hepatitis b resistance to nucleos(t)ide antiviral medications
DESCRIPTION
Hepatitis B Resistance to Nucleos(t)ide Antiviral Medications. ROBERT BROWN, MD Chief, Division of Abdominal Organ Transplantation Columbia University College of Physicians & Surgeons New York, New York. Learning Objectives (CME, CE, CPE). - PowerPoint PPT PresentationTRANSCRIPT
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Hepatitis B Resistance to Nucleos(t)ide Antiviral Medications
ROBERT BROWN, MDROBERT BROWN, MD
Chief, Division of Abdominal Organ TransplantationColumbia University College of Physicians & Surgeons
New York, New York
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Learning Objectives (CME, CE, CPE)● At the completion of this educational activity,
participants should be able to:- Discuss the mechanism of action of anti-hepatitis B
(HBV) therapeutics - Relate the mechanisms of resistance to HBV
therapies- Discuss clinical trial results regarding preventing or
treating HBV resistance to therapy- Demonstrate an understanding of treatment guideline
recommendations regarding adding or switching therapy due to development of resistance
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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.
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HBV Virion, e-Antigen, and S Proteins
Pol Protein HBsAg
DNA
VirusDane Particle
40 nmDiameter
CoreHBcAg
Filamentous ParticleUp to 200 nm Long
Spherical Particle~20 nm Diameter
Membrane
HBeAg
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CCCDNA
HBV mRNA
ER
Golgi
HBsAg
HBeAgHBV Virion
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HBV Virion Half-Life
Dandri M, et al. Hepatology. 2008;48:1079-1086.
HBeAg-Negative
Virion Half-Life: 46 minutes(range: 4 to 224 minutes)
Virion Half-Life: 150 seconds(range: 24 seconds to 13 minutes)
HBeAg-Positive
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Rate of Generation ofHBV Mutants at Peak Infection
Base Changes Fraction
Number Created per Day
Number of Possible Mutants*
Fraction of All Possible Mutants Created per Day
0 0.9968 9.97 x 1012 - -
1 0.0032 3.2 x 1010 9.6 x 103 1
2 5 x 10-6 5 x 107 4.6 x 107 0.66
3 5.4 x 10-9 5.4 x 104 1.5 x 1011 3.6 x 10-7
*Computed as 3i( ) where n=3200 is the genome length, i is the number of base changes, and ( ) is a binomial coefficient.
ni
ni
High rate of mutations predisposes the virus to antiviral resistance.Whalley SA, et al. J Exp Med. 2001;193:847-854.
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Appearance of Resistance-Related Mutations Is Associated With Virologic Breakthrough
Wild-TypeMutant
HB
V D
NA
log
10 cop
ies/
mL
Mixture
Lee CZ, et al. World J Gastroenterol. 2006;12:5301-5305.
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Viral Persistence and Mechanism for Selection of Mutant HBV Strains
Fournier C, et al. Clin Liver Dis. 2007;11:869-892.
Virus cccDNA Half-Life
HepatocyteHalf-Life
Spontaneous Errors in Viral Polymerase
Quasi-Species
Viral Persistence
Host
Selection of Resistant StrainsPhenotypic Resistance
Treatment Failure
Antivirals
Immune Response
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Antiviral Resistance: Nomenclature
Primary failure (nonresponse)
Lack of >1 log10 decrease in HBV DNA at 6 months
Secondary failure(breakthrough)
>1 log10 increase in HBV DNA above nadir in compliant patient
Lok AS, et al. Hepatology. 2007;46:254-265.
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Antiviral Resistance: Nomenclature
Genotypic resistance Detection of HBV polymerase mutation(s) associated with resistance
Phenotypic resistance Decreased in vitro susceptibility to an antiviral agent
Virologic breakthrough
Increase in HBV DNA by >1 log10 over nadir on treatment
Biochemical breakthrough
Increase in ALT on treatment
Lok AS, et al. Hepatology. 2007;46:254-265.
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Types of Virological Response
On Continuous Treatment
Months MonthsSustainedResponse
LLOD LLOD
HB
V D
NA
(Log
10 IU
/ml)
Relapse(rebound)
Primary Non-Response
MaintainedResponse
0
Breakthrough
On Treatment
Slide courtesy of ASF Lok, MD.
