treatment of hepatitis b - american college of...

Paul Y. Kwo, MD, FACG

Treatment of hepatitis B Treatment of hepatitis B


Professor of Medicine


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

Professor 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]

Indianapolis, IN 46202-5121

phone 317-274-3090

fax 317-274-3106

email [email protected]

•Nucleic Acid: 3.2 kb DNA

• Classification: Hepadnaviridae

•Nucleic Acid: 3.2 kb DNA

• Classification: Hepadnaviridae

Hepatitis B VirusHepatitis B Virus

42 nm42 nm

22 nm22 nm

HBsAgHBsAg

Classification: Hepadnaviridae

• Multiple serotypes and genotypes A-H

• Enveloped

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

Classification: Hepadnaviridae

• Multiple serotypes and genotypes A-H

• Enveloped

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

HBV DNAHBV DNA

HBcAgHBcAg42 nm42 nm

transfection of cloned HBV DNA

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

transfection of cloned HBV DNA

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

HBsAgHBsAg

22 nm22 nm

ACG 2015 Boston Hepatitis School Copyright 2015 American College of Gastroenterology

1


Prevalence of HBV: Global EstimatesPrevalence of HBV: Global Estimates

HBsAgPositive

(%)

350 million With Chronic HBV

Taiwan 10-13.8

Viet Nam 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)

000)

000)

Vaccine Licensed

HBsAg Screening of Pregnant Women Recommended

ence

(p

er 1

00,

ence

(p

er 1

00, Infant Immunization Recommended

OSHA Rule Enacted

Adolescent Immunization Recommended

Inci

de

Inci

de

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

YearYear

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


2


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%


3


Natural History of Chronic HBV Infection


HBeAgHBeAg HBV DNAHBV DNA

7

IntegrationIntegration

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

• Liver cancer is the 2nd highest cause of death by cancer 3

• 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

• Liver cancer is the 2nd highest cause of death by cancer 3

8

Liver cancer is the 2 highest cause of death by cancer

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

hepatitis B will die of liver cancer or liver disease

Liver cancer is the 2 highest cause of death by cancer

• 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.

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.


4


ChildhoodChildhood Immune ToleranceImmune Tolerance>95%



AdulthoodAdulthood

HBeAg- CHBHBeAg- CHB

<5%

Inactive carrierInactive carrier

HBeAg+ CHBHBeAg+ CHB

<15-30% of HCC

9

HCCAnd or

cirrhosis

HCCAnd or

cirrhosis

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.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

10130:678-86130:678-86


5


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

11

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

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


6


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)

US FDA dates of Approved Therapies for CHBUS FDA dates of Approved Therapies for CHB

Nucleosides/Nucleotides

Tenofovir* VIREAD® Gilead Sciences 2008Tenofovir 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

14

Interferons

Peginterferon alfa-2a* PEGASYS® RocheLaboratories 2005

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

Preferred therapies – AASLD Guidelines


7


Candidates forHBV TreatmentCandidates forHBV Treatment

APASL(2008)

EASLEASL(2012)(2012)

Keeffe et al(2008)

AASLDAASLD(2009)(2009)

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

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 preferreddue 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.


8


Treatment Guidelines:Recommendations for Patients With Cirrhosis

Treatment Guidelines:Recommendations for Patients With Cirrhosis

Compensated Cirrhosis Decompensated Cirrhosis

Preferred PotentialNot

Preferred

Tenofovir DF Peg-IFN alfa-2a*

Lamivudine

Entecavir Adefovir Telbivudine

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.

% 95%100

ETV-027

ETV 3-year Clinical Trial HBV DNA Suppression HBeAg-negative Patients

ETV 3-year Clinical Trial HBV DNA Suppression HBeAg-negative Patients

HBeAg(-) ETV Long-term Cohort (ETV-027→ETV-901)

Off-treatm

ent >

60

59%

83%93% 94% 91% 95%94%

40

60

80

100

tio

n o

f p

atie

nts

wit

h

DN

A <

300

cop

ies/

mL

(%

)

901)

18

days

4%0

20

n 93/99 4/99 56/95 79/95 84/90 72/77 67/74 54/57‡

End of Dosing Baseline Wk 12 Wk 24 Wk 48 Wk 72 Wk 96 Wk 144

Shouval D, et al. AASLD 2008; poster 927. Shouval D, et al. AASLD 2008; poster 927.

