Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD...
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Transcript of Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD...
Management of Resistance:Implications for Treatment Choices
Jean-Michel Pawlotsky, MD, PhDDirector, French National Reference Center for Viral Hepatitis B, C and deltaVirology Unit & INSERM U635 Department of Bacteriology and Virology Henri Mondor HospitalUniversite Paris XIICréteil, France
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Primary Endpoints of HBV Therapy
Stop or slow the progression of liver disease in order to
– Prevent cirrhosis
– Prevent decompensation of cirrhosis
– Prevent hepatocellular carcinoma
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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HBV DNA as a Marker of Efficacy During Treatment of HBV Literature analysis of 26 prospective studies
– Investigation of the relationship between treatment-induced changes in HBV DNA, histology, other disease activity markers
Results– Statistically significant and consistent correlations between HBV DNA,
histology, biochemical and serologic responses– HBV DNA had broader dynamic range than histology
Conclusion– Treatment-induced reduction in HBV DNA can be used to assess efficacy
– Treatment goal should be profound and durable suppression of HBV DNA
Mommeja-Marin H, et al. Hepatology. 2003;37:1309-1319.
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Endpoint of Therapy With HBV Oral Antiviral Drugs Inhibition of HBV replication
– As profound as possible
– As sustained as possible
ANTIVIRAL POTENCY
NO RESISTANCE
HBV Treatment Failureand Resistance
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Mechanisms of Resistance
Sensitive
ResistantResistant
Sensitive
Drug
Sensitive
Resistant
Discontinue Drug
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Mechanisms of Resistance
Sensitive
Resistant + FitResistant
Sensitive
Drug
Sensitive
Resistant
Discontinue Drug
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Mechanisms of Resistance
Resistant + Very Fit
Sensitive
Resistant
Sensitive
Drug
Sensitive
Resistant
Discontinue Drug
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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HBV Resistance Mutations
rtA181T/V
rtL80V/I rtM204V/I/SLAM resistance rtV173L
rtL180M
rtN236T
rtl233V ?
rtM204V/I
rtS202G/C rtM250I/VrtT184S/A/I/L
rtM204ILdT resistance
ETV resistance
845 a.a.
Terminalprotein Spacer Pol/RT RNaseH
A B C ED
YMDDGVGLSPFLLA
I(G) II(F)
ADV resistance
Allen MI, et al. Hepatology. 1998;27:1670-1677. Qi X, et al. J Hepatol. 2004;40(suppl 1):20-21. Tenney D, et al. Antimicrob Agents Chemother. 2004;48:3498-3507. Telbivudine product insert. Lai CL, et al. Gastroenterology. 2005;129:528-536. Schildgen O, et al. N Engl J Med. 2006;354:1807-1812.
rtL180M
rtL80V/I rtL180M
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Incidence of HBV Resistance
Lamivudine (nucleos[t]ide-naive patients)
Lai CL, et al. Clin Infect Dis. 2003;36:687-696.Lok AS, et al. Gastroenterology. 2003;125:1714-1722.
23
55
71 65
46
Year
1 2 3 4 5
Cu
mu
lati
ve I
nci
den
ce o
f R
esis
tan
ce (
%)
0
80
40
60
20
100
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Incidence of HBV Resistance (cont’d)
Adefovir (nucleos[t]ide-naive, HBeAg-negative patients);selection of resistance mutations with or without breakthrough
Borroto-Esoda K, et al. EASL 2006. Abstract 483.
0 3 11
1829
Year
1 2 3 4 5
Cu
mu
lati
ve I
nci
den
ce o
f R
esis
tan
ce (
%)
0
80
40
60
20
100
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Entecavir (genotypic resistance in HBeAg[+]/[-] nucleos(t)ide-naive patients)Entecavir (genotypic resistance in LAM-R patients)Entecavir (genotypic resistance plus viral rebound in LAM-R patients)
Cu
mu
lati
ve I
nci
den
ce o
f O
utc
om
e (%
)
Colonno R, et al. AASLD 2006. Abstract 110.
Incidence of HBV Resistance
0.1 0.4 1.1614
32
110
25
0
80
40
60
20
100
Year
1 2 3 4 5
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Incidence of HBV Resistance
Telbivudine
Lai CL, et al. Gastroenterology. 2005;129:528-536. Lai CL, et al. AASLD 2006. Abstract 91.
5.0? ? ?