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HBV Reverse Transcriptase Mutations Associated With Antiviral Resistance
rtL80V/I rtM204V/I/SLamivudine rtV173LrtL180M
845 a.a.
Terminalprotein Spacer Pol/RT RNaseH
A B C ED
YMDDGVGLSPFLLA
I(G) II(F) rtA181T/V rtN236TAdefovir
rtM204V/IrtS202G/C rtM250I/VrtT184S/A/I/L
Entecavir rtL180M
rtM204ITelbivudine rtL80V/I rtL180MAllen MI, et al. Hepatology. 1998;27:1670-1677.Qi X, et al. 39th EASL. Berlin, 2004. Abstract 57.Schildgen O, et al. N Engl J Med. 2006;354:1807-1812.Telbivudine full prescribing information.Tenney DJ, et al. Antimicrob Agents Chemother. 2004;48:3498-3507.
rtA181T/V* rtN236T*Tenofovir DF
*Shown in vitro, but significance in vivo is unknown(not seen in any clinical trial for up to 2 years.
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Pre-Existing HBV ResistanceMutations Detected by Line-Probe Assay
rt Mutation Prevalence (%) M204V/I 13
L80V/I 7
L180M 7
S202I 5
T184G 3
M250V 3
V173L 1
Fung SK, et al. J Hepatol. 2008;48(suppl 2):S256. Abstract 688.
Resistance mutations seen in antiviral-naïve patients (N=146)
Resistance determined by line probe assay and confirmed by direct sequencing
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Infectivity By Mutational Pattern
Villet S, et al. J Hepatol. 2008;48(suppl 2):S253. Abstract 681.
Replication in Presence of Lamivudine + AdefovirReplication Without Drug
400
350
200
150
50
0
300
250
100
120
100
80
60
40
20
0
pol Gene Mutations S Gene Mutations1 wt wt
2 T1281; V173L; L180M; A181V; M204V R79H; P120S; E164D; L173F; I195M; Y206F3 T1281; V173L; L180M; A181V; M204V; L220I; N236T P120S; E164D; L173F; I195M
4 T1281; V173L; L180M; A181V; ∆102-111 R79H; P120S; E164D; L173F; ∆102-111
5 T1281; V173L; L180M; A181V; N236T R79H; P120S; E164D; L173F
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Clinical Trial Data on Resistance
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Lamivudine Resistance
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Incidence ofLamivudine Resistance in Chronic HBV
0102030405060708090
100
1
Patie
nts
(%)
2 3 4
32%38%
45%
67%
Dienstag JL, et al. N Engl J Med. 1999;341:1256-1263.Liaw YF, et al. Gastroenterology. 2000;119:172-180.Chang TT, et al. J Gastroenterol Hepatol. 2004;19:1276-1282.
Duration of Lamivudine Therapy (years)
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Lamivudine Resistance Accelerates Progression of Liver Disease
Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.
Patie
nts
With
Dis
ease
Prog
ress
ion
(%) Wild-type (n=221)
YMDDm (n=209) (49%)
Time After Randomization (months)
0
5
10
15
20
25
0 6 12 18 24 30 36
Placebo (n=215)
5%
13%
21%
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Combination Adefovir + Lamivudine Is Superior to Adefovir Alone in Lamivudine Resistance
Lampertico P, et al. 57th AASLD. Boston, 2006. Abstract LB5.
*>1 log rebound of HBV DNA compared to on-treatment nadir.†N236T or A181T-V in patients with virologic breakthrough.
0
20
40
60
80
100
0 3 6 9 12 15 18 21 24 27 30 33 36 Months
ADV mono
Pat ie
n ts
Wit h
Viro
log i
c B
r eak
thr o
u gh
273 268 256 225 201 158 61
30%
6%
P<0.001
ADV+LAM
255 238 223 213 200 177 103
0
20
40
60
80
100
0 3 6 9 12 15 18 21 24 27 30 33 36Pa
t ien t
s w
it h A
DV -
R
229 225 217 194 179 146 57
16%
0.5%
P<0.001
ADV mono
ADV+LAM
242 227 214 205 200 174 92Patients
still at risk
Virologic Breakthrough* Adefovir Resistance†
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Entecavir for Patients With Lamivudine Resistance: 3-Year Results
Yao GB, et al. J Hepatol. 2008;48(suppl 2):S267. Abstract 715.
