Management of Resistance: Implications for Treatment Choices

1
Management of ResistanceImplications 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
2
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

3
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.
2003371309-1319.
4
Endpoint of Therapy With HBV Oral Antiviral Drugs

• Inhibition of HBV replication
• As profound as possible
• As sustained as possible

ANTIVIRAL POTENCY
NO RESISTANCE
5
HBV Treatment Failureand Resistance
6
Mechanisms of Resistance
7
Mechanisms of Resistance
8
Mechanisms of Resistance
Drug
Discontinue Drug
Sensitive
Sensitive
Sensitive
Resistant Very Fit
Resistant
Resistant
9
HBV Resistance Mutations
845 a.a.
YMDD
GVGLSPFLLA
rtV173L
rtL80V/I
rtM204V/I/S
LAM resistance
rtL180M
rtA181T/V
rtN236T
ADV resistance
rtl233V ?
rtM204V/I
ETV resistance
rtL180M
rtS202G/C
rtM250I/V
rtT184S/A/I/L
rtM204I
LdT resistance
rtL80V/I
rtL180M
Allen MI, et al. Hepatology. 1998271670-1677.
Qi X, et al. J Hepatol. 200440(suppl 1)20-21.
Tenney D, et al. Antimicrob Agents Chemother.
2004483498-3507. Telbivudine product insert.
Lai CL, et al. Gastroenterology.
2005129528-536. Schildgen O, et al. N Engl J
Med. 20063541807-1812.
10
Incidence of HBV Resistance
Lamivudine (nucleostide-naive patients)
100
80
71
65
55
60
Cumulative Incidence of Resistance ()
46
40
23
20
0
1
2
3
4
5
Year
Lai CL, et al. Clin Infect Dis.
200336687-696.Lok AS, et al. Gastroenterology.
20031251714-1722.
11
Incidence of HBV Resistance (contd)
Adefovir (nucleostide-naive, HBeAg-negative
patients) selection of resistance mutations with
or without breakthrough
100
80
60
Cumulative Incidence of Resistance ()
40
29
18
20
11
3
0
0
Borroto-Esoda K, et al. EASL 2006. Abstract 483.
12
Incidence of HBV Resistance
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
Cumulative Incidence of Outcome ()
40
32
25
20
14
10
6
1.1
1
0.1
0.4
0
Colonno R, et al. AASLD 2006. Abstract 110.
13
Incidence of HBV Resistance
Telbivudine
Telbivudine (HBeAg-positive patients)
Telbivudine (HBeAg-negative patients)
21.6
8.6
5.0
?
?
?
Lai CL, et al. Gastroenterology.
2005129528-536. Lai CL, et al. AASLD 2006.
Abstract 91.
14
Prevention ofHBV Resistance
15
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

16
Delaying Viral Resistance

• Maximally reduce virus replication
• Use highly potent antivirals

17
Entecavir vs Lamivudine
Entecavir
Lamivudine
LAM-R HBeAg
Naive HBeAg
Naive HBeAg-
0
-0.5
-2
Reduction in HBV DNA at Week 48 (log10 copies/mL)
-4
-4.5
-5.0
-5.1
-5.4
-6
P lt .0001
P lt .0001
-6.9
-8
P lt .0001
Chang T, et al. N Engl J Med. 20063541001-1010.
Lai C, et al. N Engl J Med. 20063541011-1020.
Colonno R, et al. AASLD 2006. Abstract 110.
Sherman M, et al. Gastroenterology.
20061302039-2049.
18
Entecavir vs Lamivudine (contd)
Entecavir
Lamivudine
100
90
80
72
67
60
Undetectable HBV DNA at Week 48 (lt 300 copies/mL)
()
36
40
19
20
1
0
Naive HBeAg
Naive HBeAg-
LAM-R HBeAg
Chang T, et al. N Engl J Med. 20063541001-1010.
Lai C, et al. N Engl J Med. 20063541011-1020.
Colonno R, et al. AASLD 2006. Abstract 110.
Sherman M, et al. Gastroenterology.
20061302039-2049.
19
Entecavir vs Adefovir
Week 12 Comparison
ADV (n 34)
ETV (n 35)
0
-1
-2
-3
Reduction in HBV DNA (log10 copies/mL)
-4
- 4.42
-5
-6
- 6.23
-7
P lt .0001
Wilber R, et al. NIH HBV 2006. Abstract 14.
20
Telbivudine vs LamivudineHBeAg-Positive Patients
On-Treatment (N 921)
Posttreatment (n 328)
0
-1
Lamivudine
-2
Telbivudine
-3
Mean Change in HBV DNA From Baseline(log10
copies/mL SE)
-4
-5
-5.2
-5.5
-6
-6.5
-6.6
-7
-8
Lai C, et al. HepDart 2005. Abstract 95.
21
Telbivudine vs Lamivudine HBeAg-Negative
Patients
On-Treatment (N 446)
Posttreatment (n 135)
0
-1
-1
Lamivudine
-2
-2
Telbivudine
-3
-3
Mean Change in HBV DNA From Baseline(log10
copies/mL SE)
Mean Change in HBV DNA From Baseline(log10
copies/mL SE)
-4
-4
-5
-5
-4.4
-4.7
-6
-6
-5.2
-5.3
-7
-7
-8
-8
Lai C, et al. HepDart 2005. Abstract 95.
22
Tenofovir vs Adefovir in LAM-R Patients
Adefovir (n 18) Tenofovir (n 35)
0
1
HBV DNA lt 400 copies/mL at Week 48
2
3
-2.8 log
Week 48 Reduction in HBV DNA (log10 copies/mL)
Adefovir 44Tenofovir 100
4
5
6
-5.5 log
7
P lt .001
van Bommel F, et al. Hepatology.
2004401421-1425.
23
Delaying Viral Resistance

