Transcript AASLD 2009 Guideline BACK UP SLIDES

‡
Long-term Follow-up Evaluation of the Efficacy and
Safety of Tenofovir Disoproxil Fumarate (TDF) in a
European Multicenter (Nucleos(t)ide Experienced)
Hepatitis B Virus HBV-infected Cohort
F. van Bömmel1, R. de Man2, P. Ferenci3, J.P. Bronowiki4, B. Fülöp1, H. Wedemeyer5,
A. Erhardt6, D. Hüppe7, M. Bourlière8, C. Sarrazin9, J. Trojan9, P. Buggisch10, J.
Petersen10, U. Spengler11, S. Brost12, M. Schuchmann14, H. Wasmuth15, J. Reijnders2,
K. Deterding5, K. Rutter3, H-H. Feucht16, B. Wiedenmann1, T. Berg1
1Medizinisch
Klinik m. S. Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Berlin,Germany. 2Department of
Gastroenterology and Hepatology, Erasmus MC University Medical Center , Rotterdam,Netherlands. 3Department of Internal
Medicine III, Medical University of Vienna, Vienna, Austria. 4Service d'Hépato-Gastroentérologie, CHU de Nancy, Nancy, France.
5Abteilung für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany. 6Klinik
für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum der Heinrich-Heine-Universität , Düsseldorf,
Germany.7Gastroenterologische Gemeinschaftspraxis , Gastroenterologische Gemeinschaftspraxis , Herne, Germany. 8Service
d'Hépatogastroentérologie, Hôpital St Joseph, Marseille, France. 9Department of Internal Medicine, Johann Wolfgang Goethe
University Medical Centre, Frankfurt a.M., Germany.10IFI-Institut, Asklepios Klinik St. Georg, Hamburg, Germany. 11Zentrum für
Innere Medizin, Universitätsklinikum Bonn, Bonn, Germany. 12Innere Medizin IV, Universitätsklinikum Heidelberg, Heidelberg,
Germany. 13Unité d' hépatogastroentérologie, Centre Hospitalier Général, Pau, France. 14I. Department of Internal Medicin,
Universitätsklinikum Mainz, Mainz, Germany. 15Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Germany.
16Laborgemeinschaft Hamburg, Laborgemeinschaft Hamburg, Hamburg, Germany.
60th Annual Meeting of the American Association for the Study of Liver Diseases © in Boston, MA
Oral # 221
Florian van Bömmel, MD
Charité University Hospital Berlin, Germany
I have received scientific funding
by Gilead Sciences Inc.
AND
My presentation does not include discussion of
off-label or investigational use.
‡
Aims of the Study
•
Evaluation of
1. Long-term efficacy and safety of tenofovir disoproxil
fumarate (TDF) monotherapy in treatment-experienced
patients with HBV monoinfection
2. Kinetics of HBs-antigen levels
3. Long-term renal safety
van Bömmel, et al., AASLD 2009; Oral # 221.
‡
Study Design
• Retrospective Cohort Analysis of the follow up of treatment
with TDF 300 mg QD monotherapy in HBV-monoinfected
patients with history of failure to treatment with
nucleos(t)ide analogues
• 19 centers participated in Germany, France, Austria and The
Netherlands
• Collection of data from all patients with HBV monoinfection
and TDF monotherapy in participating centers to avoid bias
van Bömmel, et al., AASLD 2009; Oral # 221.
‡
Endpoints
• Primary Endpoint:
– Virologic response, defined as HBV DNA below LLOQ (<400
copies/mL, Cobas Amplicor assay, Roche)]
• Secondary Endpoints:
– HBsAg response, defined by changes in HBsAg levels
– Renal safety; changes in glomerular filtration rate
– Frequency of resistance development
van Bömmel, et al., AASLD 2009; Oral # 221.
‡
Results: Patients
• 290 patients with chronic HBV monoinfection were treated with
TDF at the 19 participating centers between 2002 and 2009
• 96 patients were excluded due to:
– HBV DNA < 104 copies/mL at TDF baseline (n=37)
– treatment with TDF < 6 months (n=45)
– non-compliance to TDF as reported by treating physician (n=14)
• 194 patients remained in analysis population; median time on
TDF treatment 30±17 [6-86] months
van Bömmel, et al., AASLD 2009; Oral # 221.
