HBV_The First GI Conference in Palestine

8/2/2019 HBV_The First GI Conference in Palestine

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Rifaat Safadi, M.D.Liver & Gastroenterology Units

Division of MedicineJerusalem

HBV current treatment

guidelines

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


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Source ofvirus

feces blood/blood-derived

body fluids

blood/blood-derived

body fluids

blood/blood-derived

body fluids

feces

Route oftransmission

fecal-oral percutaneouspermucosal

percutaneouspermucosal

percutaneouspermucosal

fecal-oral

Chronicity no yes yes yes no

Prevention pre/post-exposure

immunization

pre/post-exposure

immunization

blood donorscreening;

risk behaviormodification

pre/post-exposure

immunization;risk behavior

modification

ensure safedrinkingwater

Viral HepatitisA DB C E


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HBsAg Prevalence8% - High

2-7% - Intermediate


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2 Billion Infected with HBV Worldwide

1525% die ofcirrhosis orliver cancer

World population6 billion

2 billion withevidence of

HBV infection

350 millionchronic HBV

Adapted from Lavanchy D. J Viral Hepatitis2004;11:97-107.


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1525% die of Cirrhosis or HCC


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Hepatitis B Vaccines


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MiddleSurfaceAntigen

LargeSurfaceAntigen

Small SurfaceAntigen

Hepatitis B Virus Structure


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1st

Plasma-derived

-HBsAg, Pre-S

3rd

Mammalian cell d.

-HBsAg, Pre-S2

-HBsAg, Pre-S2, Pre-S1

2nd

Yeast-derived,

-HBsAg

recom

binant

Generations

History of Hepatitis B Vaccines


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11

2

13055

6074

3211

722

Months

GMTmIU/ml

*p


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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


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HBV Vertical Transmission

Universal HBV vaccination for

all newborns since 1992 :

Active for all neonates

Passive if maternal HBsAg+

Vertical


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Epidemiology: Age dependent

350M chronically infected

1M cases of death per year 5-10% of liver transplant


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HBV vertical trans mission inEast 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


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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.

Global Distribution of 8 HBVGenotypes

A, B, C,D, G

F

A, D, E

B, C

AG D

H, F

D

A, B, C, D


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HBV:

Pre treatment

evaluation


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Clinical Sequelae of HBV

Acute HepatitisClinical illness

(jaundice):


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Clinical Sequelae of Chronic HBV

Chronic Hepatitis B

Active (High)Replication

Low ViralReplication

ProgressiveLiver Injury

AsymptomaticInfection

Fibrosis & Cirrhosis Hepatocellular Ca

Death 15%-25%


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IgM anti-HBc

Total anti-HBc

HBsAg

Acute

HBeAg

Chronic

anti-HBe

0 4 8 12 16 20 24 28 32 36 52 Years

HBVDNA

Chronic Hepatitis B


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Chronic HBV with Viral Replication

No evidence of acute infection

Anti-HBc IgM -

Some immuneresponse to the virus

Anti-HBc IgG +

Anti-HBs -

Anti-HBe - +

Viral markers presentfor > 6 months

HBsAg +

HBeAg + -

HBV DNA + (>100,000c/ml)

ALT, AST


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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 (~10,000copies/ml)

Serum aminotransferase levels > upper limit of

normal (ULN)

Histological grade & stage (or non-invasivemarkers) shows moderate to severe active

necroinflammation and/or fibrosis (at least A2 or F2

by METAVIR scoring) (A1)


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Pre therapeutic assessmentBiochemical 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 internationalstandard for normalization of expression of HBV DNAconcentrations.

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


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Liver biopsy is recommendedDetermining 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 enoughto precisely analyze the degree of liver injury & fibrosis (A1).

A liver biopsy is usually not required in patients with clinicalevidence of cirrhosis or in those in whom treatment isindicated irrespective of activity grade/ fibrosis stage (A1).

