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
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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
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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.
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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
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Mechanisms of Resistance
Sensitive
ResistantResistant
Sensitive
Drug
Sensitive
Resistant
Discontinue Drug
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Mechanisms of Resistance
Sensitive
Resistant + FitResistant
Sensitive
Drug
Sensitive
Resistant
Discontinue Drug
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Mechanisms of Resistance
Resistant + Very Fit
Sensitive
Resistant
Sensitive
Drug
Sensitive
Resistant
Discontinue Drug
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HBV Resistance Mutations
rtA181T/V
rtL80V/I rtM204V/I/SLAM resistance rtV173LrtL180M
rtN236Trtl233V ?
rtM204V/IrtS202G/C rtM250I/VrtT184S/A/I/LrtM204ILdT 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 ResistanceLamivudine (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
Year1 2 3 4 5
Cum
ulat
ive
Inci
denc
e of
R
esis
tanc
e (%
)
0
80
40
60
20
100
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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
Year1 2 3 4 5
Cum
ulat
ive
Inci
denc
e of
R
esis
tanc
e (%
)
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)
Cum
ulat
ive
Inci
denc
e of
O
utco
me
(%)
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
Year1 2 3 4 5
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Incidence of HBV ResistanceTelbivudine
Lai CL, et al. Gastroenterology. 2005;129:528-536. Lai CL, et al. AASLD 2006. Abstract 91.
5.0? ? ?
Year1 2 3 4 5
Cum
ulat
ive
Inci
denc
e of
R
esis
tanc
e (%
)
0
80
40
60
20
100
Telbivudine (HBeAg-positive patients)Telbivudine (HBeAg-negative patients)
21.6
8.6
Prevention ofHBV Resistance
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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
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Delaying Viral Resistance1. Maximally reduce virus replication
– Use highly potent antivirals
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Entecavir vs LamivudineLamivudineEntecavir
-6.9
-5.0 -5.1-5.4-4.5
-0.5
-8
-6
-4
-2
0Naive HBeAg+ Naive HBeAg-
LAM-RHBeAg+
Red
uctio
n in
HB
V D
NA
at
Wee
k 48
(log
10 c
opie
s/m
L)
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.
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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+
Und
etec
tabl
e H
BV
DN
A a
t W
eek
48 (<
300
cop
ies/
mL)
(%)
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
uctio
n in
HB
V D
NA
(lo
g 10 c
opie
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
hang
e in
HB
V D
NA
Fro
m B
asel
ine
(log 1
0 cop
ies/
mL
± SE
)
TelbivudineLamivudine
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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
hang
e in
HB
V D
NA
Fro
m B
asel
ine
(log 1
0 cop
ies/
mL
± SE
)
TelbivudineLamivudine
On-Treatment(N = 446)
Posttreatment(n = 135)
-8
-7
-6
-5
-4
-3
-2
-1
Mea
n C
hang
e in
HB
V D
NA
Fro
m B
asel
ine
(log 1
0 cop
ies/
mL
± SE
)
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
uctio
n in
HB
V D
NA
(log
10 c
opie
s/m
L)
3
4
5
6
Adefovir: 44%Tenofovir: 100%
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Delaying Viral Resistance1. 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
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Delaying Viral Resistance1. 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
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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 A181VAdefovir 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
hang
e in
HB
V D
NA
Fr
om B
asel
ine
(log 1
0 cop
ies/
mL)
-5.2-4.8
Lamivudine + adefovir Lamivudine + placebo
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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
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Management of HBV Resistance: Options Continue current therapy
Switch to another drug
Add on another drug
Switch and add on
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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 2 ADV Switch(n = 277)
ADV + LAM(n = 294) P Value
Virologic rebound, n (%) 41 (15) 11 (4) < .001ADV 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
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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
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