‡
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. Berg11Medizinisch 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, MDCharité 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) 142/52HBeAg positive (n) [%] 135 [70]Mean HBV DNA at baseline ± SD [range] (log10 copies/mL)
8.6 ± 0.4 [4 - 10]
Mean ALT at baseline ± SD [range] (IU/mL) 137 ± 274 [10-2044]Liver cirrhosis (n) [%] 28 [14]Mean creatinine in serum ±SD [range] (mg/dl) 0.89± 0.4 [0.3-4.3]
pre-treatment with different nucleos(t)ide analoguesPre-treatment with adefovir (n) [%]mean duration of lamivudine treatment ± SD (months) [range]
110 [57]25 ± 21 [8-126]
Pre-treatment with lamivudine (n) [%]mean duration of adefovir treatment ± SD (months) [range]
159 [82]12 ±13 [6-56]
van Bömmel, et al., AASLD 2009; Oral # 221.
‡
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 under observation (n):
194 194 145Patients with HBV DNA > 400 copies/mL (n):
194 106 32
% P
atie
nts
wit
h H
BV
DN
A <
400
co
pie
s/m
LKaplan-Meier
analysis
Months of TDF Treatment
1.0
0.8
0.6
0.4
0.2
0.0
0 3 6 9 12
van Bömmel, et al., AASLD 2009; Oral # 221.
‡Individual Kinetics of HBV DNA Levels in Patients with Detectable HBV DNA (> 400 copies/mL) after 12 Months
Treatment with Tenofovir (n=32)
van Bömmel, et al., AASLD 2009; Oral # 221.
1
2
3
4
5
6
7
12 18 24 30 36 42
HB
V D
NA
log
10 c
op
ies/
mL
Patients who achieved HBV DNA < 400 cp/mL
months of treatment
1
2
3
4
5
6
7
12 18 24 30 36 42
Patients with HBV DNA > 400 cp/mL
months of treatment
lower limit of detection
‡
1
2
3
4
5
6
7
12 18 24 30 36 42
lower limit of detectionHB
V D
NA
log
10 c
op
ies/
mL
Individual Kinetics of HBV DNA Levels in Patients with Detectable HBV DNA (> 400 copies/mL) after 12 Months Treatment with
Tenofovir (n=32)
1
2
3
4
5
6
7
12 18 24 30 36 42
Patients with HBV DNA > 400 cp/mL
months of treatmentmonths of treatment
TDF 300 mg + lamivudine 100 mg
TDF 300 mg monotherapy
van Bömmel, et al., AASLD 2009; Oral # 221.
Patients who achieved HBV DNA < 400 cp/mL
lower limit of detection
‡
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)
Patients under observation (n): 71 59 48 23 10
-0.6 log IU/mL
-p=n.s.
Error Bars 95% Cl
Mea
n H
BsA
g (
U/m
L)
5.00
4.00
3.00
2.00
1.00
0.00 BL 3 6 9 12
van Bömmel, et al., AASLD 2009; Oral # 221.
‡
1) Virologic response
2) HBsAg kinetics
3) Renal Safety
van Bömmel, et al., AASLD 2009; Oral # 221.
‡
• 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.
Sub-group Analysis: Renal Toxicity
‡
Overall Cohort (n = 181)Mean age ±SD [ra] (years) 46 ± 14 [18-77]
Mean weight ±SD [range] (kg) 75 ± 16 [39-128]
Mean height ±SD [range] (cm) 171± 10 [140-193]
Sex (m/f) 135/46
HBeAg positive (n) [%] 129 [71]
Mean HBV DNA at baseline ± SD [range] (log10 copies/mL) 8.6 ± 9.2 [4 - 10]
Mean ALT at baseline ± SD [range] (IU/mL) 136 ± 286 [10-2044]
Liver cirrhosis (n) [%] 26 [14]
Mean creatinine in serum ±SD [range] (mg/dl) 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) [%] 2 [1]
Kidney transplantation (n) [%] 5 [3]
Arterial hypertension (n) [%] 15 [8]
Diabetes mellitus (n) [%] 2 [1]
Glomerular nephritis (n) [%] 2 [1]van Bömmel, et al., AASLD 2009; Oral # 221.
Characteristics of Patients in Safety Analysis
‡GFR during TDF treatment estimated by MDRD and
Cockcroft-Gault estimation (n=181)
130.00
120.00
110.00
100.00
90.00
80.00
70.00
60.00
50.00
40.00
30.00
20.00
10.00
0.00
Patients under observation (n):181 181 134 97 54 34
-16 mL/min = -13%
p=0.002
Me
an
GF
R (
ml/
min
)
Duration of TDF Treatment
month 0 month 12 month 24 month 36 month 48 month 60month 0 month 12 month 24 month 36 month 48 month 60
Patients under observation (n):181 181 134 97 54 34
-10.3 mL/min/1.73m2 = -11%
p=0.01
Error Bars: 95% Cl
Me
an
GF
R (
mL
/min
/1.7
3 m
2 )
130.00
120.00
110.00
100.00
90.00
80.00
70.00
60.00
50.00
40.00
30.00
20.00
10.00
0.00
Duration of TDF Treatment
GFR estimated by MDRD formula GFR estimated by Cockroft-Gault formula
van Bömmel, et al., AASLD 2009; Oral # 221.
