1 Antiviral Drug Resistance and the Need for Development of New ...
Chronic Hepatitis B - Antiviral Resistance in Korea Joint Symposium/4.Antiviral... ·...
Transcript of Chronic Hepatitis B - Antiviral Resistance in Korea Joint Symposium/4.Antiviral... ·...
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Chronic Hepatitis BChronic Hepatitis B-- Antiviral Resistance in Korea Antiviral Resistance in Korea --
YoungYoung--Suk LimSuk LimUniversity of Ulsan College of MedicineUniversity of Ulsan College of Medicine
Asan Medical CenterAsan Medical CenterSeoul, KoreaSeoul, Korea
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HBV Genome
• HBV polymerase lacks proof-reading function
• Estimated mutation frequency: 1.4-3.2 x 10-5
(approximately 10-fold higher than other DNA viruses)
• HBV production rate: 1011/day
• dynamic quasispecies
• partially double-stranded DNA genome
• about 3200 nucleotides
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Evolution of HBV Resistance Mutations to Antiviral Drugs
• Primary resistance mutations
mutations directly responsible for the associated drug-resistance
• Compensatory (Secondary) mutations
- mutations that can restore replication fitness of primary resistant mutants
- ‘fix’ the primary drug-resistant mutations as a genetic archive with quasispecies memory
• Cross Resistance
mutants selected by one agent may also confer resistance to other antiviral agents
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LamivudineLamivudine--Resistance Mutations Resistance Mutations at at HBV polymerase/RT domainHBV polymerase/RT domain
LMV Resistance rtL80V/I rtV173L rtM204V/I/SrtL180M
• primary resistance mutation• compensatory mutations• rtM204 mutation confers cross resistance to entecavir,
clevudine, telbivudine, emtricitabine
845 a.a.
Terminal Protein Spacer POL/RT RNaseH
A B C ED
1 183 349 (rt1) 692 (rt 344)
F__V__LLAQ__YMDDI(G) II(F)
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Mechanisms of Resistance
S
Sensitive(wild type)
S
R
Sensitive
Resistant(rtM204V)
Lamivudine
S
Sensitive
Resistant(rtM204V+rtL180M)
R
Discontinuation
R
SensitiveS
Resistant(rtM204V+rtL180M)
LamivudineClevudineEntecavirTelbivudineEmtricitabine
R
Resistant(rtM204V+rtL180M)
SSensitive
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Clinical Definitions - HBV Resistance to Antiviral Drugs -
• Genotypic Resistance
Detection of mutations in the HBV genome, known to confer resistance
• Virologic Breakthrough
Rebound in serum HBV DNA levels, more than 1 log10 cpm (10 fold)
• Biochemical (Clinical) BreakthroughIncrease of ALT levels (or worsening histology) with virologic breakthrough
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Development of Antiviral Resistance
Antiviral DrugAntiviral DrugHBV DNA (Log)
6
5
4
3
2
1 log
Virologic Breakthrough
Development of Genotypic Resistance
Biochemical Breakthrough
ALT (IU/L)
80
40 (ULN)
nadir
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Mutant / Wild type
165 (2)
120 (1)103 (2)
25 (5)
10 (9) 3 (3) 3 (3)
0
20
40
60
80
100
120
140
160
180
Inci
denc
e
0 1 2.5 5 7.5 10
Higher Retention of Mutant Virus Go with More Subsequent Occurrence of
Viral Breakthrough
Lee CH et. al. Gastroenterology. 2006;130(4)1144
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Genotypic Assays for antiviral drug resistance of HBV
• Sequencing (direct or after cloning)
• Hybridization Assay (Line probe assay, LiPA)
• Restriction Fragment Length Polymorphism (RFLP)
• Restriction Fragment Mass Polymorphism (RFMP)
• Allele-specific PCR
• DNA Chip
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Genotypic Assays for antiviral drug resistance of HBV
• Sequencing (direct or after cloning)
- the best approach to identify new mutations
- unable to detect mixed populations of two or more HBV genotypes
- expensive and time-consuming
• Hybridization Assay (Line probe assay, LiPA)
• Restriction Fragment Length Polymorphism (RFLP)
• Restriction Fragment Mass Polymorphism (RFMP)
• Allele-specific PCR
• DNA Chip
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Genotypic Assays for antiviral drug resistance of HBV
• Sequencing (direct or after cloning)
• Hybridization Assay (Line probe assay, LiPA)
- more sensitive than direct sequencing- most commonly used method in Western countries
• Restriction Fragment Length Polymorphism (RFLP)
• Restriction Fragment Mass Polymorphism (RFMP)
