clinical care options hepatitis annual update 2009 this program is supported by educational grants...

Clinical Care Options Hepatitis Annual Update 2009

This program is supported by educational grants from

clinicaloptions.com/hepatitis


DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

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Program Faculty

Program Directors

Marion G. Peters, MD, FRACP

David L. Thomas, MD, MPH

Program Faculty

Raymond T. Chung, MD

Geoffrey M. Dusheiko, MD, FCP(SA), FRCP

Anna S. F. Lok, MD

Timothy Morgan, MD

Jean-Michel Pawlotsky, MD, PhD

Anna S. F. Lok, MDProfessor of Internal Medicine and Director of Clinical HepatologyUniversity of Michigan, Ann ArborAnn Arbor, Michigan

HBV Infection: Deciding Who and When to Treat



NIH Guidelines: Indications for HBV TreatmentPatients for Whom Therapy Is Indicated

Patients who have

Acute liver failure

Cirrhosis and clinical complications

Cirrhosis or advanced fibrosis and HBV DNA in serum

Patients who will be receiving cancer chemotherapy or immunosuppressive therapy

Adapted from Sorrell MF, et al. Ann Intern Med. 2009;150:104-110.



NIH Guidelines: Indications for HBV Treatment (cont)Patients for Whom Therapy May Be Indicated

Patients with active liver disease who do not have advanced fibrosis or cirrhosis, ie, patients with HBeAg-positive or HBeAg-negative chronic hepatitis B

Patients for Whom Immediate Therapy Is Not Routinely Indicated

Patients in the immune-tolerant phase (HBeAg positive, high levels of serum HBV DNA but normal ALT or little activity on liver biopsy)

Patients in the inactive carrier phase (HBeAg negative, low or undetectable levels of serum HBV DNA, and persistently normal ALT)

Patients who have latent HBV infection (HBV DNA without HBsAg)

Adapted from Sorrell MF, et al. Ann Intern Med. 2009;150:104-110.



Interferon Alfa Vs Nucleos(t)ide Analogue TreatmentTreatment Interferon alfa Nucleos(t)ide

Analogues

Route Subcutaneous injection Oral

Duration of treatment Finite duration ~ 12 mosLong duration, yrs to

lifelong

Antiviral activityModest, additional immunomodulatory

effectsStronger antiviral activity

HBsAg loss 1% to 3% after 1 yr Rare, 0% to 1% after 1 yr

Resistant mutants None0% to 25% after 1 yr,

varying by agent

Adverse effects Frequent Rare

Cost/yr (in US dollars) 18,000 ~ 2500-9000



LAM Genotypic Resistance in Patients Receiving PegIFN + LAM vs LAM Alone

Peginterferon alfa +Lamivudine

Lamivudine Alone

NLamivudine

Resistant, n (%)N

LamivudineResistant, n (%)

Janssen, 2005* 130 14 (11)‡ NA NA

Chan, 2005* 48 10 (21)§ 48 19 (40)

Lau, 2005* 256 9 (4) 254 69 (27)

Marcellin, 2004† 173 1 (1) 179 32 (18)

*HBeAg-positive patients.†HBeAg-negative patients.‡7 had previous lamivudine therapy with lamivudine resistance mutation at entry.§Peginterferon x 32 weeks.

Janssen HL, et al. Lancet. 2005;365:123-129. Chan HL, et al. Ann Intern Med. 2005;142:240-250. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Marcellin P, et al. N Engl J Med. 2004;351:1206-1217.



LAM + ADV vs LAM Responses at Week 104

Lamivudine + Placebo,n/N (%)

Lamivudine + Adefovir,n/N (%)

ALT normalization 19/56 (34) 15/35 (43)

HBV DNA negative(polymerase chain reaction)

8/56 (14) 14/53 (26)

HBeAg seroconversion 11/54 (20) 7/52 (13)

Lamivudine resistance mutation

15/35 (43) 6/41 (15)

Sung JJ, et al. J Hepatol. 2008;48:728-735.

