Treatment of Hepatitis B - American College of …s3.gi.org/wp-content/uploads/2015/01/15ACG_Hepatitis...Paul Y. Kwo, MD, FACG Candidates for HBV Treatment APASL (2008) EAEASLSL (2012)(2012)

Paul Y. Kwo, MD, FACG

Treatment of Hepatitis B

Paul Y Kwo, MD

Professor of MedicineProfessor of Medicine

Gastroenterology/Hepatology Division

Medical Director, Liver Transplantation

Indiana University Health

Indiana University School of Medicine

975 W. Walnut, IB 327

Indianapolis, IN 46202-5121

phone 317-274-3090

fax 317-274-3106

email [email protected]

• Nucleic Acid: 3.2 kb DNA

• Classification: Hepadnaviridae



Hepatitis B VirusHepatitis B Virus

42 nm42 nm

22 nm22 nm

p

• Multiple serotypes and genotypes A-H

• Enveloped

• In vitro model: primary hepatocyte culture and transfection of cloned HBV DNA

p


• Enveloped

• In vitro model: primary hepatocyte culture and transfection of cloned HBV DNAtransfection of cloned HBV DNA

• In vivo replication: in cytoplasm, cccDNA in nucleus; hepatocyteand other tissues, human and other primates

transfection of cloned HBV DNA


ACG's Hepatitis School - Las Vegas, NV Copyright 2015 American College of Gastroenterology

1







42 nm42 nm

22 nm22 nm

HBsAgHBsAg

p


• Enveloped


p


• Enveloped

• In vitro model: primary hepatocyte culture and transfection of cloned HBV DNAHBsAgHBsAg

HBV DNAHBV DNA

HBcAgHBcAg42 nm42 nm










42 nm42 nm

22 nm22 nm

p


• Enveloped


p


• Enveloped

• In vitro model: primary hepatocyte culture and transfection of cloned HBV DNAtransfection of cloned HBV DNA




HBsAgHBsAg

22 nm22 nm


2


Prevalence of HBV: Global EstimatesPrevalence of HBV: Global Estimates

HBsAgPositive

(%)

350 million With Chronic HBV

Taiwan 10-13.8

Vietnam 5.7-10

China 5.3-12

Africa 5-19

Philippines 5-16

Thailand 4.6-8

Japan 4.4-13

HBsAg PrevalenceHigh (>8%)Intermediate (2%-7%)Low (<2%)

Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl):S158-S168.

Indonesia 4.0

South Korea 2.6-5.1

India 2.4-4.7

Russia 1.4-8

United States 0.2-0.5

New HBV Infections by Year:United States (1966-2006)

New HBV Infections by Year:United States (1966-2006)

00)

00)

VaccineHBsAg Screening of Pregnant

Women Recommended

nce

(p

er 1

00,0

0n

ce (

per

100

,00

Infant Immunization Recommended

Vaccine Licensed

Women Recommended

OSHA Rule Enacted

Adolescent Immunization Recommended

Inci

de

nIn

cid

en

66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 00 02 04 06

YearYearWasley A, et al. MMWR Surveill Summ 2008;57:1-24.


3


HBV and Hepatocellular cancer (HCC)HBV and Hepatocellular cancer (HCC)

• Globally, commonest underlying • Globally, commonest underlying y, y gcause of HCC

• In Asia, up to 40% of HCC in HBV in noncirrhotics

• Western countries show significantly

y, y gcause of HCC

• In Asia, up to 40% of HCC in HBV in noncirrhotics

• Western countries show significantly less risk in HBV carriers

• Annual incidence: 0.2% to 2.5%

less risk in HBV carriers

• Annual incidence: 0.2% to 2.5%


4


Natural History of Chronic HBV Infection


HBeAgHBeAg HBV DNAHBV DNA

9

IntegrationIntegration

Yim HJ and Lok AS. Hepatology 2006;43:S173-81.

