management of chronic hepatitis. all cirrhotic patients periodic screening for hcc with ultrasound...
Post on 22-Dec-2015
221 views
TRANSCRIPT
All cirrhotic patientsAll cirrhotic patients
• periodic screening for HCC with periodic screening for HCC with ultrasound and alfa-feto protein ultrasound and alfa-feto protein level every 6 month is level every 6 month is recommended in CHB and CHC.recommended in CHB and CHC.
• CLD patients should be considered CLD patients should be considered for HAV vaccination. for HAV vaccination.
DiagnosisDiagnosis
Serology HBSAg-HBSAb,HBeAg-Serology HBSAg-HBSAb,HBeAg-HBeAb, HBcAb.HBeAb, HBcAb.
DNA detection methods DNA detection methods BDNA,hybridization assay,single BDNA,hybridization assay,single amplification assay 10amplification assay 1055-10-1066, PCR , PCR based assays detect 10-100 based assays detect 10-100 copies/ml.copies/ml.
Liver BX.Liver BX.
• Antiviral therapy is not indicated in Antiviral therapy is not indicated in patients with acute hepatitis.patients with acute hepatitis.
• Patients with FHF should be Patients with FHF should be considered for liver considered for liver transplantation.transplantation.
• The main efficacy of antiviral The main efficacy of antiviral therapy in chronic hepatitis B is to therapy in chronic hepatitis B is to increase the seroconversion rate.increase the seroconversion rate.
Chronic HBV Infection: Chronic HBV Infection: Target Population for TreatmentTarget Population for Treatment
• Treatment indicated in those with “active” Treatment indicated in those with “active” CHBCHB• Greatest benefit (at highest risk for disease Greatest benefit (at highest risk for disease
progression)progression)• Most likely to respond to currently available Most likely to respond to currently available
agentsagents
• ““Activity” defined byActivity” defined by• Elevated ALT/ASTElevated ALT/AST• Necroinflammation on liver biopsyNecroinflammation on liver biopsy• Elevated HBV DNA levelsElevated HBV DNA levels
HBV Treatment GuidelinesHBV Treatment Guidelines
HBeAgHBeAgHBV DNAHBV DNA(copies/mL)(copies/mL)ALTALTManagementManagement
++ < <101055NormalNormalFollow, no Follow, no
treatmenttreatment
++
≥ ≥101055NormalNormal
Consider Consider biopsy;biopsy;treat if treat if
diseaseddiseased
++ ≥ ≥101055ElevatedElevatedTreatTreat
–– < <101044NormalNormalFollow, no Follow, no
treatmenttreatment
––
≥ ≥101044NormalNormal
Consider Consider biopsy;biopsy;treat if treat if
diseaseddiseased
–– ≥ ≥101044ElevatedElevatedTreatTreatKeeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106.
Goals of Therapy in Goals of Therapy in Patients With Chronic Patients With Chronic
HBV InfectionHBV Infection• Eradication of infectionEradication of infection
• HBsAg seroconversionHBsAg seroconversion• Undetectable HBV DNAUndetectable HBV DNA
• Prevent complications of liver Prevent complications of liver diseasedisease• Histologic progression to cirrhosisHistologic progression to cirrhosis• Decompensated liver diseaseDecompensated liver disease• Liver cancerLiver cancer
Therapeutic EndpointsTherapeutic Endpoints
• HBeAg-positive patients (wild type)HBeAg-positive patients (wild type)• HBeAg seroconversion is HBeAg seroconversion is KEYKEY• Sustained suppression of HBV DNA to low or Sustained suppression of HBV DNA to low or
undetectable levelsundetectable levels• ALT normalizationALT normalization• Reduced necroinflammation on biopsyReduced necroinflammation on biopsy