Geoffrey M. Dusheiko, MD, FCP(SA), FRCP Professor of MedicineRoyal Free Hospital and School ofMedicineLondon, United Kingdom

Benefits and Risks of Hepatitis B Therapy



Evolution of Chronic HBV Therapy Over Time

Interferon alfa-2b

Lamivudine

Adefovir

Peginterferon alfa-2a

Telbivudine

Tenofovir

1990 1998 2002 2005 2006 2008

Entecavir



Factors Associated With Choosing Interferon as Initial Therapy Favorable predictors of response

• Genotype A or B > C or D

• Low HBV DNA (baseline and on treatment)

• High ALT (baseline)

Specific patient demographics

• Younger people Young woman wanting future pregnancy

Patient preference

No coinfection with HIV

Concomitant HCV infection



Factors Associated With Choosing Nucleos(t)ides as Initial Therapy Favorable predictors of response

• High ALT

• Low HBV DNA (baseline and on treatment)

Specific patient demographics

• Older people

Patient preference

Concomitant HIV infection

No HCV coinfection



Telbivudine

Cumulative Rates of Resistance With Oral Agents in Nucleos(t)ide-naive Patients

Not head-to-head trials; different patient populations and trial designs

Year

0

24

49

67 70

38

1 2 3 4 5

Pat

ien

ts (

%)

80

40

60

20

100

0

1118

29

0.2 1.2 1.24

00

17

1.2

6

1.2

Lamivudine Adefovir Entecavir Tenofovir

0.53

EASL clinical practice guidelines. J Hepatol. 2009;50:227-242. Tenney DJ, et al. EASL; 2009; Copenhagen, Denmark. Abstract 20.



Cross-Resistance Data for Nucleos(t)ide Analogues

EASL clinical practice guidelines. J Hepatol. 2009;50:227-242.

Wild type

M204I

L180M +

M204V

A181T/V

N236T

L180M + M204V/I ± I169T

±V173L ± M250V

L180M+M204V/I ±

T184G ± S202I/G

LAM S R R I S R R

LdT S R R S S R R

ETV S I I S S R R

ADV S S S R R S S

TDF S S S S I S S



Recommended Resistance Management StrategiesDrug Resistance Management Strategy

Lamivudine resistance Add adefovir or tenofovirSwitch to tenofovir/emtricitabine*

Adefovir resistance If N236T substitution: add lamivudine, entecavir, or switch to tenofovir/emtricitabine*

If A181T/V substitution:add entecavir or switch to tenofovir/emtricitabine*

Telbivudine resistance Same as for lamivudine

Entecavir resistance Switch to or add adefovir or tenofovir

Tenofovir resistance (not yet described)

?

*Not approved by the US Food and Drug Administration.

Lok AS, McMahon BJ. Hepatology. 2007;45:507-539. Ghany MG, Doo EC. Hepatology. 2009;49:S174-S184.

Jean-Michel Pawlotsky, MD, PhDProfessor, Department of VirologyHenri Mondor HospitalUniversity of Paris 12Créteil, France

Update on HCV Investigational Agents



Schematic Representation of the HCV Lifecycle

Reprinted by permission from Macmillan Publishers Ltd: NATURE Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. 36:933-938, copyright 2005. www.nature.com

Receptor bindingand endocytosis

Fusion and uncoating

Transportand release

(+) RNA

Translation andpolyprotein processing

RNAreplication

Virionassembly

Membranousweb

ER lumen

LD

LDER lumen

LD

http://www.nature.com/



Selected HCV Drugs in Clinical Development

Type of Drug Drug

Interferons Albinterferon alfa-2b Controlled-release interferon alfa-2b Interferon alfa-2bXL ITCA638 Peginterferon-lambda (PEG-rIL-29)

Ribavirin prodrug Taribavirin

Other drugs Nitazoxanide Silibinin



Selected HCV Drugs in Clinical DevelopmentHCV Inhibitors Drug

Entry inhibitors PRO206*

NS3/4A protease inhibitors Telaprevir (VX-950) Boceprevir (SCH 503034) TMC435 R7227 (ITMN-191) MK-7009 BI201335 SCH 900518

Nucleos(t)ide analogues R7128 IDX184

Nonnucleoside RdRp inhibitor GS-9190 ANA598 BI207127 VCH-916 Filibuvir (PF-00868554)

NS5A inhibitors BMS-790052

Cyclophilin inhibitors DEBIO-025 SCY-635 NIM811

HCV assembly/release inhibitors Celgosivir

*Development recently halted.



Sustained Virologic Response Rates in the PROVE 1, PROVE 2, and PROVE 3 TrialsStudy Patient Population Treatment Arm* N SVR,† n (%) P Value vs

PR48

PROVE 1[1] Treatment naive, genotype 1

PR48‡ 75 31 (41)

T12PR24§ 79 48 (61) .02

T12PR48|| 79 53 (67) .002

T12PR12¶ 17 6 (35) ND

PROVE 2[2] Treatment naive, genotype 1

PR48‡ 82 38 (46)

T12PR24§ 81 56 (69) .004

T12PR12¶ 82 49 (60) .12

T12P12# 78 28 (36) .20

PROVE 3[3]Peginterferon and ribavirin treatment failure, genotype 1

PR48‡ 114 16 (14)

T12PR24§ 115 59 (51) < .001

T24PR48** 113 59 (52) < .001

T24P24‡‡ 111 26 (23) .035

1. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838. 2. Hézode C, et al. N Engl J Med. 2009;360:1839-1850. 3. Manns M, et al. EASL 2009. Abstract 1044.