‡
Characteristics of the Eligible Patients (n=194)
Overall Cohort (n = 194)
Mean age ±SD [ra] (years)
46 ± 13 [18-77]
Mean weight ±SD [range] (kg)
75 ± 17 [39-128]
Mean height ±SD [range] (cm)
171± 10 [140-193]
Sex (m/f)
142/52
HBeAg positive (n) [%]
Mean HBV DNA at baseline ± SD [range]
(log10 copies/mL)
Mean ALT at baseline ± SD [range] (IU/mL)
Liver cirrhosis (n) [%]
Mean creatinine in serum ±SD [range] (mg/dl)
135 [70]
8.6 ± 0.4 [4 - 10]
137 ± 274 [10-2044]
28 [14]
0.89± 0.4 [0.3-4.3]
pre-treatment with different nucleos(t)ide analogues
Pre-treatment with adefovir (n) [%]
mean duration of lamivudine treatment ± SD (months) [range]
Pre-treatment with lamivudine (n) [%]
mean duration of adefovir treatment ± SD (months) [range]
van Bömmel, et al., AASLD 2009; Oral # 221.
110 [57]
25 ± 21 [8-126]
159 [82]
12 ±13 [6-56]
‡
1) Virologic response
2) HBsAg kinetics
3) Renal Safety
van Bömmel, et al., AASLD 2009; Oral # 221.
Probability of Achieving HBV DNA Levels
<400 copies/mL During 12 Months Treatment
with Tenofovir (n=194)
% Patients with HBV DNA < 400
copies/mL
1.0
Kaplan-Meier
analysis
0.8
0.6
0.4
0.2
0.0
0
3
6
9
Months of TDF Treatment
12
194
145
Patients under observation (n):
194
Patients with HBV DNA > 400 copies/mL (n):
194
van Bömmel, et al., AASLD 2009; Oral # 221.
106
32
‡
Individual Kinetics of HBV DNA Levels in Patients with
Detectable HBV DNA (> 400 copies/mL) after 12 Months
Treatment with Tenofovir (n=32)
HBV DNA log10 copies/mL
Patients who achieved HBV DNA < 400 cp/mL
‡
Patients with HBV DNA > 400 cp/mL
7
7
6
6
5
5
4
4
3
3
lower limit of detection
2
2
1
1
12
18
24
30
months of treatment
van Bömmel, et al., AASLD 2009; Oral # 221.
36
42
12
18
24
30
months of treatment
36
42
Individual Kinetics of HBV DNA Levels in Patients with Detectable‡
HBV DNA (> 400 copies/mL) after 12 Months Treatment with
Tenofovir (n=32)
HBV DNA log10 copies/mL
Patients who achieved HBV DNA < 400 cp/mL
Patients with HBV DNA > 400 cp/mL
7
7
6
6
5
5
4
4
3
3
TDF 300 mg
monotherapy
lower limit of detection
lower limit of detection
2
2
1
1
12
18
24
30
months of treatment
van Bömmel, et al., AASLD 2009; Oral # 221.
TDF 300 mg +
lamivudine 100 mg
36
42
12
18
24
30
months of treatment
36
42
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1) Virologic response
2) HBsAg kinetics
3) Renal Safety
van Bömmel, et al., AASLD 2009; Oral # 221.
Kinetic of mean HBsAg Levels
During Treatment with Tenofovir (n=71)
5.00
Mean HBsAg (U/mL)
4.00
3.00
-0.6 log IU/mL
-p=n.s.
2.00
1.00
0.00
Patients under observation (n):
van Bömmel, et al., AASLD 2009; Oral # 221.
BL
3
6
9
12
71
59
48
23
10
Error Bars 95% Cl
‡
‡
1) Virologic response
2) HBsAg kinetics
3) Renal Safety
van Bömmel, et al., AASLD 2009; Oral # 221.
