Management of Chronic Hepatitis Management of Chronic Hepatitis B & CB & C

الحاج الدين نظاممساعد استاذ

دمشق - جامعة الطب كليةالجامعي المواساة مستشفى

2008أيار

Healthy LiverHealthy Liver

Chronic Hepatitis BChronic Hepatitis B

Hepatitis B VirusHepatitis B Virus

POL

Core, HBc antigen

LHBs

MHBs

SHBs

HBs antigen

Partially double- stranded DNA

42 nm(Smallest known DNA virus)

4 Open Reading Frames:

- SS: S + Pre S1 + Pre S2

- CC: C + Pre C

- PP

- XX

HBV Genome HBV Genome

Geographic Pattern of Hepatitis B Prevalence 1997Geographic Pattern of Hepatitis B Prevalence 1997

Source: WHO, Geneva

HBsAg EndemicityHBsAg Endemicity8% and above - High

2%-8% - Intermediate

Below 2% - Low

Prevalence of HBV in SyriaPrevalence of HBV in Syria

• Intermediate HBV endemicityAt least 4 %4 % of chronic infection Statistics of Blood Transfusion Centers

• Total Population of Syria: 18 866 000 (2002)at least 750 000750 000 Syrian with chronic HBV infection

Mode of Transmission of HBV in Mode of Transmission of HBV in SyriaSyria

• Infected blood transfusion or blood products• Needle stick injuries: HCW - injection drug users • Hemodialysis• Sexual transmission: heterosexual - homosexual• Horizontal transmission: childhood - family member• Vertical Transmission (mother to newborn)• Unsafe Procedures: ear piercing-tattooing -barbering.

Natural History of Chronic Hepatitis BNatural History of Chronic Hepatitis B

Natural History of Chronic HBV Infection

AcuteInfection

Chronic Chronic CarrierCarrier

ResolutionResolution

30 - 50 Years

ChronicHepatitis

StabilisationStabilisation

ProgressionProgression

Cirrhosis

CompensatedCompensatedCirrhosisCirrhosis

Liver Cancer Death

Adapted from Feitelson, Lab Invest 1994

DecompensatedDecompensatedCirrhosisCirrhosis(Death)(Death)

Chronic Hepatitis BChronic Hepatitis B

1. HBs Ag + > 6 months

2. Serum HBV DNA >2.000 or 20.000 IU/mL

3. Persistent or intermittent elevation in ALT/AST

4. Liver biopsy showing chronic hepatitis necroinflammatory score 4 *

Types of Chronic HBV InfectionsTypes of Chronic HBV Infections

• Wild type HBe Ag + chronic hepatitis

• Mutant type HBe Ag – chronic hepatitisMore prevalent in SyriaUp to 70 %Up to 70 %

HBe Ag + & HBe Ag – Chronic HBe Ag + & HBe Ag – Chronic HepatitisHepatitis

HBe Ag + HBe Ag –

HBs Ag + +HBe AgHBe Ag ++ – –Anti-HBeAnti-HBe – – + + HBV DNA (IU/mL) > 20. 000 > 2.000 (copie/mL) > 100000 >10000ALT Elevated ElevatedNecro-inflammation + +

Initial Evaluation of patients with chronic HBV

1. 1. History & physical examinationHistory & physical examination

2. Laboratory tests for liver disease2. Laboratory tests for liver disease CBCCBCHepatic panelHepatic panel PTPT

3. Tests for HBV replication: 3. Tests for HBV replication: HBeAg /anti-HBe HBeAg /anti-HBe HBV DNA HBV DNA by PCRby PCR

4. R/O other causes of liver disease: 4. R/O other causes of liver disease: anti-HCVanti-HCVanti HDVanti HDV

Indications of Liver BiopsyIndications of Liver Biopsy

• HBs Ag +

• Chronic or intermittent elevations of ALT

• Candidate for treatment

HBV DNA > 2.000 or 20.000 IU/mL

• No contraindications for treatment

Results of Liver BiopsyResults of Liver Biopsy

• Confirming diagnosis of chronic HB

• Grading severity of necroinflammation

• Staging the fibrosis

• Excluding other inter-current disease

Scoring Systems for Chronic Scoring Systems for Chronic HepatitisHepatitis

Maximum Maximum grade scoregrade score

Maximum Maximum stage scorestage score

CommentsComments

HAI (Knodell) 18 4 Original scoring system

Sheuer 4 4 1st to separate stage & grade

METAVIR 4 4 ExcellentExcellent

Modified HAI(Ishak)

18 6 Most widely used in USA & UK

Increasing Severity of Inflammation Increasing Severity of Inflammation (Grading)(Grading)

Am J Surg Pathol 1995 ; 19 : 1409 - 1417.