• Allele-specific PCR
• DNA Chip
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Genotypic Assays for antiviral drug resistance of HBV
• Sequencing (direct or after cloning)
• Hybridization Assay (Line probe assay, LiPA)
• Restriction Fragment Length Polymorphism (RFLP)
• Restriction Fragment Mass Polymorphism (RFMP)
• Allele-specific PCR
- can detect minor HBV populations comprising up to 5% of the total viral population (about 103 cpm)
- robust high throughput manner
- most commonly used methods in Korea
• DNA Chip
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1992 1998 2003 2005 2006 1992 1998 2003 2005 2006 -- -- --
Interfer
on
Lamivu
dine
Adefovir
Entecav
ir
Clevudine
Peg-IF
N α-2a
Tenofovir
Telbivu
dine
Advances in Management of HBV Infection
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HBV Therapies Approved in Korea
For Naïve CHB
• Interferon
• Peginterferon α-2a
• Lamivudine*
• Entecavir*
• Clevudine*
For LAM-Refractory CHB
• Interferon
• Peginterferon α-2a
• Adefovir dipivoxil*
• Entecavir*
*Approved only as monotherapy and after ALT flare
or biochemical breakthrough (ALT>80 IU/L)
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New Oral Agents
Future agents
• Telbivudine (LdT)
• Tenofovir
• Emtricitabine
New experimental agents
• LB80380
• Pradefovir
• Alamifovir
• Valtorcitabine
• Torcitabine
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High potency in reducing HBV DNA level
High rate of HBeAg seroconversion
Few adverse events or toxicity
Cost-effective
Long-term, low rate of drug resistance
Ideal antiIdeal anti--viral agent viral agent
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Lamivudine-Resistance
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LMV Resistance rtL80V/I rtV173L rtM204V/I/SrtL180M
L-dT Resistance rtM204I
ADV Resistance rtA181T/V rtN236T
ETV Resistance rtT184G rtS202I rtM250V
TFV Resistance rtA194T/rtV214A/rtQ215S
HBV polymerase/RT domainHBV polymerase/RT domain
845 a.a.
Terminal Protein Spacer POL/RT RNaseH
A B C ED
1 183 349 (rt1) 692 (rt 344)
YMDDF__V__LLAQ__I(G) II(F)
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Long-term LAM therapy can lead to the emergence of resistant viruses
01020304050607080
1 2 3 4 5 6 7 8Years
Patients with
YMDDmutants
(%)
90
15%
40%
55%66% 69%
1. Leung NW, et al. Hepatology. 2001;33:1527-1532. 2. Yuen et al AASLD 2005
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High lamivudine resistance with poor early HBV suppression
Yuen et al. Hepatology. 2001; 34:785-791
Patients(%)
Serum HBV DNA Level at 6 months (copies/mL)
0
20
40
60
80
100
8% 13%
32%
64%
Serum DNA at month 6 vs.LAM resistance by month 61
< 200(n = 12)
< 3 log10(n = 23)
< 4 log10(n = 41)
> 4 log10(n = 118)
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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
% with disease
progression
Placebo (n=215)
YMDDm
WT
Placebo
5%
13%
21%
Disease Progression by YMDD Status
Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.
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Hepatitis flares and Serious Adverse Events with Lamivudine resistance mutations
Lok AS, et al. Gastroenterology. 2003;125:1714.
hepatitis flareLiver Disease Related
Serious Adverse Events
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Clinical consequencesof Lamivudine resistance
It is now clear that drug-resistant HBV is not a benign or attenuated virus.
Disease progression, loss of initial benefit, fulminant hepatic failure and death can occur.
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Management of
Lamivudine-Resistant HBV
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Continuation or Discontinuation of Lamivudine
Events within 12 mo. after emergence of YMDD mutations
ALT flare (>5x ULN)
Decompensation HBeAg seroconversion
0
25
50
75Continued (n=66)Discontinued(n=68)
% *
*
*
* P > 0.05
11% 7%
Liaw YF, et al. Antivir Ther. 2004;9:257.
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Continuation or Discontinuation of Lamivudine
• Hepatitis flares and decompensation frequently occur after emergence of YMDD mutations regardless of continuation or discontinuation of lamivudine therapy .
• Compensatory mutations will be selected during continued lamivudine treatment leading to subsequent viral rebound and possibly hepatitis flares.
• Patients with confirmed lamivudine-resistance should receive effective rescue therapy.
