HBV current treatment guidelines

Rifaat Safadi, M.D.

Liver & Gastroenterology Units Division of Medicine Jerusalem

The First GI conference in Palestine (20-22) May 2010

Viral Hepatitis
A
Source of virus
feces

E
feces

blood/ blood/ blood/ blood-derived blood-derived blood-derived body fluids body fluids body fluids percutaneous percutaneous percutaneous permucosal permucosal permucosal

Route of transmission

fecal-oral

fecal-oral

Chronicity
Prevention

no

yes

yes

yes

no

pre/postpre/postblood donor pre/postensure safe exposure exposure screening; exposure drinking immunization immunization risk behavior immunization; water modification risk behavior modification

Global Distribution of HBV

HBsAg Prevalence
8% - High 2-7% - Intermediate <2% - Low

We are an endemic area

2 Billion Infected with HBV Worldwide

2 billion with evidence of HBV infection

1525% die of cirrhosis or liver cancer

World population 6 billion

350 million chronic HBV

Adapted from Lavanchy D. J Viral Hepatitis 2004;11:97-107.

1525% die of Cirrhosis or HCC

Hepatitis B Vaccines

Hepatitis B Virus Structure

Large Surface Antigen

Small Surface Antigen

Middle Surface Antigen

History of Hepatitis B Vaccines

Generations
1st Plasma-derived -HBsAg, Pre-S

recombinant

2nd Yeast-derived, -HBsAg

3rd Mammalian cell d. -HBsAg, Pre-S2 -HBsAg, Pre-S2, Pre-S1

Efficacy of Sci-B-VacTM in Neonates (n=205, Comparative Study)

GMT significantly* higher at all points in the Sci-B-Vac group
13055

GMT mIU/ml

6074

3211 11 2 722

Months *p<0.01 Yerushalmi et al. Ped. Inf. Dis. J 1997

Sci- B-Vac in > 20 Clinical Trials

Sci-B-Vac is safe & highly immunogenic
Rapid (earlier/higher) immune responses High seroprotection rates Induces seroconversion in: high-risk patients

in non-responders

HBV Vertical Transmission

Universal HBV vaccination for all newborns since 1992 :

Vertical

Active for all neonates

Passive if maternal HBsAg+

Epidemiology: Age dependent 350M chronically infected 1M cases of death per year 5-10% of liver transplant

HBV vertical trans mission in East Jerusalem During 2005

HBcAb+: 8.4% (14/165)

Of them: 3+4 Brothers

HBsAg+: 4.4% (8/182)

Of them: 4 Brothers
Safadi R et. al., Unpublished

Global Distribution of 8 HBV Genotypes

A A, B, C, D, G H, F

D B, C D

A, D, E

F
A, B, C, D

Arauz-Ruiz P, et al. J Gen Virol. 2002;83:2059-2073. Bell SJ, et al. J Clin Virol. 2005;32:122-127. Chu CJ, et al. Gastroenterology. 2003;125:444-451. Kidd-Ljunggren K, et al. J Gen Virol. 2002;83:1267-1280. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106.

HBV: Pre treatment evaluation

Clinical Sequelae of HBV

Acute Hepatitis
Clinical illness (jaundice): <5 yrs:

<10% >5 yrs: 30-50%

Fulminant hepatitis 0.5-1%

Chronic Hepatitis B <5 yrs, 30-90% >5 yrs, 2-10%

Recovery
<5 yrs, 10-70% >5 yrs, 90-98%

Death

Clinical Sequelae of Chronic HBV

Chronic Hepatitis B

Active (High) Replication Progressive Liver Injury Fibrosis & Cirrhosis

Low Viral Replication Asymptomatic Infection Hepatocellular Ca

Death 15%-25%

Chronic Hepatitis B
Acute
HBeAg HBV DNA Chronic anti-HBe HBsAg Total antiHBc

IgM anti-HBc

0 4 8 12 16 20 24 28 32 36

52

Years

Chronic HBV with Viral Replication

Viral markers present for > 6 months HBsAg HBeAg
c/ml)

Some immune response to the virus

Anti-HBc IgG + Anti-HBs Anti-HBe

+ + -

- +

HBV DNA + (>100,000

ALT, AST No evidence of acute infection

Anti-HBc IgM -

Indications for treatment

The indications for treatment are generally the same for both HBeAg+ & HBeAgnegative CHB. Based mainly on the combination of 3 criteria: Serum HBV DNA levels > 2000 IU/ml (~10,000 copies/ml) Serum aminotransferase levels > upper limit of normal (ULN) Histological grade & stage (or non-invasive markers) shows moderate to severe active necroinflammation and/or fibrosis (at least A2 or F2 by METAVIR scoring) (A1)

Pre therapeutic assessment

Biochemical markers, AST, ALT, GGT, Alk. Phos., albumin, INR, CBC & hepatic ultrasound (A1). HBV DNA level is essential for the diagnosis, decision to treat & monitoring (A1). Follow-up using real-time PCR quantification assays is strongly recommended (A1). The WHO has defined an international standard for normalization of expression of HBV DNA concentrations.