• HBeAg-negative patients (precore and core HBeAg-negative patients (precore and core promoter mutants)promoter mutants)• HBeAg seroconversion not an endpointHBeAg seroconversion not an endpoint• Sustained suppression of HBV DNA to low or Sustained suppression of HBV DNA to low or
undetectable levelsundetectable levels• ALT normalizationALT normalization• Reduced necroinflammation on biopsyReduced necroinflammation on biopsy
Approved HBV Approved HBV TherapiesTherapies
• InterferonInterferon• PeginterferonPeginterferon• LamivudineLamivudine• Adefovir dipivoxilAdefovir dipivoxil
• Wild-type HBV, lamivudine-resistant HBVWild-type HBV, lamivudine-resistant HBV
• EntecavirEntecavir• Wild-type HBV, lamivudine-resistant HBVWild-type HBV, lamivudine-resistant HBV
InterferonInterferon
Characteristics of Interferon TreatmentCharacteristics of Interferon Treatment
Type of agentType of agentRecombinant interferon immune Recombinant interferon immune modulatormodulator
Approved for HBVApproved for HBV• Interferon alfa-2b: 1992Interferon alfa-2b: 1992• Pegylated interferon alfa-2a: Pegylated interferon alfa-2a: 20052005
Route of Route of administrationadministrationInjectionInjection
Mode of actionMode of action• Dual immunomodulatory and Dual immunomodulatory and antiviral modeantiviral mode of action of action• Exact target against HBV Exact target against HBV replicationreplication unknown unknown
Antiviral activityAntiviral activityNot applicableNot applicable
Peginterferon SummaryPeginterferon Summary
AdvantagesAdvantages• Less frequent Less frequent injections injections
than IFNthan IFN• Defined treatment intervalDefined treatment interval• High rate of HBeAg High rate of HBeAg
seroconversion in wild-type seroconversion in wild-type infectioninfection
• High rate of HBV DNA High rate of HBV DNA suppression in precore mutant suppression in precore mutant variantvariant
• High rate of HBsAg High rate of HBsAg seroconversionseroconversion
• No reports of resistance No reports of resistance mutationsmutations
DisadvantagesDisadvantages• Requires injectionRequires injection• Frequent side effectsFrequent side effects• Not recommended for Not recommended for
some patient groupssome patient groups• Decompensated Decompensated
cirrhoticscirrhotics• Liver transplant Liver transplant
recipientsrecipients• Higher costHigher cost
LamivudineLamivudine
Characteristics of Lamivudine TreatmentCharacteristics of Lamivudine Treatment
Type of agentType of agentCytidine nucleoside analogueCytidine nucleoside analogue
Approved for HBVApproved for HBV19981998
Route of Route of administrationadministrationOralOral
Mode of actionMode of actionInhibits first-strand DNA synthesisInhibits first-strand DNA synthesis
Antiviral activityAntiviral activityECEC5050: 1000 nM: 1000 nM
DosingDosing• 100 mg/day100 mg/day• Adjust for renal dysfunctionAdjust for renal dysfunction
16% 17% 18% 18% 17%
32%
22%
33%
Pe
rce
nta
ge
of
Pa
tie
nts
100 mg/day for 52 Weeks100 mg/day for 52 Weeks
0
20
40
60
HBeAg Seroconversion HBeAg Loss
Lai[1] Dienstag[2] Schalm[3] Schiff[4]
Lamivudine Treatment Lamivudine Treatment in HBeAg-Positive in HBeAg-Positive Patients for 1 YearPatients for 1 Year
1. Lai CL, et al. N Engl J Med. 1998;339:61-68. 2. Dienstag JL, et al. N Engl J Med. 1999;341:1256-1263. 3. Schalm SW, et al. Gut. 2000;46:562-568. 4. Schiff ER, et al. J Hepatol. 2003;38:818-826.
Lampertico P, et al. Hepatology. 2004;40:674A.
