Petrol hbv siham

Hepatitis B & CHepatitis B & CA quick updateA quick update

Prof Siham AbdelrehimProf Siham Abdelrehim

Faculty Of Medicine / Alexanderia Univ Faculty Of Medicine / Alexanderia Univ

[email protected] [email protected]

Impact of HepatitisImpact of Hepatitis

Hepatitis can be caused by:Hepatitis can be caused by:

Harmful consumption of alcoholHarmful consumption of alcohol

Some chemicals and drugsSome chemicals and drugs

Viruses – 5 known A, B, C, D & EViruses – 5 known A, B, C, D & E

Inflammation of the liver – natural Inflammation of the liver – natural

response to injuryresponse to injury

Scar tissue = Fibrosis Scar tissue = Fibrosis

Extensive scarring = CirrhosisExtensive scarring = Cirrhosis

HBV & HCV require long term monitoringHBV & HCV require long term monitoring

One in 12 people worldwide are One in 12 people worldwide are

living with chronic hepatitis B or Cliving with chronic hepatitis B or C

World Hepatitis AllianceWorld Hepatitis Alliance

Chronic hepatitis B & C are responsible for over 80% of the Chronic hepatitis B & C are responsible for over 80% of the worlds liver cancer (HCC) worlds liver cancer (HCC)

ASHM/NSWCC 2008

Hepatitis B and Hepatitis C: Stealth and Cunning

The hepatitis B virus (HBV) and hepatitis C virus The hepatitis B virus (HBV) and hepatitis C virus (HCV) are:(HCV) are:

• noncytopathicnoncytopathic

• hepatotropichepatotropic

• cause acute and chronic necroinflammatory cause acute and chronic necroinflammatory liver disease and hepatocellular carcinoma liver disease and hepatocellular carcinoma (HCC)(HCC)

Hepatitis B and Hepatitis C: Stealth and Cunning

• The two viruses could represent very different The two viruses could represent very different antigenic challenges to the immune response, and antigenic challenges to the immune response, and this could have an important impact on the outcome this could have an important impact on the outcome of the infection.of the infection.

• Once infection is established, differences in HBV Once infection is established, differences in HBV and HCV antigenic burden could also have an and HCV antigenic burden could also have an impact on viral clearance. In particular, it has been impact on viral clearance. In particular, it has been shown by the use of highly sensitive and specific shown by the use of highly sensitive and specific immunohistochemical reagents that HBV can infect immunohistochemical reagents that HBV can infect up to 100% of the hepatocytesup to 100% of the hepatocytes

Hepatitis B and Hepatitis C

• It is widely believed that the outcome of both infections and the pathogenesis of the associated liver diseases are determined by host-virus interactions mediated by the immune response.


• HBV is a stealth virus that establishes itself very efficiently without alerting the innate immune system to its presence, although it is readily controlled when the adaptive immune response is induced.

• In contrast, HCV strongly induces yet cunningly evades the innate immune response and also defeats the adaptive immune response by mutation and functional inactivation


• Although host factors contribute importantly to Although host factors contribute importantly to the outcome of HBV and HCV infection, viral the outcome of HBV and HCV infection, viral factors are also critically involved. Perhaps the factors are also critically involved. Perhaps the strongest evidence that viral factors play a role in strongest evidence that viral factors play a role in the outcome of HBV and HCV infection is that the outcome of HBV and HCV infection is that more than 95% of adult-onset HBV infections are more than 95% of adult-onset HBV infections are self limited, while more than 70% of adult-onset self limited, while more than 70% of adult-onset HCV infections persist.HCV infections persist.

HBVHBV

• HBV is a dynamic disease ,HBV is a dynamic disease ,changes over timechanges over time

• Risk of end stage liver disease and cancer Risk of end stage liver disease and cancer increases with ongoing inflammation and increases with ongoing inflammation and viremia in adultsviremia in adults

• Reactivation can occur even in those who have Reactivation can occur even in those who have lost HBsAglost HBsAg

20 year old student with no significant past medical history is referred for evaluation of HBsAg positivity

She is fit and healthy and asymptomatic

She denies a history of blood transfusion or intravenous-drug use.