Pro

po

rH

BV

D

†In the randomised controlled study (ETV-027), patients received 0.5mg ETV. In the 901 rollover study, patients received 1mg ETV‡ 10 patients who remained on treatment at Week 144 of ETV-901 visit had missing PCR samples


9


Studies 102/103:Virologic Suppression With Tenfovir at Year 6

Studies 102/103:Virologic Suppression With Tenfovir at Year 6

R

HBeAg- Patients(Study 102)

HBeAg+ Patients(Study 103)Response (Study 102) (Study 103)

Year 5 Year 6 Year 5 Year 6

HBV DNA < 400 copies/mLIntent-to-treat*, % (n/N)

83(291/350)

81(281/345)

65(160/248)

63(157/251)

HBV DNA < 400 copies/mLOn treatment†, % (n/N)

99(292/295)

99.6(283/284)

97(170/175)

99(167/169)

* LTE-TDF (missing = failure/addition of FTC = failure)† Ob d ( i i l d d/ dditi f FTC i l d d)

19Marcellin P, et al. AASLD 2012; abstract 374.Marcellin P, et al. AASLD 2012; abstract 374.

† Observed (missing = excluded/addition of FTC = included)

• 80% of 585 patients entering the open-label phase remained on study at Year 6; 73% of enrolled patients remained on study

• HBeAg loss/seroconversion rates of 50% and 37%, respectively, through 6 years

• 11% of HBeAg+ patients had confirmed HBsAg loss (8% with seroconversion)

• No resistance to TDF was detected through 6 years

HCC Risk in Caucasian, Chronic HBV Patients Treated With Entecavir or Tenofovir DF

HCC Risk in Caucasian, Chronic HBV Patients Treated With Entecavir or Tenofovir DF

• Multi-country cohort (Greece, Itlay, Turkey, Spain, The Netherlands) (n=1231)

• Chronic HBV with no co-infection, liver

• Multi-country cohort (Greece, Itlay, Turkey, Spain, The Netherlands) (n=1231)

• Chronic HBV with no co-infection, liver

Probability of HCC

Log-Rank P<0.001.,transplantation, or HCC

• Initiated either entecavir (43%) or tenofovir DF (55%)

• HCC 5-year incidence

• 4.2% at median of 17 months

• 13.5 new HCC cases/1000 person-years

• Strongest HCC risk factors

• Decompensated liver disease (HR: 2.78; P 0 019) l l t l t t (HR 0 97

,transplantation, or HCC

• Initiated either entecavir (43%) or tenofovir DF (55%)

• HCC 5-year incidence

• 4.2% at median of 17 months

• 13.5 new HCC cases/1000 person-years

• Strongest HCC risk factors

• Decompensated liver disease (HR: 2.78; P 0 019) l l t l t t (HR 0 97 u

mu

lati

ve P

rob

abil

ity

og a 0 00

20.9%

DecompensatedCirrhosis 29.7%

P=0.019), lower platelet count (HR: 0.97; P=0.002), older age (HR: 1.05; P=0.12)

• Asian-based HCC risk scores may not be applicable to Caucasians with chronic HBV

P=0.019), lower platelet count (HR: 0.97; P=0.002), older age (HR: 1.05; P=0.12)

• Asian-based HCC risk scores may not be applicable to Caucasians with chronic HBV

Papatheodoridis GV, et al. Hepatology. 2013;58(suppl 1):302A-303A. Abstract 190.

