Prsentation PowerPoint

1
HBV Resistance to NUCsMolecular mechanisms
andclinical consequences Prof. Jean-Michel
Pawlotsky, MD, PhD French National Reference
Center for Viral Hepatitis B, C and
delta Department of Virology INSERM U841 Henri
Mondor Hospital University of Paris 12 Créteil,
France
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IMechanisms of Virus Resistance to Antiviral
Drugs
3
Mechanisms of Resistance
sensitive
resistant
4
Mechanisms of Resistance
Drug
sensitive
resistant
5
Mechanisms of Resistance
Drug
sensitive
sensitive
resistant
resistant
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Mechanisms of Resistance
Drug
Stop drug
sensitive
sensitive
resistant
resistant
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Mechanisms of Resistance
Drug
Stop drug
sensitive
sensitive
sensitive
resistant
resistant
resistant
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Mechanisms of Resistance
Drug
Stop drug
sensitive
sensitive
sensitive
resistant
resistant
resistant fit
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Mechanisms of Resistance
Drug
Stop drug
sensitive
sensitive
sensitive
resistant
resistant
resistant very fit
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IIHBV Specificities
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Available anti-HBV NUCs

• Nucleoside analogues
• Lamivudine
• Emtricitabine
• Entecavir
• Telbivudine
• Nucleotide analogues
• Adefovir dipivoxil
• Tenofovir

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Characteristics That Predispose to Antiviral Drug
Resistance
HIV

• Viral features
• Rapid replication dynamics
• Large population sizes
• Quasispecies distribution
• Host factors
• Chronic infection
• Drug targets
• Specifically targeted antiviral therapy

HBV
HCV
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Other Factors that Influence Antiviral Drug
Resistance

• Viral factors
• Archived mutations
• Conservatory constraints on genome sequences
• Host factors
• Role of the immune response
• Drug-related factors
• Genetic barrier to resistance
• Fitness characteristics of selected variants
  (resistance profile)

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HBV Life Cycle
(Ganem Prince, N Engl J Med 20043502719-20)
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HBV Life Cycle
(Ganem Prince, N Engl J Med 20043502719-20)
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HBV Life Cycle
HBV infection is not curable
HBV resistance mutations can be archived in
cccDNA
(Ganem Prince, N Engl J Med 20043502719-20)
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Conservatory Constraints on HBV Genome Sequence
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Conservatory Constraints on HBV Genome Sequence
(Kay et al., Virus Research 2007127164-176)
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Role of the Immune Response

• In HBV infection, the immune response is present,
  strong and adapted
• It can take control of infection, especially when
  viral replication is reduced by antiviral drugs

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HBV Drug Resistance Profiles

• Drugs
• Lamivudine
• Telbivudine
• Entecavir
• Adefovir
• Tenofovir
• Tenofovir FTC

Antiviral potency /-
Genetic barrier Low Low High Low ? High ?
In vivo resistant variant fitness High High Hig
h Low Low Low
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Replication Capacity of HBV-Resistant Variants
5
4
Wild-type virus
3
pg HBV DNA/RLU (106)
LAM-resistant virus (V173L, L180M, M204V)
2
ETV-resistant virus (I169T, V173L, L180M, M204V,
M250V)
1
0
2
3
4
5
6
Days post-transfection
(Tenney DJ et al., Antimicrob Agents Chemother
2004483498507)
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Summary

• HBV has a narrower spectrum of possible natural
  polymorphisms than other viruses such as HIV or
  HCV, due to slightly slower viral kinetics and
  stronger conservatory constraints on protein
  sequences
• The immune response plays an important role in
  the control of infection during and after
  antiviral therapy
• Anti-HBV drugs with potent antiviral efficacy,
  with a high genetic barrier to resistance and/or
  that select poorly fit resistant variants in vivo
  are now available

