hepatitis b resistance to nucleos(t)ide antiviral medications

Hepatitis B Resistance to Nucleos(t)ide Antiviral Medications

ROBERT BROWN, MDROBERT BROWN, MD

Chief, Division of Abdominal Organ TransplantationColumbia University College of Physicians & Surgeons

New York, New York

2

Learning Objectives (CME, CE, CPE)● At the completion of this educational activity,

participants should be able to:- Discuss the mechanism of action of anti-hepatitis B

(HBV) therapeutics - Relate the mechanisms of resistance to HBV

therapies- Discuss clinical trial results regarding preventing or

treating HBV resistance to therapy- Demonstrate an understanding of treatment guideline

recommendations regarding adding or switching therapy due to development of resistance

3

Implications ofResistance to HBV Therapies

● Loss of clinical benefits- Loss of initial HBV DNA response with rebound- ALT increase and eventual reversion of histologic improvement- Progressive liver disease- In patients with cirrhosis, decompensation

● Development of multidrug resistance- Cross resistance- New resistance mutations

● Transmission of resistant virus

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

4

HBV Virion, e-Antigen, and S Proteins

Pol Protein HBsAg

DNA

VirusDane Particle

40 nmDiameter

CoreHBcAg

Filamentous ParticleUp to 200 nm Long

Spherical Particle~20 nm Diameter

Membrane

HBeAg

CCCDNA

HBV mRNA

ER

Golgi

HBsAg

HBeAgHBV Virion

6

HBV Virion Half-Life

Dandri M, et al. Hepatology. 2008;48:1079-1086.

HBeAg-Negative

Virion Half-Life: 46 minutes(range: 4 to 224 minutes)

Virion Half-Life: 150 seconds(range: 24 seconds to 13 minutes)

HBeAg-Positive

7

Rate of Generation ofHBV Mutants at Peak Infection

Base Changes Fraction

Number Created per Day

Number of Possible Mutants*

Fraction of All Possible Mutants Created per Day

0 0.9968 9.97 x 1012 - -

1 0.0032 3.2 x 1010 9.6 x 103 1

2 5 x 10-6 5 x 107 4.6 x 107 0.66

3 5.4 x 10-9 5.4 x 104 1.5 x 1011 3.6 x 10-7

*Computed as 3i( ) where n=3200 is the genome length, i is the number of base changes, and ( ) is a binomial coefficient.

ni

ni

High rate of mutations predisposes the virus to antiviral resistance.Whalley SA, et al. J Exp Med. 2001;193:847-854.

8

Appearance of Resistance-Related Mutations Is Associated With Virologic Breakthrough

Wild-TypeMutant

HB

V D

NA

log

10 cop

ies/

mL

Mixture

Lee CZ, et al. World J Gastroenterol. 2006;12:5301-5305.

9

Viral Persistence and Mechanism for Selection of Mutant HBV Strains

Fournier C, et al. Clin Liver Dis. 2007;11:869-892.

Virus cccDNA Half-Life

HepatocyteHalf-Life

Spontaneous Errors in Viral Polymerase

Quasi-Species

Viral Persistence

Host

Selection of Resistant StrainsPhenotypic Resistance

Treatment Failure

Antivirals

Immune Response

10

Antiviral Resistance: Nomenclature

Primary failure (nonresponse)

Lack of >1 log10 decrease in HBV DNA at 6 months

Secondary failure(breakthrough)

>1 log10 increase in HBV DNA above nadir in compliant patient

Lok AS, et al. Hepatology. 2007;46:254-265.

11

Antiviral Resistance: Nomenclature

Genotypic resistance Detection of HBV polymerase mutation(s) associated with resistance

Phenotypic resistance Decreased in vitro susceptibility to an antiviral agent

Virologic breakthrough

Increase in HBV DNA by >1 log10 over nadir on treatment

Biochemical breakthrough

Increase in ALT on treatment


12

Types of Virological Response

On Continuous Treatment

Months MonthsSustainedResponse

LLOD LLOD

HB

V D

NA

(Log

10 IU

/ml)

Relapse(rebound)

Primary Non-Response

MaintainedResponse

0

Breakthrough

On Treatment

Slide courtesy of ASF Lok, MD.