• Maximally reduce virus replication
• Use highly potent antivirals
• Raise the pharmacologic barrier to viral escape
• Reach high trough levels
• Have a tissue distribution that permits no
  sanctuaries
• Optimize patient adherence

24
Delaying Viral Resistance

• Maximally reduce virus replication
• Use highly potent antivirals
• Raise the pharmacologic barrier to viral escape
• Reach high trough levels
• Have a tissue distribution that permits no
  sanctuaries
• Optimize patient adherence
• Raise the genetic barrier to resistance
• Combination therapies

25
In Vitro Cross-resistance to Lamivudine
Resistance Mutations
Reduced susceptibility
Resistant
Fold-Change in Susceptibility Relative to Wild Type HBV Fold-Change in Susceptibility Relative to Wild Type HBV Fold-Change in Susceptibility Relative to Wild Type HBV Fold-Change in Susceptibility Relative to Wild Type HBV Fold-Change in Susceptibility Relative to Wild Type HBV Fold-Change in Susceptibility Relative to Wild Type HBV Fold-Change in Susceptibility Relative to Wild Type HBV 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 gt 1000 570 NA 864 NA 500 gt 330
L180M M204V gt 1000 gt 1000 233 182 gt 42 410 345
Dent J, et al. Hepatology. 200032457A. Ono SK,
et al. J Clin Invest. 2001107449-455. Delaney
W, et al. Antiviral Res. 200150A81. Fu L, et
al. Antimicrob Agents Chemother.
2000443402-3407. Delaney WE, et al. Antimicrob
Agents Chemother. 2001451705-1713. Delaney W,
et al. EASL 2002. Abstract 181.
26
In Vitro Cross-resistance to Lamivudine
Resistance Mutations
Reduced susceptibility
Resistant
Fold-Change in EC50 From Wild Type Fold-Change in EC50 From Wild Type Fold-Change in EC50 From Wild Type Fold-Change in EC50 From Wild Type 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 gt 700 gt 1000 gt 1000 gt 1000
Qi X, et al. EASL 2005. Abstract 75.
27
In Vitro Cross-resistance to Adefovir Resistance
Mutations
Reduced susceptibility
Resistant
IC50 Fold Change IC50 Fold Change 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 gt 24.00
Valtorcitabine (LdC) NA 87.00
Clevudine 4.90 gt 164.00
Qi X, et al. Gastroenterology. 2004126(suppl
2)A-660. Abstract 3. Qi X, et al. EASL 2005.
Abstract 536.
28
Mechanisms of HBV Resistance
Drug
Discontinue Drug
Sensitive
Sensitive
Resistant
Resistant
29
Combination in Naive Patients
Lamivudine Adefovir
Sensitive
LAM-R
ADV-R
Sensitive
LAM-R
ADV-R
LAM ADV-R
LAM ADV-R
30
Lamivudine AdefovirHBeAg-Positive, Naive
Patients
Lamivudine adefovir
Lamivudine placebo
0
-1
-2
Week 52 Mean Change in HBV DNA From Baseline
(log10 copies/mL)
-3
-4
-5
-4.8
-5.2
-6
Sung J, et al. EASL 2003. Abstract 4313.
31
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.
32
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

33
Management ofHBV Resistance
34
Management of HBV Resistance Options

• Continue current therapy
• Switch to another drug
• Add on another drug
• Switch and add on

35
Switch vs Add-on in Lamivudine-Resistant Patients
Add Adefovir
Stop Lamivudine
Lamivudine
LAM-S ADV-S
LAM-R ADV-S
LAM-S
LAM-S ADV-R
LAM-S ADV-R
LAM-S
LAM-S
ADV-R
LAM-R
LAM-R
LAM-R
36
Switch vs Add-on in Lamivudine-Resistant Patients
Continue Lamivudine Add Adefovir
Lamivudine
LAM-S
LAM-S ADV-R
LAM-S ADV-S
LAM-R ADV-S
LAM-S
LAM-R ADV-R
LAM-S ADV-R
LAM-R
LAM-R
37
Add-on Adefovir in Lamivudine-Resistant Patients
Endpoints at Year 2 ADV Switch(n 277) ADV LAM(n 294) P Value
Virologic rebound, n () 41 (15) 11 (4) lt .001
ADV genotypic resistance, n () 21 (8) 0 (0) lt .001
Adefovir resistance, presence of adefovir
resistance mutations confirmed by molecular
analysis in patients with virologic rebound
virologic rebound, gt 1 log10 copies/mL increase
in HBV DNA level.
Lampertico P, et al. EASL 2006. Abstract 116.
38
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

39
Practical Options (contd)

• 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

40
Practical Options (contd)

• Entecavir resistance
• Add adefovir
• Add tenofovir when approved

41
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