Lamivudine in HBeAg-Lamivudine in HBeAg-Negative Cirrhosis: Negative Cirrhosis:
Long-term OutcomesLong-term Outcomes
Results (N = 84)Results (N = 84)
EndpointEndpointSensitiveSensitive , ,%%
ResistantResistant , ,%%
ResistanceResistance• Genotypic Genotypic
resistanceresistance**• Clinical Clinical
resistanceresistance**
------------
63638282
Clinical Clinical decompensationdecompensation002424
HCCHCC30302727
*5-year probability
15%
40%
55%
66%
27%32%
20
40
60
80
1 2 3 4
Pat
ien
ts W
ith
Res
ista
nce
(%
)
Asia[1,2]
International[3]
USA[4]
Duration of Treatment, Years5
69%
0
1. Guan R. APDW. 2001. 2. Leung NW, et al. Hepatology. 2001;33:1527-1532. 3. Tassopoulos NC, et al. Hepatology. 1999;29:889-896. 4. Dienstag JL, et al. N Engl J Med. 1999;30:1082-1087.
Incidence of YMDD Incidence of YMDD Mutations by Duration Mutations by Duration of Lamivudine Therapyof Lamivudine Therapy
Consequences of Drug Consequences of Drug ResistanceResistance
• Relapse of HBV DNARelapse of HBV DNA• Elevated ALTElevated ALT• Decreased rate of HBeAg Decreased rate of HBeAg
seroconversionseroconversion• Loss of histologic improvementLoss of histologic improvement• Possible clinical decompensationPossible clinical decompensation
• Poorer outcomes if underlying cirrhosisPoorer outcomes if underlying cirrhosis
Perrillo RP, et al. Hepatology. 2002;36:186-194. Leung NW, et al. Hepatology. 2001;33:1527-1532.
Adefovir DipivoxilAdefovir Dipivoxil
Characteristics of Adefovir Dipivoxil TreatmentCharacteristics of Adefovir Dipivoxil Treatment
Type of agentType of agentAdenosine nucleotide analogueAdenosine nucleotide analogue
Approved for Approved for HBVHBV20022002
Mode of actionMode of action• Inhibitor of HBV DNA polymeraseInhibitor of HBV DNA polymerase• Not dependent on intracellular kinases Not dependent on intracellular kinases
for first phosphorylation stepfor first phosphorylation step
Antiviral Antiviral activityactivity
• ECEC5050: 1100 nM: 1100 nM
• Effective against wild-type and Effective against wild-type and lamivudine-resistant HBVlamivudine-resistant HBV
Dosing (oral)Dosing (oral)• 10 mg/day10 mg/day• Adjust for renal dysfunctionAdjust for renal dysfunction
HBV DNA < 400 copies/mL
ALT Normalization
HBeAg Loss HBeAg Seroconversion
14%
23%
63%
26%
0
20
40
60
80
Week 48
23%
44%
78%
46%
Week 72
Per
cen
tag
e o
f P
atie
nts
*
Marcellin P, et al. N Engl J Med. 2003;348:808-816.
HBeAg-Positive HBeAg-Positive PatientsPatients
Adefovir Efficacy at 48 Adefovir Efficacy at 48 and 72 Weeksand 72 Weeks
*Kaplan-Meier estimates
Adefovir in HBeAg-Negative Adefovir in HBeAg-Negative PatientsPatients
Virologic and Biochemical Virologic and Biochemical ResponseResponse
68%75%
71% 72%77%
67%
78% 75%
0
20
40
60
80
100
Per
cen
tag
e o
f P
atie
nts
Serum HBV DNA < 1000 copies/mL
ALT Normalization
Treatment Duration (Weeks)48 96 144 192 48 96 144 192
Hadziyannis S, et al. EASL. 2005. Abstract 492. Hadziyannis S, et al. AASLD 2005. Abstract LB14.
