Transcript Management of Resistance: Implications for Treatment Choices

Management of Resistance:
Implications for Treatment Choices
Jean-Michel Pawlotsky, MD, PhD
Director, French National Reference Center
for Viral Hepatitis B, C and delta
Virology Unit & INSERM U635
Department of Bacteriology and Virology
Henri Mondor Hospital
Universite Paris XII
Créteil, France
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Endpoint of Therapy With HBV Oral
Antiviral Drugs
 Inhibition of HBV replication
– As profound as possible
ANTIVIRAL POTENCY
– As sustained as possible
NO RESISTANCE
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HBV Treatment Failure
and Resistance
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Mechanisms of Resistance
Drug
Discontinue Drug
Sensitive
Sensitive
Resistant
Sensitive
Resistant
Resistant
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Mechanisms of Resistance
Drug
Discontinue Drug
Sensitive
Sensitive
Sensitive
Resistant
Resistant
Resistant + Fit
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Mechanisms of Resistance
Drug
Discontinue Drug
Sensitive
Sensitive
Resistant
Resistant + Very Fit
Sensitive
Resistant
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
HBV Resistance Mutations
Terminal
protein
Spacer
Pol/RT
GVGLSPFLLA
I(G)
II(F)
LAM resistance
RNaseH
845 a.a.
YMDD
A
B
C
rtL80V/I
rtV173L
rtM204V/I/S
D
E
rtL180M
ADV resistance
rtA181T/V
rtN236T
rtl233V ?
ETV resistance
rtL180M
rtM204V/I
rtT184S/A/I/L rtS202G/C
LdT resistance
rtL80V/I
rtL180M
rtM250I/V
rtM204I
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.
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Incidence of HBV Resistance
Cumulative Incidence of
Resistance (%)
Lamivudine (nucleos[t]ide-naive patients)
100
80
71
65
4
5
55
60
46
40
23
20
0
1
2
3
Year
Lai CL, et al. Clin Infect Dis. 2003;36:687-696.
Lok AS, et al. Gastroenterology. 2003;125:1714-1722.
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Incidence of HBV Resistance (cont’d)
Cumulative Incidence of
Resistance (%)
Adefovir (nucleos[t]ide-naive, HBeAg-negative patients);
selection of resistance mutations with or without breakthrough
100
80
60
40
29
18
20
11
0
0
1
3
2
3
4
5
Year
Borroto-Esoda K, et al. EASL 2006. Abstract 483.
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Incidence of HBV Resistance
Cumulative Incidence of
Outcome (%)
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)
100
80
60
40
32
25
20
0
6
0.1 1
1
14
10
0.4
2
1.1
3
4
5
Year
Colonno R, et al. AASLD 2006. Abstract 110.
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Incidence of HBV Resistance
Cumulative Incidence of
Resistance (%)
Telbivudine
Telbivudine (HBeAg-positive patients)
Telbivudine (HBeAg-negative patients)
100
80
60
40
21.6
20
8.6
5.0
0
1
2
?
?
?
3
4
5
Year
Lai CL, et al. Gastroenterology. 2005;129:528-536. Lai CL, et al. AASLD 2006. Abstract 91.
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Prevention of
HBV Resistance
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Delaying Viral Resistance
1. Maximally reduce virus replication
– Use highly potent antivirals
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Entecavir vs Lamivudine
Reduction in HBV DNA at
Week 48 (log10 copies/mL)
Entecavir
0
Naive HBeAg+
Lamivudine
Naive HBeAg-
LAM-R
HBeAg+
-0.5
-2
-4
-6
-5.4
-8
-6.9
P < .0001
-5.0
-4.5
P < .0001
-5.1
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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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Entecavir vs Lamivudine (cont’d)
Undetectable HBV DNA at
Week 48 (< 300 copies/mL) (%)
Entecavir
100
80
Lamivudine
90
72
67
60
40
20
0
36
19
1
Naive HBeAg+ Naive HBeAg- LAM-R HBeAg+
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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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Entecavir vs Adefovir
Week 12 Comparison
ADV (n = 34)
ETV (n = 35)
Reduction in HBV DNA
(log10 copies/mL)
0
-1
-2
-3
-4
-5
- 4.42
-6
- 6.23
-7
P < .0001
Wilber R, et al. NIH HBV 2006. Abstract 14.