0102030405060708090
100
Patie
nts
(%)
Normalized ALT
HBV DNA<400 copies/mL
HBeAgLoss
65%55%
7%2%
n=128 patients on long-term entecavir following lamivudine failure.
HBeAgSeroconversion
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Entecavir for LamivudineRefractory Patients: Patient Flow
ETV-026:ETV-026:HBeAg+HBeAg+
ETV-014ETV-014:Dose RangingDose Ranging
Randomized StudiesEntecavir 1.0 mg
ETV-901ETV-901
Rollover StudyEntecavir 1.0 mg
Responders1
VirologicResponders1
AnyETV-015ETV-015:Post-TransplantPost-Transplant
Non-Responders1
*Protocol-defined response criteria.Tenney DJ, et al. 18th APASL. Seoul, 2008. Abstract PL02.
Any
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Lamivudine-Refractory Cohort (HBeAg+)
*Protocol-defined response criteria.Tenney DJ, et al. 18th APASL. Seoul, 2008. Abstract PL02.
Cumulative Probability of Entecavir Resistance Through 5 Years
0
10
20
30
40
50
60
HBV DNA <300 copies/mL: 72/187 (39%), of whom 3 (4%) had subsequent genotypic entecavir resistance.
Cum
ulat
ive
Prob
abili
ty (%
)
1(n=187)
2(n=146)
3(n=80)
4(n=536)
5(n=33)
Year
ETVr = LVDr (M204V + L180M) + T184, S202 and/or M250 substitutionsETVr + virologic Breakthrough (>1 log increase from nadir)
6%
15%
36%
46%51%
1%
11%
27%
41% 43%
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Adefovir Resistance
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Adefovir Cumulative Probabilities of Virologic Outcomes and Resistance in HBeAg-Negative Patients
0102030405060708090
100
Patie
nts
(%)
0%31
Year
*Genotypic resistance plus HBV DNA rebound.†Confirmed >1 log10 copies/mL increase in HBV DNA from nadir and/or having never achieved HBV DNA suppression <104 copies/mL. ‡Virologic rebound plus ALT elevations.
23% 3% 2%
11% 8% 6%
18%13%
29%
16%11%
Genotypic resistance* (n=29)Virologic rebound† (n=18)Clinical breakthrough‡ (n=13)
540% 0%
10%
Borroto-Esoda K, et al. 41st EASL. Vienna, 2006. Abstract 483.
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Adefovir: Resistance Incidence per Periodand Cumulative Risk From 5 Clinical Trials
0102030405060708090
100
Res
ista
nce
(%)
97-144(n=221)
0-48(n=629)
Weeks
Combined analysis of 5 studies of adefovir monotherapy or combination therapy in patients with chronic HBV, with or without lamivudine resistance.
49-96(n=293)
5%2%
7% 8%15%
Per periodCumulative
145-192(n=67)
0%
Locarnini S, et al. 40th EASL. Paris, 2005. Abstract 36.
2%
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Adefovir Resistance Uncommon Among Lamivudine-Resistant Patients Receiving
Combination Adefovir + Lamivudine
0102030405060708090
100
Res
ista
nce
(%)
0%31
Year2
3% 0% 0%
11%0% 0%
18%
0%
29%
Monotherapy (n=125)Combination pre/post OLT (n=264)Combination in HIV-infected patients (n=35)
540% 0%
Hadziyannis S, et al. 41st EASL. Vienna, 2006. Abstract 499.Lampertico P, et al. 41st EASL. Vienna, 2006. Abstract 116.Benhamou Y, et al. 15th IAC. Bangkok, 2006. Abstract WeOrA1329.
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Genotypic Resistance to Adefovir in Patients With Lamivudine-Resistant HBV
Lampertico P, et al. Gastroenterology. 2007;133:1445-1451.Subjects were treated with combination adefovir + lamivudine.
Incidence (%)Months of Treatment
Adefovir Mutations
Baseline(n=145)
12(n-139)
24(n=112)
36(n=78)
48(n=39)
rtN236T 0 0 0 0 0
rt181V 1 0 0 0 0
rtA181T 3 0.7 0.9 1.3 0
Overall 4 0.7 0.9 1.3 0
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Undetectable HBV DNA(<103 copies/mL)
6%GenotypicResistance
94%No Mutations
Week 48(n=89)
Detectable HBV DNA(>103 copies/mL)
49%GenotypicResistance
51%No Mutations
Week 48(n=35)
Detectable HBV DNA (>103 copies/mL) at 48 weeks was the only significant predictor of resistance over 4 years (P=0.0003).Stepwise logistic regression analysis that included demographics, genotype, baseline fibrosis, and HBV DNA at week 48.Hadziyannis SJ, et al. Gastroenterology. 2006;131:1743-1751.