‡
Sub-group Analysis: Renal Toxicity
• 181 patients were included
• Subjects were excluded if they met the following criteria:
– HBV DNA < 104 copies/mL at TDF baseline (n=37)
– treatment with TDF < 6 months (n=45)
– availability of results for serum creatinine, age and weight
from baseline TDF treatment and during treatment
van Bömmel, et al., AASLD 2009; Oral # 221.
‡
Sub-group Analysis: Renal Toxicity
• Glomerular filtration rate (GFR) was estimated
– by MDRD (Modification of Diet in Renal Disease formula):
GFR (ml/min/1.73 m²) = 186 x (creatinine /0.95) -1.154 x (age)
– 0.203 x (0.742 for females)
x (1.21 for patients with African origin)
– by Cockcroft-Gault formula:
Ccr (mL/min) = ((140 – age) x body weight) /72 x creatinine in
serum)) x 0.85 for females
van Bömmel, et al., AASLD 2009; Oral # 221.
‡
Characteristics of Patients in Safety Analysis
Overall Cohort (n = 181)
Mean age ±SD [ra] (years)
Mean weight ±SD [range] (kg)
Mean height ±SD [range] (cm)
Sex (m/f)
HBeAg positive (n) [%]
Mean HBV DNA at baseline ± SD [range] (log10 copies/mL)
Mean ALT at baseline ± SD [range] (IU/mL)
Liver cirrhosis (n) [%]
Mean creatinine in serum ±SD [range] (mg/dl)
46 ± 14 [18-77]
75 ± 16 [39-128]
171± 10 [140-193]
135/46
129 [71]
8.6 ± 9.2 [4 - 10]
136 ± 286 [10-2044]
26 [14]
0.91± 0.4 [0,3-4,2]
Mean glomerular filtration rate (by MDRD) ±SD [range] (mL/min/1,73m)
93 ± 25 [15-174]
Mean creatinine clearance (by Cockroft-Gault) ±SD [range] (mL/min)
112 ± 36 [22-237]
Pre-existing risk factors for renal insufficiency (n = 26)
Liver transplantation (n) [%]
Kidney transplantation (n) [%]
Arterial hypertension (n) [%]
Diabetes mellitus (n) [%]
Glomerular nephritis (n) [%]
van Bömmel, et al., AASLD 2009; Oral # 221.
2 [1]
5 [3]
15 [8]
2 [1]
2 [1]
GFR during TDF treatment estimated by MDRD and
Cockcroft-Gault estimation (n=181)
GFR estimated by Cockroft-Gault formula
130.00
130.00
120.00
120.00
110.00
110.00
100.00
100.00
90.00
90.00
Mean GFR (ml/min)
Mean GFR (mL/min/1.73 m2)
GFR estimated by MDRD formula
80.00
70.00
60.00
-10.3 mL/min/1.73m2 = -11%
50.00
p=0.01
40.00
‡
80.00
70.00
-16 mL/min = -13%
60.00
p=0.002
50.00
40.00
30.00
30.00
20.00
20.00
10.00
10.00
0.00
0.00
month 0
month 12
month 24
month 36
month 48
month 60
181
134
van Bömmel, et al., AASLD 2009; Oral # 221.
97
54
month 12
month 24
month 36
month 48
month 60
Duration of TDF Treatment
Patients under observation (n):
Duration of TDF Treatment
Patients under observation (n):
181
month 0
34
181
181
134
97
54
34
Error Bars: 95% Cl
Changes in GFR during TDF treatment by
MDRD and Cockcroft-Gault estimation (n=181)
Percent Changes in GFR (%)
GFR estimated by MDRD formula
GFR estimated by Cockcroft-Gault formula
100
100
90
90
80
80
70
60
58%
n=105
70
60
50
50
40
40
22%
n=40
30
20
26%
n=48
30
6%
n=11
10
59%
n=107
1%
n=2
13%
n=23
20
10
0
1%
n=2
1%
n=2
moderate
decrease
20-30%
severe
decrease
<30%
12%
n=22
0
no
decrease
±10%
mild
decrease
10-20%
moderate
decrease
20-30%
van Bömmel, et al., AASLD 2009; Oral # 221.
severe
decrease
<30%
increase
>10 %
no
decrease
±10%
mild
decrease
10-20%
increase
>10 %
‡
Characteristics of Patients with Moderate (n=11) or ‡
Severe (n=2) Changes in GFR during TDF Treatment by
MDRD estimation
GFR estimated by MDRD formula
150
140
Mean GFR (mL/min/1.73 m2)
130
120
110
100
90
80
70
60
50
40
30
20
10
0
.
