Pawlotsky Hcv RéSistance

HHéépatite patite C: RC: Réésistancesistanceaux aux TraitementsTraitements

Prof. JeanProf. Jean --Michel PawlotskyMichel Pawlotsky

CNR des CNR des HHéépatites patites B, C et deltaB, C et deltaLaboratoire Laboratoire de de Virologie Virologie & INSERM U635& INSERM U635

HHôpital ôpital Henri Henri MondorMondorUniversitUniversit éé Paris XIIParis XII

CrCrééteilteil

HCV Resistance

• HCV resistance to IFN -αααα therapy

• HCV resistance to ribavirin ?

• HCV resistance to specific antiviral molecules

I

HCV resistance to IFN-α α α α Therapy

Incidence of Peg -IFNαααα-RibavirinTreatment Failures

2%2%

00

1515

3030

4545

6060 54%54%48%48%

58%58%

24%24%

16%16% 18%18%

Genotype Genotype 1 1 Genotypes Genotypes 2/32/3

PEGPEG--IFNIFN--αα2a+2a+ribavirin ribavirin ((Fried Fried et al)et al)

PEGPEG--IFNIFN--αα2a+2a+ribavirin ribavirin ((Hadziyannis Hadziyannis et al)et al)

PEGPEG--IFNIFN--αα2b+2b+ribavirin ribavirin ((Manns Manns et al)et al)

((Manns Manns et al, et al, Lancet Lancet 2001 ; 2001 ; Fried Fried et al, N et al, N Engl Engl J J Med Med 2002 ; 2002 ; Hadziyannis Hadziyannis et al, et al, Ann Intern Med Ann Intern Med 2004) 2004)

TreatmentTreatmentFailureFailure

TreatmentTreatmentScheduleSchedule


HostHostFactorsFactors



DiseaseDiseaseCharacteristicsCharacteristics




Viral FactorsViral FactorsDiseaseDiseaseCharacteristicsCharacteristics




Viral FactorsViral FactorsDiseaseDiseaseCharacteristicsCharacteristics




SNP and SVR in the IDEAL Trial1 3 5 7 9 11 13 15 17 19 21 X M

2 4 6 8 10 12 14 16 18 20 22 Y

-log 1

0(P

)

0.0

15.0

30.0

-log 1

0(P

)

0.0

15.0

30.0

-log 1

0(P

)

0.0

15.0

30.0

Chromosome 19 ideogram

0 M 10 M 20 M 30 M 40 M 50 M 60 M

39,623 K 39,666 K 39,708 K 39,750 K 39,793 K 39,835K

PAK4 SYCN IL28B IL29 LRFN1NCCRP1 AC011445.6IL28A GMFG

IL28B IL28AAC011445.6

39,711 K 39,721 K 39,732 K 39,743 K 39,753 K 39,764K

rs12979860P=1.37×10-28

1 3 5 7 9 11 13 15 17 19 21 X M2 4 6 8 10 12 14 16 18 20 22 Y

-log 1

0(P

)

0.0

15.0

30.0

-log 1

0(P

)

0.0

15.0

30.0

-log 1

0(P

)

0.0

15.0

30.0

Chromosome 19 ideogram

0 M 10 M 20 M 30 M 40 M 50 M 60 M

39,623 K 39,666 K 39,708 K 39,750 K 39,793 K 39,835K

PAK4 SYCN IL28B IL29 LRFN1NCCRP1 AC011445.6IL28A GMFG

IL28B IL28AAC011445.6

39,711 K 39,721 K 39,732 K 39,743 K 39,753 K 39,764K

rs12979860P=1.37×10-28

IL28B

((Ge Ge et al, Nature, 2009;461:399et al, Nature, 2009;461:399 --401)401)

rs12979860 Allele and SVR


rs12979860 Allele Frequency

12%12%

39%39%

49%49%

37%37%

16%16%

47%47%

C/CC/C C/TC/T T/TT/T

CaucasianCaucasianancestryancestry

n=871n=871

African AmericanAfrican Americanancestryancestry

n=191n=191


Geographic Distribution

(Thomas et al, Nature, 2009;461:798(Thomas et al, Nature, 2009;461:798 --801)801)