Year
1 2 3 4 5
Cu
mu
lati
ve I
nci
den
ce o
f R
esis
tan
ce (
%)
0
80
40
60
20
100
Telbivudine (HBeAg-positive patients)Telbivudine (HBeAg-negative patients)
21.6
8.6
Prevention ofHBV Resistance
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Prevention of Resistance
Experience from other therapies suggests that during prolonged antiviral therapy, resistance cannot be avoided indefinitely
Employment of appropriate therapeutic strategies can consistently delay the emergence of resistance
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Delaying Viral Resistance
1. Maximally reduce virus replication
– Use highly potent antivirals
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Entecavir vs Lamivudine
LamivudineEntecavir
-6.9
-5.0 -5.1-5.4-4.5
-0.5
-8
-6
-4
-2
0Naive HBeAg+ Naive HBeAg-
LAM-RHBeAg+
Red
uct
ion
in H
BV
DN
A a
t W
eek
48 (
log
10 c
op
ies/
mL
)
P < .0001
P < .0001 P < .0001
Chang T, et al. N Engl J Med. 2006;354:1001-1010. Lai C, et al. N Engl J Med. 2006;354:1011-1020. Colonno R, et al. AASLD 2006. Abstract 110. Sherman M, et al. Gastroenterology. 2006;130:2039-2049.
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Entecavir vs Lamivudine (cont’d)
67
90
19
36
72
10
20
40
60
80
100
Naive HBeAg+ Naive HBeAg- LAM-R HBeAg+
Un
det
ecta
ble
HB
V D
NA
at
Wee
k 48
(<
300
co
pie
s/m
L)
(%)
LamivudineEntecavir
Chang T, et al. N Engl J Med. 2006;354:1001-1010. Lai C, et al. N Engl J Med. 2006;354:1011-1020. Colonno R, et al. AASLD 2006. Abstract 110. Sherman M, et al. Gastroenterology. 2006;130:2039-2049.
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Entecavir vs Adefovir
Wilber R, et al. NIH HBV 2006. Abstract 14.
Week 12 Comparison
ADV (n = 34) ETV (n = 35)
0
-1
-2
-3
-4
-5
-6
-7
Red
uct
ion
in H
BV
DN
A
(lo
g10
co
pie
s/m
L)
- 6.23
- 4.42
P < .0001
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On-Treatment(N = 921)
Telbivudine vs Lamivudine:HBeAg-Positive Patients
Lai C, et al. HepDart 2005. Abstract 95.
-6.5
-5.5
-6.6
-5.2
Posttreatment(n = 328)
-8
-7
-6
-5
-4
-3
-2
-1
0
Mea
n C
han
ge
in H
BV
DN
A F
rom
Bas
elin
e(l
og
10 c
op
ies/
mL
± S
E)
Telbivudine
Lamivudine
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Telbivudine vs Lamivudine: HBeAg-Negative Patients
Lai C, et al. HepDart 2005. Abstract 95.
-5.3-5.2-4.7
-4.4
-8
-7
-6
-5
-4
-3
-2
-1
Mea
n C
han
ge
in H
BV
DN
A F
rom
Bas
elin
e(l
og
10 c
op
ies/
mL
± S
E)
Telbivudine
Lamivudine
On-Treatment(N = 446)
Posttreatment(n = 135)
-8
-7
-6
-5
-4
-3
-2
-1
Mea
n C
han
ge
in H
BV
DN
A F
rom
Bas
elin
e(l
og
10 c
op
ies/
mL
± S
E)
0
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2
7
1
0
-2.8 log
-5.5 log
P < .001
Tenofovir vs Adefovir in LAM-R Patients
van Bommel F, et al. Hepatology. 2004;40:1421-1425.
HBV DNA < 400 copies/mL at
Week 48
Adefovir (n = 18) Tenofovir (n = 35)
Wee
k 48
Red
uct
ion
inH
BV
DN
A (
log
10 c
op
ies/
mL
)
3
4
5
6
Adefovir: 44%Tenofovir: 100%
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Delaying Viral Resistance
1. Maximally reduce virus replication
– Use highly potent antivirals
2. Raise the “pharmacologic barrier” to viral escape
– Reach high trough levels
– Have a tissue distribution that permits no sanctuaries
– Optimize patient adherence
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
clinicaloptions.com/hep
Delaying Viral Resistance
1. Maximally reduce virus replication
– Use highly potent antivirals
2. Raise the “pharmacologic barrier” to viral escape
– Reach high trough levels
– Have a tissue distribution that permits no sanctuaries
– Optimize patient adherence
3. Raise the “genetic barrier” to resistance
– Combination therapies
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Dent J, et al. Hepatology. 2000;32:457A. Ono SK, et al. J Clin Invest. 2001;107:449-455. Delaney W, et al. Antiviral Res. 2001;50:A81. Fu L, et al. Antimicrob Agents Chemother. 2000;44:3402-3407. Delaney WE, et al. Antimicrob Agents Chemother. 2001;45:1705-1713. Delaney W, et al. EASL 2002. Abstract 181.