Her mother was diagnosed with hepatitis B and end stage of liver disease 8 months ago.

Case presentation

On Examination

No stigmata of CLD

Abdomen: soft, non-distended, non-tender, liver edge smooth, liver span 8 cm by percussion, no splenomegaly

BloodHBsAg: positive

Hepatitis C virus (HCV) antibody (Ab): negative

Case presentation

Which of the following blood tests would provide the most useful information to characterize the status of chronic hepatitis B and guide recommendations regarding antiviral therapy?

A)HBeAg, HBsAb, and hepatitis B core antibody (HBcAb)

B) HBeAg, HBeAb, and HBV genotype

C) HBeAg, HBeAb, HBV DNA viral load, and HBs Ag level

D) HBeAg, HBeAb, and HBV DNA viral load






The Emerging Role of HBV GenotypesThe Emerging Role of HBV Genotypes

There are 8 genotypes of hepatitis B (A through H) There are 8 genotypes of hepatitis B (A through H)

Although it is not routine, it may assume a role in the management of hepatitis B

Clear association with:

Precore/core promoter mutations

Rates of HBeAg clearance

Development of HBeAg-neg Chronic Hepatitis B

HBV Genotypes May Have Clinical HBV Genotypes May Have Clinical ImplicationsImplications

A,G

F

C

D

D

E

A

DD

D

C

Ba

F

A,B,C,D

Bj

A,B,C,D,G

F

H

Adapted from Fung SK et al. Hepatology. 2004;40:790-792. Copyright © 2004, American Association for the Study of Liver Disease. Reproduced with permission of John Wiley & Sons, Inc.

A – Higher rates of

sustained treatment response

B – Earlier appearance of HBeAg antibodies and slower progression (vs

C)

C – Liver disease more severe than in B,

associated with HCC

DAnti-e-positive

chronic hepatitis B and cirrhosis

higher than in A






Back to the case

AST 95 U/L ALT 132 U/L ALP N 121 mg/d Bilirubin N

HBeAg: negativeHBeAb: positiveHBV DNA: 400,000 IU/mL

Further Blood results

Case presentation

What is the significance of HBeAg -ve What is the significance of HBeAg -ve CHB? CHB?

• Clinically silent for years • Severe necroinflammation in >50%, cirrhosis in

25-40% • Rare spontaneous sustained remission • Fluctuations in viraemia and ALT • HBV DNA may be persistently < 105 copies/mL

but yet has significant liver disease

Which statement is false regarding this patient's hepatitis B status?

1.She is an inactive carrier of hepatitis B

2.She is not in the immune-tolerant phase

3. She likely has a mutation in the precore or core promoter region of the HBV genome

4.HBeAg positivity is associated with a better prognosis than HBeAg negativity

Which statement is false regarding this patient's hepatitis B status?

1.She is an inactive carrier of hepatitis B

2.She is not in the immune-tolerant phase

3. She likely has a mutation in the precore or core promoter region of the HBV genome

4.HBeAg positivity is associated with a better prognosis than HBeAg negativity

Which statement is Which statement is falsefalse regarding this regarding this patient's hepatitis B status? patient's hepatitis B status?

immunetolerance

immuneclearance

inactivecarrier

reactivation

HBeAg

Anti-HBe

HBV-DNA

ALT

• Presence of HBsAg and anti-HBe in serum

• Serum HBV DNA < 105 copies/ml

• Persistently normal serum ALT > 6 months

• Liver histology (not essential) HAI grade < 3

NIH Definition of Inactive HBsAg Carrier

Patient's hepatitis B status Patient's hepatitis B status

immunetolerance

immuneclearance

inactivecarrier

reactivation

HBeAg

Anti-HBe

HBV-DNA

ALT

DNA

Who should be considered for treatment?