Effect on HCV Kinetics (Caucasians )

∆∆H

CV

RN

A (

Log

HC

V R

NA

(Lo

g1010

IU/m

L)IU

/mL)

CT

TT-3.0

-2.0

-1.0

0

Weeks

-4.0

-5.0

2 4 120

-6.0 CC

(Thompson et al, AASLD 2009) (Thompson et al, AASLD 2009)

∆∆H

CV

RN

A (

Log

HC

V R

NA

(Lo

g1010

IU/m

L)IU

/mL)

CTTT

-3.0

-2.0

-1.0

0

Weeks

-4.0

-5.0

2 4 120

-6.0

CC

Effect on HCV Kinetics(African Americans )


SVR Predictors

<0.0001<0.00012.22.21.31.31.71.7Fasting blood sugar < 5.6 mmol/LFasting blood sugar < 5.6 mmol/L

<0.0001<0.00014.14.12.32.33.13.1HCV RNA HCV RNA ≤≤ 600,000 IU/mL600,000 IU/mL

<0.0001<0.00014.04.02.02.02.82.8Caucasian Caucasian vs vs African AmericanAfrican American

0.0040.0043.63.61.31.32.12.1Hispanic Hispanic vs vs African AmericanAfrican American

<0.0001<0.00016.76.74.14.15.25.2rs12979860 CC rs12979860 CC vs vs nonnon --CCCC

<0.0001<0.00014.04.01.81.82.72.7METAVIR score METAVIR score ≤≤F2 F2

pp--valuevalue95% CI95% CIOdds RatioOdds Ratio


Summary

• In patients infected with HCV genotype 1, the rs12979860 genotype :

• Is strongly associated with the SVR

• Explains 60% of the ethnic influence on SVR

• Influences HCV kinetics on therapy

• Is probably a marker of patient cell “resistance“to the effect of IFN -αααα through mechanisms that remain to be elucidated

Viral Resistance

• Intrinsic properties of viral strains that counteract the antiviral action of antiviral drugs

Incidence of Peg -IFNαααα-RibavirinTreatment Failures

2%2%

00

1515

3030

4545

6060 54%54%48%48%

58%58%

24%24%

16%16% 18%18%

Genotype Genotype 1 1 Genotypes Genotypes 2/32/3

PEGPEG--IFNIFN--αα2a+2a+ribavirin ribavirin ((Fried Fried et al)et al)

PEGPEG--IFNIFN--αα2a+2a+ribavirin ribavirin ((Hadziyannis Hadziyannis et al)et al)

PEGPEG--IFNIFN--αα2b+2b+ribavirin ribavirin ((Manns Manns et al)et al)

((Manns Manns et al, et al, Lancet Lancet 2001 ; 2001 ; Fried Fried et al, N et al, N Engl Engl J J Med Med 2002 ; 2002 ; Hadziyannis Hadziyannis et al, et al, Ann Intern Med Ann Intern Med 2004) 2004)

HCV Kinetics by GenotypeEC-sponsored DITTO -Trial

(Pawlotsky et al., manuscript in preparation)

00

11

22

33

44

55

66

77 HCV RNA (log IU/ml)HCV RNA (log IU/ml)

00 44 77 88 1515 2222 292911--77--2828

Genotype Genotype 44

GenotypeGenotype 11

GenotypeGenotype 33

** == significant differencesignificant difference , 4, 4 andand 11 vsvs 33

**

**

****

** ****

QuantitativeQuantitative assay cutoffassay cutoff

QualitativeQualitative assay cutoffassay cutoff


00

11

22

33

44

55

66


00 44 77 88 1515 2222 292911--77--2828

GenotypeGenotype 44

GenotypeGenotype 11

GenotypeGenotype 33


**

**

****

** ****





00

11

22

33

44

55

66


00 44 77 88 1515 2222 292911--77--2828

GenotypeGenotype 44

GenotypeGenotype 11

GenotypeGenotype 33


**

**

****

** ****





00

11

22

33

44

55

66


00 44 77 88 1515 2222 292911--77--2828

Genotype Genotype 44

GenotypeGenotype 11

GenotypeGenotype 33


**

**

****

** ****




Viral FactorsViral Factors

AntiviralAntiviralrresistanceesistance

DelayedDelayedclearanceclearance

LongerLongerhalfhalf --life oflife of

infected cellsinfected cells

Summary

• HCV resistance to IFN -αααα antiviral effect exists

• Its molecular mechanisms are unknown and probably complex

• It accounts for only a small part of IFN -αααα-based treatment failures

II

HCV Resistance to Ribavirin ?