Adefovir Therapy: HBV DNA >103 Copies/mL at Week 48 Predicts Genotypic Mutations at 4 Years
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Correlation of Viral Load With Response in Lamivudine-Resistant Subjects Receiving Adefovir
Monotherapy
Castel J, et al. J Hepatol. 2008;48(suppl 2):S255. Abstract 684.
% A
defo
vir R
esis
tanc
e
Baseline HBV DNA>6 log <6 log
Week 48 Resistance to Adefovir
*P=0.05.
*12.5%
2.9%
0%
5%
10%
15%
20%
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Add-On Adefovir + Lamivudine Prevents Emergence of Adefovir Resistance
Lampertico P, et al. J Hepatol. 2008;48(suppl 2):S259. Abstract 696.
5257
7483
78
0102030405060708090
100
% H
BV
DN
A <
35 c
/mL
1Year
2 43 5
n=63.No patient demonstrated rtN236T or rtA181V mutation at baseline or follow-up.
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Entecavir Resistance
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Development ofResistance to Entecavir
● Combination of YMDD (M204V/I + L180M) and at least 1 entecavir substitution are required for virologic rebound due to resistance
● Primary entecavir substitutions (T184, S202, M250) can emerge on lamivudine therapy
● Primary entecavir mutations also seen in “wild-type” viral quasi-species
Tenney DL, et al. Antimicrob Agent Chemother. 2004;48:3498-3507.Jardi R, et al. 57th AASLD. Boston, 2006. Abstract 966.
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Cumulative Resistance to Entecavir in Treatment-Naïve and Lamivudine-Resistant Populations
0102030405060708090
100
Res
ista
nce
(%)
0%31
Year2
0.4%
14%
1.1% 0.8%
32%39.5%
Nucleos(t)ide naïve (n=664) Lamivudine resistant (n=50)
4
6%
Resistance associated with appearance of rtT184, rtS202 or rtT184 + rtS202 mutations.Colonno R, et al. 42nd EASL. Barcelona, 2007. Abstract 781.
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Phenotypic Sensitivity to Entecavirat the Time of Viral Rebound
n=192, from all phase III clinical trials of entecavir.Tenney DJ, et al. Antimicrob Agents Chemother. 2007;51:902-911.
10000
1000
100
10
1Baseline Rebound
ETVET
V EC
50 (n
M)
Entecavir at reboundNo entecavir at rebound
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Treatment of Entecavir ResistanceWith Adefovir + Lamivudine
Yurdaydin C, et al. J Hepatol. 2008;48(suppl 2):S255. Abstract 685.
-7
-6
-5
-4
-3
-2
-1
0
Reduction in HBV DNA from Baseline
HB
V D
NA
log1
0 R
educ
tion
Week 24 Week 48
-2.47 ± 1.12-2.88 ± 1.40
n=10; lamivudine-refractory patients experiencing virologic breakthrough on entecavir.
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Telbivudine Resistance
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0
5
10
15
20
GLOBE Study: Week 52 Telbivudine Resistance (as-treated analysis)
HBeAg Positive(n=430)
Res
ista
nce
(%)
11.4%
5.3%
HBeAg Negative(n=227)
The rtM204I substitution was the most frequent mutation and was associated with virologic rebound (>1 log10 increase above nadir) in 34 of 46 patients.
HBV DNA >1000 Copies/mL>16 Weeks of Telbivudine Therapy
Telbivudine full prescribing information.
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0
10
20
30
40
50
Telbivudine Versus Lamivudine: Cumulative Resistance At Year 2
HBeAg Positive HBeAg Negative
Cum
ulat
ive
Res
ista
nce
(%)
17.8%
30.1%
35.0%
21.6%
Per Protocol HBV DNA 1 LogAbove Nadir
TelbivudineLamivudine
0
10
20
30
40
50
Cum
ulat
ive
Res
ista
nce
(%)
7.3%
16.6%
21.9%
8.6%
Per Protocol HBV DNA 1 LogAbove Nadir
TelbivudineLamivudine
Per protocol resistance: rebound with HBV DNA >5 log10 copies/mL.P<0.001; less resistance for telbivudine in all pair-wise comparisons.Lai CL, et al. 57th AASLD. Boston, 2006. Abstract 91.
