare or reactivation  ACLF
• Antiviral therapy-induced
• Emergence of viral mutants High short term mortality 60-70%
Rx options: NUCs  LT
• Following immunosuppression
Recovery
Superimposed acute hepatitis
• Superinfection with other hepatitis viruses- HAV/HEV
• Other causes: drug, toxin ..
Indications of Rx APASL HBV Guidelines 2015
HBeAg-positive

HBV DNA HBV DNA 2000-20,000IU/mL HBV DNA>20,000 IU/mL

<2000IU/mL

ALT>ULN ALT1-2x ULN ALT>2x ULN

ALT<ULN

• Monitor 3-6 mo •Monitor 3-6 mo* • Treat

• Monitor
• Assess – Fibrosis • Assess fibrosis /Bx
• Treat :
• Treat - Fibrosis2, •ALT persist 1-2
moderate- Age>35
Fibrosis2 severe Family H/o HCC,
inflammation cirrhosis
Moderate to severe inflammation on liver biopsy means : HAI by Ishak
activity score >3/18 or METAVIR activity score A2 or A3; Significant fibrosis
means F≥2 by METAVIR fibrosis score or Ishak F≥ 3.
Non-invasive – Fibroscan : LSM value of  8* , APRI
Indications of Rx APASL HBV Guidelines 2015
HBeAg-positive

HBV DNA HBV DNA 2000-20,000IU/mL HBV DNA>20,000 IU/mL

<2000IU/mL

ALT>ULN ALT1-2x ULN ALT>2x ULN

ALT<ULN

• Monitor 3-6 mo •Monitor 3-6 mo* • Treat

• Monitor
• Assess – Fibrosis • Assess fibrosis /Bx
• Treat :
• Treat - Fibrosis2, •ALT persist 1-2
moderate- Age>35
Fibrosis2 severe Family H/o HCC,
inflammation cirrhosis
Moderate to severe inflammation on liver biopsy means : HAI by Ishak
activity score >3/18 or METAVIR activity score A2 or A3; Significant fibrosis
means F≥2 by METAVIR fibrosis score or Ishak F≥ 3.
Non-invasive – Fibroscan : LSM value of  8* , APRI
High viremia, high HBsAg, no evidence of liver fibrosis
High viremia, low HBsAg, no evidence of liver fibrosis
Indications of Rx APASL HBV Guidelines 2015
HBeAg-negative

HBV DNA 2000-20,000 IU/mL HBV DNA>20,000 IU/mL

HBV DNA<2000 IU/mL, ALT>2xULN

ALT1-2x ULN ALT>2x ULN ALT 1-2x ULN ALT>2x ULN ALT<ULN
ALT<ULN

Monitor Treat Treat Monitor ALT , Treat Treat

Fibrosis2 HBV DNA, Assess Liver biopsy
Assess 1-3 mo Fibrosis optional
Fibrosis Assess Fibrosis
Bx if ≥ 35 yr
TreatFibrosis2

2 consecutive tests conducted 3 months apart.

Offer antiviral treatment
-If Age > 35 years
-- if age <35 years, >F2 metavir / Ishak > F3 fibrosis
Indications of Rx APASL HBV Guidelines 2015
HBeAg-negative

HBV DNA 2000-20,000 IU/mL HBV DNA>20,000 IU/mL

HBV DNA<2000 IU/mL, ALT>2xULN

ALT1-2x ULN ALT>2x ULN ALT 1-2x ULN ALT>2x ULN ALT<ULN
ALT<ULN

Monitor Treat Treat Monitor ALT , Treat Treat

Fibrosis2 HBV DNA, Assess Liver biopsy
Assess 1-3 mo Fibrosis optional
Fibrosis Assess Fibrosis
Bx if ≥ 35 yr
TreatFibrosis2

2 consecutive tests conducted 3 months apart.

