Management of Chronic Hepatitis

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Management of Chronic Hepatitis
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All cirrhotic patients

• periodic screening for HCC with ultrasound and
  alfa-feto protein level every 6 month is
  recommended in CHB and CHC.
• CLD patients should be considered for HAV
  vaccination.

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Diagnosis

• Serology HBSAg-HBSAb,HBeAg-HBeAb, HBcAb.
• DNA detection methods BDNA,hybridization
  assay,single amplification assay 105-106, PCR
  based assays detect 10-100 copies/ml.
• Liver BX.

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• Antiviral therapy is not indicated in patients
  with acute hepatitis.
• Patients with FHF should be considered for liver
  transplantation.
• The main efficacy of antiviral therapy in chronic
  hepatitis B is to increase the seroconversion
  rate.

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Chronic HBV Infection Target Population for
Treatment

• Treatment indicated in those with active CHB
• Greatest benefit (at highest risk for disease
  progression)
• Most likely to respond to currently available
  agents
• Activity defined by
• Elevated ALT/AST
• Necroinflammation on liver biopsy
• Elevated HBV DNA levels

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HBV Treatment Guidelines
HBeAg HBV DNA(copies/mL) ALT Management
lt 105 Normal Follow, no treatment
105 Normal Consider biopsytreat if diseased
105 Elevated Treat
lt 104 Normal Follow, no treatment
104 Normal Consider biopsytreat if diseased
104 Elevated Treat
Keeffe EB, et al. Clin Gastroenterol Hepatol.
2004287-106.
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Goals of Therapy in Patients With Chronic HBV
Infection

• Eradication of infection
• HBsAg seroconversion
• Undetectable HBV DNA
• Prevent complications of liver disease
• Histologic progression to cirrhosis
• Decompensated liver disease
• Liver cancer

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Therapeutic Endpoints

• HBeAg-positive patients (wild type)
• HBeAg seroconversion is KEY
• Sustained suppression of HBV DNA to low or
  undetectable levels
• ALT normalization
• Reduced necroinflammation on biopsy
• HBeAg-negative patients (precore and core
  promoter mutants)
• HBeAg seroconversion not an endpoint
• Sustained suppression of HBV DNA to low or
  undetectable levels
• ALT normalization
• Reduced necroinflammation on biopsy

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Approved HBV Therapies

• Interferon
• Peginterferon
• Lamivudine
• Adefovir dipivoxil
• Wild-type HBV, lamivudine-resistant HBV
• Entecavir
• Wild-type HBV, lamivudine-resistant HBV

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Interferon
Characteristics of Interferon Treatment Characteristics of Interferon Treatment
Type of agent Recombinant interferon immune modulator
Approved for HBV Interferon alfa-2b 1992 Pegylated interferon alfa-2a 2005
Route of administration Injection
Mode of action Dual immunomodulatory and antiviral mode of action Exact target against HBV replication unknown
Antiviral activity Not applicable
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Peginterferon Summary

• Advantages
• Less frequent injections than IFN
• Defined treatment interval
• High rate of HBeAg seroconversion in wild-type
  infection
• High rate of HBV DNA suppression in precore
  mutant variant
• High rate of HBsAg seroconversion
• No reports of resistance mutations

• Disadvantages
• Requires injection
• Frequent side effects
• Not recommended for some patient groups
• Decompensated cirrhotics
• Liver transplant recipients
• Higher cost