Other causes of chronic liver disease should be systematically looked for including coinfection with HDV, HCV and/or HIV. Co-morbidities, including alcoholic, autoimmune, metabolic liver disease with steatosis or steato-hepatitis should be assessed (A1).

Liver biopsy is recommended

Determining the degree of necroinflammation & fibrosis in either increased ALT or HBV DNA >2000 IU/ml (or both) (A1). To evaluate other possible causes of liver disease. The risk of severe complications is very low (1/4,00010,000). The size of the needle biopsy specimen should be large enough to precisely analyze the degree of liver injury & fibrosis (A1). A liver biopsy is usually not required in patients with clinical evidence of cirrhosis or in those in whom treatment is indicated irrespective of activity grade/ fibrosis stage (A1). There is growing interest in the use of non-invasive methods

Factors for progressive fibrogenesis

HBeAg Status

25-year survival rates in untreated CHB

100
Survival probability (%)

Inactive CHB

80
60 HBeAg-/HBV DNA+

40 20
0 0 5 10 15 20 25 Time (years) HBeAg+ persistence

Fattovich et al. Gut 2008

Hepatitis D Virus
d antigen HBsAg

RNA

Cumulative Incidence of Liver Cirrhosis for Five HBV DNA Categories

6.5

Cop/ml

P value for log-rank test, <0.001

5.6

2.5 1.4 1.0

(n=3774 pts.)
Iloeje UH et al, Gastroenterology 2006;130:678-86

HBV DNA Levels Predict Risk of HCC (REVEAL-HBV Study)

12 10 8.9
P

10.7

Crude Hazard Ratio

8 6 4 2 0

<0.01 P <0.001

2.7 1
<300 (LOQ)

1
300 <1 x 104 1 x 104 <1 x 105
1 x 106

(Reference)

Serum HBV DNA (copies/mL) 297 962

1 x 105 <1 x 106

Incidence rate 108

(per 100,000 person-years)
Chen et al., JAMA 2006;295:65-73

111

1,152

HBV therapy

Anti-HBV Active Compounds

/3

Goal of therapy
HBV infection cant be completely eradicated due to persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. To improve quality of life & survival by preventing progression to cirrhosis, decompensated cirrhosis, HCC & death.

HBV-Triggered Immune Responses

MHC class II

Antigenpresenting cell
HBV antigens

HBV
Infected Hepatocyte
HBV DNA HBV RNA HBV peptides HBsAg HBV cores

CD4+ T cell HBV

peptides

CD8+ T cell

MHC Downclass I regulations of viral replication TNF- Interferongamma CD8+

T cell
MHC class I

Stellate cell activation

Modified from: Ganem D, et al. N Engl J Med. 2004;350:1118-1129.

HBV DNA Levels Correlate Quantitatively With Histology

Correlation between HAI and HBV DNA in untreated patients (r=0.78; P=0.0001)
12 10 8 HAI 6 5 4
Median 3 Improvement 2 in HAI

Correlation between change in HBV DNA and HAI with Lam treatment (r=0.96; P<3x10-6)

4 2
0 0

1 0 2 4 6 8 10 12 Baseline HBV DNA Level (log10 copies/mL) 1 2 1 2 3 4 5

Median log10 HBV DNA Decrease

Mommeja-Marin et al., Hepatology 2003;37:1309-1319

Lamivudine for patients with chronic HBV & advanced liver disease
Increase in Child-Pugh Score (% of patients)

Diagnosis of HCC (% of patients)

Disease Progression (% of patients)

Liaw YF et al. N Engl J Med 2004;351:1521-1531.

Placebo Lamivudine

Cirrhosis Reversal following Anti viral therapy in HBV

Liaw YF et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521-31. Dienstag JL et al. Histological outcome during long-term lamivudine therapy. Gastroenterology 2003;124:105-117. Hadziyannis SJ et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology 2006;131:1743-1751. Marcellin P et al. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2008;48:750-758.