Progression of FibrosisProgression of Fibrosis(Staging)(Staging)

Am J Surg Pathol 1995 ; 19 : 1409 - 1417.

Goal of Treatment of Chronic Goal of Treatment of Chronic HBVHBV

• HBe Ag +Seroconversion of HBe Ag to anti-HBe

• HBe Ag – HBV DNA < 2.000 IU/mL

Disappearance of HBs Ag is not the goalDisappearance of HBs Ag is not the goal

أدوية التهاب الكبد الفيروسي المزمن أدوية التهاب الكبد الفيروسي المزمن بب

مليون 10 مليون وحدة/يوم 5تحت الجلد))INFINF((األنتيرفيروناألنتيرفيرون مرات/أسبوع3وحدة

مرات/أسبوع3 2 مليون وحدة/م6أطفال ميكروغرام مرة / 180تحت الجلد ))PEG-INFPEG-INF((البيغ أنتيرفيرونالبيغ أنتيرفيرون

أسبوع(YMDD ملغ/يوم )طفرة 100عن طريق الفم))LAMLAM((الالميفودينالالميفودين ملغ/يوم )سمية كلوية(10عن طريق الفم))ADVADV((األديفوفيراألديفوفير ملغ/يوم ملغ/يوم3030عن طريق الفم عن طريق الفم ))ENTENT((اإلنتيكافيراإلنتيكافير

ملغ/يوم300 عن طريق الفم )TDF(التينوفيفير

How & when to assess the How & when to assess the response response

to treatment?to treatment?

Category of Response Category of Response

Biochemical (BR)Biochemical (BR) Decrease in serum ALT to normal range

Virological (VR)Virological (VR) HBe Ag + Loss of HBe Ag HBe Ag – HBV DNA <104 copies/ml

Histological (HR)Histological (HR) Decrease in HAI by at least 2 points compared to pre-treatment liver biopsy

Complete (CR)Complete (CR) Biochemical & virological response& loss of HBs Ag

What are the predictive factors What are the predictive factors of of

response to treatment?response to treatment?

Predictive Factors of Response to Predictive Factors of Response to TherapyTherapy

• High level of ALTHigh level of ALT

• Low lever of HBV DNALow lever of HBV DNA

• Female patients

• Infection in adulthood

• Severe necro-inflammation activity in liver biopsy

Treatment of HBe Ag + chronic Treatment of HBe Ag + chronic hepatitis Bhepatitis B

• IFN First choice

• ADF Contraindication to INFIntolerance to INFNo response to INF

• ADF Lamivudine resistant mutants• ENT• TDF (First choice: ESAL-2008)

Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

No treatment Monitor every

6-12 mos

Monitor ALT every 3-12 mos (immune tolerant)

Consider biopsy if age > 35-40 yrs and treat if significant disease

Treat Adefovir,

entecavir, peginterferon, and Tenofovir are first-line options

HBeAg Positive

ALTelevated

ALT normal

HBV DNA≥ 20,000 IU/mL (105 copies/ml)

HBV DNA< 20,000 IU/mL (105 copies/ml)

Treatment of HBe Ag – chronic Treatment of HBe Ag – chronic hepatitis Bhepatitis B

• IFN First choice

• ADF Contraindication to INFIntolerance to INFNo response to INF

• ADF Lamivudine resistant mutants(YMDDYMDD)• ENT• TDF

In view of the need for long term treatment, IFN or ADF, ENT, TDF is preferred

Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

No treatment Monitor every

6-12 mos

Monitor ALT and HBV DNA or

Consider biopsy since ALT often fluctuates and treat if significant disease

Treat Adefovir,

entecavir, peginterferon, and Tenofovir are first-line options

Long-term treatment required (oral agents)

HBeAg Negative

ALTelevated

HBV DNA≥ 2000 IU/mL (104copies/ml)

HBV DNA< 2000 IU/mL (104copies/ml)

ALTnormal

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

No treatment May choose to treat or observe If treat: adefovir, entecavir, or combination

treatment May be a role for combination therapy

Treat with adefovir or entecavir May be a role for combination therapy Significant clinical consequences associated with

lamivudine resistance in this population

HBV DNA (PCR)

HBV DNA≥ 2000 IU/mL

HBV DNA < 2000 IU/mL

HBeAg+ HBeAg-

استمرار العالج

انقالب مصلي ال إنقالب مصلي

أوقف العالج بعدشهراً 6-12 عالج مستمر

Keeffe et al. Clin Gastroenterol Hepatol. 2004;2:7.