Cu

Time Since Initiation of Treatment (Years)

0 1 2 3 4 5

No Cirrhosis2.5%

Cirrhosis


10


InterferonInterferon

• Short fixed duration therapy (16-48 weeks)

• No Renal toxicity

• Ideal for patients with high ALT and medium to low DNA

• Short fixed duration therapy (16-48 weeks)

• No Renal toxicity

• Ideal for patients with high ALT and medium to low DNA

• Has stopping rules and “continuation” rules

• Chance of DNA suppression long-term is less than 20%

• HBsAg loss is 10%

• Same as with Nuc therapy

HB A t i b t t i (t t) l b t t il bl

• Has stopping rules and “continuation” rules

• Chance of DNA suppression long-term is less than 20%

• HBsAg loss is 10%

• Same as with Nuc therapy

HB A t i b t t i (t t) l b t t il bl

21

• HBsAg quant is best stopping (test) rule, but not available in the US

• HBsAg quant is best stopping (test) rule, but not available in the US

of those achieved 45%

HBsAg Reduction at Week 24 of PEG INF can Predict of Future HBsAg Clearance

HBsAg Reduction at Week 24 of PEG INF can Predict of Future HBsAg Clearance

HBsAg clearance at 5 years post-treatment (N=13/29)achieved HBV DNA

≤ 10,000 copies/mLat 1 year post-treatment (N=29/67)

43%

45%

SUSTAINEDIMMUNE CONTROL

Among HBeAg-negative patients who achieved HB A d li ≥10% f

22Marcellin P, et al. APASL 2010.Marcellin P, et al. APASL 2010.

*56% of patients achieved HBsAg decline ≥10% at week 24

IMMUNE CONTROLHBsAg decline ≥10% from baseline at Week 24 of treatment*


11


NIDDKD Cohort: HBsAg Lossby Mode of HBeAg ClearanceNIDDKD Cohort: HBsAg Lossby Mode of HBeAg Clearance

• Treatment-induced HBeAg clearance (n=51)

• Interferon related: 86%

• Treatment-induced HBeAg clearance (n=51)


Probability of HBsAg Loss byMode of HBeAg Clearance


• Cumulative incidence of HBeAg loss per year (P=0.02)

• Spontaneous: 1.6%

• Nucleoside analog induced: 4.4%

• Interferon induced: 6.3%

• Most significant predictors of HBsAg loss


• Cumulative incidence of HBeAg loss per year (P=0.02)

• Spontaneous: 1.6%

• Nucleoside analog induced: 4.4%

• Interferon induced: 6.3%

• Most significant predictors of HBsAg loss il

ity

of

HB

sAg

Lo

ss

Interferon-RelatedHBeAg Loss (n=19)

NucleosideAnalog-Related

HBeAg Loss (n=2)loss

• Mode of HBeAg loss

• Race

loss

• Mode of HBeAg loss

• Race

Abdalla A, et al. Hepatology. 2013;58(suppl 1):627A. Abstract 883.

NIDDKD: National Institute of Diabetes and Digestiveand Kidney Diseases.

0 5 10 15 20 25Years

Pro

bab

Spontaneous Lossof HBeAg (n=8)

HBsAg Loss in HBeAg-Positive and HBeAg-Negative Patients

HBsAg Loss in HBeAg-Positive and HBeAg-Negative Patients

Pat

ien

ts (

%)

3 0%

5%

10%

8%

15%

Lamivudine52 weeks

Adefovir5 Years

Entecavir96 weeks

Tenofovir DF4 years

Telbivudine52 weeks

PegIFNα72 weeks

Lok AS, et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org.Heathcote EJ, et al. Hepatology. 2010;52(suppl):556A-557A. Abstract 477.Gish RG, et al. J Viral Hepatitis. 2010;17:16-22.

PegIFNα+ LAM

72 weeks

1.5%

3.0%

1%


12


When can treatment be stopped? When can treatment be stopped?

IFN defined duration, 12 months for both HBeAg+ and HBeAg patients

IFN defined duration, 12 months for both HBeAg+ and HBeAg patientsHBeAg- patients

Nucleos(t)ide analogues until treatment endpoint

• HBeAg+ patients HBeAg seroconversion + >6 mos consolidation Rx, ~50% after 5 yr Rx

• HBeAg- patients endpoint not defined, HBsAg loss

HBeAg- patients

Nucleos(t)ide analogues until treatment endpoint

• HBeAg+ patients HBeAg seroconversion + >6 mos consolidation Rx, ~50% after 5 yr Rx

• HBeAg- patients endpoint not defined, HBsAg loss ~5% after 5 yr Rx

• Cirrhotics life-long Rx?