13

HBV Reverse Transcriptase Mutations Associated With Antiviral Resistance

rtL80V/I rtM204V/I/SLamivudine rtV173LrtL180M

845 a.a.

Terminalprotein Spacer Pol/RT RNaseH

A B C ED

YMDDGVGLSPFLLA

I(G) II(F) rtA181T/V rtN236TAdefovir

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

Entecavir rtL180M

rtM204ITelbivudine rtL80V/I rtL180MAllen MI, et al. Hepatology. 1998;27:1670-1677.Qi X, et al. 39th EASL. Berlin, 2004. Abstract 57.Schildgen O, et al. N Engl J Med. 2006;354:1807-1812.Telbivudine full prescribing information.Tenney DJ, et al. Antimicrob Agents Chemother. 2004;48:3498-3507.

rtA181T/V* rtN236T*Tenofovir DF

*Shown in vitro, but significance in vivo is unknown(not seen in any clinical trial for up to 2 years.

14

Pre-Existing HBV ResistanceMutations Detected by Line-Probe Assay

rt Mutation Prevalence (%) M204V/I 13

L80V/I 7

L180M 7

S202I 5

T184G 3

M250V 3

V173L 1

Fung SK, et al. J Hepatol. 2008;48(suppl 2):S256. Abstract 688.

Resistance mutations seen in antiviral-naïve patients (N=146)

Resistance determined by line probe assay and confirmed by direct sequencing

15

Infectivity By Mutational Pattern

Villet S, et al. J Hepatol. 2008;48(suppl 2):S253. Abstract 681.

Replication in Presence of Lamivudine + AdefovirReplication Without Drug

400

350

200

150

50

0

300

250

100

120

100

80

60

40

20

0

pol Gene Mutations S Gene Mutations1 wt wt

2 T1281; V173L; L180M; A181V; M204V R79H; P120S; E164D; L173F; I195M; Y206F3 T1281; V173L; L180M; A181V; M204V; L220I; N236T P120S; E164D; L173F; I195M

4 T1281; V173L; L180M; A181V; ∆102-111 R79H; P120S; E164D; L173F; ∆102-111

5 T1281; V173L; L180M; A181V; N236T R79H; P120S; E164D; L173F

Clinical Trial Data on Resistance

Lamivudine Resistance

18

Incidence ofLamivudine Resistance in Chronic HBV

0102030405060708090

100

1

Patie

nts

(%)

2 3 4

32%38%

45%

67%

Dienstag JL, et al. N Engl J Med. 1999;341:1256-1263.Liaw YF, et al. Gastroenterology. 2000;119:172-180.Chang TT, et al. J Gastroenterol Hepatol. 2004;19:1276-1282.

Duration of Lamivudine Therapy (years)

19

Lamivudine Resistance Accelerates Progression of Liver Disease

Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.

Patie

nts

With

Dis

ease

Prog

ress

ion

(%) Wild-type (n=221)

YMDDm (n=209) (49%)

Time After Randomization (months)

0

5

10

15

20

25

0 6 12 18 24 30 36

Placebo (n=215)

5%

13%

21%

20

Combination Adefovir + Lamivudine Is Superior to Adefovir Alone in Lamivudine Resistance

Lampertico P, et al. 57th AASLD. Boston, 2006. Abstract LB5.

*>1 log rebound of HBV DNA compared to on-treatment nadir.†N236T or A181T-V in patients with virologic breakthrough.

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24 27 30 33 36 Months

ADV mono

Pat ie

n ts

Wit h

Viro

log i

c B

r eak

thr o

u gh

273 268 256 225 201 158 61

30%

6%

P<0.001

ADV+LAM

255 238 223 213 200 177 103

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24 27 30 33 36Pa

t ien t

s w

it h A

DV -

R

229 225 217 194 179 146 57

16%

0.5%

P<0.001

ADV mono

ADV+LAM

242 227 214 205 200 174 92Patients

still at risk

Virologic Breakthrough* Adefovir Resistance†

21

Entecavir for Patients With Lamivudine Resistance: 3-Year Results

Yao GB, et al. J Hepatol. 2008;48(suppl 2):S267. Abstract 715.

