Transcript Chronic Hepatitis B

‫‪Management of Chronic Hepatitis B & C‬‬
‫نظام الدين الحاج‬
‫استاذ مساعد‬
‫كلية الطب ‪ -‬جامعة دمشق‬
‫مستشفى المواساة الجامعي‬
‫أيار ‪2008‬‬
Healthy Liver
Chronic Hepatitis B
Hepatitis B Virus
Core, HBc antigen
SHBs
HBs antigen
POL
LHBs
MHBs
Partially doublestranded DNA
42 nm
(Smallest known
DNA virus)
HBV Genome
4 Open Reading Frames:
- S:
S + Pre S1 + Pre S2
- C:
C + Pre C
-P
-X
Geographic Pattern of Hepatitis B Prevalence 1997
HBsAg Endemicity
8% and above - High
2%-8% - Intermediate
Source: WHO, Geneva
Below 2% - Low
Prevalence of HBV in Syria
• Intermediate HBV endemicity
At least 4 % of chronic infection
Statistics of Blood Transfusion Centers
• Total Population of Syria: 18 866 000 (2002)
at least 750 000 Syrian with chronic HBV infection
Mode of Transmission of HBV in Syria
•
•
•
•
•
•
•
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 B
Natural History of Chronic HBV
Infection Compensated
Resolution
Acute
Infection
Stabilisation
Chronic
Hepatitis
Chronic
Carrier
Cirrhosis
Cirrhosis
Liver
Cancer
Progression Decompensated
Cirrhosis
(Death)
30 - 50 Years
Adapted from Feitelson, Lab Invest 1994
Death
Chronic 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 Infections
• Wild type
HBe Ag + chronic hepatitis
• Mutant type
HBe Ag – chronic hepatitis
More prevalent in Syria
Up to 70 %
HBe Ag + & HBe Ag – Chronic Hepatitis
HBe Ag +
HBs Ag
HBe Ag
Anti-HBe
HBV DNA (IU/mL)
(copie/mL)
ALT
Necro-inflammation
+
+
–
> 20. 000
> 100000
Elevated
+
HBe Ag –
+
–
+
> 2.000
>10000
Elevated
+
Initial Evaluation of patients with chronic HBV
1. History & physical examination
2. Laboratory tests for liver disease
CBC
Hepatic panel
PT
3. Tests for HBV replication:
HBeAg /anti-HBe
HBV DNA
by PCR
4. R/O other causes of liver disease:
anti-HCV
anti HDV
Indications 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 Biopsy
• Confirming diagnosis of chronic HB
• Grading severity of necroinflammation
• Staging the fibrosis
• Excluding other inter-current disease
Scoring Systems for Chronic Hepatitis
Maximum Maximum Comments
grade score stage score
HAI (Knodell)
18
4
Original scoring system
Sheuer
4
4
1st to separate stage &
grade
METAVIR
4
4
Excellent
Modified HAI
(Ishak)
18
6
Most widely used in USA
& UK
Increasing Severity of Inflammation
(Grading)
Am J Surg Pathol 1995 ; 19 : 1409 - 1417.
Progression of Fibrosis
(Staging)
Am J Surg Pathol 1995 ; 19 : 1409 - 1417.
Goal of Treatment of Chronic HBV
• HBe Ag +
Seroconversion of HBe Ag to anti-HBe
• HBe Ag –
HBV DNA < 2.000 IU/mL
Disappearance of HBs Ag is not the goal
‫أدوية التهاب الكبد الفيروسي المزمن ب‬
‫األنتيرفيرون)‪(INF‬‬
‫‪ 5‬مليون وحدة‪/‬يوم‬
‫تحت الجلد‬
‫‪ 10‬مليون وحدة ‪ 3‬مرات‪/‬أسبوع‬
‫أطفال ‪ 6‬مليون وحدة‪/‬م‪ 3 2‬مرات‪/‬أسبوع‬
‫البيغ أنتيرفيرون)‪(PEG-INF‬‬
‫الالميفودين)‪(LAM‬‬
‫تحت الجلد ‪ 180‬ميكروغرام مرة ‪ /‬أسبوع‬
‫عن طريق الفم‬
‫‪ 100‬ملغ‪/‬يوم (طفرة ‪)YMDD‬‬
‫‪ 10‬ملغ‪/‬يوم (سمية كلوية)‬
‫األديفوفير)‪ (ADV‬عن طريق الفم‬
‫عن طريق الفم ‪ 30‬ملغ‪/‬يوم‬
‫اإلنتيكافير)‪(ENT‬‬
‫‪ 300‬ملغ‪/‬يوم‬
‫عن طريق الفم‬
‫التينوفيفير)‪(TDF‬‬
How & when to assess the response
to treatment?
Category of Response
Biochemical (BR)
Decrease in serum ALT to normal range
Virological (VR)
HBe Ag + Loss of HBe Ag
HBe Ag – HBV DNA <104 copies/ml
Histological (HR)
Decrease in HAI by at least 2 points
compared to pre-treatment liver biopsy
Complete (CR)
Biochemical & virological response
& loss of HBs Ag
What are the predictive factors of
response to treatment?
