‡ Long-term Follow-up Evaluation of the Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF) in a European Multicenter (Nucleos(t)ide Experienced)

‡

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


‡

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


‡

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


‡

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]


Gilead User

should I switch the mean duration of LAm and ADV (last, 3rd from last)? A comments in the deck you sent indicates they are switched and in the wrong place

‡

1) Virologic response

2) HBsAg kinetics

3) Renal Safety


‡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


‡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

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


Patients who achieved HBV DNA < 400 cp/mL

lower limit of detection

‡


2) HBsAg kinetics

3) Renal Safety


‡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


‡


2) HBsAg kinetics

3) Renal Safety


‡

• 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


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


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


GFR estimated by MDRD formula GFR estimated by Cockroft-Gault formula


‡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%


‡Characteristics of Patients with Moderate (n=11) or Severe (n=2) Changes in GFR during TDF Treatment by

MDRD estimation


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)


‡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)


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


‡

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


‡

Acknowledgments

• This work was supported by the German Network

of Excellence (HEPNET) and

• the European network VIRGIL

• Funded in part by Gilead Sciences, Inc.


Documents

‡ Long-term Follow-up Evaluation of the Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF) in a European Multicenter (Nucleos(t)ide Experienced)