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Lamivudine
Characteristics of Lamivudine Treatment Characteristics of Lamivudine Treatment
Type of agent Cytidine nucleoside analogue
Approved for HBV 1998
Route of administration Oral
Mode of action Inhibits first-strand DNA synthesis
Antiviral activity EC50 1000 nM
Dosing 100 mg/day Adjust for renal dysfunction
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Lamivudine Treatment in HBeAg-Positive Patients
for 1 Year
100 mg/day for 52 Weeks
60
Lai1
Dienstag2
Schalm3
Schiff4
40
33
32
Percentage of Patients
22
18
18
20
17
17
16
0
HBeAg Seroconversion
HBeAg Loss
1. Lai CL, et al. N Engl J Med. 199833961-68.
2. Dienstag JL, et al. N Engl J Med.
19993411256-1263. 3. Schalm SW, et al. Gut.
200046562-568. 4. Schiff ER, et al. J Hepatol.
200338818-826.
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Lamivudine in HBeAg-Negative Cirrhosis Long-term
Outcomes
Results (N 84) Results (N 84) Results (N 84)
Endpoint Sensitive, Resistant,
Resistance Genotypic resistance Clinical resistance --- --- 63 82
Clinical decompensation 0 24
HCC 30 27
5-year probability
Lampertico P, et al. Hepatology. 200440674A.
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Incidence of YMDD Mutations by Duration of
Lamivudine Therapy
80
Asia1,2
69
66
International3
60
55
USA4
Patients With Resistance ()
40
40
32
27
20
15
0
1
2
3
4
5
Duration of Treatment, Years
1. Guan R. APDW. 2001. 2. Leung NW, et al.
Hepatology. 2001331527-1532. 3. Tassopoulos NC,
et al. Hepatology. 199929889-896. 4. Dienstag
JL, et al. N Engl J Med. 1999301082-1087.
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Consequences of Drug Resistance

• Relapse of HBV DNA
• Elevated ALT
• Decreased rate of HBeAg seroconversion
• Loss of histologic improvement
• Possible clinical decompensation
• Poorer outcomes if underlying cirrhosis

Perrillo RP, et al. Hepatology. 200236186-194.
Leung NW, et al. Hepatology. 2001331527-1532.
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Adefovir Dipivoxil
Characteristics of Adefovir Dipivoxil Treatment Characteristics of Adefovir Dipivoxil Treatment
Type of agent Adenosine nucleotide analogue
Approved for HBV 2002
Mode of action Inhibitor of HBV DNA polymerase Not dependent on intracellular kinases for first phosphorylation step
Antiviral activity EC50 1100 nM Effective against wild-type and lamivudine-resistant HBV
Dosing (oral) 10 mg/day Adjust for renal dysfunction
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HBeAg-Positive PatientsAdefovir Efficacy at 48
and 72 Weeks
78
80
Week 48
63
Week 72
60
46
44
Percentage of Patients
40
26
23
23
20
14
0
HBV DNA lt 400 copies/mL
ALT Normalization
HBeAg Loss
HBeAg Seroconversion
Kaplan-Meier estimates
Marcellin P, et al. N Engl J Med.
2003348808-816.
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Adefovir in HBeAg-Negative PatientsVirologic and
Biochemical Response
Serum HBV DNA lt 1000 copies/mL
ALT Normalization
100
78
80
77
75
75
72
71
69
68
67
67
60
Percentage of Patients
40
20
0
48
96
144
192
48
96
144
192
240
240
Treatment Duration (Weeks)
n 69 58 69 65 55 64
53 64 59 55
Hadziyannis S, et al. EASL. 2005. Abstract 492.
Hadziyannis S, et al. AASLD 2005. Abstract LB14.
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Entecavir
Characteristics of Entecavir Treatment Characteristics of Entecavir Treatment
Type of agent Deoxyguanine nucleoside analogue
Approved for HBV 2005
Mode of action Inhibits HBV replication in 3 ways Priming of HBV DNA polymerase Reverse transcription of the negative DNA strand from pregenomic RNA Synthesis of the positive DNA strand
Antiviral activity EC50 4 nM for wild-type HBV, 26 nM for lamivudine-resistant HBV Effective against wild-type and lamivudine-resistant HBV
Dosing (oral) 0.5 mg (wild type) or 1 mg (lam-R) daily Adjust for renal dysfunction
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Entecavir vs Lamivudine in Nucleoside-Naive
HBeAg CHB
Results at 48 Weeks
Entecavir 0.5 mg/day (n 354)
Lamivudine 100 mg/day (n 355)
P NS
P lt .05
P lt .05
100
25
80
21
80
72
68
18
62
20
60
60
60
15
Percentage of Patients
Percentage of Patients
40
Percentage of Patients
40
10
20
20
5
0
0
0
Histological Improvement(n 314 with evaluable
histology in each group)
HBeAg Seroconversion
ALT Normalization( 1.00 x ULN)
Chang TT, et al. Hepatology. 200440193A.
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HBeAg-Positive Patients Treated up to 96 Weeks
With Entecavir
Cumulative Outcome by Week 96
Sustained Responses 24 Weeks Off Therapy
100
100
P lt .0001
80
80
80
71
69
60
60
Percentage of Patients
Percentage of Patients
39
40
40
31
31
29
26
20
20
0
0
HBeAg Seroconversion
Undetectable HBV DNA
HBeAg Seroconversion
Undetectable HBV DNA
Entecavir (n 354)
Entecavir (n 111)
Lamivudine (n 355)
Lamivudine (n 93)
Undetectable HBV DNA, lt 300 copies/mL
Gish R, et al. AASLD 2005. Abstract 181.
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ETV vs LAM in Nucleoside-Naive HBeAg-Negative
Patients
Results at 48 Weeks
Entecavir 0.5 mg/day (n 325)
Lamivudine 100 mg/day (n 313)
90
P lt .05
78
100
80
90
P lt .05
71
70
80
72
60
Patients Achieving Response ()
Patients Achieving Response ()
50
60
40
40
30
20
20
10
0
0
ALT Normalization( 1.00 x ULN)
HBV DNA lt 300 copies/mL (PCR)
Shouval D, et al. Hepatology. 200440728A.
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Incidence of Resistance in Patients Treated With
Antivirals