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IIIHBV Resistance to Approved Drugs
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HBV Drug Primary Resistance Mutations
845 a.a.
YMDD
GVGLSPFLLA
II(F)
A
B
C
E
D
I(G)
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HBV Drug Primary Resistance Mutations
845 a.a.
YMDD
GVGLSPFLLA
II(F)
A
B
C
E
D
I(G)
rtM204V/I/S
rt A181V/T
rtN236T
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Lamivudine Resistance
845 a.a.
YMDD
GVGLSPFLLA
II(F)
A
B
C
E
D
I(G)
LAM Resistance rtL80V/I rtV173L
rtM204V/I/S rtL180M
rtA181V/T
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Incidence of HBV Resistance
(Lai et al., Clin Infec Dis 200336687-96 Lok
et al., Gastroenterology 20031251714-22)
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Telbivudine Resistance
845 a.a.
YMDD
GVGLSPFLLA
II(F)
A
B
C
E
D
I(G)
LAM Resistance rtL80V/I rtV173L
rtM204I rtL180M
rtA181V/T ?
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Incidence of HBV Resistance
Telbivudine
Telbivudine (HBeAg-positive)
100
Telbivudine (HBeAg-negative)
80
Cumulative Incidence of Resistance ()
60
40
21.6
20
8.6
5
0
1
2
3
4
5
Year
(Lai et al., AASLD 2006)
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Entecavir Resistance
845 a.a.
YMDD
GVGLSPFLLA
II(F)
A
B
C
E
D
I(G)
LAM Resistance rtL180M rtM204V/I
rtT184S/A/I/L rtS202G/C
rtM250I/V
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Incidence of HBV Resistance
Genotypic entecavir resistance (naive)
Entecavir resistance viral breakthrough (naive)
100
80
60
Cumulative incidence
40
20
1.2
0.8
1.2
0.8
1.2
0.8
1.2
0.2
0.5
0.2
0.2
0
1
2
3
4
5
6
Year
(Tenney et al., EASL 2009)
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Incidence of HBV Resistance
Genotypic entecavir resistance (LAM-R)
Entecavir resistance viral breakthrough (LAM-R)
100
80
57
60
Cumulative incidence
51
46
43
41
40
36
27
20
15
11
6
1
0
1
2
3
4
5
6
Year
(Tenney et al., EASL 2009)
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Adefovir Resistance
845 a.a.
YMDD
GVGLSPFLLA
II(F)
A
B
C
E
D
I(G)
ADV Resistance rtA181V/T
rtN236T
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Incidence of HBV Resistance
Adefovir (nucleos(t)ide naive, HBeAg-) Selection
of resistance mutations with or without
breakthrough(genotypic resistance)
100
80
Cumulative Incidence of Resistance ()
60
40
29
18
20
11
3
0
0
1
2
3
4
5
Year
(Borroto-Esoda et al., EASL 2006)
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Tenofovir Resistance

• Long-term experience in HIV-HBV co-infected
  patients indicates
• No resistance in most cohort studies, although
  tenofovir has been mostly prescribed in
  combination with LAM / FTC
• Observations with the rtA194T mutant with no
  apparent phenotypic and clinical impact
• Experience in clinical trials (72 weeks) and
  small scale cohort studies in monotherapy
  indicates
• No resistance within the time frame of observation

(Lacombe et al, AIDS 2006 Benhamou et al,
Hepatology 2006 Peters et al Hepatology 2006
Sheldon et al, Antiviral Therapy 2005 Delaney et
al, Antimicrob. Agents Chemother 2006 Van Bommel
et al, AASLD 2007 Snow-Lampart et al, EASL 2008)
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Cross-Resistance Data for the Most Frequent
Variants
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IVClinical Consequencesof HBV Resistance
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The HBV DNA level is a major determinant of
HBV-related liver disease progression
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Role of HBV DNA Load in HBV Disease Progression
(Cirrhosis)
N3,582
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36.2
Baseline HBV DNA Level (copies/mL)
106 105lt106 104lt105 300lt104 lt300
30
23.5
20
Cumulative incidence liver cirrhosis
9.8
10
5.9
4.5
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Year of follow-up
(Iloeje UH, et al. Gastroenterology
2006130678-86)
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Role of HBV DNA Load in HBV Disease Progression
(HCC)
16
N3,582
14.89
14
Baseline HBV DNA Level (copies/mL)
12.17
12
106 105lt106 104lt105 300lt104 lt300
10
Cumulative Incidence of HCC ()
8
6
4
3.57
2
1.37
1.30
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Year of Follow-up
(Iloeje UH, et al. Gastroenterology
2006130678-86)
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Goal of Therapy

• To improve quality of life and survival by
  preventing progression of the disease to
  cirrhosis, decompensated cirrhosis, end-stage
  liver disease, HCC and death

(EASL CPGs Management of chronic hepatitis B J
Hepatol 200950227-42)
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Goal of Therapy

• This goal can be achieved
• If HBV replication can be suppressed in a
  sustained manner
• The accompanying reduction in histological
  activity of chronic hepatitis lessening the risk
  of cirrhosis and decreasing the risk of HCC

(EASL CPGs Management of chronic hepatitis B J
Hepatol 200950227-42)
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Histologic Improvement as a Function of HBV DNA
Decrease

• Meta-analysis of 26 prospective trials

(Mommeja-Marin et al., Hepatology
2003371309-19)
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Clinical Outcome of Lamivudine Resistance
25
Placebo (n215)
21
YMDD mutants (n209) (49)
20
Wild type (n221)
15
Patients with diseaseprogression ()
13
10
5
5
0
0
6
12
18
24
30
36
Time (months)
(Liaw et al., N Eng J Med 2004)
45
On-Treatment LamivudinePrognosis according to
viral load
HCC
Survival
1.0
1.0
(N116)
HBV DNA lt105 copies/mL
p0.027
0.8
0.8
HBV DNA gt105 copies/mL
(N69)
0.6
0.6
Cumulative survival
Incidence of HCC
0.4
0.4
(N87)
plt0.001
0.2
0.2
(N192)
0.0
0.0
0
12
24
36
48
60
72
Months
Months
(Di Marco V, et al., Hepatology 200440883-9)
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Conclusions

• HBV resistance is associated with high HBV DNA
  levels on therapy
• High HBV DNA levels are associated with
  progression of liver disease
• Sustained suppression of HBV replication must be
  restored urgently