0102030405060708090

100

Patie

nts

(%)

Normalized ALT

HBV DNA<400 copies/mL

HBeAgLoss

65%55%

7%2%

n=128 patients on long-term entecavir following lamivudine failure.

HBeAgSeroconversion

22

Entecavir for LamivudineRefractory Patients: Patient Flow

ETV-026:ETV-026:HBeAg+HBeAg+

ETV-014ETV-014:Dose RangingDose Ranging

Randomized StudiesEntecavir 1.0 mg

ETV-901ETV-901

Rollover StudyEntecavir 1.0 mg

Responders1

VirologicResponders1

AnyETV-015ETV-015:Post-TransplantPost-Transplant

Non-Responders1

*Protocol-defined response criteria.Tenney DJ, et al. 18th APASL. Seoul, 2008. Abstract PL02.

Any

23

Lamivudine-Refractory Cohort (HBeAg+)

*Protocol-defined response criteria.Tenney DJ, et al. 18th APASL. Seoul, 2008. Abstract PL02.

Cumulative Probability of Entecavir Resistance Through 5 Years

0

10

20

30

40

50

60

HBV DNA <300 copies/mL: 72/187 (39%), of whom 3 (4%) had subsequent genotypic entecavir resistance.

Cum

ulat

ive

Prob

abili

ty (%

)

1(n=187)

2(n=146)

3(n=80)

4(n=536)

5(n=33)

Year

ETVr = LVDr (M204V + L180M) + T184, S202 and/or M250 substitutionsETVr + virologic Breakthrough (>1 log increase from nadir)

6%

15%

36%

46%51%

1%

11%

27%

41% 43%

Adefovir Resistance

25

Adefovir Cumulative Probabilities of Virologic Outcomes and Resistance in HBeAg-Negative Patients

0102030405060708090

100

Patie

nts

(%)

0%31

Year

*Genotypic resistance plus HBV DNA rebound.†Confirmed >1 log10 copies/mL increase in HBV DNA from nadir and/or having never achieved HBV DNA suppression <104 copies/mL. ‡Virologic rebound plus ALT elevations.

23% 3% 2%

11% 8% 6%

18%13%

29%

16%11%

Genotypic resistance* (n=29)Virologic rebound† (n=18)Clinical breakthrough‡ (n=13)

540% 0%

10%

Borroto-Esoda K, et al. 41st EASL. Vienna, 2006. Abstract 483.

26

Adefovir: Resistance Incidence per Periodand Cumulative Risk From 5 Clinical Trials

0102030405060708090

100

Res

ista

nce

(%)

97-144(n=221)

0-48(n=629)

Weeks

Combined analysis of 5 studies of adefovir monotherapy or combination therapy in patients with chronic HBV, with or without lamivudine resistance.

49-96(n=293)

5%2%

7% 8%15%

Per periodCumulative

145-192(n=67)

0%

Locarnini S, et al. 40th EASL. Paris, 2005. Abstract 36.

2%

27

Adefovir Resistance Uncommon Among Lamivudine-Resistant Patients Receiving

Combination Adefovir + Lamivudine

0102030405060708090

100

Res

ista

nce

(%)

0%31

Year2

3% 0% 0%

11%0% 0%

18%

0%

29%

Monotherapy (n=125)Combination pre/post OLT (n=264)Combination in HIV-infected patients (n=35)

540% 0%

Hadziyannis S, et al. 41st EASL. Vienna, 2006. Abstract 499.Lampertico P, et al. 41st EASL. Vienna, 2006. Abstract 116.Benhamou Y, et al. 15th IAC. Bangkok, 2006. Abstract WeOrA1329.

28

Genotypic Resistance to Adefovir in Patients With Lamivudine-Resistant HBV

Lampertico P, et al. Gastroenterology. 2007;133:1445-1451.Subjects were treated with combination adefovir + lamivudine.