• Direct inhibition of HCV RNA -dependent RNA polymerase ?

• Depletion of intracellular GTP pools via IMPDH inhibition ?

• RNA mutagenesis leading to "error catastrophe" ?

• Enhancement of IFN -induced responses in the liver ?

Ribavirin ’s Antiviral Mechanisms

Ribavirin ’s Antiviral Effect

(Pawlotsky et al., Gastroenterology 2004;126:703-14 )

--1.01.0

--0.50.5

0.00.0

0.50.5

00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424 2626 2828

Mean HCV RNA decrease (log IU/ml)Mean HCV RNA decrease (log IU/ml)

Time (days)Time (days)

ControlsControls

RibavirinRibavirinmonotherapymonotherapy

--1.51.5

--1.01.0

--0.50.5

0.00.0

+0.5+0.5

00 22 44 66 88 1010 1212 1414

DaysDays

HCV RNA changes (log IU/ml)HCV RNA changes (log IU/ml)

--1.51.5

--1.01.0

--0.50.5

0.00.0

+0.5+0.5

00 22 44 66 88 1010 1212 1414

DaysDays


--1.51.5

--1.01.0

--0.50.5

0.00.0

+0.5+0.5

00 22 44 66 88 1010 1212 1414

DaysDays


--1.51.5

--1.01.0

--0.50.5

0.00.0

+0.5+0.5

00 22 44 66 88 1010 1212 1414

DaysDays


(Pawlotsky et al., Gastroenterology 2004;126:703-14 )

Ribavirin ’s Antiviral Effect

Summary

• Ribavirin mechanisms of action in chronic hepatitis C remain unknown

• Ribavirin direct antiviral effect is modest and transient

• Long -term ribavirin administration does not select for specific resistance substitutions

III

HCV Resistance to Specific Inhibitors

HCV ResistanceHCV Resistance

• Definition� Selection of viral variants bearing amino acid

substitutions that alter the drug target and thereby confer reduced susceptibility to the drug

• Resistant variants are pre-existing at baseline as minor viral populations� All single mutants� ~10% of double mutants

(Pawlotsky JM, (Pawlotsky JM, Ther Ther Adv Adv Gastroenterol Gastroenterol 2009;2:2052009;2:205 --219; 219; Perelson Perelson AS, unpublished data) AS, unpublished data)

sensitivesensitive

resistantresistant

Mechanisms of Resistance

sensitivesensitive

resistantresistant

DrugDrug


sensitivesensitive

resistantresistant

DrugDrug

resistantresistant


sensitivesensitive

sensitivesensitive

resistantresistant

DrugDrug Stop drugStop drug

resistantresistant


sensitivesensitive

sensitivesensitive

resistantresistant

sensitivesensitive

resistantresistant


resistantresistant


sensitivesensitive

sensitivesensitive

resistantresistant

sensitivesensitive

resistant + fitresistant + fit


resistantresistant


sensitivesensitive

sensitivesensitive

resistantresistant


resistantresistant


sensitivesensitive

resistant + very fitresistant + very fit

sensitivesensitive

DAA Drugs Targets

Virion assembly

RNA replication

(+) RNA

Fusion and uncoating

Translation and polyprotein processing

Transport and

release

Receptor binding and endocytosis

Viral entry inhibitorsViral entry inhibitorsHepatitis C immunoglobulin Hepatitis C immunoglobulin HCIgHCIg))HCVHCV--Ab 68 and Ab 65 (monoclonal Ab)Ab 68 and Ab 65 (monoclonal Ab)

HCV RNA translation inhibitorsHCV RNA translation inhibitorsISIS 14803 (antisense) ISIS 14803 (antisense) AVI AVI –– 4065 (antisense) 4065 (antisense) Heptazyme (ribozyme)Heptazyme (ribozyme)VGXVGX--410C (small molecule IRES inhibitor)410C (small molecule IRES inhibitor)TT 033 (TT 033 (siRNAsiRNA ) )