Predictive Factors of Response to Therapy
• High level of ALT
• Low lever of HBV DNA
• Female patients
• Infection in adulthood
• Severe necro-inflammation activity in liver biopsy
Treatment of HBe Ag + chronic hepatitis B
• IFN
• ADF
• ADF
• ENT
• TDF
First choice
Contraindication to INF
Intolerance to INF
No response to INF
Lamivudine resistant mutants
(First choice: ESAL-2008)
HBeAg Positive
HBV DNA
< 20,000 IU/mL (105 copies/ml)
HBV DNA
≥ 20,000 IU/mL (105 copies/ml)
ALT
 No treatment
 Monitor every
6-12 mos
normal
 Monitor ALT every
3-12 mos (immune
tolerant)
 Consider biopsy if age >
35-40 yrs and treat if
significant disease
Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.
ALT
elevated
 Treat
 Adefovir, entecavir,
peginterferon, and
Tenofovir are first-line
options
Treatment of HBe Ag – chronic hepatitis B
• IFN
• ADF
• ADF
• ENT
• TDF
First choice
Contraindication to INF
Intolerance to INF
No response to INF
Lamivudine resistant mutants(YMDD)
In view of the need for long term treatment, IFN or
ADF, ENT, TDF is preferred
HBeAg Negative
HBV DNA
< 2000 IU/mL (104copies/ml)
HBV DNA
≥ 2000 IU/mL (104copies/ml)
ALT
normal
 No treatment
 Monitor every
6-12 mos
 Monitor ALT and HBV
DNA or
 Consider biopsy since
ALT often fluctuates
and treat if significant
disease
Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.
ALT
elevated
 Treat
 Adefovir, entecavir,
peginterferon, and
Tenofovir are first-line
options
 Long-term treatment
required (oral agents)
HBV DNA (PCR)
HBV DNA
< 2000 IU/mL
HBV DNA
≥ 2000 IU/mL
 Treat with adefovir or entecavir
 May be a role for combination therapy
 Significant clinical consequences associated with lamivudine
resistance in this population




No treatment
May choose to treat or observe
If treat: adefovir, entecavir, or combination treatment
May be a role for combination therapy
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.
‫‪HBeAg+‬‬
‫‪HBeAg‬‬‫ال إنقالب مصلي‬
‫عالج مستمر‬
‫انقالب مصلي‬
‫استمرار العالج‬
‫أوقف العالج بعد‬
‫‪ 12-6‬شهرا‬
‫‪Keeffe et al. Clin Gastroenterol Hepatol. 2004;2:7.‬‬
Side 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 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 Therapy
• CBC
½ dose
Stop
• Thyroid tests
q 2 weeks to 8 weeks then q 8 weeks
WBC
< 1 500 / mm
Neutrophils < 750 / mm
Platelets
< 50 000 / mm
WBC
< 1 000 / mm
Neutrophils < 500 / mm
Platelets
< 25 000 / mm
q 3 - 4 months
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 State
• 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 population
FP & US every 6 months
‫‪ ~20%‬فقد ‪ HBeAg‬و‬
‫حدوث انقالب مصلي‬
‫يمكن إيقاف العالج‬
‫بعد ‪ 12-6‬شهرا‬
‫بحاجة لعالج طويل‬
‫األمد‬
‫عدم حدوث انقالب مصلي‬
‫بعد سنة‬
‫بحاجة لعالج طويل‬
‫األمد‬
‫‪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
vaccine of HBV?
Schedule of Vaccine
Standard
Rapid
Accelerated
0, 1, 6 months
0, 1, 2 months
0, 7, 21 days
Higher antibody levels
after 3rd dose
Rapid protection
Rapid protection
4th dose at 12 months
4th dose at 12 months
for those at intermediate risk
for those at high-risk
Indications of HBV vaccine
• Universal
All infants
All children & adolescents not vaccinated
• 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 Vaccine
• Minimal reactions
Local pain: only local pain more frequent in PCT
Mild & transient fever: mostly lasting only 24 h
• Anaphylaxis
Incidence 1 / 600 000 vaccine doses
Epinephrine should always be available
No severe or fatal anaphylactic reaction reported
• Demyelinating diseases
Not support for causal relationship
Efficacy of HBV Vaccine & Age
Efficacy of the vaccine depends on age
Newborns
100 %
< 20 years
95 %
< 40 years
90 %
Vertical Transmission
• Mother with HBsAg + & HBeAg +
80 - 90 % infected newborns
90 % of infected infants become chronic carriers
• Mother with HBsAg + & HBeAg –
15 %
90%
infected newborns
of infected infants become chronic carriers
How to prevent the vertical
transmission of HBV?
