Prsentation PowerPoint

1
No Resistance No Disease Progression 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
2
The HBV DNA level is a major determinant of
HBV-related liver disease progression
3
Histologic Improvement as a Function of HBV DNA
Decrease

• Meta-analysis of 26 prospective trials

(Mommeja-Marin et al., Hepatology
2003371309-19)
4
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)
5
HBV Resistance

• HBV resistance must be prevented by all means
• HBV resistance must be treated when it occurs

6
IPrevention of HBV Resistance
7
Virological Endpoint of HBV Therapies

• Inhibition of HBV replication
• as profound as possible,
• as sustained as possible.

8
Virological Endpoint of HBV Therapies

• Inhibition of HBV replication
• as profound as possible,
• ANTIVIRAL POTENCY
• as sustained as possible.

9
Virological Endpoint of HBV Therapies

• Inhibition of HBV replication
• as profound as possible,
• ANTIVIRAL POTENCY
• as sustained as possible.
• HIGH BARRIER TO RESISTANCE

10
HBeAg-Positive Patients
HBe seroconversion
Undetectable HBV DNA
Normal ALT
100
90
77
80
74
69
68
67
70
66
60
60
48
50
39
39
40
30
30
26
25
22
22
21
21
20
12
10
0
LdT
LdT
LdT
LAM
ADV
ETV
TDF
LAM
ADV
ETV
TDF
LAM
ADV
ETV
TDF
PEG-IFN
PEG-IFN
PEG-IFN
(EASL CPGs Management of chronic hepatitis B J
Hepatol 200950227-42)
11
HBeAg-Negative Patients
Undetectable HBV DNA
Normal ALT
100
92
90
88
90
78
77
80
74
74
72
72
70
63
60
51
50
38
40
30
20
10
0
LdT
LdT
LAM
ADV
ETV
TDF
LAM
ADV
ETV
TDF
PEG-IFN
PEG-IFN
(EASL CPGs Management of chronic hepatitis B J
Hepatol 200950227-42)
12
Entecavir vs LamivudineNaïve, HBeAg-()
Patients, Week 96
plt0.0001
ETV 0.5 mg OD (n354)
100
87
80
79
LVD 100 mg OD (n355)
80
Cumulative proportionof patients ()
60
39

31
40
26
20
5
3
0
HBV DNAlt 300 copies/ml
ALTnormalisation
HBeseroconversion
HBsAgloss
(Entecavir Summary of Product Characteristics.
Bristol-Myers Squibb Pharma EEIG. August 2007 De
Man RA, et al., 12th ISVHLD)
13
Long-Term Entecavir EfficacyNaïve, HBeAg-()
Patients, Weeks 48-144
100
48 weeks 96 weeks 144 week
90
n354 for all analyses
87
82
80
80
68
67
Cumulative proportion of patients ()
60
39
49
40
31
22
21
20
N/A
0
HBeAgloss
HBV DNA lt 300 copies/mL
ALT normalisation
HBe seroconversion
(Chang TT, et al. N Engl J Med.2006354100110
Chang TT, et al., J Gastroenterol and Hepatol
2006 21(suppl 2) A89 Chang T, et al. AASLD
2006)
14
Entecavir vs LamivudineNaïve, HBeAg-(-)
Patients, Week 96
plt0.0001
p0.05
94
100
89
ETV 0.5 mg OD (n325)
84
77
80
LVD 100 mg OD (n313)
60
Cumulative proportionof patients ()
40
20
0
HBV DNAlt 300 copies/ml
ALTnormalisation
(Entecavir Summary of Product Characteristics,
Bristol-Myers Squibb Pharma 2007 Manns M, et al.
ISVHLD 2006)
15
Entecavir vs AdefovirNaïve, HBeAg-() Patients
0
ETV 0.5 mg OD (n33)
-1
ADV 1.0 mg OD (n32)
Primary efficacy end point plt0.0001
-2
-3
4.42
Mean change in HBV DNA (log10 copies/mL)
-4
5.08
-5
6.23
-6
7.28
-7
-8
0
4
8
12
16
20
24
28
32
36
40
44
48
Treatment duration (weeks)
(Sherman M et al. ISVHLD 2006 Wilber R, et al .
NIH Workshop 2006 Leung N et al. DDW 2007)
16
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
17
Entecavir ResistanceNaive patients
Detection limit
18
Entecavir ResistanceNaive patients
Detection limit
19
Entecavir ResistanceNaive patients
Detection limit
LVDr M204V
20
Entecavir ResistanceNaive patients
Primary resistance
Detection limit
LVDr M204V
LVDr L180M

21
Entecavir ResistanceNaive patients
Secondary resistance
Primary resistance
Detection limit
ETVr T184, S202 or M250
LVDr M204V
LVDr L180M