Hepatitis B: Natural HistoryHepatitis B: Natural History

• If it is not treated, in 1/3 of patients, hepatitis B can

cause liver damage leading to cirrhosis and liver

cancer1

• Hepatitis B is responsible for 80% of primary liver

cancer globally which is almost always fatal2

• If it is not treated, in 1/3 of patients, hepatitis B can

cause liver damage leading to cirrhosis and liver

cancer1

• Hepatitis B is responsible for 80% of primary liver

cancer globally which is almost always fatal2cancer globally, which is almost always fatal• Liver cancer is the 2nd highest cause of death by cancer 3

• Without appropriate treatment or monitoring, 1 in 4 persons with

chronic hepatitis B will die of liver cancer or liver disease

cancer globally, which is almost always fatal• Liver cancer is the 2nd highest cause of death by cancer 3

• Without appropriate treatment or monitoring, 1 in 4 persons with

chronic hepatitis B will die of liver cancer or liver disease

1. WHO. Available at: www.who.int/csr/disease/hepatitis/en/;2. Hepatitis B Foundation. Hepatitis B and Primary Liver Cancer. Available at http://www.hepb.org/professionals/hepb_and_liver_cancer.htm. Accessed 4 February 2010;3. WHO. Cancer Fact Sheet. Available at http://www.who.int/mediacentre/factsheets/fs297/en/index.html.


5


ChildhoodChildhood Immune ToleranceImmune Tolerance>95%



AdulthoodAdulthood

HBeAg- CHBHBeAg- CHB

<5%

Inactive carrierInactive carrier

HBeAg+ CHBHBeAg+ CHB

HCCAnd or

cirrhosis

HCCAnd or

cirrhosis

<15-30% of HCC associated with HBV occurs in the absence of cirrhosis or advanced fibrosis

Pungpapong S, et al. Mayo Clin Proc 2007;82:967-5; Chen DS. J Gastroenterol Hepatol 1993;8:470-5;Seeff LB, et al. N Engl J Med 1987;316:965-70; Lok ASF, McMahon BJ. Hepatology 2009;50:1-36.

HBV DNA vs. Liver Cirrhosis : REVEAL data

HBV DNA vs. Liver Cirrhosis : REVEAL data

130:678-86


6


HBV DNA vs. HCC : REVEAL DataHBV DNA vs. HCC : REVEAL Data

Aiming for True Inactive Carrier StatusAiming for True Inactive Carrier Status

Milestone 1: Start of decline of HBV DNA

Milestone 2: HBeAg/ anti-HBe sero-conversion

Milestone 3: HBV DNA decreased to undetectable

Milestone 4: Clearance of

HBsAg

Milestone 5: Clearance of

cccDNA

HBeAg(+), anti-HBe(-) HBeAg(-), anti-HBe(+)

Undetectable level of HBV DNA

HBeAg/anti-HBe status

HBV DNA >109 copies/mL

HBV DNA level

conversion undetectable

Low HBV DNA (<2000 IU/mL) for reduced progression risk

This is where we would like our patients to be

Immune tolerance

HBsAg+ HBsAg-

ALT level

HBsAg status

Immune clearance Inactive carrier state

Immune control

Functional cure>>>CURE


7


Goals of therapy for Hepatitis BGoals of therapy for Hepatitis B

Liver histology Improves Serum HBV DNA declines

Prevention of Death, Cirrhosis, and HCC

ALT normalizationSeroconversion (loss of HBeAg, production of anti-Hbe,

loss of HBsAg)

U.S. FDA dates of Approved Therapies for CHBU.S. FDA dates of Approved Therapies for CHB

Nucleosides/Nucleotides

Tenofovir* VIREAD® Gilead Sciences 2008

Telbivudine TYZEKA™ Idenix / Novartis 2006

Entecavir* BARACLUDE™ Bristol-Myers Squibb 2005

Adefovir dipivoxil HEPSERA™ Gilead Sciences 2002

Lamivudine EPIVIR-HBV® GlaxoSmithKline 1998

Interferons

Peginterferon alfa-2a* PEGASYS® RocheLaboratories 2005

Interferon alfa-2b, recombinant INTRON® A Schering / Merck 1992

Preferred therapies – AASLD Guidelines


8


Candidates forHBV TreatmentCandidates forHBV Treatment

APASL(2008)

EASLEASL(2012)(2012)

Keeffe et al(2008)

AASLDAASLD(2009)(2009)

HBV DNA HBV DNA threshold (IU/L)threshold (IU/L)