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0
10
20
30
50
Patie
nts
(%)
43.7%
End of treatment
24 weeks post-treatment
7/16 5/16
31.2%40
HBsAg seroconversion
In 13% of patientsat week 72
Shi et al. APASL 2007
Peg-Interferon alfa-2ain Asian patients with NA resistance
12 wks PEGASYS + LAM → 12 wks of PEGASYS monotherapyHBeAg seroconversion
(with HBV DNA <105 copies/mL)
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Peters MG et al, Gastroenterology 2004; 126: 91-101
Adefovir alone or in combination with lamivudine in lamivudine-resistant HBV
(small, short-term study)
* p<0.001 comparedto lamivudine
ADV+LAM* (n=20)
ADV (n= 19)*
LAM (n=19)
Weeks of Therapy0 8 16 24 32 40 48
Change in HBV DNA
(log10
copies/mL)
37% frequency of grade 3 ALT flare in switchover to ADV alone
0.00.0
-- 3.63.6-- 4.04.0
-5
-4
-3
-2
-1
0
1
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Increased Risk of Adefovir Resistance inPatients with Lamivudine-Resistant CHB
after Adefovir Monotherapy
Incidence of ADV-Resistance at 48 wks of ADV monotherapy
Genotypicmutation
Virologic breakthrough
0
10
20naive (n=38)
LMV-resistant (n=57)
%*
*
0%
18%
7%0%
* P < 0.01
Lee YS, et al. Hepatology 2006;43:1385.
Genotypic assay ; RFMP
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Cumulative Incidence of Adefovir-Resistance in Lamivudine-Resistant CHB patients treated
with Adefovir MonotherapyGenotypic Resistance Virologic Breakthrough
25.4%Genotypic assay
; RFMP
Yeon JE, et al. Gut 2006;55:1488.
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Adding-on vs. Switching-to Adefovir in Lamivudine-Resistant HBeAg(-) CHB
Incidence of Genotypic Resistance
Genotypic assay ; direct sequencing
ADV
LAM + ADV
Rapti I, et al. Hepatology 2007;45:307.
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When should we add Adefovir on Lamivudine ?
Lampertico P, et al. Hepatology 2005;42:1414.
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Achievement of PCR Undetectability on Entecavir
40%40%
NaNaïïveve
HBeAg +HBeAg +
LVD RefractoryLVD Refractory
0 0 50 100 150
N = 319N = 319
N = 345N = 345
N = 178N = 178
HBeAg HBeAg --
% P
atie
nts
w/H
BV
DN
A <
300
Cop
ies/
mL
10
20
30
40
50
70
60
80
90
100
Treatment (Weeks)
94%94%
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Genotypic resistance in naive patientsGenotypic resistance in naive patientsGenotypic resistance in LAMGenotypic resistance in LAM--R patientsR patientsGenotypic resistance plusGenotypic resistance plus viral rebound in LAMviral rebound in LAM--R patientsR patients
Colonno R, et al. Hepatology. 2006;44:229A-230A.
Incidence of Entecavir Resistance
1 2 30
10
20
30
40
0.1 0.4 1.1
6
14
32
1
10
25
Genotypic assay ; direct sequencing
Year
%
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ETV Resistance Profile• ETV-R was only observed in patients with preexisting
LAM-R virus (M204 V/I and/or L180M).
• Resistance to ETV appears to occur through a two-hit mechanism with initial selection of M204V/I mutation followed by amino acid substitutions at rtI169, rtT184, rtS202, or rtM250.
• LAM should be discontinued to decrease the risk of entecavir resistance.
T184, S202 or M250
M204V ± L180MM204V ± L180M
Lamivudine Entecavir
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Tenofovir for Lamivudine-Resistant CHB
• Nucleotide analogue, structurally similar to adefovir, equipotent in wild-type and LAM-R HBV (In vitro).
• Because tenofovir appears to be less nephrotoxic, the approved dose is much higher than that of adefovir, 300 mg versus 10 mg daily.
• Thus, tenofovir has more potent antiviral activity than adefovir.
• No randomized controlled trials in HBV.
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* including HIV/HBV coinfection (n=21), and HBV/kidney Tpl (n=5).Van Bommel et al. Hepatology. 2004;40:1421-1425.
HB
V D
NA
(log
copi
es/m
L)10
Weeks
Tenofovir vs Adefovir in Patients with Lamivudine Resistance
(not randomized)
Tenofovir*(300 mg/day, n=35)
Adefovir(10 mg/day, n=18)
P < 0.001
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Recommendations for the Tx of LAM-R CHB• It is better to start rescue therapy as soon as genotypic
resistance is detected before the development of virologic breakthrough.
• Therefore, careful monitoring of genotypic resistance is needed during antiviral therapy for early detection and early rescue of drug resistance.
• Adefovir add-on is preferred over switch (increased rate of adefovir resistance with switch) and preferred over entecavir (high rate of novel mutations in patients with lamivudine resistance).
• If entecavir is used, lamivudine should be stopped as continued presence of lamivudine-resistant mutations will increase the risk of entecavir resistance.
• Tenofovir, 300 mg daily, appears to be superior to ADV, 10 mg daily, in suppressing LAM-resistant strain HBV.