‡Changes in GFR during TDF treatment by
MDRD and Cockcroft-Gault estimation (n=181)
0
10
20
30
40
50
60
70
80
90
100
nodecrease
milddecrease
moderatedecrease
severedecrease
increase>10
58%n=105
22%n=40
6%n=11 1%
n=2
13%n=23
GFR estimated by MDRD formula
Per
cen
t C
han
ges
in
GF
R (
%)
%±10% 10-20% 20-30% <30%
0
10
20
30
40
50
60
70
80
90
100
nodecrease
milddecrease
moderatedecrease
severedecrease
increase>10
59%n=107
26%n=48
1%n=2
1%n=2
12%n=22
GFR estimated by Cockcroft-Gault formula
%±10% 10-20% 20-30% <30%
van Bömmel, et al., AASLD 2009; Oral # 221.
‡Characteristics of Patients with Moderate (n=11) or Severe (n=2) Changes in GFR during TDF Treatment by
MDRD estimation
van Bömmel, et al., AASLD 2009; Oral # 221.
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
150
. 0 12 24 36 48 60 .
GFR estimated by MDRD formula
Mea
n G
FR
(m
L/m
in/1
.73
m2)
Duration of TDF Treatment
‡Characteristics of Patients with Moderate (n=11) or Severe (n=2) Changes in GFR during TDF Treatment
by MDRD estimation (cont’d)
moderate decrease. 20-30 % (n=11) severe decrease. > 30 % (n=2)
51.02
115.61
68.82
75.83
67.0169.5891.7983.34
31.4033.46
88.8066.6971.45
63.82
128.56
82.91
95.33
84.82107.74113.3497.92
41.6142.40
140.1389.9891.01
33
4
49
13
40
10170
00
0
1233
0
19
2
19
50
152924
5238
19
18
45
90.49106.941.171.00327740m11
143.06158.330.760.70397635m12
50.0161.231.441.19336154m13
98.35119.801.211.01247219m10
75.9684.821.13.93387554m9
51.5746.072.231.76839249m5
56.4766.11.72.63134256w6103.04126.22.89.75467144m7121.23179.541.18.823410034m8
2.05
.881.10
1.09
1.68
0.86
0.89
34.02
92.0569.09107.73
133.76
95.7480.91113.40
m
mmm AH
86
82
68
31
62
72
7695
4
3
2
1
no.
57
55
6250
51.02
115.61
68.82
75.83
67.01
69.5891.7983.34
31.4033.46
88.80
66.69
71.45
63.82
128.56
82.91
95.33
84.82
107.74113.3497.92
41.6142.40
140.13
89.98
91.01
33
4
13
10170
00
33
0
19
19
152924
5238
45
90.49106.943211
0.760.70397635m12
50.0161.231.441.19336154m13
98.35119.801.211.01247219m10
51.5746.072.231.76839249m5
56.4766.11.72.63134256w6103.04126.22.89.75467144m7121.23179.541.18.823410034m8
2.05
1.09
1.68
0.60
0.89
32.90
92.05
69.09
107.73
42.05
95.74
80.91
113.40mm
sexSecondary diseases
86
31
TDF LAM ADV
62
7695
weight
4
1
57
6250
age start of TDF EOBS
LT
nonenonenone
none
none
none
none
AH
AH. DM
KT
KT
Treatment duration (months):
Creatinine (mg/dL) at:
MDMR (mL/min/1.73m2) at:
start of TDF EOBS
Cockcroft-Gault (mL/min) at:
start of TDF EOBS
GFR
AH=arterial hypertension, DM=diabetes mellitus, KT=kidney transplant LT=liver transplant, EBOS=end of observationvan Bömmel, et al., AASLD 2009; Oral # 221.
‡Changes in GFR during TDF treatment in Patients with elevated Creatinine Levels at baseline by MDRD and
Cockcroft-Gault formula (n=10)
van Bömmel, et al., AASLD 2009; Oral # 221.
Mea
n G
FR
(m
L/m
in)
Duration of Treatment (months)
120
100
80
60
40
20
0
GFR by Cockroft-Gault formula
0 12 24 36 48
Mea
n G
FR
(m
L/m
in/1
,73
m2 )
Duration of Treatment (months)
120
100
80
60
40
20
0
GFR by MDRD
0 12 24 36 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 follow-up 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.