HBeAg positiveHBeAg positiveHBeAg negativeHBeAg negative

20,0002000

20002000

20,0002000

20,0002000-20,000

ALT:ALT:Normal rangeNormal range

- - Use revised,lower range

(M: 30 U/L; F: 19 U/L)

Use revised,lower range

(M: 30 U/L; F: 19 U/L)

When to treat:When to treat:key factorskey factors

HBV DNAand ALT

HBV DNAand ALT

HBV DNAand ALT

HBV DNAand ALTkey factorskey factors and ALT and ALT and ALT and ALT

BiopsyBiopsy Consider in certain groups

Consider incertain groups

Consider in certain groups

Consider incertain groups

Lok AS, et al. Hepatology 2009;50:661-662. Available at: http://www.aasld.org/Pages/Default.aspx.Keeffe EB, et al. Clin Gastroenterol Hepatol 2008;6:1315-1341.EASL. J Hepatol 2012 vol. 57 j 167–185.Liaw Y-F, et al. Hepatol Int 2008;2:263-283.

Treatment Guidelines: Recommendations for First-Line Therapy in Patients Without Cirrhosis

Treatment Guidelines: Recommendations for First-Line Therapy in Patients Without Cirrhosis

HBeAg Positive or Negative Chronic HBVg g

Preferred Alternative Not Preferred

Tenofovir DF Adefovir Lamivudine

Entecavir Telbivudine*

Peg-IFN alfa-2a

*HBV DNA must be undetectable at 24 weeks to continue (Keeffe). AASLD guidelines: lamivudine and telbivudine not preferred due to relatively high rate of resistance. Adefovir not preferred due to weak antiviral activity and relatively high rate of resistance in HBeAg-negative studies.

Lok AS, et al. Hepatology 2009;50:661-662. Available at: http://www.aasld.org.Keeffe EB, et al. Clin Gastroenterol Hepatol 2008;6:1315-1341.


9


Treatment Guidelines:Recommendations for Patients With Cirrhosis

Treatment Guidelines:Recommendations for Patients With Cirrhosis

Compensated Cirrhosis Decompensated CirrhosisCompensated Cirrhosis

Preferred PotentialNot

Preferred

Tenofovir DF Peg-IFN alfa-2a*

Lamivudine

Entecavir Adefovir Telbivudine

Decompensated Cirrhosis

PreferredNot

Preferred

Tenofovir DF plus lamivudine

Peg-IFN alfa-2aand alfa-2b†

Tenofovir DF

Entecavir

Keeffe EB, et al. Clin Gastroenterol Hepatol 2008;6:1315-1341.

Note: therapies are approved for monotherapy only. *Early cirrhosis only.†Contraindicated.

A tool to minimize resistance: HBV Roadmap:

Definitions of Virologic Response

A tool to minimize resistance: HBV Roadmap:

Definitions of Virologic ResponsePrimary Non-Response at Week 12

Early Predictors of Efficacyat Week 24

Primary Non Response at Week 12 (HBV DNA <1 log10 IU/mL decrease from baseline)

Keeffe EB, et al. Clin Gastroenterol Hepatol 2008;6:1315-1341.

CompleteResponse(PCR Negative)

PartialResponse

(HBV DNA >60 to <2000 IU/mL)

InadequateResponse

(HBV DNA >2000 IU/mL)


10


HBV Roadmap:Treatment Response to HBV DNA


Early Predictors of Efficacyat Week 24at Week 24


PartialResponse


InadequateResponse


Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

No Changein Treatment



Early Predictors of Efficacyat Week 24at Week 24


PartialResponse


InadequateResponse



LowGenetic Barrier Drug

Switch or add alternative drugMore frequent monitoring

(every 3 months)

HighGenetic Barrier Drug

No change in treatmentMore frequent monitoring

(every 3 months)


11




Early Predictors of Efficacyt W k 24at Week 24


PartialResponse


InadequateResponse



Switch or AddAlternative TherapyNarrow Monitoring

Frequency

Cirrhosis Reversal Following Lamivudine Rx in HBV

Cirrhosis Reversal Following Lamivudine Rx in HBV

Courtesy of Ian Wanless, MD.


