Management of Chronic Hepatitis B & C نظام الدين الحاج استاذ مساعد كلية...
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Transcript of Management of Chronic Hepatitis B & C نظام الدين الحاج استاذ مساعد كلية...
Management of Chronic Hepatitis Management of Chronic Hepatitis B & CB & C
الحاج الدين نظاممساعد استاذ
دمشق - جامعة الطب كليةالجامعي المواساة مستشفى
2008أيار
Hepatitis B VirusHepatitis B Virus
POL
Core, HBc antigen
LHBs
MHBs
SHBs
HBs antigen
Partially double- stranded DNA
42 nm(Smallest known DNA virus)
Geographic Pattern of Hepatitis B Prevalence 1997Geographic Pattern of Hepatitis B Prevalence 1997
Source: WHO, Geneva
HBsAg EndemicityHBsAg Endemicity
8% and above - High
2%-8% - Intermediate
Below 2% - Low
Prevalence of HBV in SyriaPrevalence of HBV in Syria
• Intermediate HBV endemicity
At 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 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 hepatitis
More prevalent in Syria
Up 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 by HBV DNA by
PCRPCR
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 وحدة/يوم 5تحت الجلد))INFINF((األنتيرفيروناألنتيرفيرون مرات/أسبوع3 مليون وحدة 10
مرات/أسبوع3 2 مليون وحدة/م6أطفال
ميكروغرام مرة / 180تحت الجلد ))PEG-INFPEG-INF((البيغ أنتيرفيرونالبيغ أنتيرفيرونأسبوع
ملغ/يوم )طفرة 100عن طريق الفم))LAMLAM((الالميفودينالالميفودينYMDD)
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
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 بعدشهرا{ 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 weeks
½ dose WBC < 1 500 / mm
Neutrophils < 750 / mm
Platelets < 50 000 / mm
Stop WBC < 1 000 / mm
Neutrophils < 500 / mm
Platelets < 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
شهرا{12-6بعد
بحاجة لعالج طويلعدم حدوث انقالب األمد
مصلي
بعد 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.
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 protection
4th dose at 12 months
for those at intermediate risk
Rapid protection
4th 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 contacts
CRF & hemodialysis patients
Repeated blood transfusions
Homosexuals
Sexual partners of HBV carriers Illicit injection drug users
Adverse Events of VaccineAdverse Events of Vaccine
• Minimal reactionsMinimal reactionsLocal 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
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 / week
No more than 10 MU per dose
• LAM 3 mg / kg / day
No 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
1a, 1b 2a, 2b,
3a
1a, 1b 2a, 2b,
2c, 3a
4
5a
1b
1b, 6
1b, 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
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 infection
Treated HCV< detectable level
–– ++ AIDS Hemodialysis
Early infectionCleveland 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
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-RNA
PCRPCR
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 78
Weeks
Lo
g H
CV
RN
A (
IU/m
l)
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 78
Weeks
Lo
g H
CV
RN
A (
IU/m
l)
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 78
Weeks
Lo
g H
CV
RN
A (
IU/m
l)
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 78
Weeks
Lo
g H
CV
RN
A (
IU/m
l)
Relapse
Null response
Partial response