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Tenofovir DF Resistance
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Tenofovir DF Versus Adefovir as Monotherapyin Patients With Lamivudine Resistance
-7
-6
-5
-4
-3
-2
-1
0
24
*P<0.001 versus adefovir.
Cha
nge
in H
BV
DN
A(lo
g 10 c
opie
s/m
L)
-5.2*
-2.6
36
van Bömmel F, et al. Hepatology. 2004;40:1421-1425.
48
-5.4*
-3.0
-5.5*
-2.8
Tenofovir DF (n=35)Adefovir (n=18)
Week
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Tenofovir DF Versus Adefovir Monotherapyin Lamivudine-Refractory Patients
● Single center study of patients with persistent lamivudine-resistant HBV
● Study arms- Tenofovir DF (n=35)
• 72 to 130 weeks
- Adefovir (n=18)• 60 to 80 weeks
● No evidence of tenofovir DF resistance at 48 weeks
van Bömmel F, et al. Hepatology. 2004;40:1421-1425.
HBV DNA <105 Copies/mL
0102030405060708090
100
Patie
nts
(%)
100%
44%
Tenofovir DF Adefovir
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Study 103 (HBeAg+):HBV DNA <400 Copes/mL (ITT)
0
10203040
5060708090
100
Patie
nts
(%)
Patie
nts
(%)
0 8 16 24 32 40 48 56 64 72 80 88 96
78%
WeeksWeeks
Double-BlindDouble-Blind
Heathcote EJ, et al. Hepatology. 2008;48(suppl):92A. Abstract 158.
Open-LabelOpen-LabelTDF to TDFADV to TDF
76%78%
P<0.001
13%
P=0.801
Includes 5 patients who had HBV DNA <400 copies/mL at week 96 on FTC/TDF.
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Study 102 (HBeAg-):HBV DNA <400 Copes/mL (ITT)
0
10203040
5060708090
100
Patie
nts
(%)
Patie
nts
(%)
0 8 16 24 32 40 48 56 64 72 80 88 96
91%
WeeksWeeks
Double-BlindDouble-Blind Open-LabelOpen-LabelTDF to TDFADV to TDF
93%
89%P<0.001
63%
P=0.166
Marcellin P, et al. Hepatology. 2008;48(suppl):88A. Abstract 146.
18% of patients were lamivudine experienced and of these 93% and 96% of TDF to TDF and ADV to TDF patients had HBV DNA <400 copies/mL at week 96.
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Study 103 and 102:Virologic Analysis Plan
● All patients- At baseline- Yearly if HBV DNA >400 copies/mL
(> 69 IU/mL)- At discontinuation of tenofovir DF
monotherapy if HBV DNA > 400 copies/mL
● Any patient post baseline with- Conserved site changes in pol/RT- Virologic breakthrough*- Polymorphic site changes (>1 patient)
Genotyping(HBV pol / RT)
Phenotyping(HBV pol / RT)
Snow-Lampart A, et al. Hepatology. 2008;48(suppl):745A. Abstract 977.
*Confirmed 1 log10 increase in HBV DNA and/or confirmed HBV DNA >400 copies/mL after achieving HBV DBA <400 copies/mL.
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Study 103 and 102:Resistance Surveillance at Week 96
Study 103HBeAg+(n=154)
Study 102HBeAg-(n=235)
Total(n=359)
Number of patients included in the week 96 resistance surveillance who had HBV DNA >400 copies/mL
18 6 24
Without virologic breakthrough With virologic breakthrough
153
24
177
Categories
After 96 weeks of tenofovir DF monotherapy Discontinued tenofovir DF monotherapy between week 48 and 92 Added emtricitabine to open-label tenofovir DF between week 72 to 96
30
15
22
2
52
17
Snow-Lampart A, et al. Hepatology. 2008;48(suppl):745A. Abstract 977.
Median duration of tenofovir DF monotherapy at time of discontinuation/addition of emtricitabine was 80 weeks.