Side Effects of InterferonSide Effects of Interferon

• Influenza-like symptoms• Alopecia • Neutropenia & thrombocytopenia • Depression• Induction of autoimmune disease (thyroid,….)• Cardiac complication: MI, AP • Erythema at injection site• Loss of libido• Diabetes mellitus

Contraindications of InterferonContraindications of Interferon

• Current psychosis or a history of psychosis

• Uncontrolled depressive illness

• Presence of active auto-immune disease

• Neutropenia or thrombocytopenia

• Decompensated cirrhosis

• Symptomatic heart disease

• Uncontrolled seizures

Follow-up of Patients on IFN Follow-up of Patients on IFN TherapyTherapy

• CBC q 2 weeks to 8 weeks then q 8 weeks½ dose WBC < 1 500 / mmNeutrophils < 750 / mmPlatelets < 50 000 / mm Stop WBC < 1 000 / mmNeutrophils < 500 / mmPlatelets < 25 000 / mm

• Thyroid tests q 3 - 4 months

Inactive HBs Ag Carrier State*Inactive HBs Ag Carrier State*1. HBs Ag + > 6 months

2. HBe Ag – , anti-HBe +

3. Serum HBV DNA < 20.000 IU/mL

4. Persistently normal ALT/AST levels

5. Liver biopsy: absence of significant hepatitis necroinflammatory score < 4

* Previously described as ‘healthy’ carrier state

Follow-up of Inactive HBs Ag Carrier Follow-up of Inactive HBs Ag Carrier StateState

• ALT q 6-12 months

• If ALT >1-2 x ULN: check serum HBV DNA level & exclude other causes of liver disease

• Consider screening for HCC in relevant populationFP & US every 6 monthsFP & US every 6 months

بحاجة لعالج طويلاألمد

وHBeAg فقد 20%~حدوث انقالب مصلي

يمكن إيقاف العالج شهرا12ً-6بعد

بحاجة لعالج طويلعدم حدوث انقالب األمد

مصليبعد سنة

Dienstag et al, N Engl J Med. 1999;341:1256-1263. Marcellin et al. N Engl J Med. 2003;348:808-816.Chang et al. Hepatology. 2004;40)4 suppl(:193A.

How & to whom you give the How & to whom you give the

vaccine of HBV?vaccine of HBV?

StandardStandard

0, 1, 6 months0, 1, 6 months

RapidRapid

0, 1, 2 months0, 1, 2 months

AcceleratedAccelerated

0, 7, 21 days0, 7, 21 days

Higher antibody levels after 3rd dose

Rapid protection4th dose at 12 months

for those at intermediate risk

Rapid protection4th dose at 12 months for those at high-risk

Schedule of VaccineSchedule of Vaccine

Indications of HBV vaccineIndications of HBV vaccine

• UniversalUniversal All infants All children & adolescents not vaccinated• High risk group High risk group Health care workers

Household contactsCRF & hemodialysis patientsRepeated blood transfusionsHomosexuals

Sexual partners of HBV carriers Illicit injection drug users

Adverse Events of VaccineAdverse Events of Vaccine• Minimal reactionsMinimal reactions

Local pain: only local pain more frequent in PCTMild & transient fever: mostly lasting only 24 h

• AnaphylaxisAnaphylaxisIncidence 1 / 600 000 vaccine dosesEpinephrine should always be available No severe or fatal anaphylactic reaction reported

• Demyelinating diseasesDemyelinating diseasesNot support for causal relationship

Efficacy of HBV Vaccine & AgeEfficacy of HBV Vaccine & Age

Efficacy of the vaccine depends on age

Newborns 100 %100 %

< 20 years 95 %95 %

< 40 years 90 %90 %

Vertical TransmissionVertical Transmission

• Mother with HBsAg + & HBeAg + 80 - 90 %80 - 90 % infected newborns 90 %90 % of infected infants become chronic carriers

• Mother with HBsAg + & HBeAg – 15 %15 % infected newborns 90%90% of infected infants become chronic carriers

How to prevent the vertical How to prevent the vertical transmission of HBV?transmission of HBV?