Offer antiviral treatment
-If Age > 35 years
-- if age <35 years, >F2 metavir / Ishak > F3 fibrosis
High viremia, high HBsAg, no evidence of liver fibrosis
High viremia, low HBsAg, no evidence of liver fibrosis
 Issues for HBV Treatment in Normal ALT

Merits Demerits
• Risks of HBV related disease • Low response
• Non-cirrhotic HCC • ? Life-long therapy,
• Impact on HBV compliance
epidemiology/Transmission • Drug resistance
• Good follow-up and Less • Costs, no reimbursement
drop-out of infected
 How Long to treat! End point
• Life long !!
• Resistance
• How to monitor if HBV DNA < 6 IU at 2 yr
• Monitor with qHBsAg levels
• Risk of HCC
 End points of HBV Treatment
Parameter Absoloute Functional Apparent
measured cure cure virological cure
Risk of death from Same as person who Same as person To be determined
liver disease was never infected with naturally
resolved infection
Viral load Undetectable Undetectable Undetectable
HBsAg Undetectable Undetectable Undetectable
cccDNA Undetectable Undetectable Undetectable or
repressed

HBsAb Present Variable Present of absent

Treatment status Off-drug Off-drug Off-drug
 End points of HBV Treatment
Parameter Absoloute Functional Apparent
measured cure cure virological cure
Risk of death from Same as person who Same as person To be determined
liver disease was never infected with naturally
resolved infection
Viral load Undetectable Undetectable Undetectable
HBsAg Undetectable Undetectable Undetectable
cccDNA Undetectable Undetectable Undetectable or
repressed

HBsAb Present Variable Present of absent

Treatment status Off-drug Off-drug Off-drug

Current drugs Unable to achieve these endpoints

Review Strategy
 STOPPING RULES ON THERAPY IN CHB
INFECTION
3.6. STOPPING RULES ON THERAPY IN CHB INFECTION

3.6.1
Nucleos(t)ide Analogues

Optimal duration of NA therapy

3.6.1.7 HBeAg- +ve : Unknown, Can be
stopped after at least 1 yr [A1] but preferably
3 yrs [C1] of additional therapy after HBeAg
seroconversion with undetectable HBV DNA
and normal ALT.].
STOPPING RULES ON THERAPY IN CHB INFECTION
3.6. STOPPING RULES ON THERAPY IN CHB INFECTION
Nucleos(t)ide Analogues
3.6.1

Optimal duration of NA therapy

• HBeAg-ve: Unknown. Can be withdrawn after HBsAg
loss, anti-HBs seroconversion or at least 12 months of a
post HBsAg clearance consolidation period. [B1].

• After stopping NAs, monitor 3 mo. for 6 mo., then 6 mo

A2].
• NA should be continued indefinitely in cirrhotic patients.
[B1].
• NA be continued life-long in decompensated cirrhotic
[B1].
STOPPING RULES DURING THERAPY IN CHRONIC
HBV INFECTION
J H Kao
With interferons

• To Whom: Treatment naïve with raised ALT [A1].

• Duration: 48 wk for both HBeAg +ve/-ve (A1).
• HBV genotyping: recommended before IFN therapy in
regions endemic for HBV genotype A and D [A1].

[
3.6. STOPPING RULES DURING THERAPY

3.6.2 Therapy with interferons J H Kao

HBeAg +ve:

If unable to achieve qHBsAg <20,000 IU/ml

(genotype B and C ) or any decline in HBsAg levels
(genotype A and D ) by week 12, and <20,000
IU/ml by week 24 (genotype A-D ), stopping IFN be
considered (B2).
[
 STOPPING RULES DURING THERAPY

Therapy with interferons J H Kao

HBeAg-negative: specially genotype D, who fail to

achieve decline in HBsAg levels and a > 2 log10
IU/ml decline in DNA by mo. 3, stopping Peg-IFN
be considered (B2).
[
3.7.TREATMENT STRATEGIES FOR FIRST LINE THERAPY IN
PRECIRRHOTIC CHRONIC HEPATITIS B: NUCLEOS(T)IDE
ANALOGUES OR INTERFERONS OR COMBINATION
Fu-Sheng Wang Shiv K Sarin

3.7.7 NAs: Finite-duration treatment with a NA is achievable

for HBeAg+ve who seroconvert to anti-HBe on treatment, but
duration is unpredictable prior to therapy and the treatment
continuation post anti-HBe seroconversion. [A1].

