management of resistance: implications for treatment choices

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

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



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.



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

– As profound as possible

– As sustained as possible

ANTIVIRAL POTENCY

NO RESISTANCE

HBV Treatment Failureand Resistance



Mechanisms of Resistance

Sensitive

ResistantResistant

Sensitive

Drug

Sensitive

Resistant

Discontinue Drug




Sensitive

Resistant + FitResistant

Sensitive

Drug

Sensitive

Resistant

Discontinue Drug




Resistant + Very Fit

Sensitive

Resistant

Sensitive

Drug

Sensitive

Resistant

Discontinue Drug



HBV Resistance Mutations

rtA181T/V

rtL80V/I rtM204V/I/SLAM resistance rtV173LrtL180M

rtN236Trtl233V ?

rtM204V/IrtS202G/C rtM250I/VrtT184S/A/I/LrtM204ILdT 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



Incidence of HBV ResistanceLamivudine (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

Year1 2 3 4 5

Cum

ulat

ive

Inci

denc

e of

R

esis

tanc

e (%

)

0

80

40

60

20

100



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

Year1 2 3 4 5

Cum

ulat

ive

Inci

denc

e of

R

esis

tanc

e (%

)

0

80

40

60

20

100



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)

Cum

ulat

ive

Inci

denc

e of

O

utco

me

(%)

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

Year1 2 3 4 5



Incidence of HBV ResistanceTelbivudine

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

5.0? ? ?

Year1 2 3 4 5

Cum

ulat

ive

Inci

denc

e of

R

esis

tanc

e (%

)

0

80

40

60

20

100

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

21.6

8.6

Prevention ofHBV Resistance



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



Delaying Viral Resistance1. Maximally reduce virus replication

– Use highly potent antivirals



Entecavir vs LamivudineLamivudineEntecavir

-6.9

-5.0 -5.1-5.4-4.5

-0.5

-8

-6

-4

-2

0Naive HBeAg+ Naive HBeAg-

LAM-RHBeAg+

Red

uctio

n in

HB

V D

NA

at

Wee

k 48

(log

10 c

opie

s/m

L)

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.



Entecavir vs Lamivudine (cont’d)

67

90

19

36

72

10

20

40

60

80

100

Naive HBeAg+ Naive HBeAg- LAM-R HBeAg+

Und

etec

tabl

e H

BV

DN

A a

t W

eek

48 (<

300

cop

ies/

mL)

(%)

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.



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

uctio

n in

HB

V D

NA

(lo

g 10 c

opie

s/m

L)

- 6.23

- 4.42

P < .0001



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

hang

e in

HB

V D

NA

Fro

m B

asel

ine

(log 1

0 cop

ies/

mL

± SE

)

TelbivudineLamivudine



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

hang

e in

HB

V D

NA

Fro

m B

asel

ine

(log 1

0 cop

ies/

mL

± SE

)

TelbivudineLamivudine

On-Treatment(N = 446)

Posttreatment(n = 135)

-8

-7

-6

-5

-4

-3

-2

-1

Mea

n C

hang

e in

HB

V D

NA

Fro

m B

asel

ine

(log 1

0 cop

ies/

mL

± SE

)

0



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

uctio

n in

HB

V D

NA

(log

10 c

opie

s/m

L)

3

4

5

6

Adefovir: 44%Tenofovir: 100%





2. Raise the “pharmacologic barrier” to viral escape

– Reach high trough levels

– Have a tissue distribution that permits no sanctuaries

– Optimize patient adherence





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



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



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



IC50 Fold Change

N236T A181VAdefovir 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



Mechanisms of HBV Resistance

Sensitive

ResistantResistant

Sensitive

Drug

Sensitive

Resistant

Discontinue Drug



Combination in Naive Patients

Lamivudine + Adefovir

LAM-R ADV-R

Sensitive

LAM-R ADV-R

Sensitive

LAM + ADV-R LAM + ADV-R



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

hang

e in

HB

V D

NA

Fr

om B

asel

ine

(log 1

0 cop

ies/

mL)

-5.2-4.8

Lamivudine + adefovir Lamivudine + placebo



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



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

Management ofHBV Resistance



Management of HBV Resistance: Options Continue current therapy

Switch to another drug

Add on another drug

Switch and add on



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



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



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 2 ADV Switch(n = 277)

ADV + LAM(n = 294) P Value

Virologic rebound, n (%) 41 (15) 11 (4) < .001ADV genotypic resistance, n (%) 21 (8) 0 (0) < .001



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



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



Practical Options (cont’d) Entecavir resistance

– Add adefovir

– Add tenofovir when approved



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

management of resistance: implications for treatment choices

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