Incidence (%)Months of Treatment

Adefovir Mutations

Baseline(n=145)

12(n-139)

24(n=112)

36(n=78)

48(n=39)

rtN236T 0 0 0 0 0

rt181V 1 0 0 0 0

rtA181T 3 0.7 0.9 1.3 0

Overall 4 0.7 0.9 1.3 0

29

Undetectable HBV DNA(<103 copies/mL)

6%GenotypicResistance

94%No Mutations

Week 48(n=89)

Detectable HBV DNA(>103 copies/mL)

49%GenotypicResistance

51%No Mutations

Week 48(n=35)

Detectable HBV DNA (>103 copies/mL) at 48 weeks was the only significant predictor of resistance over 4 years (P=0.0003).Stepwise logistic regression analysis that included demographics, genotype, baseline fibrosis, and HBV DNA at week 48.Hadziyannis SJ, et al. Gastroenterology. 2006;131:1743-1751.

Adefovir Therapy: HBV DNA >103 Copies/mL at Week 48 Predicts Genotypic Mutations at 4 Years

30

Correlation of Viral Load With Response in Lamivudine-Resistant Subjects Receiving Adefovir

Monotherapy

Castel J, et al. J Hepatol. 2008;48(suppl 2):S255. Abstract 684.

% A

defo

vir R

esis

tanc

e

Baseline HBV DNA>6 log <6 log

Week 48 Resistance to Adefovir

*P=0.05.

*12.5%

2.9%

0%

5%

10%

15%

20%

31

Add-On Adefovir + Lamivudine Prevents Emergence of Adefovir Resistance

Lampertico P, et al. J Hepatol. 2008;48(suppl 2):S259. Abstract 696.

5257

7483

78

0102030405060708090

100

% H

BV

DN

A <

35 c

/mL

1Year

2 43 5

n=63.No patient demonstrated rtN236T or rtA181V mutation at baseline or follow-up.

Entecavir Resistance

33

Development ofResistance to Entecavir

● Combination of YMDD (M204V/I + L180M) and at least 1 entecavir substitution are required for virologic rebound due to resistance

● Primary entecavir substitutions (T184, S202, M250) can emerge on lamivudine therapy

● Primary entecavir mutations also seen in “wild-type” viral quasi-species

Tenney DL, et al. Antimicrob Agent Chemother. 2004;48:3498-3507.Jardi R, et al. 57th AASLD. Boston, 2006. Abstract 966.

34

Cumulative Resistance to Entecavir in Treatment-Naïve and Lamivudine-Resistant Populations

0102030405060708090

100

Res

ista

nce

(%)

0%31

Year2

0.4%

14%

1.1% 0.8%

32%39.5%

Nucleos(t)ide naïve (n=664) Lamivudine resistant (n=50)

4

6%

Resistance associated with appearance of rtT184, rtS202 or rtT184 + rtS202 mutations.Colonno R, et al. 42nd EASL. Barcelona, 2007. Abstract 781.

35

Phenotypic Sensitivity to Entecavirat the Time of Viral Rebound

n=192, from all phase III clinical trials of entecavir.Tenney DJ, et al. Antimicrob Agents Chemother. 2007;51:902-911.

10000

1000

100

10

1Baseline Rebound

ETVET

V EC

50 (n

M)

Entecavir at reboundNo entecavir at rebound

36

Treatment of Entecavir ResistanceWith Adefovir + Lamivudine

Yurdaydin C, et al. J Hepatol. 2008;48(suppl 2):S255. Abstract 685.

-7

-6

-5

-4

-3

-2

-1

0

Reduction in HBV DNA from Baseline

HB

V D

NA

log1

0 R

educ

tion

Week 24 Week 48

-2.47 ± 1.12-2.88 ± 1.40

n=10; lamivudine-refractory patients experiencing virologic breakthrough on entecavir.

Telbivudine Resistance

38

0

5

10

15

20

GLOBE Study: Week 52 Telbivudine Resistance (as-treated analysis)

HBeAg Positive(n=430)

Res

ista

nce

(%)

11.4%

5.3%

HBeAg Negative(n=227)

The rtM204I substitution was the most frequent mutation and was associated with virologic rebound (>1 log10 increase above nadir) in 34 of 46 patients.

HBV DNA >1000 Copies/mL>16 Weeks of Telbivudine Therapy

Telbivudine full prescribing information.