n = 69 58 69 65 55 64 53 64 59 55
67%
240
69%
240
EntecavirEntecavirCharacteristics of Entecavir TreatmentCharacteristics of Entecavir Treatment
Type of agentType of agentDeoxyguanine nucleoside analogueDeoxyguanine nucleoside analogue
Approved for HBVApproved for HBV20052005
Mode of actionMode of actionInhibits HBV replication in 3 waysInhibits HBV replication in 3 ways• Priming of HBV DNA polymerasePriming of HBV DNA polymerase• Reverse transcription of the negative Reverse transcription of the negative
DNA strand from pregenomic RNADNA strand from pregenomic RNA• Synthesis of the positive DNA strandSynthesis of the positive DNA strand
Antiviral activityAntiviral activity• ECEC5050 = 4 nM for wild-type HBV, 26 nM = 4 nM for wild-type HBV, 26 nM for lamivudine-resistant HBVfor lamivudine-resistant HBV
• Effective against wild-type and Effective against wild-type and lamivudine-resistant HBVlamivudine-resistant HBV
Dosing (oral)Dosing (oral)• 0.50.5 mg (wild type) or 1 mg (lam-R) mg (wild type) or 1 mg (lam-R) dailydaily
• Adjust for renal dysfunctionAdjust for renal dysfunction
Entecavir 0.5 mg/day (n = 354) Lamivudine 100 mg/day (n = 355)
Histological Improvement(n = 314 with evaluable
histology in each group)
72%62%
0
20
40
60
80
Per
cen
tag
e o
f P
atie
nts
P = NS
21%18%
0
5
10
15
20
25
HBeAg Seroconversion
68%60%
ALT Normalization(≤ 1.00 x ULN)
0
20
40
60
80
P < .05 P < .05
Per
cen
tag
e o
f P
atie
nts
Chang TT, et al. Hepatology. 2004;40:193A.
Results at 48 Weeks
Entecavir vs Entecavir vs Lamivudine in Lamivudine in
Nucleoside-Naive Nucleoside-Naive HBeAg+ CHBHBeAg+ CHB
Per
cen
tag
e o
f P
atie
nts
100
HBeAgSeroconversion
Gish R, et al. AASLD 2005. Abstract 181.
Cumulative Outcome by Week 96
Per
cen
tag
e o
f P
atie
nts
Entecavir (n = 354) Lamivudine (n = 355)
80
3931
26
0
20
40
60
80
100
HBeAgSeroconversion
Undetectable HBV DNA*
P < .0001
Sustained Responses 24 Weeks Off Therapy
31
71
29
69
0
20
40
60
80
100
Entecavir (n = 111) Lamivudine (n = 93)
Undetectable HBV DNA*
*Undetectable HBV DNA, < 300 copies/mL
HBeAg-Positive HBeAg-Positive Patients Treated up to Patients Treated up to
96 Weeks With 96 Weeks With EntecavirEntecavir
Per
cen
tag
e o
f P
atie
nts
Results at 48 WeeksEntecavir 0.5 mg/day (n = 325) Lamivudine 100 mg/day (n = 313)
90%
72%
0
20
40
60
80
100
HBV DNA < 300 copies/mL (PCR)
P < .05
Pat
ien
ts A
chie
vin
g
Res
po
nse
(%
)
ALT Normalization(≤ 1.00 x ULN)
78%
71%
0
10
20
30
40
50
60
70
80
90
Pat
ien
ts A
chie
vin
g
Res
po
nse
(%
)
P < .05
Shouval D, et al. Hepatology. 2004;40:728A.
ETV vs LAM in ETV vs LAM in Nucleoside-Naive Nucleoside-Naive HBeAg-Negative HBeAg-Negative
PatientsPatients
Year 4Year 2
•Viral mutations conferring resistance are less frequent Viral mutations conferring resistance are less frequent and delayed in onset with ADV and ETV vs LAMand delayed in onset with ADV and ETV vs LAM
24%
2%
42%
11%
53%
70%
0
20
40
60
80
Year 1 Year 3
Inci
den
ce o
f R
esis
tan
ce (
%)
LAM[2]
(YMDD)
ADV (N236T + A181V)[1]
ETV- Lam-R[3]
(L180M + M204V)
6%
18%ETV- Rx naive[3]9%
1. Westland CE, et al. Hepatology. 2003;38:96-103. 2. Lai CL, et al. Clin Infect Dis. 2003; 36:687-696. 3. Colonno R, et al. AASLD 2005. Abstract 962.