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0
2
4
6
8
10
Study 103 and 102: Patients Who Were Viremic or Had Virologic Breakthrough (week 72-96)
HBV DNA >400 copies/mL
Patie
nts
(num
ber)
1(50%)
NoChange
HBeAg+ (n=12)HBeAg- (n=2)
Three HBeAg+ patients with HBV DNA >400 copies/mL were unable to be genotyped (PCR negative).Conserved site changes observed in one patient each at positions rtL101L/F and rtV173L + rtL180M + rtM204V.No two patients developed the same polymorphic site changes.
8(67%)
1(50%)
0(0%)
2(17%)
2(17%)
Polymorphic ConservedSite Changes
0
2
4
6
8
10
Virologic Breakthrough
Patie
nts
(num
ber)
3(75%)
NoChange
HBeAg+ (n=3)HBeAg- (n=4)
2(67%)
1(25%)
0(0%)
0(0%)
1(33%)
Polymorphic ConservedSite Changes
Snow-Lampart A, et al. Hepatology. 2008;48(suppl):745A. Abstract 977.
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Study 103 (HBeAg+): Phenotypic Analysis of the Two Tenofovir DF-Treatment Patients Harboring
Conserved Site Changes in HBV pol/RT
Snow-Lampart A, et al. Hepatology. 2008;48(suppl):745A. Abstract 977.
pol/RTTenofovir DF
EC50 (µM)Fold
Change†
Patient #8356 Baseline Wild type 12.4 + 3.6 Week 72 rtL101L/F 13.8 + 0.6 1.1 Week 72 (clone) rtL101F 10.0 + 6.2 0.7
Patient 7916 Baseline Wild-type 9.9 + 3.4 Week 72 rtV173L, rtL180M, tM204V 12.5 + 6.3 1.3
*Clonal analysis of the baseline sample showed the presence of the LAM-R mutations at a frequency of 6.5%.†Fold change: last on tenofovir DF EC50/ baseline EC50. Fold changes <2X are within the assay variability.Development of conserved site changes was not associated with phenotypic resistance to tenofovir DF.
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Study 103 and 102: Phenotypic Analysis ofSeven Tenofovir DF-Treatment Patients
With Virologic Breakthrough
Snow-Lampart A, et al. Hepatology. 2008;48(suppl):745A. Abstract 977.
*Fold change: last on TDF EC50/ baseline EC50. Fold changes <2X are within the assay variability.Virologic breakthrough was not associated with phenotypic resistance to tenofovir DF.
Tenofovir DFEC50 (µM)
Fold Change*
Patient 1674 Baseline Week 72
8.0 + 1.07.7 + 1.5
1.0Patient 1669 Baseline Week 96
9.7 + 4.111.1 + 7.7 1.1
Patient 6852 Baseline Week 96
12.2 + 4.710.5 + 4.4 0.9
Patient 7957 Baseline Week 80
10.3 + 0.78.3 + 1.5 0.8
Tenofovir DFEC50 (µM)
Fold Change*
Patient 1533 Baseline Week 96
11.2 + 5.311.3 + 5.7
1.0Patient 3958 Baseline Week 88
11.3 + 4.011.1 + 2.5 1.1
Patient 4957 Baseline Week 88
12.2 + 0.811.6 + 4.6 1.0
Study 102 (HBeAg-)Study 103 (HBeAg+)
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Study 103 and 102:Resistance and Virologic Breakthrough● No HBV pol/RT amino acid substitutions associated with resistance
to tenofovir DF were detected through 96 weeks of tenofovir DF monotherapy- Annual resistance surveillance on-going through year 8 (week 384)
● Virologic breakthrough was rare (study 103: 2.4%; study 102: 1.6%)- Not associated with phenotypic resistance to tenofovir DF- Majority of patients with virologic breakthrough had evidence of non-
adherence
● Development of conserved site changes was rare and not associated with phenotypic resistance to tenofovir DF
Snow-Lampart A, et al. Hepatology. 2008;48(suppl):745A. Abstract 977.