3.7.8 Long-term treatment with NA(s) is necessary for

patients who are not expected or fail to achieve a sustained
off-treatment virological response and require extended
therapy. [ A1].

3.7.10 Little advantage of de novo combination of two NAs

in NA naive patients receiving either entecavir or tenofovir
[C2].
Immune Modulation via Viral load
Reduction

Nucleoside Analogues
Tenofovir :
Influence of Viral Load Reduction

• HBV Specific CD8

• T Regs
• PD1
• TLRs
• Chemokines
Immune Restoration with Reduction of HBV DNA
10

HBV DNA ( Log 10 copies/ml)

eAg-ve
Pati et al J Clin
eAg+ve
10 8 Immunol 2011

HBV DNA ( Log 10 copies/ml)

P=0.002 P=0.001
8 6

6 4

4
2
2
0
Baseline 4 Wk 12 Wk 24 Wk
0
Baseline 4 Wk 12 Wk 24 Wk B
A

Frequencies of CD3+CD8+/PBMCs(%)
eAg +ve eAg -ve
Frequencies of CD3+CD8+/PBMCs(%)

*
50 50 *
NS
*
40 40

30 30

20 20

10 10

0 0
Baseline 4 Wk 12 Wk 24 Wk Baseline 4 Wk 12 Wk 24 Wk
C
D

eAg +ve HBV (Log) 10 10

10 Tregs 10 e Ag -ve

% Frequency of CD4+CD25+ Tregs

% Frequency of CD4+CD25+ Tregs

HBV DNA (Log copies/mL)

8 8
HBV DNA( Log copies/ml)

8 8

6 6 6 6
P= 0.006
R=0.07
R=0.68
4 4 4 4

2 2
2 2

0 0
Baseline 4 Wk 12 Wk 24 Wk 0 0
F
E Baseline 4 Wk 12 Wk 24 Wk
Tenofovir :
Influence of Viral Load Reduction

• HBV Specific CD8 

• T Regs 
• PD1 
• TLRs 
• Chemokines 
Sequential combination therapy

A low pre-treatment HBV-DNA

Better T-cell response to HBV proteins

Simultaneous combination therapy of PEG-Interferon-α

and oral nucleoside analogues (NUCs) have shown
variable conflicting benefits.
 Sequential Therapy in Chronic Hepatitis B

Reduce viral load → Peg (Sarin et al 2005 )

Reduce Viral load → IFN + Lam →Lam (Sarin et al 2006)

Immune modulate →Peg + Lam →Lam (Chen et al)

 EASL - 2014
Treatment protocol
Prospective randomized controlled trial

[A] Tenofovir 300 mg

Tenofovir 300 mg OD Tenofovir 300 mg OD
OD

PEG-IFN α2b 1.5 mcg/kg

Tenofovir 300 mg Subcutaneous weekly Tenofovir 300 mg OD
[B]
OD plus
Tenofovir 300 mg OD

Lead in Period Sequential therapy Follow up period

(Week 0 to week 12) (week 12 to week 24) (week 24 to week 48)
 Rates of HBeAg loss from Baseline to Week 48

EASL - 2014
 Comparison of Combined Responses*
in each group

EASL - 2014
ILBS
Carry Home Message
HBV: Indications and End-points
• 2015 Guidelines – Fibrosis, ALT,
APASL School of
Hepatology
Viremia important
shivsarin@gmail.com • Treat - NA, IFN
• End-points – Serocoversion,
persistent HBV DNA –ve 3 yrs
• Sequential Therapy, option