22
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)
23
Tenofovir vs AdefovirNaïve, HBeAg-() Patients
1
0
Randomized Double Blind
Open Label TDF
9
8
7
6
5
Mean (95 CI) HBV DNA (Log10 Copies/mL)
4
3
P0.073
LLOQ
2
1
0
0
4
8
1
2
1
6
2
0
2
4
2
8
3
2
3
6
4
0
4
4
4
8
5
2
5
6
6
0
6
4
6
8
7
2
7
6
W
e
e
k
s

o
n

S
t
u
d
y

9
0
A
D
V
N


9
0

9
0

8
5

8
5

8
5

8
5

8
5

8
5

8
1

8
1

8
1
1
7
6
T
D
F
N

1
7
6
1
7
6
1
6
5
1
6
5
1
6
5
1
6
0
1
6
0
1
6
0
1
4
5
1
4
5
1
4
5
(Marcellin M et al., N Engl J Med
20083592442-55)
24
Tenofovir vs AdefovirNaïve, HBeAg-(-) Patients
8
Open Label TDF
Randomized Double Blind
7
6
5
Mean (95 CI) HBV DNA (Log10 Copies/mL)
4
3
P0.524
LLOQ
2
LLOQ
1
0
0
4
8
1
2
1
6
2
0
2
4
2
8
3
2
3
6
4
0
4
4
4
8
5
2
5
6
6
0
6
4
6
8
7
2
7
6
W
e
e
k
s

o
n

S
t
u
d
y
1
2
5
A
D
V
N

1
2
5
1
2
5
1
2
1
1
2
1
1
2
1
1
1
7
1
1
7
1
1
7
1
1
1
1
1
1
1
1
1
2
5
0
T
D
F
N

2
5
0
2
5
0
2
3
9
2
3
9
2
3
9
2
4
0
2
4
0
2
4
0
2
2
6
2
2
6
2
2
6
(Marcellin M et al., N Engl J Med
20083592442-55)
25
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 (2 years) 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)
26
EASL Clinical Practice Guidelines

• The most potent drugs with the optimal resistance
  profile should be used as first-line
  monotherapies
• Entecavir
• Tenofovir

(EASL CPGs Management of chronic hepatitis B J
Hepatol 200950227-42)
27
IITreatment of HBV Resistance
28
Mechanisms of Resistance
Drug
Stop drug
sensitive
sensitive
sensitive
resistant
resistant
resistant
29
Switch vs Add-on in HBV Resistant Patients
LAM-S
LAM-R
30
Switch vs Add-on in HBV Resistant Patients
LAM-S ADV-R
LAM-S
LAM-R
31
Switch vs Add-on in HBV Resistant Patients
Lamivudine
LAM-S
LAM-S ADV-R
LAM-S
LAM-R
LAM-R
32
Switch vs Add-on in HBV Resistant Patients
Lamivudine
Stop Lamivudine
LAM-S ADV-R
LAM-S
LAM-S ADV-R
LAM-S
LAM-S
LAM-R
LAM-R
LAM-R
33
Switch vs Add-on in HBV Resistant Patients
Lamivudine
Stop Lamivudine
Add adefovir
LAM-S ADV-S
LAM-R ADV-S
LAM-S ADV-R
LAM-S
LAM-S ADV-R
LAM-S
LAM-S
LAM-R
LAM-R
LAM-R
ADV-R
34
Switch vs Add-on in HBV Resistant Patients
Lamivudine
LAM-S
LAM-S ADV-R
LAM-S
LAM-R
LAM-R
35
Switch vs Add-on in HBV Resistant Patients
Continue lamivudine Add adefovir
Lamivudine
LAM-S
LAM-S ADV-R
LAM-S ADV-S
LAM-R ADV-S
LAM-S
LAM-S ADV-R
LAM-R
LAM-R
36
Switch vs Add-on in HBV 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
HBV Cross-Resistance
(EASL CPGs Management of chronic hepatitis B J
Hepatol 200950227-42)
38
EASL Clinical Practice Guidelines

• In case of resistance, an appropriate rescue
  therapy should be initiated with the most
  effective antiviral effect and the minimal risk
  to induce multiple drug-resistant strains
• Therefore, adding-on a second drug without
  cross-resistance is the only efficient strategy
• The safety of some combinations on the long term
  is unknown

(EASL CPGs Management of chronic hepatitis B J
Hepatol 200950227-42)
39
EASL Clinical Practice Guidelines
the long-term safety of these combinations is
unknown not seen so far
(EASL CPGs Management of chronic hepatitis B J
Hepatol 200950227-42)
40
Conclusions

• The most potent drugs with the optimal resistance
  profile (entecavir or tenofovir) should be used
  as first-line monotherapies for chronic hepatitis
  B
• In case of resistance, adding-on a second drug
  without cross-resistance is the only efficient
  strategy