~5% after 5 yr Rx

• Cirrhotics life-long Rx?

Cirrhosis Reversal Following Lamivudine Rx in HBV

Cirrhosis Reversal Following Lamivudine Rx in HBV

Courtesy of Ian Wanless, MD.


13


Types of Virological ResponseTypes of Virological Response

On Continuous TreatmentOn Treatment

On Continuous Treatment

LLOD LLOD

V D

NA

(L

og

10 I

U/m

l)

Relapse

Primary non-response Breakthrough

Breakthrough

Months MonthsSustainedResponse

HB

V

MaintainedResponse

0

Antiviral Resistance: Nomenclature

Antiviral Resistance: Nomenclature

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

Phenotypic resistance Decreased in vitro susceptibility to an antiviralagent

Virologic breakthrough Increase in HBV DNA by >1 log10 over nadir ontreatment

Biochemical breakthrough

Increase in ALT on treatment

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


14


Not head to head trialsDifferent patient populations and trial designsce

(%

)Differences in Development of

Resistance with Long-term Treatment in Nuc-naïve Patients

Differences in Development of Resistance with Long-term Treatment

in Nuc-naïve Patients

Different patient populations and trial designs

wit

h r

esis

tan

c

29

Pat

ien

ts 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.

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.

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 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 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, .


15


Tenofovir + Entecavir for Multidrug resistant HBV infection

Tenofovir + Entecavir for Multidrug resistant HBV infection

• 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

• HBIG and HB vaccine to infants of HBsAg+• HBIG and HB vaccine to infants of HBsAg+

HBVHBV

Indications for HBV vaccinationIndications for HBV vaccination

HBIG and HB vaccine to infants of HBsAg mothers

• Routine vaccination of infants and adolescents

• Catch-up vaccination of children

HBIG and HB vaccine to infants of HBsAg mothers

• Routine vaccination of infants and adolescents

• Catch-up vaccination of children

• Vaccination of adults at risk of infection• Vaccination of adults at risk of infection


16


10

HBV DNA Level andPerinatal Transmission of HBV

HBV DNA Level andPerinatal Transmission of HBV

Perinatal Transmission

2

4

6

8

Ra

te (

%)

2.9%

6.6%

8.5%

0

2

>108All Infantsof HBV DNA-

Positive Mothers

0% 0%

HBeAg-PositiveMothers

Wiseman E, et al. Med J Aust. 2009;190:489-492.

<105 105-108

Maternal HBV DNA (copies/mL)No cases of transmission from mothers with HBV DNA <8 log10 copies/mL.

One case of escape mutation identified.

Treatment during pregnancyTreatment during pregnancy

• Xu et al• Xu et al

• Primary endpoint HBsAg + infant at 1 yr

• Secondary endpoint HBsAb+, HBV DNA+

• Primary endpoint HBsAg + infant at 1 yr

• Secondary endpoint HBsAb+, HBV DNA+Xu WM, Cui YT, Wang L, et al. Efficacy and safety of lamivudine in late pregnancy for the prevention of mother-child transmission of hepatitis B; a multicentre, randomized, double-blind, placebo-controlled study. Hepatology. 2004;40:272A. [Abstract #246].


