Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD...

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Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis B, C and delta Virology Unit & INSERM U635 Department of Bacteriology and Virology Henri Mondor Hospital Universite Paris XII Créteil, France

Transcript of Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD...

Page 1: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Management of Resistance:Implications for Treatment Choices

Jean-Michel Pawlotsky, MD, PhDDirector, French National Reference Center for Viral Hepatitis B, C and deltaVirology Unit & INSERM U635 Department of Bacteriology and Virology Henri Mondor HospitalUniversite Paris XIICréteil, France

Page 2: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

clinicaloptions.com/hep

Primary Endpoints of HBV Therapy

Stop or slow the progression of liver disease in order to

– Prevent cirrhosis

– Prevent decompensation of cirrhosis

– Prevent hepatocellular carcinoma

Page 3: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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HBV DNA as a Marker of Efficacy During Treatment of HBV Literature analysis of 26 prospective studies

– Investigation of the relationship between treatment-induced changes in HBV DNA, histology, other disease activity markers

Results– Statistically significant and consistent correlations between HBV DNA,

histology, biochemical and serologic responses– HBV DNA had broader dynamic range than histology

Conclusion– Treatment-induced reduction in HBV DNA can be used to assess efficacy

– Treatment goal should be profound and durable suppression of HBV DNA

Mommeja-Marin H, et al. Hepatology. 2003;37:1309-1319.

Page 4: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Endpoint of Therapy With HBV Oral Antiviral Drugs Inhibition of HBV replication

– As profound as possible

– As sustained as possible

ANTIVIRAL POTENCY

NO RESISTANCE

Page 5: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

HBV Treatment Failureand Resistance

Page 6: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Mechanisms of Resistance

Sensitive

ResistantResistant

Sensitive

Drug

Sensitive

Resistant

Discontinue Drug

Page 7: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Mechanisms of Resistance

Sensitive

Resistant + FitResistant

Sensitive

Drug

Sensitive

Resistant

Discontinue Drug

Page 8: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Mechanisms of Resistance

Resistant + Very Fit

Sensitive

Resistant

Sensitive

Drug

Sensitive

Resistant

Discontinue Drug

Page 9: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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HBV Resistance Mutations

rtA181T/V

rtL80V/I rtM204V/I/SLAM resistance rtV173L

rtL180M

rtN236T

rtl233V ?

rtM204V/I

rtS202G/C rtM250I/VrtT184S/A/I/L

rtM204ILdT resistance

ETV resistance

845 a.a.

Terminalprotein Spacer Pol/RT RNaseH

A B C ED

YMDDGVGLSPFLLA

I(G) II(F)

ADV resistance

Allen MI, et al. Hepatology. 1998;27:1670-1677. Qi X, et al. J Hepatol. 2004;40(suppl 1):20-21. Tenney D, et al. Antimicrob Agents Chemother. 2004;48:3498-3507. Telbivudine product insert. Lai CL, et al. Gastroenterology. 2005;129:528-536. Schildgen O, et al. N Engl J Med. 2006;354:1807-1812.

rtL180M

rtL80V/I rtL180M

Page 10: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Incidence of HBV Resistance

Lamivudine (nucleos[t]ide-naive patients)

Lai CL, et al. Clin Infect Dis. 2003;36:687-696.Lok AS, et al. Gastroenterology. 2003;125:1714-1722.

23

55

71 65

46

Year

1 2 3 4 5

Cu

mu

lati

ve I

nci

den

ce o

f R

esis

tan

ce (

%)

0

80

40

60

20

100

Page 11: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Incidence of HBV Resistance (cont’d)

Adefovir (nucleos[t]ide-naive, HBeAg-negative patients);selection of resistance mutations with or without breakthrough

Borroto-Esoda K, et al. EASL 2006. Abstract 483.