12


Effect of LAM on Incidence of HCC in CHB and Advanced Fibrosis

Lami dine

Placebo

no

sis

of

HC

C

(%)

10

P = .047

Liaw YF, et al. N Engl J Med 2004;351:1521-1531.

Months

Lamivudine

Dia

g 0

60 12 18 24 30 36

Types of Virological ResponseTypes of Virological Response

On Treatment

On Continuous Treatment

LLOD LLODNA

(L

og

10 I

U/m

l)

Relapse

Primary non-response Breakthrough

Breakthrough

Months MonthsSustainedResponse

LLOD LLOD

HB

V D

N

MaintainedResponse

0


13


Implications ofResistance to HBV Therapies

Implications ofResistance to HBV Therapies

• Loss of clinical benefits

• Loss of initial HBV DNA response with rebound

• ALT increase and eventual reversion of histologic improvement

• Progressive liver disease

• In patients with cirrhosis, decompensation

• Development of multidrug resistance

• Cross resistance

• New resistance mutations

• Transmission of resistant virus

Keeffe EB, et al. Clin Gastroenterol Hepatol 2006;4:936-962.Lok AS, et al. Hepatology 2009;50:661-662. Available at: http://www.aasld.org.

Antiviral Resistance: Nomenclature

Antiviral Resistance: Nomenclature

Genotypic resistance Detection of HBV polymerase mutation(s)associated with resistance

Phenotypic resistance Decreased in vitro susceptibility to an antiviralagent

Virologic breakthrough

Increase in HBV DNA by >1 log10 over nadir ontreatmentbreakthrough treatment

Biochemical breakthrough

Increase in ALT on treatment

Lok AS, et al. Hepatology 2009;50:661-662. Available at: http://www.aasld.org.


14


Factors associated with antiviral resistanceFactors associated with antiviral resistance

DRUGVIRUS DRUG

HOST

• Daily production• Replication fidelity

• Pre-existent mutations

• Potency• Genetic barrier to

resistance

HOST• Prior Rx• Compliance• Immune Status• Pharmacogenetics• Body Size

What causes antiviral-resistant HBV mutants to become dominant?

• Survival of the fittest: selection of virus with survival advantage in the presence of antiviral therapy

SS

S SSR

R RR

Antiviral Therapy

S

SS

R

R R R RS


15


Manifestations ofAntiviral Resistance

7

8 HBV DNA

2

3

4

5

6

7

HB

V D

NA

(lo

g10

IU/m

L)

ALT

(U

/L)

ALT

GenotypicResistance

VirologicBreakthrough

VirologicRebound

HepatitisFlare

0

1

2H

-1 0 1 2 3

Years on Treatment

Upper Limit of Normal

BiochemicalBreakthrough

Lok AS, et al. Hepatology 2009;50:661-662. Available at: http://www.aasld.org.

Consequences of Antiviral Resistance

• Loss of initial virologic biochemical and• Loss of initial virologic, biochemical and histological response

• Hepatitis flares, hepatic decompensation and death

• Increased risk of HBV recurrence post-liver transplantp

• Limit future treatment options

• Transmission to treatment-naïve persons → public health problem


16


Not head to head trialsDifferent patient populations and trial designsce

(%

)Differences in Development of

Resistance with Long-term Treatment in Nuc-naïve Patients

Different patient populations and trial designs

wit

h r

esis

tan

cP

atie

nts

w

Lamivudine1 Adefovir2 Entecavir3-6 Telbivudine7,8 Tenofovir9,10

1. Lok ASF, et al. Gastroenterology 2003;125:1714-22; 2. Hadziyannis SJ, et al. Gastroenterology 2006;131:1743-1752; 3. Colonno RJ, et al. Hepatology 2006;44:1656-65; 4. Colonno RJ, et al, Hepatology 2006, 44 (Suppl 1):229; 5. Colonno RJ, et al. J Hepatol. 2007;46(Suppl 1):S294; 6. Tenney DJ et al. Gastroenterology 2009;136(Suppl 1):A-865;7. Telbivudine (Tyzeka®) prescribing information; May 2009; Novartis Pharmaceuticals, East Hanover, NJ; 8. Lai CL, Hepatology 2006;44(Suppl 1):222A.9. Tenofovir (Viread®) prescribing information; May. 2009; Gilead Sciences, Foster City, CA; 10. Snow-Lampart A et al. Hepatology 2008;48(Suppl 1):745A.