SVR Rates in the SPRINT-1 Trial in Treatment-Naive Patients Infected With Genotype 1 HCV

Treatment Arm N SVR, n (%) P Value vs Control

Control* 104 39 (38) --

P/R/B 28 wks† 107 58 (54) .013

P/R 4 wks -> P/R/B 24 wks‡ 103 58 (56) .0005

P/R/B 48 wks§ 103 69 (67) < .0001

P/R 4 wks -> P/R/B 44 wks|| 103 77 (75) < .0001

P/low-dose R/B 48 wks¶ 59 21 (36) NR*Control: peginterferon alfa-2b 1.5 g/kg/wk + weight-based ribavirin (800-1400 mg/day) for 48 wks.†P/R/B 28 wks = boceprevir 800 mg 3 times daily + peginterferon alfa-2b + weight-based ribavirin for 28 wks (no lead-in phase).‡P/R 4 wks -> P/R/B 24 wks: peginterferon alfa-2b + weight-based ribavirin for 4 wks (lead-in phase), then boceprevir + peginterferon alfa-2b + weight-based ribavirin for 24 wks.§P/R/B 48 wks: boceprevir + peginterferon alfa-2b + weight-based ribavirin for 48 weeks (no lead-in phase).||P/R 4 wks -> P/R/B 44 wks: peginterferon alfa-2b + weight-based ribavirin for 4 wks (lead-in phase), then boceprevir + peginterferon alfa-2b + weight-based ribavirin for 44 wks.¶P/low-dose R/B 48 wks: boceprevir + peginterferon alfa-2b + low weight-based dose ribavirin (400-1000 mg/day) for 48wks.

Kwo P, et al. EASL 2009. Abstract 4.

Raymond T. Chung, MDAssociate Professor of MedicineDepartment of MedicineHarvard Medical SchoolDirector of HepatologyMedical Director, Liver Transplant ProgramMassachusetts General HospitalBoston, Massachusetts

Mechanisms of Response and Nonresponse to HCV Treatment



RIG-1

IKK-TBK1

Cytoplasm Endosome

IRF-3

Nucleus

Interferon

TRIF TLR3

5'-pppCardif

Reprinted from Journal of Hepatology, Vol 50, Andrew W. Tai and Raymond T. Chung, Treatment failure in hepatitis C: Mechanisms of non-response, 412-420, Copyright (2009), with permission from Elsevier. http://www.sciencedirect.com/science/journal/01688278

Recognition of HCV RNA by RIG-I & TLR3 & Activation of Type I Interferon Transcription

http://www.sciencedirect.com/science/journal/01688278



PegIFN/RBV

SVRRVR

Slow virologic response

0

1

2

3

4

5

6

7

8

2 log10 decline

Limit of detection

Weeks

0 4 12 18 24 30 36 42 48 54 60 66 728 78

HC

V R

NA

(lo

g10

IU

/mL

)

Null response/nonresponse

Classification of Interferon Response and Nonresponse



Proposed Mechanisms of Suppression of Innate and Adaptive Immune Responses by HCV Structural and Nonstructural Proteins Protein Innate Immunity Adaptive Immunity

Core SOCS3 induction leads to inhibition of STAT1 phosphorylation[1]

Direct binding to STAT1 leads to proteasomal degradation and inhibition of STAT1 phosphorylation[2,3]

PP2A upregulation leads to STAT1 hypomethylation and binding by PIAS1[4]

Inhibition of T cell proliferation by binding to gC1q receptor[9]

E2 Binding and inhibition of PKR[5] No known role

NS3-4A Cleavage of the adaptor proteins Cardif and TRIF[4,6,7]

No known role

NS5A Binding and inhibition of PKR[8] No known role

NS5B No known role Error prone RNA polymerase leads to high viral mutation rates and escape from adaptive immune responses[10]

1. Bode JG, et al. FASEB J. 2003;17:488-490. 2. Lin W, et al. Gastroenterology. 2005;128:1034-1041. 3. Lin W, et al. J Virol. 2006;80:9226-9235. 4. Duong FH, et al. Gastroenterology. 2004;126:263-277. 5. Taylor DR, et al. Science. 1999;285:107-110. 6. Meylan E, et al. Nature. 2005;437:1167-1172. 7. Li K, et al. Proc Natl Acad Sci U S A. 2005;102:2992-2997. 8. Gale MJ Jr, et al. Virology. 1997;230:217-227. 9. Kittlesen DJ, et al. J Clin Invest. 2000;106:1239-1249. 10. Timm J, et al. J Exp Med. 2004;200:1593-1604.