Distribution of Ishak fibrosis scores at phase III baseline, after 48 weeks of entecavir treatment, and at the time of the long-term biopsy
(median: 6 years entecavir treatment [range 37 years]) among histologically evaluable patients in the Long-Term Histology Cohort (N=57).
60

50
Number of patients

Ishak Fibrosis Score 40

6 5

30

4 3 2 1 0

20

10

Missing

0 Baseline Week 48 Long-term

Reduction in fibrosis following long-term entecavir therapy in a 60 yo, HBeAg-negative, Caucasian male.
The baseline biopsy shows an Ishak score of 6, indicating cirrhosis, which is unchanged at Week 48, and the Week 268 biopsy shows an Ishak score of 2, indicating minimal fibrosis

268 week

48 week

Baseline

Virological Endpoint of Therapy

Inhibition of HBV replication: As profound as possible As sustained as possible

Test
Dot blot

Sensitivity of HBV DNA Method Assays Range of quantification

Rapid test

Abbott
Digene Chiron Amplicor Monitor

Liquid hybridisation
RNA-DNA hybrid Branched DNA Quantitative PCR

106 105
104 103 102

End-points of therapy
(1) In HBeAg+ & HBeAgnegative patients, the ideal is sustained HBsAg loss with/out seroconversion to anti-HBs. Associated with a definitive remission of HBV & an improved long-term outcome (A1). (2) In HBeAg+ patients, durable HBe seroconversion is associated with improved prognosis (A1). (3) To reduce HBV DNA as possible, ideally < the lower limit of detection (1015 IU/ml), then lead to: o biochemical remission, o histological improvement o prevention of complications.

Response Rates in CHB:

Randomized clinical trials
HBeAg(-)
100 90 80 70 60 50 40 30 20 10 0 72

HBeAg(+)
90
88 92 80 70 60 50 51 40 39 25 67 60 74

63

30
20 10 0

21

PEG LA AD

ET

Ld

TD

PEG LA AD

ET

Ld

TD

Undetectable HBV DNA

Rates of mutations increased in different NUCs

%
70
67 70
EASL Clinical Practice Guidelines

Undetectable HBV DNA

60 50 40 30
49
38 29 24 18 0.5 11 3 0 0.2 1.2 1.2 1.2 4 22

Year 1 Year 2 Year 3 Year 4 Year 5

20 10
0
LA

AD

ET

Ld

TD

Risk of Resistance Development Increases with Suboptimal Viral Suppression

100 80
Patients with Lamivudine Resistance (%)

Analysis of 159 HBeAgpositive patients treated with Lamivudine for median 29 months follow-up 64%

100 80
Patients with ADV 60 Resistance at Week 144 40 (%)

Analysis of 114 HBeAgnegative patients treated with Adefovir 67%

60 40 20 0 32% 8%
200

26%

13%
3 log10 4 log10

20

4%
0
>4 log10

< 3 log

3 - 6 log

> 6 log

HBV DNA levels at 24 weeks (copies/mL)

Yuen MF et al. Hepatology. 2001;34:785-791.

HBV DNA level at week 48 (copies/mL)

Locarnini S, et al. J Hepatology 2005;42(Suppl 2):16,Abstract 36.

Response Rates in CHB:

Randomized clinical trials
HBeAg(-)
100 90 80 70 60 50 40 30 20 10 0 72

HBeAg(+)
90
88 92 80 70 60 50 51 40 39 25 67 60 74

63

30
20 10 0

21

PEG LA AD

ET

Ld

TD

PEG LA AD

ET

Ld

TD

Undetectable HBV DNA

Main respective advantages & disadvantages of PEG- interferon & NUCs in the treatment of CHB
Advantages

PEG-interferon :

NUCs:

Finite duration
Absence of resistance Higher rates of HBe & HBs seroconversion

Potent antiviral effect

Good tolerance Oral administration

Disadvant.

Moderate antiviral effect Poor tolerance Subcutaneous injections

Indefinite duration Risk of resistance Lower rates of

HBe/ HBs seroconversion

How effective are nucleoside treatment strategies at achieving HBsAg clearance?