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Adefovir-Resistance
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LMV Resistance rtL80V/I rtV173L rtM204V/I/SrtL180M
L-dT Resistance rtM204I
ADV Resistance rtA181T/V rtN236TETV Resistance rtS184G rtS202I rtM250V
TFV Resistance rtA194T/rtV214A/rtQ215S
HBV polymerase/RT domainHBV polymerase/RT domain
845 a.a.
Terminal Protein Spacer POL/RT RNaseH
A B C ED
1 183 349 (rt1) 692 (rt 344)
YMDDF__V__LLAQ__I(G) II(F)
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Incidence of Adefovir Resistance with Adefovir Monotherapy
in HBeAg-Negative NA naïve CHB Patients
Borroto-Esoda K. EASL 2006. Abstract 483.
30 311
18
29
08
13 16
0 2 6 10 11
Year 1 Year 2 Year 3 Year 4 Year 50
20
40
60
80
100
Patie
nts
(%)
Genotypic resistance Virologic rebound† Clinical breakthrough
*Cumulative probabilities calculated by life-table analysis.†Presence of 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 ≤ 4 log10 copies/mL.
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Higher HBV DNA at Year 1 Predictive of Year 3 ADV Resistance
Locarnini S, et al. EASL 2005. Abstract 36.
HBV DNA at Year 1 (log10 copies/mL)
Genotypic Resistance at Year 3 (%)
4%
67%
26%
0
20
40
60
80
100
(n = 80)< 3
(n = 31)3-6
(n = 3)> 6
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Risk factors for the development of adefovir resistance
• Old age
• High baseline HBV DNA load
• Suboptimal early viral suppression
• Short-duration of LAM overlap in LAM-R HBV
(adding-on is better than switching to ADV)
• Presence of LAM-R HBV mutants
; The main LMV resistance mutations rtM204V/I do not confer cross-resistance to adefovir, but the minor LMV resistance mutations rtA181T as well as the rtQ215S are partially cross-resistant to lamivudine in vitro.
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Management of
Adefovir-Resistant HBV
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In Vitro Cross-Resistance Analysis
Drugs Efficacy against various HBV strains
Wild LAM-R ADF-Rtype (L180M+M204V) (N236T)
Lamivudine + - +
Clevudine + - +
Telbivudine + - +
Emtricitabine + - +
Entecavir + +/- +
Adefovir + + -
Tenofovir + + +/-1. Zoulim F. Antiviral Res. 2004;64(1):1-15. 2. Brunelle et al. Hepatology. 2005;41:1391-1398. 3. Locarnini et al. EASL 2005. Abstract 36.
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Practical Optionsfor the Tx of ADR-R CHB
• In patients with no prior exposure to other NA
– add lamivudine
– add (> or switch to) entecavir
• In patients with prior LAM-R, switched to ADV
– add lamivudine
– add (> or switch to) entecavir
– switch to tenofovir (when approved)
in combination with lamivudine or entecavir
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Case: Adding on LMV for ADV-R
Marcellin P and Asselah T. J Hepatol 2005;43:920.Yeon JE, et al., Gut 2006;55:1488-1495.Villeneuve JP, et al. J Hepatol 2003;39:1085–1089.
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S.K. Fung SK, et al., J Hepatol 2006;44:283–290.
Case: Switching to ETV for ADV-R
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Ratziu V, et al., Comp Hepatol 2006;5:1.
Case: Switching to Tenofovir for ADV-R
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Prevention of Antiviral Drug Resistance in Patients with CHB
• Current therapy of CHB has limited long-term efficacy.
• Once antiviral-resistant HBV mutants have been selected, they are archived (retained in the virus population) persistently even if treatment is stopped.
• Thus, the best way to reduce the emergence of drug resistance is to select the right patients, right time to start treatment and the right antiviral agent(s).
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Prevention of Antiviral Drug Resistance in Patients with CHB
• Select the right patients
Patients with minimal disease and those who are unlikely to achieve sustained response should not be treated with NA
• Select right time to start treatment
• Select the right antiviral agent(s)
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Prevention of Antiviral Drug Resistance in Patients with CHB
• Select the right patients
• Select right time to start treatment
Start therapy at right time with clear indication to maximize antiviral activity
• Select the right antiviral agent(s)
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Prevention of Antiviral Drug Resistance in Patients with CHB
• Select the right patients
• Select right time to start treatment
• Select the right antiviral agent(s)
The most potent NA with the lowest rate of genotypic resistance should be administered.
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APASL Seoul 2008APASL Seoul 20082008. 3. 232008. 3. 23--2626
See you in Seoul, KoreaSee you in Seoul, Koreaありがとうございましたありがとうございました..
Thank you for your attention!!Thank you for your attention!!