Treat

Treat

What level of HBV DNA would you start What level of HBV DNA would you start treatment? treatment?

a. HBV DNA ≥ log 10 4 a. HBV DNA ≥ log 10 4

b. HBV DNA ≥ log 10 5 b. HBV DNA ≥ log 10 5

c. Any level of HBV DNA c. Any level of HBV DNA

HBV Treatment Guidelines

HBeAgHBV DNA(IU/ml)*

ALT Management

+< 20,000 Normal# Follow, no treatment

+≥ 20,000 Normal

Consider biopsy;treat if diseased

+ ≥ 20,000 Elevated Treat

–< 2,000 Normal Follow, no treatment

–≥ 2,000 Normal

Consider biopsy;treat if diseased

–≥ 2,000 Elevated Treat

*1 IU = 5.6 copies; #Normal ALT for men = 30 U/ml and for women = 19 U/mlKeeffe EB, et al. Clin Gastroenterol Hepatol.2006.

What level of HBV DNA would you start What level of HBV DNA would you start treatment? treatment?

a. HBV DNA ≥ log 10 4 a. HBV DNA ≥ log 10 4

b. HBV DNA ≥ log 10 5 b. HBV DNA ≥ log 10 5

c. Any level of HBV DNA + ALT elevated c. Any level of HBV DNA + ALT elevated

≥ 2,000 c/ml

IU = 5.6 copies

Evolution of Chronic HBV Therapy Over Time

Interferon alfa-2b

Lamivudine

Adefovir

Peginterferon alfa-2a

Telbivudine

Tenofovir

1990 1998 2002 2005 2006 2008

Entecavir

TreatmentTreatment

Nucleoside Analogues -- Lamivudine, EntecavirNucleoside Analogues -- Lamivudine, Entecavir

• LamivudineLamivudine• Dose : 100 mg PO q dailyDose : 100 mg PO q daily• Good for reducing the risk of progression to hepatic decompensation in patients Good for reducing the risk of progression to hepatic decompensation in patients

with cirrhosis or advanced fibrosiswith cirrhosis or advanced fibrosis• Pregnancy category B--Not teratogenic in animal studies and successful use with Pregnancy category B--Not teratogenic in animal studies and successful use with

pregnant womenpregnant women• Problem: High rates of resistant mutationsProblem: High rates of resistant mutations• Side effect: lactic acidosisSide effect: lactic acidosis

• Entecavir – 1Entecavir – 1stst line line• 0.5 to 1mg PO0.5 to 1mg PO• very effective; low resistance and greater than 90% HBV DNA clearance rate in very effective; low resistance and greater than 90% HBV DNA clearance rate in

HBeAg positive ptsHBeAg positive pts• Side effect: lactic acidosisSide effect: lactic acidosis

Treatment cont.Treatment cont.

Nucleotide analoguesNucleotide analogues

• TenovirTenovir• Dose: 300mg qdDose: 300mg qd• Highly effective with low resistanceHighly effective with low resistance• Well toleratedWell tolerated

• Adefovir – 1Adefovir – 1stst line line • Dose: 10mg dailyDose: 10mg daily• Resistance less than TenovirResistance less than Tenovir• Side effect: nephrotoxicity and lactic acidSide effect: nephrotoxicity and lactic acid

NAs: Potency versus resistance

Likelihood of resistance development

Potency of HBV DNA suppression

LAM

LdTETVTDF

ADV

Nucleoside analogue

Nucleotide analogue

More potent than Adefovir

HBV life cycleHBV life cycle

Hepatocyte-specific receptorHepatocyte-specific receptor

Nuclear steps require liver-specific Nuclear steps require liver-specific elementselements

Reverse transcriptionReverse transcriptionEssential for virion Essential for virion

formationformationIntegration NOT essential Integration NOT essential

(contrast to (contrast to retroviruses)retroviruses)

Neutralizing antibodies (HBsAg-specific)

HBV polymerase inhibitors(Lamivudine, Adefovir, Entecavir,Tenofovir)

What is the most appropriate management strategy at this time?