There is growing interest in the use of non-invasive methods


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Factors forprogressivefibrogenesis


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25-year survival rates in untreated CHB

0

100

80

60

40

20

0 5 10 15 20 25

Sur

vivalprobability(%)

Inactive CHB

HBeAg-/HBV DNA+

HBeAg+ persistence

Fattovich et al. Gut 2008 Time (years)

HBeAg Status


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HBsAg

RNA

d antigen

Hepatitis D Virus


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Cumulative Incidence of Liver Cirrhosisfor Five HBV DNA Categories

Iloeje UH et al, Gastroenterology 2006;130:678-86

2.5

1.4

1.0

5.6

6.5

Pvalue for log-rank test,


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

P


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HBVtherapy


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Anti-HBV Active Compounds

/3


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Goal of therapy

To improve quality of life & survival by preventing progression to cirrhosis, decompensated cirrhosis, HCC & death.

HBV infection cant be completely eradicateddue to persistence of covalently closedcircular DNA (cccDNA) in the nucleus of

infected hepatocytes.


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HBV-Triggered Immune Responses

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

MHC

class II

HBVpeptides

HBV

MHCclass I

MHCclass I

TNF-Interferon-

gamma

Down-regulationsof viral

replication

HBV DNA

HBsAg

HBVpeptides

CD8+T cell

Antigen-presenting cell

CD8+T cell

InfectedHepatocyte

HBV cores

HBV RNA

HBVantigens

CD4+T cell

Stellate cell activation


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2 4 6 8 10 1200

2

4

6

810

12

HAI

Baseline HBV DNA Level(log10 copies/mL)

1 2 3 4 5

2

1

0

1

2

3

4

5

Median log10 HBV DNA Decrease

MedianImprovement

in HAI

Correlation between HAI andHBV DNA in untreated patients

(r=0.78; P=0.0001)

Correlation between change inHBV DNA and HAI with Lamtreatment (r=0.96; P


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Lamivudine for patients with chronic

HBV & advanced liver disease

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

Increase in Child-Pugh Score(% of patients)

Diagnosis of HCC(% of patients)

Disease Progression(% of patients)

PlaceboLamivudine


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Liaw YF et al. Lamivudine for patients with chronic hepatitis Band advanced liver disease. N Engl J Med 2004;351:1521-31.

Dienstag JL et al. Histological outcome during long-termlamivudine therapy. Gastroenterology 2003;124:105-117.

Hadziyannis SJ et al. Long-term therapy with adefovir dipivoxilfor 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 adefovirdipivoxil for the treatment of hepatitis B e antigen-positive

chronic hepatitis B. Hepatology 2008;48:750-758.

Cirrhosis Reversal followingAnti viral therapy in HBV

Distribution of Ishak fibrosis scores at phase III baseline


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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).

Ishak Fibrosis Score

12

3

4

5

6

Missing

0

0

10

20

30

40

50

60

Baseline Week 48 Long-term

Nu

mberofpatients

Reduction in fibrosis following long-term entecavir


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

indicating minimal fibrosis

268 week

48 week

Baseline


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Virological Endpoint of Therapy

Inhibition of HBV replication:

As profound as possible As sustained as possible


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Sensitivity of HBV DNA

AssaysTest Method Range of quantification

Dot blot Rapid test

Abbott Liquid hybridisation

Digene RNA-DNA hybrid

Chiron Branched DNA

Amplicor Quantitative PCRMonitor

106

105

103

102

104


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End-points of therapy(1) In HBeAg+ & HBeAgnegative patients, the ideal is

sustained HBsAg loss with/out seroconversion toanti-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 < thelower limit of detection (1015 IU/ml), then lead to:

o biochemical remission,

o histological improvement

o prevention of complications.