Incidence of Resistance Incidence of Resistance in in
Patients Treated With Patients Treated With AntiviralsAntivirals
• Nearly 4 million persons in United States infectedNearly 4 million persons in United States infected• Approximately 35,000 new cases yearlyApproximately 35,000 new cases yearly• 85% of new cases become chronic85% of new cases become chronic
• 10,000-20,000 HCV-related deaths per year10,000-20,000 HCV-related deaths per year• Number expected to triple in next 10-20 yearsNumber expected to triple in next 10-20 years
• Leading cause ofLeading cause of• Chronic liver diseaseChronic liver disease• CirrhosisCirrhosis• Liver cancerLiver cancer• Liver transplantationLiver transplantation
Hepatitis C Virus Hepatitis C Virus Infection:Infection:
Magnitude of the Magnitude of the ProblemProblem
Goals of HCV TherapyGoals of HCV Therapy
• Primary goal of treatment is to Primary goal of treatment is to eradicate the viruseradicate the virus
• Additional goalsAdditional goals• Slow disease progression Slow disease progression • Minimize risk of hepatocellular carcinomaMinimize risk of hepatocellular carcinoma• Improve liver histologyImprove liver histology• Enhance quality of lifeEnhance quality of life• Prevent transmission of virusPrevent transmission of virus• Reduce extrahepatic manifestationsReduce extrahepatic manifestations
DrugDrugRecommended DosageRecommended Dosage
Pegylated Pegylated interferonsinterferons
•Peginterferon Peginterferon alfa-2balfa-2b
•Peginterferon Peginterferon alfa-2aalfa-2a
•with RBV; with RBV; 1.0 µg/kg SQ once weekly 1.5 1.0 µg/kg SQ once weekly 1.5
µg/kg SQ once weekly combined µg/kg SQ once weekly combined monotherapymonotherapy
•180180 µg SQ once weekly combined µg SQ once weekly combined with ribavirin or as monotherapywith ribavirin or as monotherapy
Interferon Interferon alfacon-1alfacon-1
•99 µg SQ TIW; 15 µg TIW for µg SQ TIW; 15 µg TIW for nonrespondersnonresponders
RibavirinRibavirin•800-1400800-1400 mg PO daily depending mg PO daily depending on weight and genotypeon weight and genotype
Overview of Current FDA-Overview of Current FDA-Approved Treatments for HCVApproved Treatments for HCV
SVR Rates: Progress in SVR Rates: Progress in the Treatment of the Treatment of
Chronic Hepatitis CChronic Hepatitis C
McHutchison J, et al. N Engl J Med. 1998;339:1485-1492. Poynard T, et al. Lancet. 1998;352: 1426-1432.
100
80
60
40
20
0
19
43
6
IFN24 Weeks
IFN48 Weeks
IFN/RBV48 Weeks
SVR Rates With Standard Interferon
Pat
ien
ts (
%)
•Peginterferon alfa-Peginterferon alfa-2b 1.5 2b 1.5
µg/kg/wk + ribavirin µg/kg/wk + ribavirin 800 mg/d for 800 mg/d for
48 weeks48 weeks
•Peginterferon alfa-Peginterferon alfa-2a 180 µg/wk + 2a 180 µg/wk +
weight-based weight-based ribavirin (1000 or ribavirin (1000 or
1200 mg/d) for 48 1200 mg/d) for 48 weeksweeks
SVR Rates: Progress in SVR Rates: Progress in the Treatment of the Treatment of
Chronic Hepatitis CChronic Hepatitis C
46
76
56
Overall Genotype1
Genotype2/3
n = 298 n = 140n = 453
42
82
100
80
60
40
20
0
54
Overall Genotype1
Genotype2/3
Su
stai
ned
Vir
olo
gic
R
esp
on
se (
%)
n = 348 n = 163n = 511
Alberti A, et al. J Hepatol. 1999;31(suppl 1):17-24.