17


Treatment during pregnancyTreatment during pregnancy

• Xu et al: Improved outcomes for the• Xu et al: Improved outcomes for the• Xu et al: Improved outcomes for the infants

• Xu et al: Improved outcomes for the infants

HBsAb positive 84%vs. 61% (p=0.008)HBsAb positive 84%vs. 61% (p=0.008)

Treatment of HBV: Special CasesTreatment of HBV: Special Cases• Prophylactic treatment during chemotherapy to prevent

reactivation (Rx from 1 wk before to 3-12 mo after)1

• % with hepatitis: 53% untreated vs. 14% lamivudine-treated

• Prophylactic treatment during chemotherapy to prevent reactivation (Rx from 1 wk before to 3-12 mo after)1

• % with hepatitis: 53% untreated vs. 14% lamivudine-treated

• Treatment of women during the third trimester of pregnancy to reduce rate of vertical transmission2

• Studies limited; use in women with HBV DNA >108 c/mL

• HBV/HIV coinfection3

• If HAART needed, then tenofovir + emtricitabine or lamivudine

• Treatment of women during the third trimester of pregnancy to reduce rate of vertical transmission2

• Studies limited; use in women with HBV DNA >108 c/mL

• HBV/HIV coinfection3

• If HAART needed, then tenofovir + emtricitabine or lamivudine

• Prophylactic treatment after liver transplantation to prevent reinfection3

• Prophylactic treatment after liver transplantation to prevent reinfection3

1Kohrt H, et al. Aliment Pharmacol Ther. 2006;24:1003-1016.2Xu WM, et al. Hepatology. 2004;40:272A-273A.3Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.


18


HBV Reactivation FollowingRituximab-Containing Chemotherapy

HBV Reactivation FollowingRituximab-Containing Chemotherapy

• Single-center cohort with a variety of hematologic diagnoses (n=62) (2011-2013)

• Single-center cohort with a variety of hematologic diagnoses (n=62) (2011-2013)

Cumulative Rate ofHBV Reactivation

)• HBsAg negative, anti-HBc positive

• HBV DNA <10 IU/mL

• No concomitant liver disease or prior HBV treatment

• Reactivation: HBV DNA >10 IU/mL regardless of HBsAg status

• Follow-up: 36.6 months

• High rate of reactivation

)• HBsAg negative, anti-HBc positive

• HBV DNA <10 IU/mL

• No concomitant liver disease or prior HBV treatment

• Reactivation: HBV DNA >10 IU/mL regardless of HBsAg status

• Follow-up: 36.6 months

• High rate of reactivation

y o

f H

BV

Rea

ctiv

atio

n (

%) 9-Month Cumulative

Rate: 29.3%

• Majority occurred within the first 6 months (86.7%)

• Presence of low anti-HBs levels was not protective against HBV reactivation

• Majority occurred within the first 6 months (86.7%)

• Presence of low anti-HBs levels was not protective against HBV reactivation

Seto W, et al. Hepatology. 2013;58(suppl 1):224A. Abstract 34.

Pro

bab

ilit

y

Months

0 12 24 36 48 60 72 84 96

Hepatitis B reactivation recommendationsigh-Risk Patients (Anticipated Incidence of HBV Reactivation, >

10% of Cases)

Hepatitis B reactivation recommendationsigh-Risk Patients (Anticipated Incidence of HBV Reactivation, >

10% of Cases) • Tenofovir/Entecavir preferred agents

• Continue antiviral therapy for at least 6 months after

• Tenofovir/Entecavir preferred agents

• Continue antiviral therapy for at least 6 months afterContinue antiviral therapy for at least 6 months after discontinuation of immunosuppressive therapy (at least 12 months for B-cell–depleting agents).

• Hepatitis B surface antigen (HBsAg)-positive/anti-hepatitis B core antibody (HBc)–positive patients treated with B-cell–depleting agents (eg, rituximab, ofatumumab)

• HBsAg positive/anti HBc positive patients treated with

Continue antiviral therapy for at least 6 months after discontinuation of immunosuppressive therapy (at least 12 months for B-cell–depleting agents).

• Hepatitis B surface antigen (HBsAg)-positive/anti-hepatitis B core antibody (HBc)–positive patients treated with B-cell–depleting agents (eg, rituximab, ofatumumab)

• HBsAg positive/anti HBc positive patients treated with• HBsAg-positive/anti-HBc–positive patients treated with anthracycline derivatives (eg, doxorubicin, epirubicin)

• HBsAg-positive/anti-HBc–positive patients treated with moderate-dose (10-20 mg prednisone daily or equivalent) or high-dose (> 20 mg prednisone daily or equivalent) corticosteroids daily for ≥ 4 weeks.