Response Rates in CHB


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Response Rates in CHB:Randomized clinical trials

63

72

51

90 8892

0

1020

30

40

50

60

70

80

90

100

PEG LA AD ET Ld TD

Undetectable HBV DNA

HBeAg(-) HBeAg(+)

25

39

21

67

60

74

0

10

20

30

40

50

60

70

80

PEG LA AD ET Ld TD

Rates of mutations increased in


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UndetectableHBVDNA

%

Rates of mutations increased indifferent NUCs

24

0

0.2

4

0

38

3

0.5

22

49

11

1.2

67

18

1.2

70

29

1.2

0

10

20

30

40

50

60

70

LA AD ET Ld TD

Year 1

Year 2

Year 3

Year 4

Year 5

EASL Clinical Practice Guidelines


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Risk of Resistance Development Increases

with Suboptimal Viral Suppression

8%13%

32%

64%

0

20

40

60

80

100

200 3 log10 4 log10 >4 log10

HBV DNA levels at 24 weeks (copies/mL)

Patientswith

LamivudineResistance

(%)

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

Analysis of 159 HBeAg-

positive patients treated

with Lamivudinefor median

29 months follow-up

0

20

40

60

80

100

< 3 log 3 - 6 log > 6 log

4%

26%

67%

Locarnini S, et al. J Hepatology2005;42(Suppl 2):16,Abstract 36.

HBV DNA level at week 48 (copies/mL)

Patientswith ADV

Resistanceat

Week 144(%)

Analysis of 114 HBeAg-

negative patients treated

with Adefovir

Response Rates in CHB:


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Response Rates in CHB:Randomized clinical trials

63

72

51

90 8892

0

10

20

30

40

50

60

70

80

90

100

PEG LA AD ET Ld TD

Undetectable HBV DNA

HBeAg(-) HBeAg(+)

25

39

21

67

60

74

0

10

20

30

40

50

60

70

80

PEG LA AD ET Ld TD

Main respective advantages & disadvantages of


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

Advantages

Disadvant.

PEG-interferon : NUCs:

Finite duration Potent antiviral effect

Absence of resistance Good tolerance

Higher rates of HBe & Oral administration

HBs seroconversion

Moderate antiviral effect Indefinite duration

Poor tolerance Risk of resistance

Subcutaneous injections Lower rates of

HBe/ HBs

seroconversion


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How effective are nucleoside treatmentstrategies at achieving HBsAg clearance?

PEG-IFN LAM ADV ETV LdT

HBsAg loss in

HBeAg-neg CHB3%


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Predictors of response for IFN

Pre-treatment factors for HBe seroconversion:

low viral load (3 times ULN), &

high activity scores on liver biopsy (A2) (B2).

During treatment, an HBV DNA decrease to 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 HBVDNA) 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 genotypedoesnt influence the response to any

NUC.

Treatment failure


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Treatment failure

It is important to checkfor compliance!

Definitions of response on NUC therapy


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Definitions of response on NUC therapy

Virological breakthrough: a confirmed increase in

HBV DNA level > 1 log10 IU/ml compared to thenadir (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 & selectionof drug-resistant HBV variants (resistance) (A1).

HBV resistance to NUCs: selection of HBV variants

with amino acid substitutions that confer reducedsusceptibility to the administered NUC(s).

Resistance may result in primary treatment failure or

virological breakthrough on therapy (A1).

Treatment failure


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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


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Treatment failure(2) Partial virological response:

o With all available NUCs.o In lamivudine, adefovir or telbivudine with apartial 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


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WT;18; 39%

Lam;15; 33%

Adf; 3; 7%

Ent; 2; 4%

NoViremia;8; 17%

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

C R i t With HBV D


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V173L L180M A181V A184G S202I M204I M204V N236T M250V

LAMLamivudine

ETVEntecavir

LdTTelbivudine

FTCEmtricitabine

ADVAdefovir

YMDD

Cross Resistance With HBV Drugs

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

TDTenofovir

Special groups of patients


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Special groups of patients

Immunotolerant patients: most patients under 30

years of age with persistently normal ALT levels anda 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 slightlyelevated 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


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Patients with cirrhosis

Compensated & detectable HBV DNA may be

considered for treatment even if ALT levels arenormal &/or HBV DNA levels


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Thank YouRifaat Safadi M.D

Definitions of response on interferon-


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Definitions of response on interferon-

Primary non-response:

Documents

HBV_The First GI Conference in Palestine