39

0

10

20

30

40

50

Telbivudine Versus Lamivudine: Cumulative Resistance At Year 2

HBeAg Positive HBeAg Negative

Cum

ulat

ive

Res

ista

nce

(%)

17.8%

30.1%

35.0%

21.6%

Per Protocol HBV DNA 1 LogAbove Nadir

TelbivudineLamivudine

0

10

20

30

40

50

Cum

ulat

ive

Res

ista

nce

(%)

7.3%

16.6%

21.9%

8.6%

Per Protocol HBV DNA 1 LogAbove Nadir

TelbivudineLamivudine

Per protocol resistance: rebound with HBV DNA >5 log10 copies/mL.P<0.001; less resistance for telbivudine in all pair-wise comparisons.Lai CL, et al. 57th AASLD. Boston, 2006. Abstract 91.

Tenofovir DF Resistance

41

Tenofovir DF Versus Adefovir as Monotherapyin Patients With Lamivudine Resistance

-7

-6

-5

-4

-3

-2

-1

0

24

*P<0.001 versus adefovir.

Cha

nge

in H

BV

DN

A(lo

g 10 c

opie

s/m

L)

-5.2*

-2.6

36

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

48

-5.4*

-3.0

-5.5*

-2.8

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

Week

42

Tenofovir DF Versus Adefovir Monotherapyin Lamivudine-Refractory Patients

● Single center study of patients with persistent lamivudine-resistant HBV

● Study arms- Tenofovir DF (n=35)

• 72 to 130 weeks

- Adefovir (n=18)• 60 to 80 weeks

● No evidence of tenofovir DF resistance at 48 weeks


HBV DNA <105 Copies/mL

0102030405060708090

100

Patie

nts

(%)

100%

44%

Tenofovir DF Adefovir

43

Study 103 (HBeAg+):HBV DNA <400 Copes/mL (ITT)

0

10203040

5060708090

100

Patie

nts

(%)

Patie

nts

(%)

0 8 16 24 32 40 48 56 64 72 80 88 96

78%

WeeksWeeks

Double-BlindDouble-Blind

Heathcote EJ, et al. Hepatology. 2008;48(suppl):92A. Abstract 158.

Open-LabelOpen-LabelTDF to TDFADV to TDF

76%78%

P<0.001

13%

P=0.801

Includes 5 patients who had HBV DNA <400 copies/mL at week 96 on FTC/TDF.

44

Study 102 (HBeAg-):HBV DNA <400 Copes/mL (ITT)

0

10203040

5060708090

100

Patie

nts

(%)

Patie

nts

(%)

0 8 16 24 32 40 48 56 64 72 80 88 96

91%

WeeksWeeks

Double-BlindDouble-Blind Open-LabelOpen-LabelTDF to TDFADV to TDF

93%

89%P<0.001

63%

P=0.166

Marcellin P, et al. Hepatology. 2008;48(suppl):88A. Abstract 146.

18% of patients were lamivudine experienced and of these 93% and 96% of TDF to TDF and ADV to TDF patients had HBV DNA <400 copies/mL at week 96.

45

Study 103 and 102:Virologic Analysis Plan

● All patients- At baseline- Yearly if HBV DNA >400 copies/mL

(> 69 IU/mL)- At discontinuation of tenofovir DF

monotherapy if HBV DNA > 400 copies/mL

● Any patient post baseline with- Conserved site changes in pol/RT- Virologic breakthrough*- Polymorphic site changes (>1 patient)

Genotyping(HBV pol / RT)

Phenotyping(HBV pol / RT)

Snow-Lampart A, et al. Hepatology. 2008;48(suppl):745A. Abstract 977.

*Confirmed 1 log10 increase in HBV DNA and/or confirmed HBV DNA >400 copies/mL after achieving HBV DBA <400 copies/mL.