• HBsAg-positive/anti-HBc–positive patients treated with anthracycline derivatives (eg, doxorubicin, epirubicin)

• HBsAg-positive/anti-HBc–positive patients treated with moderate-dose (10-20 mg prednisone daily or equivalent) or high-dose (> 20 mg prednisone daily or equivalent) corticosteroids daily for ≥ 4 weeks.

Reddy et al Gastroenterology 2015;148:215–219


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• Tenfovir/Entecavir preferred, continue treatment for 6 months after discontinuation of immunosuppressive therapy

• HBsAg-positive/anti-HBc–positive or HBsAg-negative/anti-HBc–positive patients treated with tumor necrosis factor alpha inhibitors (eg etanercept adalimumab

• Tenfovir/Entecavir preferred, continue treatment for 6 months after discontinuation of immunosuppressive therapy

• HBsAg-positive/anti-HBc–positive or HBsAg-negative/anti-HBc–positive patients treated with tumor necrosis factor alpha inhibitors (eg etanercept adalimumab

Hepatitis B reactivation recommendationsModerate-Risk Patients (HBV Reactivation, 1%-10% of Cases)

Hepatitis B reactivation recommendationsModerate-Risk Patients (HBV Reactivation, 1%-10% of Cases)

treated with tumor necrosis factor alpha inhibitors (eg, etanercept, adalimumab, certolizumab, infliximab)

• HBsAg-positive/anti-HBc–positive or HBsAg-negative/anti-HBc–positive patients treated with other cytokine or integrin inhibitors (eg, abatacept, ustekinumab, natalizumab, vedolizumab)

• HBsAg-positive/anti-HBc–positive or HBsAg-negative/anti-HBc–positive patients treated with tyrosine kinase inhibitors (eg, imatinib, nilotinib)

HBsAg positive/anti HBc positive patients treated with low dose (< 10 mg

treated with tumor necrosis factor alpha inhibitors (eg, etanercept, adalimumab, certolizumab, infliximab)

• HBsAg-positive/anti-HBc–positive or HBsAg-negative/anti-HBc–positive patients treated with other cytokine or integrin inhibitors (eg, abatacept, ustekinumab, natalizumab, vedolizumab)

• HBsAg-positive/anti-HBc–positive or HBsAg-negative/anti-HBc–positive patients treated with tyrosine kinase inhibitors (eg, imatinib, nilotinib)

HBsAg positive/anti HBc positive patients treated with low dose (< 10 mg• HBsAg-positive/anti-HBc–positive patients treated with low-dose (< 10 mg prednisone daily or equivalent) corticosteroids for ≥ 4 weeks

• HBsAg-negative/anti-HBc–positive patients treated with moderate-dose (10-20 mg prednisone daily or equivalent) or high-dose (> 20 mg prednisone daily or equivalent) corticosteroids daily for ≥ 4 weeks

• HBsAg-negative/anti-HBc–positive patients treated with anthracycline derivatives (eg, doxorubicin, epirubicin).

• HBsAg-positive/anti-HBc–positive patients treated with low-dose (< 10 mg prednisone daily or equivalent) corticosteroids for ≥ 4 weeks

• HBsAg-negative/anti-HBc–positive patients treated with moderate-dose (10-20 mg prednisone daily or equivalent) or high-dose (> 20 mg prednisone daily or equivalent) corticosteroids daily for ≥ 4 weeks

• HBsAg-negative/anti-HBc–positive patients treated with anthracycline derivatives (eg, doxorubicin, epirubicin).