Virus
Viral loadHCV genotypeQuasispecies
Environment
Alcohol or drugsHBV coinfectionHIV coinfection
SteatosisIron
NASH
Factors That May Factors That May Influence the Outcome Influence the Outcome
of Hepatitis Cof Hepatitis CHost
SexAge
RaceGenetics
Immune responseDuration of Infection
Baseline FactorBaseline FactorSustained Virologic Response Sustained Virologic Response RatesRates
PegIFN alfa-2a + RBV PegIFN alfa-2a + RBV OR OR PegIFN PegIFN alfa-2b + RBValfa-2b + RBV
HCV RNA, %HCV RNA, %[1,2][1,2]
• < < 22 x 10x 1066 copies/mL copies/mL• < < 22 x 10x 1066 copies/mL copies/mL
62-7862-7842-5342-53
Genotype, %Genotype, %[1,2][1,2]
• 22 or 3or 3• 11
76-8276-8242-4642-46
Genotype 1 and high Genotype 1 and high viral loadviral load% ,% ,
30-4130-41
Liver histology, %Liver histology, %[1,2][1,2]
• Stage 0-2Stage 0-2• Stage 3-4Stage 3-4
55-5755-5741-4441-44
AgeAge[1,2][1,2]Older age, lower SVROlder age, lower SVR**
WeightWeight[1,2][1,2]Higher weight, lower SVRHigher weight, lower SVR**
Race, %Race, %[3,4][3,4]
• BlackBlack• WhiteWhite
525219-2819-28
Predictors of Sustained Virologic Predictors of Sustained Virologic Response: Fixed FactorsResponse: Fixed Factors
Virologic Monitoring Markers Virologic Monitoring Markers and Definitions of Response to and Definitions of Response to
TreatmentTreatmentRapid Virologic Rapid Virologic
Response (RVR)Response (RVR)HCV RNA undetectable by Week 4HCV RNA undetectable by Week 4
Early Virologic Early Virologic Response (EVR)Response (EVR)
≥ ≥22 log decline in HCV RNA by Week 12log decline in HCV RNA by Week 12
End of End of Treatment Treatment
(EOT) Response(EOT) Response Undetectable HCV RNA at end of treatmentUndetectable HCV RNA at end of treatment
Partial Virologic Partial Virologic ResponseResponse
≥ ≥22 log decline in HCV RNA by Week 12, but HCV log decline in HCV RNA by Week 12, but HCV RNA detectable at Week 24RNA detectable at Week 24
Sustained Sustained Virologic Virologic
Response (SVR)Response (SVR)
HCV RNA negativity 12-24 weeks after HCV RNA negativity 12-24 weeks after treatment endtreatment end
Week 12 Stopping Rule: Patients Week 12 Stopping Rule: Patients Without EVR Unlikely to Achieve Without EVR Unlikely to Achieve
SVRSVR• Week 12 viral kinetics predictor of SVRWeek 12 viral kinetics predictor of SVR
• Only 1.6% of patients who fail to meet EVR criteria Only 1.6% of patients who fail to meet EVR criteria achieve SVR (NPV: 98.4%) achieve SVR (NPV: 98.4%)
• 2 log cutoff at Week 12 optimal for predicting response2 log cutoff at Week 12 optimal for predicting response • Poor PPV of Week 12 EVR (68%)Poor PPV of Week 12 EVR (68%)
• Week 12 HCV RNA predictor of treatment Week 12 HCV RNA predictor of treatment failurefailure but not but not predictor of predictor of success success in achieving SVRin achieving SVR
• Week 12 stopping rule included in current Week 12 stopping rule included in current guidelinesguidelines• ~ 20% of patients can stop early, lowering total treatment ~ 20% of patients can stop early, lowering total treatment
costs by 16% and decreasing unnecessary side effectscosts by 16% and decreasing unnecessary side effects
PPV of HCV RNAUndetectability Determining SVR
8680 76
0
20
40
60
80
100
Week 4 Week 12 Week 24
PP
V f
or
SV
R (
%)
Time to Undetectable HCV RNA
•Pooled data from PegIFN alfa-2b/RBV and PegIFN Pooled data from PegIFN alfa-2b/RBV and PegIFN alfa-2a/RBV phase III trialsalfa-2a/RBV phase III trials