Active & Passive Immunization

• Immediately after Delivery1st dose Vaccine HBIG (200 IU)

• 1 month after delivery 2nd dose Vaccine

• 2 month after delivery 3rd dose Vaccine

in 2 different sites

Treatment of HBV Infection in Treatment of HBV Infection in ChildrenChildren

Treated as adults with modification of dosesTreated as adults with modification of doses

• IFN: 6 MU / m2 3 times / weekNo more than 10 MU per dose

• LAM 3 mg / kg / dayNo more than 100 mg / day

• ADF: Not yet approved for treatment in children

Treatment of HBV infection in CRF & KTTreatment of HBV infection in CRF & KT

Data on all 4 agents are limitedData on all 4 agents are limitedThere are no guideline or consensusThere are no guideline or consensus

• IFN: CRF Indicated with surveillanceKT Can lead to rejection

• LAM:CRF Indicated with surveillanceKT Indicated

• ADF: Limited data with this drug• TDF: CRF Indicated with surveillance

KT Indicated

HBs Ag PositiveHBs Ag Positive

ALT HBe Ag anti-HBe Diagnosis

Normal + – Immunotolerant phase

Very high + – Acute infection

High + – Chronic infection

High – + Chronic infection

Normal – + Inactive carrier state

Hepatology 2007; 45: 507 - 539.

Chronic Hepatitis CChronic Hepatitis C

HCV GenomeHCV Genome

N Engl J Med, 2001 ; 345 : 41 - 52

Natural History of HCV InfectionNatural History of HCV Infection

N Engl J Med, 2001 ; 345 : 41 - 52

1a, 1b 2a, 2b,

3a

1a, 1b 2a, 2b,

2c, 3a

4

5a

1b

1b, 61b,

3a

1b, 3a

3b

4

Fang et al. Clin Liver Dis. 1997

HCV Infection HCV Infection Worldwide Genotype DistributionWorldwide Genotype Distribution

1a, 1b, 2b, 3a

2a

Genotype Distribution Genotype Distribution

28%

59%

10%

n= 636

Assessing Predicting Length Response Sustained

Method Screen Confirmation of Therapy to Therapy Response

ALT/AST X

Enzyme Ximmunoassay (EIA)

HCV RNA qualitative X Xassay

HCV RNA quantitative X Xassay

HCV genotype X

CDC. MMWR. 1998.

Utility of Diagnostic Tests in Utility of Diagnostic Tests in HCVHCV

Interpretation of Hepatitis C Interpretation of Hepatitis C TestingTesting

Anti HCV Anti HCV HCV RNAHCV RNA InterpretationInterpretation

–– –– No infection

++ + + HCV present

++ –– Resolved infectionTreated HCV< detectable level

–– ++ AIDS Hemodialysis Early infection

Cleveland Clinic Journal of Medicine 2003 ; 70 : S7 - S13.

Algorithm for Laboratory Algorithm for Laboratory Investigation of Suspected HCV Investigation of Suspected HCV

InfectionInfection

Cleveland Clinic Journal of Medicine 2003 ; 70 : S7 - S13.

Goals of Therapy in CHCGoals of Therapy in CHC

• No virus1

• Arrest progression(necrosis/fibrosis)

• No symptoms

• Reduce progression of fibrosis1

• Reduce progression to cirrhosis2

• Prevent decompensation

• Prevent HCC2

1. Worman. Hepatitis C: Sourcebook 2002; 2. Peters et al. Medscape HIV/AIDS eJournal. 2002;8(1).

Secondary objective=delay/preventPrimary objective = cure

Milestones in therapy of chronic Milestones in therapy of chronic hepatitis Chepatitis C

Available Drugs in CHCAvailable Drugs in CHC• IFN: 3 M units, 3 times weekly

• Peg-IFN : - Peg-IFN 2a 180 gm weekly - Peg-IFN 2b 1.5 gm/kg weekly

• Ribavirin : 800 - 1200 mg daily

• Combination therapyCombination therapy: IFN or Peg-IFN with Ribavirin

• Monotherapy: Special cases

Negative Predictive Factors of Negative Predictive Factors of Response to therapy in HCVResponse to therapy in HCV