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Tenofovir DF Following Adefovir Monotherapy in Lamivudine Resistance● 20 patients with persistent HBV DNA on adefovir
monotherapy (mean 15 months) following viral breakthrough on lamivudine switched to tenofovir DF
● Tenofovir therapy results- HBV DNA <400 copies/mL: 19 of 20 patients- Normalization of elevated ALT: 10 of 14 patients- 4 patients lost HBeAg- Presence of lamivudine-resistance mutations did not impact
therapy with tenofovir DF• No tenofovir DF or adefovir resistance mutations were noted
van Bömmel F, et al. Hepatology. 2006;44:318-325.
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No Evidence for Tenofovir DF Resistance in Lamivudine-Resistant HBV Patients Treated for up to 5 Years
● Retrospective study- 69 patients with lamivudine-resistant HBV- Treated with tenofovir DF 300 mg daily (except 1 patient treated
every other day because of renal insufficiency)- Followed for at least 6 months and up to 59 months
● 68/69 patients had undetectable HBV DNA (<400 copies/mL) at end of observation period
● No evidence of tenofovir DF resistance● HBeAg seroconversion documented in 36% of patients
after a mean duration of 14 + 9 months of treatment● HBsAg lost in 8% of patients after 16 + 6 months van Bömmel F, et al. 57th AASLD. Boston, 2006. Abstract 971.
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0102030405060708090
100
No Resistance Seen in Treatment-NaïvePatients Treated With Tenofovir DF (week 48)
HBeAg Negative
Tenofovir DF(n=250)
Adefovir(n=125)
Patie
nts
(%)
HBV DNA <169 copies/mL
67%
Heathcote EJ, et al. 58th AASLD. Boston, 2007. Abstract LB6.Marcellin P, et al. 58th AASLD. Boston, 2007. Abstract LB2.
91%
0102030405060708090
100
HBeAg Positive
Tenofovir DF(N=176)
Adefovir(N=90)
Patie
nts
(%)
HBV DNA <169 copies/mL
9%
69%
No tenofovir DF resistance mutations detected at week 48.
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Tenofovir DF Efficacy in Lamivudine-Naïve and Lamivudine-Experienced Subjects
Manns M, et al. J Hepatol. 2008;48(suppl 2):S33. Abstract 74.
P=0.456P=0.247
P=0.718
% P
atie
nts
Complete Response
Histological Improvement
HBV DNA<400 copies/mL
68 72
86
7480
88
0102030405060708090
100 Lamivudine naïve (n=377)Lamivudine experienced (n=49)
Primary and Secondary Endpoints
No resistance to tenofovir DF was documented at week 48 for any subject.
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Weeks on Study
Tenofovir DF ± Emtricitabine inSubjects Remaining Viremic on Adefovir
Berg T, et al. J Hepatol. 2008;48(suppl 2):S34. Abstract 76.
P=0.988. No treatment-emergent resistance documented. Response to therapy identical with or without baseline resistance mutations.
Perc
enta
ge (%
)
0
10
20
30
40
50
60
70
100
0 4 8 12 16 20 24 28 32 36 40 44 48
53TDF n= 53 53 53 53 53 53 53 53 53 53 53 53 53 53 52FTC/TDF n= 52 52 52 52 52 52 52 52 50 50 50 52 52 52
Tenofovir DF + emtricitabine Tenofovir DF80
90
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Resistance in Experimental/UnapprovedAntiviral Agents
Clevudine
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Resistance to Clevudine● Limited clinical data available● In a trial of emtricitabine + clevudine
- 3 patients entered with lamivudine-associated mutations• L180M plus M204V
- 2 patients were assigned to the combination regimen of emtricitabine + clevudine• Neither patient responded to therapy
• Serum HBV DNA levels only declined 0.5 to 0.6 log10 copies/mL
Lim SG, et al. Antimicrob Agents Chemother. 2006;50:1642-1648.
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Resistance in Experimental/UnapprovedAntiviral Agents
Emtricitabine
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Resistance to Emtricitabine● Structurally similar to lamivudine
- Cross-resistance to lamivudine is primary limitation
● Lamivudine resistance mutations rtM204I + L180M also confer resistance to emtricitabine- Year 1: 9% to 16% of patients- Year 2: 19% to 37% of patients
● May be more beneficial in combination with tenofovir DF and other agents
Gish RG, et al. Semin Liver Dis. 2005;25(suppl 1):29-39.