Active & Passive Immunization
• Immediately after Delivery
1st dose Vaccine
in 2 different sites
HBIG (200 IU)
• 1 month after delivery
2nd dose Vaccine
• 2 month after delivery
3rd dose Vaccine
Treatment of HBV Infection in Children
Treated 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 & KT
Data on all 4 agents are limited
There are no guideline or consensus
• IFN:
• LAM:
• ADF:
• TDF:
CRF Indicated with surveillance
KT Can lead to rejection
CRF Indicated with surveillance
KT Indicated
Limited data with this drug
CRF Indicated with surveillance
KT Indicated
HBs 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 C
HCV Genome
N Engl J Med, 2001 ; 345 : 41 - 52
Natural History of HCV Infection
N Engl J Med, 2001 ; 345 : 41 - 52
HCV Infection
Worldwide Genotype Distribution
1a, 1b
2a, 2b, 2c,
3a
1a, 1b
2a, 2b,
3a
2a
4
4
1b,
3a
1b
1b,
6
3b
1a, 1b,
2b, 3a
5a
1b,
3a
Fang et al. Clin Liver Dis. 1997
Genotype Distribution
59%
28%
10%
n= 636
Utility of Diagnostic Tests in HCV
Method
Screen
ALT/AST
X
Enzyme
immunoassay (EIA)
X
HCV RNA qualitative
assay
Confirmation
Length
of Therapy
X
Predicting
Sustained
Response
X
HCV RNA quantitative
assay
HCV genotype
Assessing
Response
to Therapy
X
X
X
CDC. MMWR. 1998.
Interpretation of Hepatitis C Testing
Anti HCV
HCV RNA
Interpretation
–
–
No infection
+
+
HCV present
+
–
Resolved infection
Treated HCV
< detectable level
–
+
AIDS
Hemodialysis
Early infection
Cleveland Clinic Journal of Medicine 2003 ; 70 : S7 - S13.
Algorithm for Laboratory Investigation
of Suspected HCV Infection
Cleveland Clinic Journal of Medicine 2003 ; 70 : S7 S13.
Goals of Therapy in CHC
Primary objective = cure
Secondary objective=delay/prevent
• No virus1
• Reduce progression of fibrosis1
• Arrest progression
(necrosis/fibrosis)
• Reduce progression to cirrhosis2
• No symptoms
• Prevent decompensation
• Prevent HCC2
1. Worman. Hepatitis C: Sourcebook 2002; 2. Peters et al. Medscape HIV/AIDS eJournal. 2002;8(1).
Milestones in therapy of chronic hepatitis C
Available Drugs in CHC
• IFN:
3 M units, 3 times weekly
• Peg-IFN :
- Peg-IFN  2a
- Peg-IFN  2b
180 gm weekly
1.5 gm/kg weekly
• Ribavirin :
800 - 1200 mg daily
• Combination therapy:
IFN or Peg-IFN with Ribavirin
• Monotherapy:
Special cases
Negative Predictive Factors of
Response to therapy in HCV
•
Genotype 1
•
High 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 1/4
Peg-IFN  2a 180 gm weekly
Peg-IFN  2b
1.5 gm/kg weekly
Ribavirin
800 -1200 mg daily
For 12 weeks – EVR
HCV-RNA
PCR
or
+
Treatment of CHC
Log HCV RNA (IU/ml)
Sustained Virological Response
10
9
8
7
6
5
4
3
2
1
0
Interferon-based therapy
2-log decline
SVR
-6
0
6 12 18 24 30 36 42 48 54 60 66 72 78
Weeks
Detection limit (50 IU/ml)
Treatment of CHC Genotype 2/3
Peg-IFN  2a
180 gm weekly
or
Peg-IFN  2b
1.5 gm/kg weekly
+
Ribavirin
800 mg daily
For 24 weeks - No need for EVR - SVR: 80-82%
Or
IFN
3 Million Unit 3 / week +
Ribavirin
1000 -1200 mg/d
For 48 weeks if EVR achieved - SVR: 79%
Treatment of Acute Hepatitis C
• 20% recovery within 3 months
• Waiting 3 months before treatment
IFN 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/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/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 CHC
•
•
•
•
•
•
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%
Log HCV RNA (IU/ml)
Treatment of CHC
Relapse
10
9
8
7
6
5
4
3
2
1
0
Interferon-based therapy
2-log decline
Relapse
SVR
-6
0
6 12 18 24 30 36 42 48 54 60 66 72 78
Weeks
Detection limit (50 IU/ml)
Treatment of CHC
Log HCV RNA (IU/ml)
Null Response
10
9
8
7
6
5
4
3
2
1
0
Interferon-based therapy
Null response
Relapse
SVR
-6
0
6 12 18 24 30 36 42 48 54 60 66 72 78
Weeks
Detection limit (50 IU/ml)
Treatment of CHC
Log HCV RNA (IU/ml)
Partial Response
10
9
8
7
6
5
4
3
2
1
0
Interferon-based therapy
Null response
Relapse
Partial response
SVR
-6
0
6 12 18 24 30 36 42 48 54 60 66 72 78
Weeks
Detection limit (50 IU/ml)
Cirrhosis