• Genotype 1Genotype 1• High viral loadHigh viral load• Alcohol consumption1

• Older age at time of infection (>40 years)1

• Male gender1

• Obesity• Other co morbidities:

– HIV/HCV coinfection2

– HBV/HCV coinfection3

1. Poynard et al. Lancet. 1997; 2. Di Martino et al. Hepatology. 2001; 3. Lana et al. Med Clin (Barc). 2001

Treatment of CHC Genotype Treatment of CHC Genotype 1/41/4

Peg-IFN 2a 180 gm weekly oror Peg-IFN 2b 1.5 gm/kg weekly ++Ribavirin 800 -1200 mg daily

For 12 weeks – EVRFor 12 weeks – EVR

HCV-RNAHCV-RNAPCRPCR

Treatment of CHCTreatment of CHCSustained Virological ResponseSustained Virological Response

SVR

2-log decline

Interferon-based therapy

0123456789

10

-6 0 6 12 18 24 30 36 42 48 54 60 66 72 78Weeks

Log

HC

V R

NA

(IU

/ml)

Detection limit (50 IU/ml)

Treatment of CHC Genotype 2/3Treatment of CHC Genotype 2/3

Peg-IFN 2a 180 gm weekly oror Peg-IFN 2b 1.5 gm/kg weekly ++Ribavirin 800 mg daily

For 24 weeks - No need for EVR - SVR: 80-82% For 24 weeks - No need for EVR - SVR: 80-82% OrOr

IFN 3 Million Unit 3 / week ++ Ribavirin 1000 -1200 mg/d

For 48 weeks if EVR achieved - SVR: 79%For 48 weeks if EVR achieved - SVR: 79%

Treatment of Acute Hepatitis CTreatment of Acute Hepatitis C

• 20% recovery within 3 months

• Waiting 3 months before treatment

IFN monotherapy for 6 monthsIFN monotherapy for 6 months

• 5 M daily / 4 weeks followed by

• 5 M 3 Weekly / 20 weeks

98 % of 44 patients had negative HCV-RNA by 24 w

Jaeckel et al. Treatment of acute hepatitis C with interferon alpha-2b. N Engl J Med 2001; 345

HCV & Renal failure/dialysisHCV & Renal failure/dialysis• High prevalence of HCV in dialysis units in Syria

• Anti-HCV may be negative

• Ribavirin is contra-indicated

• IFN monotherapy is the treatment

• Response to treatment is higher in CRF patients for the same genotype

HCV & Renal failure/dialysisHCV & Renal failure/dialysis

• A tentative of viral eradication should be given before kidney transplantation

• If failed and if the liver functions are stable & the liver biopsy doesn’t show advanced liver disease, kidney transplantation is authorized

Treatment of Cirrhosis in CHCTreatment of Cirrhosis in CHC

We treat if:We treat if:• Bilirubine < 1.5mg/dl• Serum albumin > 3.4 g/dl• INR < 1.5• WBC > 1500• Platelets > 75000• No ascitis, no encephalopathy

SVR: 43%SVR: 43%

Treatment of CHCTreatment of CHCRelapseRelapse

SVR

2-log decline

Interferon-based therapy

0123456789

10

-6 0 6 12 18 24 30 36 42 48 54 60 66 72 78Weeks

Log

HC

V R

NA

(IU

/ml)

Relapse

Detection limit (50 IU/ml)

Treatment of CHCTreatment of CHCNull ResponseNull Response

SVR

Interferon-based therapy

0123456789

10

-6 0 6 12 18 24 30 36 42 48 54 60 66 72 78Weeks

Log

HC

V R

NA

(IU

/ml)

Relapse

Null response

Detection limit (50 IU/ml)

Treatment of CHCTreatment of CHCPartial ResponsePartial Response

SVR

Interferon-based therapy

Detection limit (50 IU/ml)

0123456789

10

-6 0 6 12 18 24 30 36 42 48 54 60 66 72 78Weeks

Log

HC

V R

NA

(IU

/ml)

Relapse

Null response

Partial response

CirrhosisCirrhosis