46

Study 103 and 102:Resistance Surveillance at Week 96

Study 103HBeAg+(n=154)

Study 102HBeAg-(n=235)

Total(n=359)

Number of patients included in the week 96 resistance surveillance who had HBV DNA >400 copies/mL

18 6 24

Without virologic breakthrough With virologic breakthrough

153

24

177

Categories

After 96 weeks of tenofovir DF monotherapy Discontinued tenofovir DF monotherapy between week 48 and 92 Added emtricitabine to open-label tenofovir DF between week 72 to 96

30

15

22

2

52

17


Median duration of tenofovir DF monotherapy at time of discontinuation/addition of emtricitabine was 80 weeks.

47

0

2

4

6

8

10

Study 103 and 102: Patients Who Were Viremic or Had Virologic Breakthrough (week 72-96)

HBV DNA >400 copies/mL

Patie

nts

(num

ber)

1(50%)

NoChange

HBeAg+ (n=12)HBeAg- (n=2)

Three HBeAg+ patients with HBV DNA >400 copies/mL were unable to be genotyped (PCR negative).Conserved site changes observed in one patient each at positions rtL101L/F and rtV173L + rtL180M + rtM204V.No two patients developed the same polymorphic site changes.

8(67%)

1(50%)

0(0%)

2(17%)

2(17%)

Polymorphic ConservedSite Changes

0

2

4

6

8

10

Virologic Breakthrough

Patie

nts

(num

ber)

3(75%)

NoChange

HBeAg+ (n=3)HBeAg- (n=4)

2(67%)

1(25%)

0(0%)

0(0%)

1(33%)

Polymorphic ConservedSite Changes


48

Study 103 (HBeAg+): Phenotypic Analysis of the Two Tenofovir DF-Treatment Patients Harboring

Conserved Site Changes in HBV pol/RT


pol/RTTenofovir DF

EC50 (µM)Fold

Change†

Patient #8356 Baseline Wild type 12.4 + 3.6 Week 72 rtL101L/F 13.8 + 0.6 1.1 Week 72 (clone) rtL101F 10.0 + 6.2 0.7

Patient 7916 Baseline Wild-type 9.9 + 3.4 Week 72 rtV173L, rtL180M, tM204V 12.5 + 6.3 1.3

*Clonal analysis of the baseline sample showed the presence of the LAM-R mutations at a frequency of 6.5%.†Fold change: last on tenofovir DF EC50/ baseline EC50. Fold changes <2X are within the assay variability.Development of conserved site changes was not associated with phenotypic resistance to tenofovir DF.

49

Study 103 and 102: Phenotypic Analysis ofSeven Tenofovir DF-Treatment Patients

With Virologic Breakthrough


*Fold change: last on TDF EC50/ baseline EC50. Fold changes <2X are within the assay variability.Virologic breakthrough was not associated with phenotypic resistance to tenofovir DF.

Tenofovir DFEC50 (µM)

Fold Change*

Patient 1674 Baseline Week 72

8.0 + 1.07.7 + 1.5

1.0Patient 1669 Baseline Week 96

9.7 + 4.111.1 + 7.7 1.1


12.2 + 4.710.5 + 4.4 0.9


10.3 + 0.78.3 + 1.5 0.8

Tenofovir DFEC50 (µM)

Fold Change*


11.2 + 5.311.3 + 5.7

1.0Patient 3958 Baseline Week 88

11.3 + 4.011.1 + 2.5 1.1


12.2 + 0.811.6 + 4.6 1.0

Study 102 (HBeAg-)Study 103 (HBeAg+)

50

Study 103 and 102:Resistance and Virologic Breakthrough● No HBV pol/RT amino acid substitutions associated with resistance

to tenofovir DF were detected through 96 weeks of tenofovir DF monotherapy- Annual resistance surveillance on-going through year 8 (week 384)

● Virologic breakthrough was rare (study 103: 2.4%; study 102: 1.6%)- Not associated with phenotypic resistance to tenofovir DF- Majority of patients with virologic breakthrough had evidence of non-

adherence

● Development of conserved site changes was rare and not associated with phenotypic resistance to tenofovir DF


51

Tenofovir DF Following Adefovir Monotherapy in Lamivudine Resistance● 20 patients with persistent HBV DNA on adefovir

monotherapy (mean 15 months) following viral breakthrough on lamivudine switched to tenofovir DF

