Management of Chronic Management of Chronic HepatitisHepatitis

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 transplantation.considered for liver 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 GuidelinesHBeAgHBeAgHBV DNAHBV DNA

(copies/mL)(copies/mL)ALTALTManagementManagement

++ < <101055NormalNormalFollow, no Follow, no treatmenttreatment

++

≥ ≥101055NormalNormalConsider Consider biopsy;biopsy;treat if treat if

diseaseddiseased++ ≥ ≥101055ElevatedElevatedTreatTreat–– < <101044NormalNormalFollow, no Follow, no

treatmenttreatment––

≥ ≥101044NormalNormalConsider Consider biopsy;biopsy;treat if treat if

diseaseddiseased–– ≥ ≥101044ElevatedElevatedTreatTreat

Keeffe 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

InterferonInterferonCharacteristics 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 SummaryAdvantagesAdvantages

• 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

LamivudineLamivudineCharacteristics of Lamivudine TreatmentCharacteristics of Lamivudine Treatment

Type of agentType of agentCytidine nucleoside analogueCytidine nucleoside analogueApproved for HBVApproved for HBV19981998Route of Route of administrationadministrationOralOral

Mode of actionMode of actionInhibits first-strand DNA synthesisInhibits first-strand DNA synthesisAntiviral activityAntiviral activityECEC5050: 1000 nM: 1000 nMDosingDosing• 100 mg/day100 mg/day

• Adjust for renal dysfunctionAdjust for renal dysfunction

16% 17% 18% 18% 17%

32%

22%

33%

Perc

enta

ge o

f Pat

ient

s

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 OutcomesResults (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

Patie

nts

With

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 DipivoxilCharacteristics of Adefovir Dipivoxil TreatmentCharacteristics of Adefovir Dipivoxil Treatment

Type of agentType of agentAdenosine nucleotide analogueAdenosine nucleotide analogueApproved 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 stepAntiviral Antiviral activityactivity

• ECEC5050: 1100 nM: 1100 nM• Effective against wild-type and Effective against wild-type and

lamivudine-resistant HBVlamivudine-resistant HBVDosing (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

Perc

enta

ge o

f Pat

ient

s*

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

Perc

enta

ge o

f Pat

ient

s

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 analogueApproved 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

Perc

enta

ge o

f Pat

ient

s

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

Perc

enta

ge o

f Pat

ient

s

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

Perc

enta

ge o

f Pat

ient

s100

HBeAgSeroconversion

Gish R, et al. AASLD 2005. Abstract 181.

Cumulative Outcome by Week 96

Perc

enta

ge o

f Pat

ient

s

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

Perc

enta

ge o

f Pat

ient

s

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

Patie

nts

Ach

ievi

ng

Res

pons

e (%

)

ALT Normalization(≤ 1.00 x ULN)

78%71%

0

10

20

30

40

50

60

70

80

90

Patie

nts

Ach

ievi

ng

Res

pons

e (%

)

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

denc

e of

Res

ista

nce

(%)

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 eradicate Primary goal of treatment is to eradicate

the virusthe 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 DosagePegylated 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

Patie

nts

(%)

•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

Sust

aine

d Vi

rolo

gic

Res

pons

e (%

)

n = 348 n = 163n = 511

Alberti A, et al. J Hepatol. 1999;31(suppl 1):17-24.

VirusViral load

HCV genotypeQuasispecies

EnvironmentAlcohol or drugsHBV coinfectionHIV coinfection

SteatosisIron

NASH

Factors That May Factors That May Influence the Outcome Influence the Outcome

of Hepatitis Cof Hepatitis CHostSexAge

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/mL62-7862-78

42-5342-53Genotype, %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 3-455-5755-57

41-4441-44AgeAge[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• WhiteWhite5252

19-2819-28

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

86 80 76

0

20

40

60

80

100

Week 4 Week 12 Week 24

PPV

for S

VR (%

)

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 responseSVR91 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

Patie

nts

(%)

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

02040

60

80

100

All Patients < 600,000 ≥ 600,000

Patie

nts

(%)

< 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 involvementintra +extra hepatic ducts involvement 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 progressionNon shown to delay disease progression

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 microgramsnormal 80-160 micrograms//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 weight in mmol/gdry weight to the patient age in years HHI >1.9 = 93%of patientsage in 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

DiagnosisDiagnosis

CT scan, MRICT scan, MRI

TreatmentTreatment • Theraputic phlebotomy is expected to Theraputic phlebotomy is expected to

reverse LV reverse LV dysfunction ,varieces,hypogonadism<40 dysfunction ,varieces,hypogonadism<40 years and improve DM controlyears and improve DM control

• arthropathy generally show no response arthropathy generally show no response to iron removal.to iron removal.

• 1unit =500cc will remove 200-250mg of 1unit =500cc will remove 200-250mg of iron which will be compensated from iron which will be compensated from tissue stores.tissue stores.

TreatmentTreatment • DietDiet• vitCvitC• AlcoholAlcohol• chelation therapychelation therapy• liver transplantationliver transplantation

• Liver Transplantation Liver Transplantation When?When?