Reduced susceptibility
Fold-Change in Susceptibility Relative to Wild Type HBV
HBV mutations 3TC L-FMAU L-Fd4C ETV FTC LdC LdT
Wild type 1 1 1 1 1 1 1
L180M 5 5 3 1 11 12 9.4
M204I > 1000 570 NA 864 NA 500 > 330
L180M + M204V > 1000 > 1000 233 182 > 42 410 345
In Vitro Cross-resistance to Lamivudine Resistance Mutations
Resistant
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Fold-Change in EC50 From Wild Type
Compound M204V + L180M M204V + L180M + V173L M204I M204I + L180M
Tenofovir 0.8 1.8 2.1 0.7
Adefovir 1.1 1.1 1.8 2.1
Entecavir 37 164 471 38
Lamivudine > 700 > 1000 > 1000 > 1000
In Vitro Cross-resistance to Lamivudine Resistance Mutations
Qi X, et al. EASL 2005. Abstract 75.
Reduced susceptibility Resistant
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IC50 Fold Change
N236T A181V
Adefovir 7.30 4.20
Tenofovir 4.60 1.80
Entecavir 0.67 12.10
Lamivudine 2.10 14.10
Emtricitabine 2.60 14.10
Telbivudine (LdT) 2.40 > 24.00
Valtorcitabine (LdC) NA 87.00
Clevudine 4.90 > 164.00
In Vitro Cross-resistance to Adefovir Resistance Mutations
Qi X, et al. Gastroenterology. 2004;126(suppl 2):A-660. Abstract 3. Qi X, et al. EASL 2005. Abstract 536.
Reduced susceptibility Resistant
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Mechanisms of HBV Resistance
Sensitive
ResistantResistant
Sensitive
Drug
Sensitive
Resistant
Discontinue Drug
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Combination in Naive Patients
Lamivudine + Adefovir
LAM-R ADV-R
Sensitive
LAM-R ADV-R
Sensitive
LAM + ADV-R LAM + ADV-R
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Lamivudine + Adefovir:HBeAg-Positive, Naive Patients
Sung J, et al. EASL 2003. Abstract 4313.
-6
-5
-4
-3
-2
-1
0
Wee
k 52
Mea
n C
han
ge
in H
BV
DN
A
Fro
m B
asel
ine
(lo
g10
co
pie
s/m
L)
-5.2-4.8
Lamivudine + adefovir Lamivudine + placebo
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Adefovir Resistance
Locarnini S, et al. EASL 2005. Abstract 36.
All adefovir-resistant patients (22 reported to date) were on adefovir monotherapy
– 20 from adefovir monotherapy trials
– 2 from adefovir + lamivudine trials but had stopped lamivudine
No adefovir resistance observed to date when adefovir is added to ongoing lamivudine
No adefovir resistance observed to date in treatment-naive patients treated with adefovir + FTC or adefovir + lamivudine
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Summary
HBV resistance may be delayed for many years by
– Using highly potent antiviral drugs with optimized pharmacologic profiles
– Improving patients’ adherence to therapy
– Using first-line combinations of drugs without cross-resistance
Management ofHBV Resistance
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Management of HBV Resistance: Options Continue current therapy
Switch to another drug
Add on another drug
Switch and add on
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Switch vs Add-on in Lamivudine-Resistant Patients
LAM-SADV-S
LAM-RADV-S
ADV-R
Add AdefovirStop LamivudineLamivudine
LAM-R
LAM-S
LAM-S
LAM-R
LAM-SADV-R
LAM-S
LAM-R
LAM-SADV-R
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LAM-RADV-R
Switch vs Add-on in Lamivudine-Resistant Patients
Continue LamivudineContinue LamivudineAdd AdefovirAdd Adefovir
LAM-SADV-R
Lamivudine
LAM-R
LAM-S
LAM-S
LAM-R
LAM-SADV-R
LAM-SADV-S
LAM-RADV-S
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Add-on Adefovir in Lamivudine-Resistant Patients
Lampertico P, et al. EASL 2006. Abstract 116.
Adefovir resistance, presence of adefovir resistance mutations confirmed by molecular analysis in patients with virologic rebound; virologic rebound, > 1 log10 copies/mL increase in HBV DNA level.
Endpoints at Year 2ADV Switch
(n = 277)ADV + LAM
(n = 294)P Value
Virologic rebound, n (%) 41 (15) 11 (4) < .001
ADV genotypic resistance, n (%)
21 (8) 0 (0) < .001
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Practical Options
Lamivudine resistance
– Switch to entecavir
– Continue lamivudine and add adefovir
– Switch to telbivudine and add adefovir
– Switch to entecavir and add adefovir
– Consider tenofovir instead of adefovir when approved
– Consider tenofovir/FTC formulation when approved
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Practical Options (cont’d)
Adefovir resistance
– Add lamivudine
– Add telbivudine
– Add entecavir
– Switch to tenofovir when approved in combination with lamivudine, telbivudine, or entecavir
– Switch to tenofovir/FTC when approved
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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Practical Options (cont’d)
Entecavir resistance
– Add adefovir
– Add tenofovir when approved
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Summary
HBV resistance can be delayed
– By using highly potent antivirals
– By improving adherence
– By using combination therapies
When resistance occurs
– Consider add-on therapy rather than switching to second monotherapy
– Consider using the most potent available antiviral combination