● Tenofovir therapy results- HBV DNA <400 copies/mL: 19 of 20 patients- Normalization of elevated ALT: 10 of 14 patients- 4 patients lost HBeAg- Presence of lamivudine-resistance mutations did not impact

therapy with tenofovir DF• No tenofovir DF or adefovir resistance mutations were noted


52

No Evidence for Tenofovir DF Resistance in Lamivudine-Resistant HBV Patients Treated for up to 5 Years

● Retrospective study- 69 patients with lamivudine-resistant HBV- Treated with tenofovir DF 300 mg daily (except 1 patient treated

every other day because of renal insufficiency)- Followed for at least 6 months and up to 59 months

● 68/69 patients had undetectable HBV DNA (<400 copies/mL) at end of observation period

● No evidence of tenofovir DF resistance● HBeAg seroconversion documented in 36% of patients

after a mean duration of 14 + 9 months of treatment● HBsAg lost in 8% of patients after 16 + 6 months van Bömmel F, et al. 57th AASLD. Boston, 2006. Abstract 971.

53

0102030405060708090

100

No Resistance Seen in Treatment-NaïvePatients Treated With Tenofovir DF (week 48)

HBeAg Negative

Tenofovir DF(n=250)

Adefovir(n=125)

Patie

nts

(%)

HBV DNA <169 copies/mL

67%

Heathcote EJ, et al. 58th AASLD. Boston, 2007. Abstract LB6.Marcellin P, et al. 58th AASLD. Boston, 2007. Abstract LB2.

91%

0102030405060708090

100

HBeAg Positive

Tenofovir DF(N=176)

Adefovir(N=90)

Patie

nts

(%)

HBV DNA <169 copies/mL

9%

69%

No tenofovir DF resistance mutations detected at week 48.

54

Tenofovir DF Efficacy in Lamivudine-Naïve and Lamivudine-Experienced Subjects

Manns M, et al. J Hepatol. 2008;48(suppl 2):S33. Abstract 74.

P=0.456P=0.247

P=0.718

% P

atie

nts

Complete Response

Histological Improvement

HBV DNA<400 copies/mL

68 72

86

7480

88

0102030405060708090

100 Lamivudine naïve (n=377)Lamivudine experienced (n=49)

Primary and Secondary Endpoints

No resistance to tenofovir DF was documented at week 48 for any subject.

55

Weeks on Study

Tenofovir DF ± Emtricitabine inSubjects Remaining Viremic on Adefovir

Berg T, et al. J Hepatol. 2008;48(suppl 2):S34. Abstract 76.

P=0.988. No treatment-emergent resistance documented. Response to therapy identical with or without baseline resistance mutations.

Perc

enta

ge (%

)

0

10

20

30

40

50

60

70

100

0 4 8 12 16 20 24 28 32 36 40 44 48

53TDF n= 53 53 53 53 53 53 53 53 53 53 53 53 53 53 52FTC/TDF n= 52 52 52 52 52 52 52 52 50 50 50 52 52 52

Tenofovir DF + emtricitabine Tenofovir DF80

90

Resistance in Experimental/UnapprovedAntiviral Agents

Clevudine

57

Resistance to Clevudine● Limited clinical data available● In a trial of emtricitabine + clevudine

- 3 patients entered with lamivudine-associated mutations• L180M plus M204V

- 2 patients were assigned to the combination regimen of emtricitabine + clevudine• Neither patient responded to therapy

• Serum HBV DNA levels only declined 0.5 to 0.6 log10 copies/mL

Lim SG, et al. Antimicrob Agents Chemother. 2006;50:1642-1648.

Resistance in Experimental/UnapprovedAntiviral Agents

Emtricitabine

59

Resistance to Emtricitabine● Structurally similar to lamivudine

- Cross-resistance to lamivudine is primary limitation

● Lamivudine resistance mutations rtM204I + L180M also confer resistance to emtricitabine- Year 1: 9% to 16% of patients- Year 2: 19% to 37% of patients

● May be more beneficial in combination with tenofovir DF and other agents

Gish RG, et al. Semin Liver Dis. 2005;25(suppl 1):29-39.