The hepatitis B virus (HBV) polymerase open reading frame

Lok et al Hepatology 2007;46:254-265


17


In Vitro HBV Cross-resistance

LAM

ETV

LdT

Locarnini S, et al. Antivir Ther 2004;9:679-693.

Selection of mutations in YMDD motif may affect future treatment options

Thus lamivudine should not be first line treatment

LdT

ADV

Diagnosis of Antiviral Resistance

• Determination of virologic breakthrough• Increase in serum HBV DNA by > 1.0 log as compared with

nadirnadir

• Rule out non-HBV-related causes of treatment failure• Adherence

• Confirm resistance with HBV mutant detection• Characterization of mutations will help guide future therapy

(cross-resistance)

• Note that clinical resistance (biochemical breakthrough) lags behind viral resistancebreakthrough) lags behind viral resistance • Rescue therapy should be considered in patients with viral

resistance to prevent hepatitis flares• Rescue therapy is more effective when initiated at the time of

viral resistance, prior to clinical resistance*

Adapted from Lok ASF, McMahon BJ. Hepatology 2007;45:507-539.*Lampertico P, Hepatology 2005; 2: 1414-1419.


18


Summary: Guidelines for Management of Antiviral-Resistant HBV

Summary: Guidelines for Management of Antiviral-Resistant HBV

Resistance Rescue Therapy

Lamivudine Add adefovir or tenofovir DFStop lamivudine switch to emtricitabine/tenofovir DFStop lamivudine, switch to emtricitabine/tenofovir DF

Adefovir Add lamivudineStop adefovir, switch to:

Emtricitabine/tenofovir DFSwitch to or add entecavir (if no prior lamivudine resistance)

Entecavir Switch to tenofovir DF or emtricitabine/tenofovir DF

Telbivudine Add adefovir or tenofovir DFTelbivudine Add adefovir or tenofovir DFStop telbivudine, switch to emtricitabine/tenofovir DF

Adefovir/Lamivudine

Consider tenofovir emtricitabine DF, or tenofovir+ entecavir

Lamivudine Entecavir

Consider tenofovir or tenofovir DF/emtricitabine

Lok AS, et al. Hepatology 2009;50:661-662. Lok et al. Hepatology 2007;46:254-265.

Tenofovir + Entecavir for Multidrug resistant HBV infection


• 57 subjects received ETV 0.5 or 1 mg with TDF 300 mg• 57 subjects received ETV 0.5 or 1 mg with TDF 300 mg5 subjects ece ed 0 5 o g t 300 g5 subjects ece ed 0 5 o g t 300 g

Peterson Journal of Hepatology 2012 vol. 56 j 520–526


19




• 51/57 (90%) of patients achieving HBV-DNA undetectability(LLoD 80IU/ml)

• 51/57 (90%) of patients achieving HBV-DNA undetectability(LLoD 80IU/ml)

Peterson Journal of Hepatology 2012 vol. 56 j 520–526

SummarySummaryPrevention

• Avoid unnecessary treatment

• Initiate treatment with potent antiviral that has lowInitiate treatment with potent antiviral that has low rate of drug resistance (tenofovir or entecavir) or with combination therapy

• Switch to alternative therapy in patients with primary non-response

Monitoring

• Test for serum HBV DNA (PCR assay) every 3-6 months during treatment

• Check for medication compliance in patients with virologic breakthrough

• Confirm antiviral resistance with genotype testing


20


SummarySummary

Treatment

• Guided by genotypic assays

• Add on therapy or switch therapy per guidelines

• Rescue therapies for multi-drug resistance

• tenofovir + entecavir

• tenofovir DF/emtricitabine


21

Treatment of Hepatitis B - American College of …s3.gi.org/wp-content/uploads/2015/01/15ACG_Hepatitis...Paul Y. Kwo, MD, FACG Candidates for HBV Treatment APASL (2008) EAEASLSL (2012)(2012)

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