0
12
24
36
Duration of TDF Treatment
van Bömmel, et al., AASLD 2009; Oral # 221.
48
60
.
Characteristics of Patients with Moderate (n=11) or
Severe (n=2) Changes in GFR during TDF Treatment
by MDRD estimation (cont’d)
GFR
Secondary
no. sex age weight diseases
1
2
3
m 50
m 62
m 55
95
76
4
5
m
m
w
m
m
m
m
m
m
m
57
49
62
92
56
44
34
6
7
8
9
10
11
12
13
Treatment duration
Creatinine
(months):
(mg/dL) at:
TDF LAM ADV
MDMR
Cockcroft-Gault
(mL/min/1.73m2) at:
(mL/min) at:
start
of TDF
EOBS
start
of TDF
EOBS
start
of TDF
EOBS
1.09
1.10
.88
91.01
89.98
89.98
140.13
140.13
71.45
66.69
66.69
88.80
88.80
113.40
80.91
80.91
95.74
95.74
107.73
69.09
69.09
92.05
92.05
31
68
82
45
18
19
33
12
0
0.89
0.86
0.60
KT
86
83
38
52
0
0
1.68
1.76
2.05
2.23
42.40
41.61
33.46
31.40
133.76
42.05
46.07
32.90
34.02
51.57
42
71
100
none
none
none
13
46
34
24
29
15
0
17
10
.63
.75
.82
.72
.89
1.18
56.47
103.04
121.23
75
38
50
40
.93
1.13
84.82
75.96
19
72
none
none
83.34
91.79
69.58
67.01
67.01
66.11
126.22
179.54
54
97.92
113.34
107.74
84.82
84.82
24
19
13
1.01
1.21
95.33
75.83
119.80
98.35
40
77
32
106.94
90.49
0.70
1.17
0.76
68.82
39
49
4
82.91
76
2
19
1.00
35
none
none
128.56
115.61
158.33
143.06
54
61
LT
33
0
33
1.19
1.44
63.82
51.02
61.23
50.01
72
AH
AH
AH. DM
KT
AH=arterial hypertension, DM=diabetes mellitus, KT=kidney transplant LT=liver transplant, EBOS=end of observation
van Bömmel, et al., AASLD 2009; Oral # 221.
moderate decrease. 20-30 % (n=11) severe decrease. > 30 % (n=2)
‡
Changes in GFR during TDF treatment in Patients with‡
elevated Creatinine Levels at baseline by MDRD and
Cockcroft-Gault formula (n=10)
GFR by Cockroft-Gault formula
120
120
100
100
80
80
Mean GFR
(mL/min)
Mean GFR (mL/min/1,73 m2)
GFR by MDRD
60
60
40
40
20
20
0
0
0
12
24
36
Duration of Treatment (months)
van Bömmel, et al., AASLD 2009; Oral # 221.
48
0
12
24
36
Duration of Treatment (months)
48
‡
Summary
• Treatment with TDF in this cohort of treatment-experienced
patients resulted in potent suppression of HBV DNA
• No virologic breakthrough was observed during the followup period, also in patients with incomplete response at
months 12
• There was no significant decrease in mean HBsAg-levels
• A mild (10%) reduction in glomerular filtration rate was
observed in many patients, however TDF treatment did not
need to be adjusted or interrupted due to renal toxicity
van Bömmel, et al., AASLD 2009; Oral # 221.
‡
Conclusion
• TDF monotherapy is an effective and well
tolerated option for long term treatment in HBV
monoinfected patients with prior treatment
experience, including those with pre-existing
renal dysfunction
van Bömmel, et al., AASLD 2009; Oral # 221.
‡
Acknowledgments
• This work was supported by the German Network
of Excellence (HEPNET) and
• the European network VIRGIL
• Funded in part by Gilead Sciences, Inc.
van Bömmel, et al., AASLD 2009; Oral # 221.