0 3 11

1829

Year

1 2 3 4 5

Cu

mu

lati

ve I

nci

den

ce o

f R

esis

tan

ce (

%)

0

80

40

60

20

100

Page 12: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Entecavir (genotypic resistance in HBeAg[+]/[-] nucleos(t)ide-naive patients)Entecavir (genotypic resistance in LAM-R patients)Entecavir (genotypic resistance plus viral rebound in LAM-R patients)

Cu

mu

lati

ve I

nci

den

ce o

f O

utc

om

e (%

)

Colonno R, et al. AASLD 2006. Abstract 110.

Incidence of HBV Resistance

0.1 0.4 1.1614

32

110

25

0

80

40

60

20

100

Year

1 2 3 4 5

Page 13: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Incidence of HBV Resistance

Telbivudine

Lai CL, et al. Gastroenterology. 2005;129:528-536. Lai CL, et al. AASLD 2006. Abstract 91.

5.0? ? ?

Year

1 2 3 4 5

Cu

mu

lati

ve I

nci

den

ce o

f R

esis

tan

ce (

%)

0

80

40

60

20

100

Telbivudine (HBeAg-positive patients)Telbivudine (HBeAg-negative patients)

21.6

8.6

Page 14: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Prevention ofHBV Resistance

Page 15: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Prevention of Resistance

Experience from other therapies suggests that during prolonged antiviral therapy, resistance cannot be avoided indefinitely

Employment of appropriate therapeutic strategies can consistently delay the emergence of resistance

Page 16: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Delaying Viral Resistance

1. Maximally reduce virus replication

– Use highly potent antivirals

Page 17: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Entecavir vs Lamivudine

LamivudineEntecavir

-6.9

-5.0 -5.1-5.4-4.5

-0.5

-8

-6

-4

-2

0Naive HBeAg+ Naive HBeAg-

LAM-RHBeAg+

Red

uct

ion

in H

BV

DN

A a

t W

eek

48 (

log

10 c

op

ies/

mL

)

P < .0001

P < .0001 P < .0001

Chang T, et al. N Engl J Med. 2006;354:1001-1010. Lai C, et al. N Engl J Med. 2006;354:1011-1020. Colonno R, et al. AASLD 2006. Abstract 110. Sherman M, et al. Gastroenterology. 2006;130:2039-2049.

Page 18: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Entecavir vs Lamivudine (cont’d)

67

90

19

36

72

10

20

40

60

80

100

Naive HBeAg+ Naive HBeAg- LAM-R HBeAg+

Un

det

ecta

ble

HB

V D

NA

at

Wee

k 48

(<

300

co

pie

s/m

L)

(%)

LamivudineEntecavir

Chang T, et al. N Engl J Med. 2006;354:1001-1010. Lai C, et al. N Engl J Med. 2006;354:1011-1020. Colonno R, et al. AASLD 2006. Abstract 110. Sherman M, et al. Gastroenterology. 2006;130:2039-2049.

Page 19: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Entecavir vs Adefovir

Wilber R, et al. NIH HBV 2006. Abstract 14.

Week 12 Comparison

ADV (n = 34) ETV (n = 35)

0

-1

-2

-3

-4

-5

-6

-7

Red

uct

ion

in H

BV

DN

A

(lo

g10

co

pie

s/m

L)

- 6.23

- 4.42

P < .0001

Page 20: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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On-Treatment(N = 921)

Telbivudine vs Lamivudine:HBeAg-Positive Patients

Lai C, et al. HepDart 2005. Abstract 95.

-6.5

-5.5

-6.6

-5.2

Posttreatment(n = 328)

-8

-7

-6

-5

-4

-3

-2

-1

0

Mea

n C

han

ge

in H

BV

DN

A F

rom

Bas

elin

e(l

og

10 c

op

ies/

mL

± S

E)

Telbivudine

Lamivudine

Page 21: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Telbivudine vs Lamivudine: HBeAg-Negative Patients

Lai C, et al. HepDart 2005. Abstract 95.

