treatment of hepatitis b - american college of...
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Paul Y. Kwo, MD, FACG
Treatment of hepatitis B Treatment of hepatitis B
Paul Y. Kwo, MD, FACG
Professor of Medicine
Paul Y. Kwo, MD, FACG
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
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Paul Y. Kwo, MD, FACG
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.
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Paul Y. Kwo, MD, FACG
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%
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Paul Y. Kwo, MD, FACG
Natural History of Chronic HBV Infection
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.
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Paul Y. Kwo, MD, FACG
ChildhoodChildhood Immune ToleranceImmune Tolerance>95%
Natural History of Chronic HBV Infection
Natural History of Chronic HBV Infection
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
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Paul Y. Kwo, MD, FACG
HBV DNA vs. HCC : REVEAL DataHBV DNA vs. HCC : REVEAL Data
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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
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Paul Y. Kwo, MD, FACG
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
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Paul Y. Kwo, MD, FACG
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.
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Paul Y. Kwo, MD, FACG
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
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Paul Y. Kwo, MD, FACG
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
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Paul Y. Kwo, MD, FACG
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*
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Paul Y. Kwo, MD, FACG
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)
• Interferon related: 86%
Probability of HBsAg Loss byMode of HBeAg Clearance
• Interferon related: 86%
• 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
• Interferon related: 86%
• 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%
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Paul Y. Kwo, MD, FACG
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.
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Paul Y. Kwo, MD, FACG
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.
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Paul Y. Kwo, MD, FACG
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, .
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Paul Y. Kwo, MD, FACG
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
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Paul Y. Kwo, MD, FACG
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].
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Paul Y. Kwo, MD, FACG
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.
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Paul Y. Kwo, MD, FACG
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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Paul Y. Kwo, MD, FACG
• 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
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Paul Y. Kwo, MD, FACG
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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Paul Y. Kwo, MD, FACG
• 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
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Paul Y. Kwo, MD, FACG
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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