Possible Approaches to Overcoming Interferon ResistanceApproach Proposed Mechanism(s)

NS3-4A protease inhibitors Inhibition of Cardif and TRIF cleavage by NS3-4A and restoration of interferon β activation[1-3]

S-adenosyl-L-methionine and betaine

Restoration of STAT1 methylation and rescue from PIAS1 inhibition[4]

High-dose ribavirin Interferon sensitization by increasing ISG expression and decreasing expression of inhibitors

of interferon signaling[5]

Reversal of insulin resistance

Decreasing SOCS3 expression[6]

Targeting host cofactors of HCV life cycle

1. Meylan E, et al. Nature. 2005;437:1167-1172. 2. Li XD, et al. Proc Natl Acad Sci U S A. 2005;102:17717-17722. 3. Li K, et al. Proc Natl Acad Sci U S A. 2005;102:2992-2997. 4. Duong FH, et al. Hepatology. 2006;43:796-806. 5. Feld JJ, et al. Hepatology. 2007;46:1548-1563. 6. Walsh MJ, et al. Gut. 2006;55:529-535.

Timothy Morgan, MDProfessor, Medicine School of Medicine University of California (Irvine)Orange, California

Update in the Diagnosis and Management of Decompensated Cirrhosis



Categories of Conditions Causing Hepatic EncephalopathyType Description (Cause) Category

A Acute liver failure

B Portosystemic bypass (shunt)

C Cirrhosis EpisodicPersistentMinimal

Mullen KD. Aliment Pharmacol Ther. 2007;25(suppl 1):11-16.Haussinger D, et al. Gut. 2008;57:1156-1165.



West Haven Criteria of Severity of Hepatic EncephalopathyGrade Description

Minimal Normal standard clinical exam; abnormal responses to detailed psychometric tests

1 Euphoria or anxiety; shortened attention span; mild lack of awareness

2 Lethargy or apathy; mild distortion of place or time; mild personality changes; impaired performance on addition/subtraction

3 Confusion, disorientation, or somnolence to semistupor but responsive to verbal stimuli

4 Coma

Atterbury CE, et al. Am J Dig Dis. 1978;23:398-406.



Clinical Hepatic Encephalopathy Staging ScaleItem Score*

0 11. Does the patient know which month it is (eg, January, February)? Yes No2. Does the patient know the day of the week (eg, Monday, Tuesday)? Yes No3. Can the patient count backward from 10 to 1 without making mistakes or

stopping?Yes No

4. If asked to do so, does the patient raise arms? Yes No5. Does the patient understand what you are saying? (Based on answers to

questions 1-4)Yes No

6. Is the patient awake and alert? Yes No7. Is the patient fast asleep and difficult to awake/arouse? Yes No8. Can the patient talk? Yes No9. Can the patient speak correctly? (ie, can you understand what they say, and

do they speak without stammering)Yes No

*Clinical hepatic encephalopathy staging scale score is the sum of scores for all 9 questions. Range is from 0 (no hepatic encephalopathy) to 9.

Ortiz M, et al. Aliment Pharmacol Ther. 2007;26:859-867.



Algorithm for Screening Cirrhotic Patients for Esophageal Varices*

*No previous esophageal variceal bleeding

Continued observation;do not perform EGDCirrhosis

Yes

No

EGD

No varices

Repeat EGD in 3 yrs

Small varices

Repeat EGD in 2 yrs

Moderate or large varices

NSBB adjusted to the maximal tolerated doses to heart rates of

55-60 beats/min

EVL every 2-4 wks until obliterated;repeat at 1-3 mos followed

by 6-12 mos

Intolerant of NSBBor patient prefers EVL

Red markings on

varices or Child B/C?

Yes

No



Acute Variceal Hemorrhage

Intravenous:octreotide 50 µg bolusfollowed by 50 µg/hr

for 3-5 days

Endoscopy within 12 hrs withbanding of moderate/large

varices

Antibiotics for 7 days

EGD and EVL every 2 wksuntil varices are obliterated

EGD (and EVL) after 1-3 mosand again every 6-12 mos

Intravenous: Ceftriaxone 1 g/24 hrs

Ciprofloxacin 400 mg/12 hrs

Oral: Norfloxacin 400 mg BID

Ciprofloxacin 500 mg BID

or

Algorithm for the Management of Acute Variceal Hemorrhage



NSBB + EVL

TIPS or distal splenorenal shunt

Yes

Continue NSBB + EVLNoRebleeding from

varices or portal hypertension?