A) Start lamivudine 100 mg once daily

B) Start adefovir 10 mg once daily

C) Start entecavir 0.5 mg once daily

D) Start Tenofovir 300 mg

E) Observation; follow liver function tests every 3 months for 1 year

Back to the case

What is the most appropriate management strategy at this time?

A) Start lamivudine 100 mg once daily

B) Start adefovir 10 mg once daily

C) Start entecavir 0.5 mg once daily

D) Start Tenofovir 300 mg

E) Observation; follow liver function tests every 3 months for 1 year

She received lamivudine continuously

After 6 ms her laboratory studies were as follows:

AST N

ALT N

HBV DNA -ve

What are your recommendations at this time?

A) Continue to follow serum aminotransferases and HBV DNA levels at 6 months intervals

B) Continue lamivudine 100 mg once daily for at least 3 years after HBV load is undetectable

C) Given that the HBV load is undetectable, her disease is classified as inactive and she no longer needs regular follow-up at all.

D) Given that the HBV load is undetectable, she needs regular follow HBsAg level

What are your recommendations at this time?

All except

A) Continue to follow serum aminotransferases and HBV DNA levels at 6 months intervals

B) Continue lamivudine 100 mg once daily for at least 3 years after HBV load is undetectable

C) Given that the HBV load is undetectable, her disease is classified as inactive and she no longer needs regular follow-up at all.

D) Given that the HBV load is undetectable, she needs regular follow HBsAg level

She has now been on lamivudine continuously for more than 2 years

Her most recent laboratory studies were as follows:

AST N

ALT N

HBV DNA -ve

HBsAg titre 54320

qHBsAg can predict spontaneous HBsAg loss qHBsAg can predict spontaneous HBsAg loss in HBV carriersin HBV carriers

Serum HBsAg level <100 IU/ml at 1 year post-HBeAg Serum HBsAg level <100 IU/ml at 1 year post-HBeAg seroconversion can predict HBsAg loss within 6 seroconversion can predict HBsAg loss within 6 yearsyears11

HBsAg <10 IU/ml is the strongest predictor of HBsAg HBsAg <10 IU/ml is the strongest predictor of HBsAg loss in HBeAg-negative patients who have HBV loss in HBeAg-negative patients who have HBV DNA <2000 IU/mlDNA <2000 IU/ml22

Decreasing HBsAg level (<200 IU/ml or a decrease of Decreasing HBsAg level (<200 IU/ml or a decrease of 1 log 10 IU/ml) can predict HBsAg seroclearance 1 log 10 IU/ml) can predict HBsAg seroclearance in inactive CHB patientsin inactive CHB patients33

1. Tseng, Kao et al. Gastroenterology 20112. Tseng, Kao et al. Hepatology 20123. Chen YC, et al. Clin Gastroenterol Hepatol 2011

HBsAg level is an important risk factor in patients HBsAg level is an important risk factor in patients with low HBV DNA level (<2000 IU/mL)with low HBV DNA level (<2000 IU/mL)

Tseng, Kao. Gastroenterology 2012; Chan HL. Gastroenterology 2012

ERADICATE-B (2688 HBV carriers)

5-fold risk increase by univariate analysis

HBV DNA, HBsAg and ALT levels HBV DNA, HBsAg and ALT levels during different phases of CHBduring different phases of CHB

Janssen et al. Gut 2012.

The case

• She was continued on lamivudine. After 36 months She was continued on lamivudine. After 36 months HBV DNA below detectable levels. ALT 20 U/l HBV DNA below detectable levels. ALT 20 U/l

• Well until 6 months later her ALT 90 U/l Well until 6 months later her ALT 90 U/l • Repeat HBV DNA 6,000 IU/ml Repeat HBV DNA 6,000 IU/ml

• What is the cause for her virologic and biochemical What is the cause for her virologic and biochemical breakthrough? breakthrough?

