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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 pkwo@iu.edu
• 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
p
• Multiple serotypes and genotypes A-H
• Enveloped
• In vitro model: primary hepatocyte culture and transfection of cloned HBV DNA
p
• Multiple serotypes and genotypes A-H
• 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
• In vivo replication: in cytoplasm, cccDNA in nucleus; hepatocyteand other tissues, human and other primates
ACG's Hepatitis School - Las Vegas, NV Copyright 2015 American College of Gastroenterology
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Paul Y. Kwo, MD, FACG
• 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
p
• Multiple serotypes and genotypes A-H
• Enveloped
• In vitro model: primary hepatocyte culture and transfection of cloned HBV DNA
p
• 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; hepatocyteand other tissues, human and other primates
transfection of cloned HBV DNA
• In vivo replication: in cytoplasm, cccDNA in nucleus; hepatocyteand other tissues, human and other primates
• 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
p
• Multiple serotypes and genotypes A-H
• Enveloped
• In vitro model: primary hepatocyte culture and transfection of cloned HBV DNA
p
• Multiple serotypes and genotypes A-H
• 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
• In vivo replication: in cytoplasm, cccDNA in nucleus; hepatocyteand 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
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.
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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
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.
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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
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
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Paul Y. Kwo, MD, FACG
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
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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)
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
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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 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.
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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 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)
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Paul Y. Kwo, MD, FACG
HBV Roadmap:Treatment Response to HBV DNA
HBV Roadmap:Treatment Response to HBV DNA
Early Predictors of Efficacyat Week 24at Week 24
CompleteResponse(PCR Negative)
PartialResponse
(HBV DNA >60 to <2000 IU/mL)
InadequateResponse
(HBV DNA >2000 IU/mL)
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.
No Changein Treatment
HBV Roadmap:Treatment Response to HBV DNA
HBV Roadmap:Treatment Response to HBV DNA
Early Predictors of Efficacyat Week 24at Week 24
CompleteResponse(PCR Negative)
PartialResponse
(HBV DNA >60 to <2000 IU/mL)
InadequateResponse
(HBV DNA >2000 IU/mL)
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.
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)
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Paul Y. Kwo, MD, FACG
HBV Roadmap:Treatment Response to HBV DNA
HBV Roadmap:Treatment Response to HBV DNA
Early Predictors of Efficacyt W k 24at Week 24
CompleteResponse(PCR Negative)
PartialResponse
(HBV DNA >60 to <2000 IU/mL)
InadequateResponse
(HBV DNA >2000 IU/mL)
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.
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.
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Paul Y. Kwo, MD, FACG
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
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Paul Y. Kwo, MD, FACG
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.
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Paul Y. Kwo, MD, FACG
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
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Paul Y. Kwo, MD, FACG
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
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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
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
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Paul Y. Kwo, MD, FACG
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.
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Paul Y. Kwo, MD, FACG
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
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
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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
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
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Paul Y. Kwo, MD, FACG
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
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