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Cross Resistance
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Sequential MonotherapyCan Lead to Multidrug Resistance
● Analysis of phenotypic and genotypic evolution of resistance in 2 patients- Combination therapy after first failure
• Lamivudine lamivudine + adefovir lamivudine + adefovir + HBV immune globulin (post OLT)
• Single viral species with mutations at rtV173L + L180M + A181V + N236T noted on combination, plus sP120S associated with HBV immune globulin escape
- Sequential monotherapy• Interferon lamivudine entecavir• Sequence on entecavir contained mixture of 3 quasispecies containing
rtS202G + rtL180M + M204V (lamivudine mutations despite absence of lamivudine)
● Authors suggest de novo combination therapy may help prevent development of multidrug resistance mutations
Villet S, et al. 56th AASLD. San Francisco, 2005. Abstract 981.
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In Vitro Cross-Resistance With Lamivudine/Nucleoside Associated Mutations
Yang H, et al. Antivir Ther. 2005;10:625-633.*Fold-resistance calculated as the wild-type EC50/mutant EC50.
Fold Resistance*
L180M + M204VV173L + L180M
+ M204V M204I L180M + M204IAdefovir 1.1 1.1 1.8 2.1
Tenofovir DF 0.8 1.8 2.1 0.7
Entecavir 37 164 471 38
Lamivudine >700 >1000 >1000 >1000
Emtricitabine >2000 898 >2000 845
Clevudine >1600 >1600 >1600 >1600
Telbivudine >322 >322 >322 >322
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Treatment Guidelines:Managing Resistance
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Monitoring for Antiviral Resistance● Test serum HBV DNA prior to therapy and at
3-month intervals ● Primary non-responders should be offered
combination or alternative therapy● Inquire about medication compliance when
virologic breakthrough is seen● Genotyping should be performed to confirm
resistance and determine specific mutations
Lok AS, et al. Hepatology. 2007;46:254-265.
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AASLD Guidelines: Options for Lamivudine/Telbivudine Resistance
● Add adefovir or tenofovir DF- No evidence of resistance at 3 years when used in
combination with lamivudine
● Switch to emtricitabine + tenofovir DF (fixed-dose combination)
● Switch to entecavir- Risk of subsequent entecavir resistance and
multidrug resistance
Lok AS, et al. Hepatology. 2007;46:254-265.
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AASLD Guidelines:Options for Adefovir Resistance
● Add lamivudine● Switch to emtricitabine + tenofovir DF
(fixed-dose combination)● Add/switch to entecavir
- Caution with switch if prior lamivudine resistance
Lok AS, et al. Hepatology. 2007;46:254-265.
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AASLD Guidelines:Options for Entecavir Resistance
● Add adefovir or tenofovir DF● Note
- Clinical data on efficacy of alternative therapies is not currently available
Lok AS, et al. Hepatology. 2007;46:254-265.
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AASLD Guidelines:Options for Multidrug Resistance
● Multidrug resistance to lamivudine and adefovir- Consider tenofovir DF + emtricitabine, tenofovir,
entecavir
● Multidrug resistance to lamivudine and entecavir- Consider tenofovir DF or tenofovir DF + emtricitabine
● Therapy with two nucleosides or two nucleotides not recommended due to competitive inhibition
Lok AS, et al. Hepatology. 2007;46:254-265.
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Summary: AASLD Guidelines for Management of Antiviral-Resistant HBV
Resistance Rescue TherapyLamivudineTelbivudine
Add adefovir or tenofovir DFSwitch to: Emtricitabine + tenofovir DF (fixed-dose combination) Entecavir (risk of entecavir resistance)
Adefovir Add lamivudineSwitch to: Emtricitabine + tenofovir DF (fixed-dose combination) Entecavir (if no prior lamivudine resistance)
Entecavir Add adefovir or tenofovir DF
Multidrug Multidrug resistance to lamivudine + adefovir: Consider emtricitabine + tenofovir DF (fixed-dose combination), tenofovir DF, entecavirMultidrug resistance to lamivudine + entecavir: Consider tenofovir DF or emtricitabine + tenofovir DF (fixed-dose combination)
Lok AS, et al. Hepatology. 2007;46:254-265.
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Summary● Antiviral resistance is likely to become more important
as additional patients are sustained on long-term therapy
● HBV DNA monitoring is single most-important test to determine if patients are developing resistance to therapy
● Treatment of resistance depends on knowledge of patient treatment history
● Combination therapy and/or switching to non-cross resistant agents depends on clinical judgment