Virological Response to LAM (4 Years): Resistance Exceeds Efficacy

% p

atie

nts

1 HBV DNA < 105 copies/mL 2 Re-appearance of HBV DNA > 105 copies/mL

39%48%

63%

89%

61%52%

37%

11%

0

20

40

60

80

100

1 year 2 years 3 years 4 years

Virological response 1 Virological Breakthrough2

Extended LAM therapy in HBeAg(-) CHB:The Italian experience (616 patients)

Worsening of liver disease

Rise in serum transaminases

Once Viral Resistance has developedOnce Viral Resistance has developedAdd or Switch?Add or Switch?

Should we continue or stop the Should we continue or stop the lamivudine? If continue for how lamivudine? If continue for how long? long?

Besides lamivudine, are there any Besides lamivudine, are there any other options? other options?

What treatment options for lamivudine What treatment options for lamivudine resistant ?resistant ?

a. switch to adefovir a. switch to adefovir

b. lamivudine combines with adefovir b. lamivudine combines with adefovir

c. switch to entecavir c. switch to entecavir

d. switch to interferon d. switch to interferon

Rescue Therapy for Antiviral-Rescue Therapy for Antiviral-Resistant HBVResistant HBV

• Lamivudine-R Lamivudine-R • Add adefovir/tenofovirAdd adefovir/tenofovir• Switch to tenofovir or switch to entecavir (risk of Switch to tenofovir or switch to entecavir (risk of

subsequent entecavir-R)subsequent entecavir-R)

• Adefovir-R* Adefovir-R* • Add lamivudine or switch to tenofovir Add lamivudine or switch to tenofovir • Switch to entecavir (if no prior LAM-R)Switch to entecavir (if no prior LAM-R)

• Entecavir-R* Entecavir-R* • Add or switch to adefovir or tenofovirAdd or switch to adefovir or tenofovir

• Multidrug R → ???Multidrug R → ???

Back to the patientBack to the patient

• Started on tenofovir 300mg /dStarted on tenofovir 300mg /d

• Seen by me every 6 ms ALT 49 -ve DNA , HBsAg 5000Seen by me every 6 ms ALT 49 -ve DNA , HBsAg 5000

• Any mistakes in treatment?Any mistakes in treatment?

• What medication should we use next?What medication should we use next?

HBV ControlHBV Control

InflammatoryInflammatory: : normalize serum ALT.normalize serum ALT.

VirologicVirologic: : decrease HBV DNA.decrease HBV DNA.

ImmuneImmune: : seroconversionseroconversion HBeAg to HBeAbHBeAg to HBeAb HBsAg to HBsAbHBsAg to HBsAb

HBV never “cured” but controlled

Therapeutic endpoints over timeTherapeutic endpoints over time

TIME

Loss of HBeAg

Loss of HBV DNA

Anti-HBe+Loss ofHBsAg

Anti-HBs+Improvedhistology

Antiviral Treatment of HBeAg (+) Antiviral Treatment of HBeAg (+) mild-moderate liver diseasemild-moderate liver disease

ALT > 2 ULN and/or histology > F1

Lamivudine/Adefovir/Entecavir/Tenofovir

No Yes

Continue treatment for at least 6 months

ALT normal?

NoDrug resistance ?

HBeAg seroconversion?

YesContinue therapy

Antiviral Treatment of HBeAg (-) Antiviral Treatment of HBeAg (-) mild-moderate liver diseasemild-moderate liver disease

ALT > 2 ULN and/or histology > F1

Lamivudine/Adefovir/Entecavir/Tenofovir

NoYes

Continue treatment indefinitely

ALT normal

ALT↑Drug resistance ?