-5.3-5.2-4.7

-4.4

-8

-7

-6

-5

-4

-3

-2

-1

Mea

n C

han

ge

in H

BV

DN

A F

rom

Bas

elin

e(l

og

10 c

op

ies/

mL

± S

E)

Telbivudine

Lamivudine

On-Treatment(N = 446)

Posttreatment(n = 135)

-8

-7

-6

-5

-4

-3

-2

-1

Mea

n C

han

ge

in H

BV

DN

A F

rom

Bas

elin

e(l

og

10 c

op

ies/

mL

± S

E)

0

Page 22: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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2

7

1

0

-2.8 log

-5.5 log

P < .001

Tenofovir vs Adefovir in LAM-R Patients

van Bommel F, et al. Hepatology. 2004;40:1421-1425.

HBV DNA < 400 copies/mL at

Week 48

Adefovir (n = 18) Tenofovir (n = 35)

Wee

k 48

Red

uct

ion

inH

BV

DN

A (

log

10 c

op

ies/

mL

)

3

4

5

6

Adefovir: 44%Tenofovir: 100%

Page 23: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

clinicaloptions.com/hep

Delaying Viral Resistance

1. Maximally reduce virus replication

– Use highly potent antivirals

2. Raise the “pharmacologic barrier” to viral escape

– Reach high trough levels

– Have a tissue distribution that permits no sanctuaries

– Optimize patient adherence

Page 24: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

clinicaloptions.com/hep

Delaying Viral Resistance

1. Maximally reduce virus replication

– Use highly potent antivirals

2. Raise the “pharmacologic barrier” to viral escape

– Reach high trough levels

– Have a tissue distribution that permits no sanctuaries

– Optimize patient adherence

3. Raise the “genetic barrier” to resistance

– Combination therapies

Page 25: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Dent J, et al. Hepatology. 2000;32:457A. Ono SK, et al. J Clin Invest. 2001;107:449-455. Delaney W, et al. Antiviral Res. 2001;50:A81. Fu L, et al. Antimicrob Agents Chemother. 2000;44:3402-3407. Delaney WE, et al. Antimicrob Agents Chemother. 2001;45:1705-1713. Delaney W, et al. EASL 2002. Abstract 181.

Reduced susceptibility

Fold-Change in Susceptibility Relative to Wild Type HBV

HBV mutations 3TC L-FMAU L-Fd4C ETV FTC LdC LdT

Wild type 1 1 1 1 1 1 1

L180M 5 5 3 1 11 12 9.4

M204I > 1000 570 NA 864 NA 500 > 330

L180M + M204V > 1000 > 1000 233 182 > 42 410 345

In Vitro Cross-resistance to Lamivudine Resistance Mutations

Resistant

Page 26: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Fold-Change in EC50 From Wild Type

Compound M204V + L180M M204V + L180M + V173L M204I M204I + L180M

Tenofovir 0.8 1.8 2.1 0.7

Adefovir 1.1 1.1 1.8 2.1

Entecavir 37 164 471 38

Lamivudine > 700 > 1000 > 1000 > 1000

In Vitro Cross-resistance to Lamivudine Resistance Mutations

Qi X, et al. EASL 2005. Abstract 75.

Reduced susceptibility Resistant

Page 27: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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IC50 Fold Change

N236T A181V

Adefovir 7.30 4.20

Tenofovir 4.60 1.80

Entecavir 0.67 12.10

Lamivudine 2.10 14.10

Emtricitabine 2.60 14.10

Telbivudine (LdT) 2.40 > 24.00

Valtorcitabine (LdC) NA 87.00

Clevudine 4.90 > 164.00

In Vitro Cross-resistance to Adefovir Resistance Mutations

Qi X, et al. Gastroenterology. 2004;126(suppl 2):A-660. Abstract 3. Qi X, et al. EASL 2005. Abstract 536.