• Viral mutations conferring resistance are less
  frequent and delayed in onset with ADV and ETV
  vs LAM

80
70
60
ADV (N236T A181V)1
53
42
LAM2 (YMDD)
Incidence of Resistance ()
40
ETV- Lam-R3 (L180M M204V)
24
20
18
ETV- Rx naive3
11
9
6
2
0
Year 4
Year 2
Year 1
Year 3
1. Westland CE, et al. Hepatology.
20033896-103. 2. Lai CL, et al. Clin Infect
Dis. 2003 36687-696. 3. Colonno R, et al. AASLD
2005. Abstract 962.
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Hepatitis C Virus InfectionMagnitude of the
Problem

• Nearly 4 million persons in United States
  infected
• Approximately 35,000 new cases yearly
• 85 of new cases become chronic
• 10,000-20,000 HCV-related deaths per year
• Number expected to triple in next 10-20 years
• Leading cause of
• Chronic liver disease
• Cirrhosis
• Liver cancer
• Liver transplantation

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Goals of HCV Therapy

• Primary goal of treatment is to eradicate the
  virus
• Additional goals
• Slow disease progression
• Minimize risk of hepatocellular carcinoma
• Improve liver histology
• Enhance quality of life
• Prevent transmission of virus
• Reduce extrahepatic manifestations

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Overview of Current FDA-Approved Treatments for
HCV
Drug Recommended Dosage
Pegylated interferons Peginterferon alfa-2b Peginterferon alfa-2a with RBV 1.0 µg/kg SQ once weekly 1.5 µg/kg SQ once weekly combined monotherapy 180 µg SQ once weekly combined with ribavirin or as monotherapy
Interferon alfacon-1 9 µg SQ TIW 15 µg TIW for nonresponders
Ribavirin 800-1400 mg PO daily depending on weight and genotype
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SVR Rates Progress in the Treatment of Chronic
Hepatitis C
SVR Rates With Standard Interferon
100
80
60
Patients ()
43
40
19
20
6
0
IFN 24 Weeks
IFN 48 Weeks
IFN/RBV 48 Weeks
McHutchison J, et al. N Engl J Med.
19983391485-1492. Poynard T, et al. Lancet.
1998352 1426-1432.
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SVR Rates Progress in the Treatment of Chronic
Hepatitis C