Time to Undetectable HCV RNA Time to Undetectable HCV RNA Identified as Best Predictor of Identified as Best Predictor of
SVRSVR
End-of-treatment response
SVR91 90 90
13
91
6048
20
20
40
60
80
100
Week 4Week 12Week 24
NegativeNegativeNegative
< 2 log dropNegativeNegative
< 2 log drop< 2 log drop
Negative
Any dropAny dropPositive
Pat
ien
ts (
%)
Relationship Between SVR and Relationship Between SVR and Time to HCV RNA Time to HCV RNA UndetectabilityUndetectability
• Retrospective analysis of genotype 1 patients receiving Retrospective analysis of genotype 1 patients receiving 48 weeks of PegIFN alfa-2a + RBV48 weeks of PegIFN alfa-2a + RBV
• Patients with undetectable HCV RNA by Week 4 on Patients with undetectable HCV RNA by Week 4 on PegIFN alfa-2a + RBV treated for total of 24 weeksPegIFN alfa-2a + RBV treated for total of 24 weeks
• SVR rate for Week 4 responders (per-protocol SVR rate for Week 4 responders (per-protocol analysis) analysis)
• Overall: 87% Overall: 87% –– Genotype 1: 84% Genotype 1: 84% – – Genotype 4: 100%Genotype 4: 100%
• Higher baseline, Week 4 viral load predictive of Higher baseline, Week 4 viral load predictive of relapserelapse
Baseline Viral Load (IU/mL)
Relapse Rate Based on Week 4 Viral Load (ITT Analysis)
7 51522
10
38
0
20
40
60
80
100
All Patients < 600,000 ≥ 600,000
Pat
ien
ts (
%)
< 10 IU/mL10-49 IU/mL
Week 4 HCV RNA
Week 4 Response as a Week 4 Response as a Predictor of SVRPredictor of SVR
Anti-HCV Treatment Anti-HCV Treatment ParadigmParadigm
is Changingis Changing• New interferonsNew interferons• Oral interferon inducersOral interferon inducers• Ribavirin alternatives Ribavirin alternatives • Immune therapiesImmune therapies• Telapovir.Telapovir.• VIRAL ENZYME INHIBITORSVIRAL ENZYME INHIBITORS
AI liver diseaseAI liver disease
PBCPBC clinical evidence women =95% age 30-65clinical evidence women =95% age 30-65 Biochemical cholestasisBiochemical cholestasis IgMIgM AMA 2 >1/40AMA 2 >1/40 BX middle size duct destruction ,granuloma BX middle size duct destruction ,granuloma
in 32% staging 1-4in 32% staging 1-4 2,4,5 definite PBC one criteria probable PBC 2,4,5 definite PBC one criteria probable PBC +ve AMA alone is predictive of developing +ve AMA alone is predictive of developing
PBC laterPBC later
Treatment of PBCTreatment of PBC
Treat complicationsTreat complications progression of the diseaseprogression of the disease Ursodeoxycholic acidUrsodeoxycholic acid MethotrexateMethotrexate CombinationCombination
Recommendation for Rx Recommendation for Rx PBCPBC
UDCA 13 -15mg/kg day divided UDCA 13 -15mg/kg day divided LFT 2 -3 month if normal LB at LFT 2 -3 month if normal LB at
18 -24 month if stable cont if 18 -24 month if stable cont if not or no response add not or no response add
colchicine 0.6mg Bid follow up colchicine 0.6mg Bid follow up LB at 1-2 years then Q 3 yearsLB at 1-2 years then Q 3 years
PSCPSC
clinical associated with IBD in 70-90% clinical associated with IBD in 70-90% male predominancemale predominance
PANCA in 85%PANCA in 85% -ve AAb-ve AAb ERCP ERCP intra +extra hepatic ducts intra +extra hepatic ducts
involvementinvolvement LB LB fibrosing oblitrative cholangitis mostly fibrosing oblitrative cholangitis mostly
involving medium size ducts and ductopenia involving medium size ducts and ductopenia of small ducts.of small ducts.