Treat Today

To Prevent Tomorrow

Treat Today

To Prevent Tomorrow

HBV PreventionHBV Prevention

• Active immunizationActive immunization• Recombinant subunit vaccine produced in yeast (HBsAg)Recombinant subunit vaccine produced in yeast (HBsAg)• Combination vaccine with HAV available (Twinrix)Combination vaccine with HAV available (Twinrix)• Highly effectiveHighly effective• Component of routine childhood vaccine seriesComponent of routine childhood vaccine series• Recommended for high risk adultsRecommended for high risk adults

• Health care and long-term care facility workers, HD Health care and long-term care facility workers, HD patients, IVDU, travelers, chronic liver diseasepatients, IVDU, travelers, chronic liver disease

• Seroconversion rate declines with age and Seroconversion rate declines with age and immunosuppressionimmunosuppression

• >95% for age < 30 yo, but only 50% for age > 60 yo>95% for age < 30 yo, but only 50% for age > 60 yo

• Passive immunizationPassive immunization• Immune globulin available for post-exposure Immune globulin available for post-exposure

prophylaxisprophylaxis

A hepatitis panel is ordered for a 27 year old female as part A hepatitis panel is ordered for a 27 year old female as part of a routine workup for abdominal pain. of a routine workup for abdominal pain.

Results of serological testing a negative for HBeAg and Results of serological testing a negative for HBeAg and HBsAg, but HBsAg, but positive for IgG HBcAbpositive for IgG HBcAb. .

The patient has been exposed to Hep B.The patient has been exposed to Hep B.

a.a. Patient has recoveredPatient has recovered

b.b. Patient is in acute infective disease statePatient is in acute infective disease state

c.c. Window periodWindow period

d.d. Chronically infectedChronically infected

e.e. Patient was never infectedPatient was never infected

IgG HBcAb????

THANK YOU

Hepatitis C virus (HCV)Hepatitis C virus (HCV) Family: Family: FlaviviridaeFlaviviridae EnvelopedEnveloped Non-segmented positive (+) strand RNA genomeNon-segmented positive (+) strand RNA genome

Cambridge University Press

HCV Clinical ManifestationsHCV Clinical Manifestations TransmissionTransmission

– IVDU, sexual (less than HBV), transfusion, IVDU, sexual (less than HBV), transfusion, transplanttransplant

– VerticalVertical

Primary symptomsPrimary symptoms– Acute infection often asymptomaticAcute infection often asymptomatic– Only 20% clear infection Only 20% clear infection (contrast with HBV)(contrast with HBV)

ComplicationsComplications– 70-80% progress to chronic infection70-80% progress to chronic infection– 20% will develop cirrhosis (over 20 years)20% will develop cirrhosis (over 20 years)– HCC risk increased (1-4% per year)HCC risk increased (1-4% per year)– Extrahepatic manifestationsExtrahepatic manifestations

– Mixed cryoglobulinemiaMixed cryoglobulinemia

HCV Diagnosis and TreatmentHCV Diagnosis and Treatment DiagnosisDiagnosis

– SerologiesSerologies– Viral genome detection (RT-PCR)Viral genome detection (RT-PCR)

TreatmentTreatment– Interferon Interferon (frequent adverse reactions)(frequent adverse reactions)– RibavirinRibavirin

– Rapid resistance if use aloneRapid resistance if use alone– Combination therapy most effective (IFNCombination therapy most effective (IFN + Rib) + Rib)

– <50% sustained response<50% sustained response– Active area of investigation for new targets/drugsActive area of investigation for new targets/drugs

– R7128 and IDX184 - polymerase inhibitorsR7128 and IDX184 - polymerase inhibitors– VX-950 (Telaprevir) - protease inhibitorVX-950 (Telaprevir) - protease inhibitor– Debio-025 – cyclophilin inhibitorDebio-025 – cyclophilin inhibitor

– Liver transplantation Liver transplantation

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Petrol hbv siham