• Peginterferon alfa-2b 1.5 µg/kg/wk
  ribavirin 800 mg/d for 48 weeks

• Peginterferon alfa-2a 180 µg/wk weight-based
  ribavirin (1000 or 1200 mg/d) for 48 weeks

100
82
76
80
56
60
Sustained Virologic Response ()
54
46
42
40
20
n 298
n 140
n 453
n 348
n 163
n 511
0
Overall
Genotype 1
Genotype 2/3
Overall
Genotype 1
Genotype 2/3
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Factors That May Influence the Outcome of
Hepatitis C
Host Sex Age Race Genetics Immune
response Duration of Infection
Virus Viral load HCV genotype Quasispecies
Environment Alcohol or drugs HBV coinfection HIV
coinfection Steatosis Iron NASH
Alberti A, et al. J Hepatol. 199931(suppl
1)17-24.
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Predictors of Sustained Virologic Response Fixed
Factors
Baseline Factor Sustained Virologic Response Rates
Baseline Factor PegIFN alfa-2a RBV OR PegIFN alfa-2b RBV
HCV RNA, 1,2 lt 2 x 106 copies/mL gt 2 x 106 copies/mL 62-78 42-53
Genotype, 1,2 2 or 3 1 76-82 42-46
Genotype 1 and high viral load, 30-41
Liver histology, 1,2 Stage 0-2 Stage 3-4 55-57 41-44
Age1,2 Older age, lower SVR
Weight1,2 Higher weight, lower SVR
Race, 3,4 Black White 52 19-28
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Virologic Monitoring Markers and Definitions of
Response to Treatment
Rapid Virologic Response (RVR) HCV RNA undetectable by Week 4
Early Virologic Response (EVR) 2 log decline in HCV RNA by Week 12
End of Treatment (EOT) Response Undetectable HCV RNA at end of treatment
Partial Virologic Response 2 log decline in HCV RNA by Week 12, but HCV RNA detectable at Week 24
Sustained Virologic Response (SVR) HCV RNA negativity 12-24 weeks after treatment end
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Week 12 Stopping Rule Patients Without EVR
Unlikely to Achieve SVR

• Week 12 viral kinetics predictor of SVR
• Only 1.6 of patients who fail to meet EVR
  criteria achieve SVR
  (NPV 98.4)
• 2 log cutoff at Week 12 optimal for predicting
  response
• Poor PPV of Week 12 EVR (68)
• Week 12 HCV RNA predictor of treatment failure
  but not predictor of success in
  achieving SVR
• Week 12 stopping rule included in current
  guidelines
• 20 of patients can stop early, lowering total
  treatment costs by 16 and decreasing unnecessary
  side effects

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Time to Undetectable HCV RNA Identified as Best
Predictor of SVR

• Pooled data from PegIFN alfa-2b/RBV and PegIFN
  alfa-2a/RBV phase III trials

PPV of HCV RNA Undetectability Determining SVR
100
86
80
76
80
PPV for SVR ()
60
40
20
0
Week 4
Week 12
Week 24
Time to Undetectable HCV RNA
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Relationship Between SVR and Time to HCV RNA
Undetectability

• Retrospective analysis of genotype 1 patients
  receiving 48 weeks of PegIFN alfa-2a RBV

End-of-treatment response
100
91
91
90
90
SVR
80
60
60
48
Patients ()
40
13
20
2
0
Week 4 Week 12 Week 24
Negative Negative Negative
lt 2 log drop Negative Negative
lt 2 log drop gt 2 log drop Negative
Any drop Any drop Positive
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Week 4 Response as a Predictor of SVR

• Patients with undetectable HCV RNA by Week 4 on
  PegIFN alfa-2a RBV treated for total of 24
  weeks
• SVR rate for Week 4 responders (per-protocol
  analysis)
• Overall 87 Genotype 1 84
  Genotype 4 100
• Higher baseline, Week 4 viral load predictive of
  relapse