Treatment of PSCTreatment of PSC• Medication tried Medication tried - D penicillamine- D penicillamine - steroid- steroid - cyclosporine- cyclosporine - azathioprine- azathioprine - UDCA- UDCA - Tacrolimus- Tacrolimus Non shown to delay disease Non shown to delay disease
progressionprogression
Treatment of PSCTreatment of PSC
Endoscopic therapyEndoscopic therapy
surgical managementsurgical management
Liver transplantationLiver transplantation
AIHAIH AIH scoring system .Is this AIH scoring system .Is this
highly accurate?highly accurate?
LBLB characterized by interface characterized by interface hepatitishepatitis
Treatment of AIHTreatment of AIH
• Corticosteroid are the main stay Corticosteroid are the main stay +azathioprine+azathioprine
• Response rate up to 90% Response rate up to 90% • Effective even in advanced diseaseEffective even in advanced disease• reduction ,maintenance (daily)reduction ,maintenance (daily)• Failure rate 20% Failure rate 20% • Alternatives (cyclosporine,Fk506)Alternatives (cyclosporine,Fk506)• Future therapy Tcell Future therapy Tcell
vaccine,lymphokines, MAbvaccine,lymphokines, MAb
Wilson’s DiseaseWilson’s Disease
• Low serum copper Low serum copper ((normal 80-160 normal 80-160 microgramsmicrograms//dLdL))
• Low serum ceruloplasmin <20 mg/dL (normal 20-Low serum ceruloplasmin <20 mg/dL (normal 20-60)60)
• Increased urinary copper >100 microg/24 h Increased urinary copper >100 microg/24 h (normal 10-80 microg/24 h)(normal 10-80 microg/24 h)
• Renal involvementRenal involvement• Hypercalciuria and nephrocalcinosisHypercalciuria and nephrocalcinosis• Secondary Fanconi syndromeSecondary Fanconi syndrome
• HypoparathyroidismHypoparathyroidism• Coombs negative hemolytic anemiaCoombs negative hemolytic anemia• Abnormal transaminasesAbnormal transaminases
• DD--penicillamine is the initial therapy penicillamine is the initial therapy of choice.of choice.
• Zinc is the recommended therapy Zinc is the recommended therapy during pregnancy as Dduring pregnancy as D--penicillamine penicillamine and Trientine are both teratogenic in and Trientine are both teratogenic in animals and Danimals and D--penicillamine is penicillamine is teratogenic in humansteratogenic in humans..
• Low copper diet, with 1 mgLow copper diet, with 1 mg//d initially d initially
Hereditary Hereditary HemochromatosisHemochromatosis
• Transferrin saturation=serum Transferrin saturation=serum iron/TIBC >60% in male ,>50% in iron/TIBC >60% in male ,>50% in femalefemale
• Serum ferritin in fasting state Serum ferritin in fasting state • 62%diagnosed during routine 62%diagnosed during routine
screening screening • 14% during family screening.14% during family screening.
diagnosisdiagnosis• High TS + high ferr =93%senstHigh TS + high ferr =93%senst• Age above 35 normal ferrt + normal TS Age above 35 normal ferrt + normal TS
=97%NPV=97%NPV• Liver biopsyLiver biopsy HI concentration >1000mcg/g HI concentration >1000mcg/g • HHI = ratio of iron concentration of liver dry HHI = ratio of iron concentration of liver dry
weight in mmol/gdry weight to the patient age weight in mmol/gdry weight to the patient age in years HHI >1.9 = 93%of patientsin years HHI >1.9 = 93%of patients
• 1.5-1.9 genetic studies for C282Y andH63D 1.5-1.9 genetic studies for C282Y andH63D
TreatmentTreatment
• Theraputic phlebotomy is expected to Theraputic phlebotomy is expected to reverse LV reverse LV dysfunction ,varieces,hypogonadism<4dysfunction ,varieces,hypogonadism<40 years and improve DM control0 years and improve DM control
• arthropathy generally show no arthropathy generally show no response to iron removal.response to iron removal.
• 1unit =500cc will remove 200-250mg 1unit =500cc will remove 200-250mg of iron which will be compensated from of iron which will be compensated from tissue stores.tissue stores.
TreatmentTreatment
• DietDiet• vitCvitC• AlcoholAlcohol• chelation therapychelation therapy• liver transplantationliver transplantation