How do we screen for HCC in HBV How do we screen for HCC in HBV • No studies define unequivocally the best modality for diagnosing HCC•Ultrasonography (US)every 6 months with alpha-g p y ( ) y pfetoprotein (AFP) every six months is current standard of care for screening high risk patients

•US has technical limitations (operator dependence, reduced efficacy in those with elevated BMI)•US if subject has normal BMI

•AFP alone is not sufficient unless imaging modalities are g gnot available•Our practice at IU: MRI every 9 months or Dual Phase Spiral CT , or US every 6 months if normal BMI

•MRI or US preferred due to radiation risk with CT scan


20


AASLD Guidelines: HBVAASLD Guidelines: HBV• Surveillance recommended in at-risk groups

– Specific hepatitis B carriers

Asian males >40 years– Asian males >40 years

– Asian females >50 years

– Africans >20 years

– All HBV cirrhotic ptsp

– Family history of hepatoma

• Patients should be screened at 6-month intervals

• US and AFP level

Other Clinical PearlsOther Clinical Pearls

• Avoid entecavir use in HBV/HIV

• leads to HIV resistance

• Avoid entecavir use in HBV/HIV

• leads to HIV resistance

• Check HIV serology prior to initiating entecavir

• Telbivudine /Tenofovir are pregancy category B

• Useful in young females trying to conceive

• Acute HBV in pregnancy

• Low rate of resistance if HBV undetected by week 24 but must

• Check HIV serology prior to initiating entecavir

• Telbivudine /Tenofovir are pregancy category B

• Useful in young females trying to conceive

• Acute HBV in pregnancy

• Low rate of resistance if HBV undetected by week 24 but must• Low rate of resistance if HBV undetected by week 24 but must monitor for resistance

• Low rate of resistance if HBV undetected by week 24 but must monitor for resistance


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• Chronic HBV infection: HBsAg+ > 6 months• Chronic HBV infection: HBsAg+ > 6 months

Who Should be Treated?

Indications for treatment of chronic hepatitis B

Indications for treatment of chronic hepatitis B

Chronic HBV infection: HBsAg 6 months

• Evidence of virus replication: serum HBV DNA >104-5 copies/ml (2000-20,000 IU/ml)

• Evidence of liver damage: elevated ALT and/or

Chronic HBV infection: HBsAg 6 months

• Evidence of virus replication: serum HBV DNA >104-5 copies/ml (2000-20,000 IU/ml)

• Evidence of liver damage: elevated ALT and/or• Evidence of liver damage: elevated ALT and/or chronic hepatitis on biopsy

• Evidence of liver damage: elevated ALT and/or chronic hepatitis on biopsy

SummarySummaryPrevention

• Avoid unnecessary treatment

• Initiate treatment with potent antiviral that has low rate of drug resistance (tenfovir or entecavir) or with combinationdrug resistance (tenfovir 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• 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


22


Summary of GuidelinesTreatment of Hepatitis B

Summary of GuidelinesTreatment of Hepatitis B

When to start therapy• Elevated HBV DNA [>20,000 IU/mL for HBeAg(+) and

When to start therapy• Elevated HBV DNA [>20,000 IU/mL for HBeAg(+) and [ g( )

2,000 IU/mL for HBeAg(-)] plus elevated ALT, and/or significant disease on liver biopsy

When to stop or alter therapy• HBeAg(+): HBeAg seroconversion and (-) HBV DNA

• HBeAg(-): ?long-term therapy

[ g( )2,000 IU/mL for HBeAg(-)] plus elevated ALT, and/or significant disease on liver biopsy

When to stop or alter therapy• HBeAg(+): HBeAg seroconversion and (-) HBV DNA

• HBeAg(-): ?long-term therapyg( ) g py

• Inadequate VR (≥2,000 IU/mL) at week 24

• Development of antiviral drug resistance

g( ) g py

• Inadequate VR (≥2,000 IU/mL) at week 24

• Development of antiviral drug resistance

SummarySummary

TreatmentTreatment

• Guided by genotypic assays

• Add on therapy or switch therapy per guidelines

• Rescue therapies for multi-drug resistance

• tenofovir+entecavir

• Guided by genotypic assays

• Add on therapy or switch therapy per guidelines

• Rescue therapies for multi-drug resistance

• tenofovir+entecavir• tenofovir+entecavir

• tenofovir DF/emtricitabine

• tenofovir+entecavir

• tenofovir DF/emtricitabine


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treatment of hepatitis b - american college of...

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