Reduced susceptibility Resistant

Page 28: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Mechanisms of HBV Resistance

Sensitive

ResistantResistant

Sensitive

Drug

Sensitive

Resistant

Discontinue Drug

Page 29: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Combination in Naive Patients

Lamivudine + Adefovir

LAM-R ADV-R

Sensitive

LAM-R ADV-R

Sensitive

LAM + ADV-R LAM + ADV-R

Page 30: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Lamivudine + Adefovir:HBeAg-Positive, Naive Patients

Sung J, et al. EASL 2003. Abstract 4313.

-6

-5

-4

-3

-2

-1

0

Wee

k 52

Mea

n C

han

ge

in H

BV

DN

A

Fro

m B

asel

ine

(lo

g10

co

pie

s/m

L)

-5.2-4.8

Lamivudine + adefovir Lamivudine + placebo

Page 31: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Adefovir Resistance

Locarnini S, et al. EASL 2005. Abstract 36.

All adefovir-resistant patients (22 reported to date) were on adefovir monotherapy

– 20 from adefovir monotherapy trials

– 2 from adefovir + lamivudine trials but had stopped lamivudine

No adefovir resistance observed to date when adefovir is added to ongoing lamivudine

No adefovir resistance observed to date in treatment-naive patients treated with adefovir + FTC or adefovir + lamivudine

Page 32: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Summary

HBV resistance may be delayed for many years by

– Using highly potent antiviral drugs with optimized pharmacologic profiles

– Improving patients’ adherence to therapy

– Using first-line combinations of drugs without cross-resistance

Page 33: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Management ofHBV Resistance

Page 34: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Management of HBV Resistance: Options Continue current therapy

Switch to another drug

Add on another drug

Switch and add on

Page 35: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Switch vs Add-on in Lamivudine-Resistant Patients

LAM-SADV-S

LAM-RADV-S

ADV-R

Add AdefovirStop LamivudineLamivudine

LAM-R

LAM-S

LAM-S

LAM-R

LAM-SADV-R

LAM-S

LAM-R

LAM-SADV-R

Page 36: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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LAM-RADV-R

Switch vs Add-on in Lamivudine-Resistant Patients

Continue LamivudineContinue LamivudineAdd AdefovirAdd Adefovir

LAM-SADV-R

Lamivudine

LAM-R

LAM-S

LAM-S

LAM-R

LAM-SADV-R

LAM-SADV-S

LAM-RADV-S

Page 37: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Add-on Adefovir in Lamivudine-Resistant Patients

Lampertico P, et al. EASL 2006. Abstract 116.

Adefovir resistance, presence of adefovir resistance mutations confirmed by molecular analysis in patients with virologic rebound; virologic rebound, > 1 log10 copies/mL increase in HBV DNA level.

Endpoints at Year 2ADV Switch

(n = 277)ADV + LAM

(n = 294)P Value

Virologic rebound, n (%) 41 (15) 11 (4) < .001

ADV genotypic resistance, n (%)

21 (8) 0 (0) < .001

Page 38: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Practical Options

Lamivudine resistance

– Switch to entecavir

– Continue lamivudine and add adefovir

– Switch to telbivudine and add adefovir

– Switch to entecavir and add adefovir

– Consider tenofovir instead of adefovir when approved

– Consider tenofovir/FTC formulation when approved

Page 39: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Practical Options (cont’d)

Adefovir resistance

– Add lamivudine

– Add telbivudine

– Add entecavir

– Switch to tenofovir when approved in combination with lamivudine, telbivudine, or entecavir

– Switch to tenofovir/FTC when approved

Page 40: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Practical Options (cont’d)

Entecavir resistance

– Add adefovir

– Add tenofovir when approved

Page 41: Management of Resistance: Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis.

Focus on the Virus: A New Paradigm for the Management and Treatment of HBV

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Summary

HBV resistance can be delayed

– By using highly potent antivirals

– By improving adherence

– By using combination therapies

When resistance occurs

– Consider add-on therapy rather than switching to second monotherapy

– Consider using the most potent available antiviral combination