Algorithm for Secondary Prophylaxis of Variceal Hemorrhage

Secondary Prophylaxis of Variceal Hemorrhage



Uncomplicated ascites

AASLD Recommended Treatment for Uncomplicated Ascites

Runyon BA, AASLD Practice Guidelines Committee. Hepatology. 2009;49:2087-2107.

2 g/day sodium diet

Furosemide 40 mg orally daily (maximum 160 mg orally daily)

Spironolactone 100 mg orally daily(maximum 400 mg orally daily)

+

+



Refractory ascites

Recommended Treatment for Refractory Ascites

Runyon BA, AASLD Practice Guidelines Committee. Hepatology. 2009;49:2087-2107. Moore KP, et al. Gut. 2006;55(Suppl 6):vi1-vi12.

Treatment: LVP with intravenous albumin for each 6-8 g/L of ascites removed

TIPS if: Frequent LVP required,

bilirubin < 3 mg/dL,CTP < 11-12,

no hepatic encephalopathy



Diagnostic Criteria for Hepatorenal Syndrome Cirrhosis with ascites

Serum creatinine > 1.5 mg/dL

No improvement of serum creatinine (decrease to < 1.5 mg/dL) after at least 2 days with diuretic withdrawal and volume expansion with albumin (1 g/kg body weight per day, maximum of 100 g/day)

Absence of shock

No current or recent treatment with nephrotoxic drugs

Absence of parenchymal kidney disease as indicated by proteinuria > 500 mg/day, microhematuria (< 50 red blood cells per high-power field) and/or abnormal renal ultrasonography

Salerno F, et al. Gut .2007;56:1310-1318.



Hepatorenal syndrome

Recommended Treatment for Hepatorenal Syndrome

Salerno F, et al. Gut .2007;56:1310-1318.Angeli P, et al. J Hepatol. 2008;48(suppl 1):S93-S103.

Diagnosis: Creatinine > 1.5 mg/dL after intravenous albumin 1 g/kg/day for 2 days,

no shock or nephrotoxic drugs, no intrinsic renal disease

Treatment of HRS-1:Midodrine 5 mg orally 3 TID (15 mg TID maximum)

Octreotide subcutaneously 100 µg TID (200 µg TID maximum)Albumin intravenously 20-50 g/day



Modified Child-Turcotte-Pugh Score

Child-Turcotte-Pugh Class

– A = 5-6 points

– B = 7-9 points

– C = 10-15 points

Factor 1 Point 2 Points 3 Points

Albumin, g/dL > 3.5 3.5-2.8 < 2.8

Bilirubin, mg/dL < 2.0 2.0-3.0 > 3.0

International normalized ratio < 1.7 1.7-2.3 > 2.3

Ascites Absent Easily controlled Large or resistant

Hepatic encephalopathy Absent Mild (1.0-2.0) Chronic

Pugh RN, et al. Br J Surg. 1973;60:646-649.



Spontaneous Bacterial Peritonitis

No previous SBP

Oral norfloxacin 400 mg QD ororal ciprofloxacin 500 mg QD

Previous SBP

No antibiotics

Yes

No

Prophylaxis of Spontaneous Bacterial Peritonitis

Terg R, et al. J Hepatol. 2008;48:774-779.Fernández J, et al. Gastroenterology. 2007;133:818-824.

Ascites protein < 1.5 g/dL and 1 of the following: CTP ≥ 9 and bilirubin

≥ 3 mg/dL, or creatinine ≥ 1.2 mg/dL, sodium < 130 mEq/L, or

BUN ≥ 25 mg/dL



AASLD Recommendations for HCC Monitoring Patient PopulationsPatients for Whom HCC Surveillance Is Recommended

Hepatitis B carriers Asian males 40 yrs of age and older or Asian females 50 yrs of age and older Cirrhosis Family history of hepatocellular carcinoma Africans 20 yrs of age and older Noncirrhotic patients with HBeAg, high HBV DNA, elevated alanine aminotransferase, and/or

inflammation on liver biopsy

Hepatitis C, with bridging fibrosis or cirrhosis

Alcoholic cirrhosis

Genetic hemochromatosis with cirrhosis

Primary biliary cirrhosis (with histological cirrhosis)

Consider screening patients with the following conditions if they have cirrhosis Alpha-1 antitrypsin deficiency Nonalcoholic steatohepatitis Autoimmune hepatitis

Bruix J, et al. Hepatology. 2005;42:1208-1236.

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