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Mean Change in HBV DNA From Baseline
(log10 copies/mL ± SE)
Telbivudine vs Lamivudine:
HBeAg-Positive Patients
0
On-Treatment
(N = 921)
Posttreatment
(n = 328)
-1
Lamivudine
-2
Telbivudine
-3
-4
-5
-6
-7
-5.2
-5.5
-6.5
-6.6
-8
Lai C, et al. HepDart 2005. Abstract 95.
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Mean Change in HBV DNA From Baseline
(log10 copies/mL ± SE)
Telbivudine vs Lamivudine:
HBeAg-Negative Patients
0
On-Treatment
(N = 446)
Posttreatment
(n = 135)
-1
Lamivudine
-2
Telbivudine
-3
-4
-5
-6
-4.4
-4.7
-5.2
-7
-5.3
-8
Lai C, et al. HepDart 2005. Abstract 95.
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Tenofovir vs Adefovir in LAM-R
Patients
Week 48 Reduction in
HBV DNA (log10 copies/mL)
Adefovir (n = 18)
Tenofovir (n = 35)
0
HBV DNA
< 400 copies/mL at
Week 48
1
2
3
Adefovir: 44%
Tenofovir: 100%
-2.8 log
4
5
6
7
-5.5 log
P < .001
van Bommel F, et al. Hepatology. 2004;40:1421-1425.
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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
clinicaloptions.com/hep
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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
clinicaloptions.com/hep
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
In Vitro Cross-resistance to
Lamivudine Resistance Mutations
Reduced susceptibility
Resistant
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
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.
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Abstract 181.
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
In Vitro Cross-resistance to
Lamivudine Resistance Mutations
Reduced susceptibility
Resistant
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
> 700
> 1000
> 1000
> 1000
Lamivudine
Qi X, et al. EASL 2005. Abstract 75.
clinicaloptions.com/hep
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
In Vitro Cross-resistance to Adefovir
Resistance Mutations
Reduced susceptibility
Resistant
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
Qi X, et al. Gastroenterology. 2004;126(suppl 2):A-660. Abstract 3.
Qi X, et al. EASL 2005. Abstract 536.
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Mechanisms of HBV Resistance
Drug
Discontinue Drug
Sensitive
Sensitive
Resistant
Sensitive
Resistant
Resistant
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Combination in Naive Patients
Lamivudine + Adefovir
Sensitive
LAM-R
ADV-R
Sensitive
LAM-R
ADV-R
LAM + ADV-R
LAM + ADV-R
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Lamivudine + Adefovir:
HBeAg-Positive, Naive Patients
Week 52 Mean Change in HBV DNA
From Baseline (log10 copies/mL)
Lamivudine + adefovir
Lamivudine + placebo
0
-1
-2
-3
-4
-5
-6
Sung J, et al. EASL 2003. Abstract 4313.
-4.8
-5.2
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Adefovir Resistance
 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
Locarnini S, et al. EASL 2005. Abstract 36.
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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 crossresistance
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Management of
HBV Resistance
Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Management of HBV Resistance:
Options
 Continue current therapy
 Switch to another drug
 Add on another drug
 Switch and add on
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Switch vs Add-on in LamivudineResistant Patients
Lamivudine
LAM-S
ADV-R
Stop Lamivudine
LAM-S
LAM-S
LAM-R
LAM-S
ADV-R
Add Adefovir
LAM-S LAM-R
ADV-S ADV-S
LAM-S
LAM-R
LAM-R
ADV-R
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Switch vs Add-on in LamivudineResistant Patients
Lamivudine
LAM-S
ADV-R
Continue Lamivudine
Add Adefovir
LAM-S
LAM-S LAM-R
ADV-S ADV-S
LAM-S
LAM-R
LAM-R
LAM-S
ADV-R
LAM-R
ADV-R
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Add-on Adefovir in LamivudineResistant Patients
Endpoints at Year 2
ADV Switch ADV + LAM
P Value
(n = 277)
(n = 294)
Virologic rebound, n (%)
41 (15)
11 (4)
< .001
ADV genotypic resistance, n (%)
21 (8)
0 (0)
< .001
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.
Lampertico P, et al. EASL 2006. Abstract 116.
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
Practical Options (cont’d)
 Entecavir resistance
– Add adefovir
– Add tenofovir when approved
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Focus on the Virus: A New Paradigm for the Management and Treatment of HBV
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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