Relapse Rate Based on Week 4 Viral Load (ITT
Analysis)
100
80
Week 4 HCV RNA
60
Patients ()
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lt 10 IU/mL
40
22
10-49 IU/mL
15
10
20
7
5
0
All Patients
lt 600,000
600,000
Baseline Viral Load (IU/mL)
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Anti-HCV Treatment Paradigmis Changing

• New interferons
• Oral interferon inducers
• Ribavirin alternatives
• Immune therapies
• Telapovir.
• VIRAL ENZYME INHIBITORS

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AI liver disease

• PBC
• clinical evidence women 95 age 30-65
• Biochemical cholestasis
• IgM
• AMA 2 gt1/40
• BX middle size duct destruction ,granuloma in 32
  staging 1-4
• 2,4,5 definite PBC one criteria probable PBC
• ve AMA alone is predictive of developing PBC
  later

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Treatment of PBC

• Treat complications
• progression of the disease
• Ursodeoxycholic acid
• Methotrexate
• Combination

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Recommendation for Rx PBC

• UDCA 13 -15mg/kg day divided LFT 2 -3 month if
  normal LB at 18 -24 month if stable cont if not
  or no response add colchicine 0.6mg Bid follow up
  LB at 1-2 years then Q 3 years

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PSC

• clinical associated with IBD in 70-90 male
  predominance
• PANCA in 85
• -ve AAb
• ERCP intra extra hepatic ducts involvement
• LB fibrosing oblitrative cholangitis mostly
  involving medium size ducts and ductopenia of
  small ducts.

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Treatment of PSC

• Medication tried
• - D penicillamine
• - steroid
• - cyclosporine
• - azathioprine
• - UDCA
• - Tacrolimus
• Non shown to delay disease progression

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Treatment of PSC

• Endoscopic therapy
• surgical management
• Liver transplantation

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• AIH
• AIH scoring system .Is this highly accurate?
• LB characterized by interface hepatitis

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Treatment of AIH

• Corticosteroid are the main stay azathioprine
• Response rate up to 90
• Effective even in advanced disease
• reduction ,maintenance (daily)
• Failure rate 20
• Alternatives (cyclosporine,Fk506)
• Future therapy Tcell vaccine,lymphokines, MAb

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Wilsons Disease

• Low serum copper (normal 80-160 micrograms/dL)
• Low serum ceruloplasmin lt20 mg/dL (normal 20-60)
• Increased urinary copper gt100 microg/24 h (normal
  10-80 microg/24 h)
• Renal involvement
• Hypercalciuria and nephrocalcinosis
• Secondary Fanconi syndrome
• Hypoparathyroidism
• Coombs negative hemolytic anemia
• Abnormal transaminases

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• D-penicillamine is the initial therapy of choice.
• Zinc is the recommended therapy during pregnancy
  as D-penicillamine and Trientine are both
  teratogenic in animals and D-penicillamine is
  teratogenic in humans.
• Low copper diet, with 1 mg/d initially

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Hereditary Hemochromatosis

• Transferrin saturationserum iron/TIBC gt60 in
  male ,gt50 in female
• Serum ferritin in fasting state
• 62diagnosed during routine screening
• 14 during family screening.

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diagnosis
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diagnosis

• High TS high ferr 93senst
• Age above 35 normal ferrt normal TS 97NPV
• Liver biopsy HI concentration gt1000mcg/g
• HHI ratio of iron concentration of liver dry
  weight in mmol/gdry weight to the patient age in
  years HHI gt1.9 93of patients
• 1.5-1.9 genetic studies for C282Y andH63D

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Diagnosis

• CT scan, MRI

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Treatment

• Theraputic phlebotomy is expected to reverse LV
  dysfunction ,varieces,hypogonadismlt40 years and
  improve DM control
• arthropathy generally show no response to iron
  removal.
• 1unit 500cc will remove 200-250mg of iron which
  will be compensated from tissue stores.

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Treatment

• Diet
• vitC
• Alcohol
• chelation therapy
• liver transplantation

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• Liver Transplantation When?