Cross Resistance

61

Sequential MonotherapyCan Lead to Multidrug Resistance

● Analysis of phenotypic and genotypic evolution of resistance in 2 patients- Combination therapy after first failure

• Lamivudine lamivudine + adefovir lamivudine + adefovir + HBV immune globulin (post OLT)

• Single viral species with mutations at rtV173L + L180M + A181V + N236T noted on combination, plus sP120S associated with HBV immune globulin escape

- Sequential monotherapy• Interferon lamivudine entecavir• Sequence on entecavir contained mixture of 3 quasispecies containing

rtS202G + rtL180M + M204V (lamivudine mutations despite absence of lamivudine)

● Authors suggest de novo combination therapy may help prevent development of multidrug resistance mutations

Villet S, et al. 56th AASLD. San Francisco, 2005. Abstract 981.

62

In Vitro Cross-Resistance With Lamivudine/Nucleoside Associated Mutations

Yang H, et al. Antivir Ther. 2005;10:625-633.*Fold-resistance calculated as the wild-type EC50/mutant EC50.

Fold Resistance*

L180M + M204VV173L + L180M

+ M204V M204I L180M + M204IAdefovir 1.1 1.1 1.8 2.1

Tenofovir DF 0.8 1.8 2.1 0.7

Entecavir 37 164 471 38

Lamivudine >700 >1000 >1000 >1000

Emtricitabine >2000 898 >2000 845

Clevudine >1600 >1600 >1600 >1600

Telbivudine >322 >322 >322 >322

Treatment Guidelines:Managing Resistance

64

Monitoring for Antiviral Resistance● Test serum HBV DNA prior to therapy and at

3-month intervals ● Primary non-responders should be offered

combination or alternative therapy● Inquire about medication compliance when

virologic breakthrough is seen● Genotyping should be performed to confirm

resistance and determine specific mutations


65

AASLD Guidelines: Options for Lamivudine/Telbivudine Resistance

● Add adefovir or tenofovir DF- No evidence of resistance at 3 years when used in

combination with lamivudine

● Switch to emtricitabine + tenofovir DF (fixed-dose combination)

● Switch to entecavir- Risk of subsequent entecavir resistance and

multidrug resistance


66

AASLD Guidelines:Options for Adefovir Resistance

● Add lamivudine● Switch to emtricitabine + tenofovir DF

(fixed-dose combination)● Add/switch to entecavir

- Caution with switch if prior lamivudine resistance


67

AASLD Guidelines:Options for Entecavir Resistance

● Add adefovir or tenofovir DF● Note

- Clinical data on efficacy of alternative therapies is not currently available


68

AASLD Guidelines:Options for Multidrug Resistance

● Multidrug resistance to lamivudine and adefovir- Consider tenofovir DF + emtricitabine, tenofovir,

entecavir

● Multidrug resistance to lamivudine and entecavir- Consider tenofovir DF or tenofovir DF + emtricitabine

● Therapy with two nucleosides or two nucleotides not recommended due to competitive inhibition


69

Summary: AASLD Guidelines for Management of Antiviral-Resistant HBV

Resistance Rescue TherapyLamivudineTelbivudine

Add adefovir or tenofovir DFSwitch to: Emtricitabine + tenofovir DF (fixed-dose combination) Entecavir (risk of entecavir resistance)

Adefovir Add lamivudineSwitch to: Emtricitabine + tenofovir DF (fixed-dose combination) Entecavir (if no prior lamivudine resistance)

Entecavir Add adefovir or tenofovir DF

Multidrug Multidrug resistance to lamivudine + adefovir: Consider emtricitabine + tenofovir DF (fixed-dose combination), tenofovir DF, entecavirMultidrug resistance to lamivudine + entecavir: Consider tenofovir DF or emtricitabine + tenofovir DF (fixed-dose combination)


70

Summary● Antiviral resistance is likely to become more important

as additional patients are sustained on long-term therapy

● HBV DNA monitoring is single most-important test to determine if patients are developing resistance to therapy

● Treatment of resistance depends on knowledge of patient treatment history

● Combination therapy and/or switching to non-cross resistant agents depends on clinical judgment

hepatitis b resistance to nucleos(t)ide antiviral medications

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