HBsAg clearance following: 1 year of PEG-IFN and 6 months post-treatment follow-up or 1 year of NUC treatment

PEG-IFN HBsAg loss in

LAM

ADV

ETV

LdT

HBeAg-neg CHB

3%

<1%

<1%

<1%

<1%

Marcellin et al. NEJM 2004 Lau et al. NEJM 2005 Janssen et al. Lancet 2005 Hoofnagle et al. Hepatology 2007

Predictors of response for IFN

Pre-treatment factors for HBe seroconversion: low viral load (<107 IU/ml), high ALT (>3 times ULN), & high activity scores on liver biopsy (A2) (B2).

During treatment, an HBV DNA decrease to < 20,000 IU/ml at 12 weeks: 50% chance of HBe sero- conversion in HBeAg+ 50% chance of sustained response in HBeAgneg.
During treatment, HBeAg decrease at week 24 may predict HBe seroconversion (B2).

Predictors of response for NUCs

Pre-treatment factors for HBe seroconversion: low viral load (< 107 IU/ml), high ALT (>3 times ULN), high activity scores on liver biopsy (at least A2). During treatment with Lam, Adv or LdT, a virological response at 24 or 48 weeks (undetectable HBV DNA) is associated with a lower incidence of resistance, i.e. an improved chance of maintained virological response, and HBe seroconversion in HBeAg+ patients (B1). HBV genotype doesnt influence the response to any NUC.

Treatment failure

It is important to check for compliance!

Definitions of response on NUC therapy

Virological breakthrough: a confirmed increase in HBV DNA level > 1 log10 IU/ml compared to the nadir (lowest value) HBV DNA level on therapy; it usually precedes a biochemical breakthrough. The main causes of virological breakthrough on NUC therapy are poor adherence to therapy & selection of drug-resistant HBV variants (resistance) (A1). HBV resistance to NUCs: selection of HBV variants with amino acid substitutions that confer reduced susceptibility to the administered NUC(s). Resistance may result in primary treatment failure or virological breakthrough on therapy (A1).

Treatment failure
(1) Primary non-response: Rare with Lam., telbivudine, entecavir or tenofovir. More frequent with adefovir (~20%). A rapid switch to tenofovir or entecavir is recommended (B1). In a compliant patient, identification of resistance mutations can formulate a rescue strategy based on an early change to a more potent drug that is active against the resistant variant (B1).

Treatment failure
(2) Partial virological response: o With all available NUCs. o In lamivudine, adefovir or telbivudine with a partial virological response at week 24:

Change to entecavir or tenofovir Or addition of a more potent drug that does not share cross-resistance:
add tenofovir to lamivudine or telbivudine add entecavir to adefovir (A1).

HBV Mutants: Total of 44 tests, Hadassah T. Saadi & R. Safadi, 2009

Ent; 2; 4%

No Viremia; 8; 17%

WT; 18; 39%

Adf; 3; 7%

Lam; 15; 33%

Cross Resistance With HBV Drugs

YMDD
V173L LAM
Lamivudine

L180M

A181V A184G

S202I

M204I

M204V N236T

M250V

ETV
Entecavir

LdT
Telbivudine

FTC
Emtricitabine

ADV
Adefovir

TD
Tenofovir

Yang H. et al. Hepatology 2003;38:705A; Lai CL et al Hepatology 2003;38:262A

Special groups of patients

Immunotolerant patients: most patients under 30 years of age with persistently normal ALT levels and a high HBV DNA level (usually above 107 IU/ml), without any suspicion of liver disease and without a family history of HCC or cirrhosis do not require immediate liver biopsy or therapy. Follow-up is mandatory (B1). Patients with mild CHB: patients with slightly elevated ALT (less than 2 times ULN) and mild histological lesions (less than A2/F2) may not require therapy. Follow-up is mandatory (B1).

Patients with cirrhosis

Compensated & detectable HBV DNA may be considered for treatment even if ALT levels are normal &/or HBV DNA levels <2000 IU/ml (B1). Decompensated cirrhosis require urgent antiviral treatment. Rapid & profound viral suppression & efficacious prevention of resistance are particularly needed in this group. Significant improvement can be associated with control of viral replication, but patients with very advanced liver disease may not always benefit if treated at this late stage & should be considered for transplantation (A1).

Thank You
Rifaat Safadi M.D

Definitions of response on interferon-

Primary non-response: <1 log10 IU/ml decrease in HBV DNA level from baseline at 3 mon of therapy. Virological response: HBV DNA <2000 IU/ml at 24 wks. Undetectable HBV DNA by real-time PCR within 48 wks of therapy. Serological response: HBe seroconversion in patients with HBeAg+ CHB. Partial virological response: HBV DNA decrease >1 log10 IU/ml but detectable by real-time PCR.