Posttranslational processing inhibitorsPosttranslational processing inhibitorsNS3NS3--4A serine proteinase inhibitors4A serine proteinase inhibitors

BILN 2061BILN 2061ITMN 191ITMN 191VXVX--950 950 SCH 503034SCH 503034ACHACH--806/GS806/GS--91329132

HCV replication inhibitorsHCV replication inhibitorsNS5B polymerase inhibitorsNS5B polymerase inhibitors

MKMK--06080608HCVHCV--796796R1626R1626JTKJTK--003003NMNM--283283XTL 2125XTL 2125

Cyclophilin B inhibitorsCyclophilin B inhibitorsDEBIODEBIO--025025NIM 811NIM 811

NS5A inhibitorsNS5A inhibitorsAA--831, A831, A--689689

Helicase inhibitorsHelicase inhibitorsQU663 QU663 RRecombinant Ab fragmentsecombinant Ab fragments

Virus assembly and release inhibitorsVirus assembly and release inhibitorsUTUT--231B (231B (iminosugariminosugar --glucosidase glucosidase inhibitor)inhibitor)Celgosivir (glucosidase inhibitor) Celgosivir (glucosidase inhibitor)

Phase of DevelopmentPhase of Development

**

**

****

PreclinicalPreclinical II IIII IIIIII IVIV

**

**

**

HCV DAA Drug Development

(Pawlotsky JM, Chevaliez S, McHutchison JG, Gastroe nterology 2007;132:1979-98)

IRES

RNA-Dependent RNA Polymerase

NS3 Protease

Targets for New HCV Inhibitors

Resistance to NS3/4A Protease Inhibitors

Antiviral Efficacy of NS3/4A Protease Inhibitors

-3.33 days300 mg bidIBMS-650032

II

II

II

II

II

III

III

Phase

-4.27 days400 mg bidNarlaprevir

-4.78 days

-4.014 days240 mg qdBI201335

700 mg bidMK-7009

-3.814 days200 mg q8hITMN-191/R7227

-4.17 days200 mg qdTMC435

-1.67 days400 mg tidBoceprevir

-4.4 14 days750 mg q8hTelaprevir

Median/mean logHCV RNA reduction

DurationDoseDrug

MacrocyclicMacrocyclic LinearLinear

BILN 2061BILN 2061((CiluprevirCiluprevir ))

R7227 R7227 (ITMN(ITMN--191)191)

VXVX--950950(Telaprevir)(Telaprevir)

SCH503034SCH503034(Boceprevir)(Boceprevir)

A156V/TA156V/T, , D168A/VD168A/V, ,

R155QR155Q

A156S/V,A156S/V,D168AD168A, Q41R, , Q41R, F43S, S138T, F43S, S138T,

S489LS489L

A156S/T/VA156S/T/V A156S/TA156S/T, , T54A, V170AT54A, V170A

No dataNo data No dataNo dataA156S/T/VA156S/T/V, , R155K/TR155K/T, ,

T54A, V36A/MT54A, V36A/M

V36M/A, V36M/A, T54A/S, T54A/S, R155KR155K

In v

itro

In v

itro

In v

ivo

In v

ivo

((Kwong Kwong et al., et al., Curr Opin PharmacolCurr Opin Pharmacol , 2008;8:522, 2008;8:522 --531; 531; Susser Susser et al., J et al., J Hepatol Hepatol 2009;50(2009;50(SupplSuppl .1):S7) .1):S7)

Amino Acid Substitutions Associated with ResistanceAmino Acid Substitutions

Associated with Resistance

Asp168

Ala156

Arg155

Thr54

Val36

(Pawlotsky J(Pawlotsky J --M, M, Ther Ther Adv Adv Gastroenterol Gastroenterol 2009;2: 2052009;2: 205 --219) 219)

Amino Acid Substitutions Associated with ResistanceAmino Acid Substitutions

Associated with Resistance

Telaprevir (Vertex & Tibotec )

Paramètres Associésà la Résistance

• Niveau de résistance au m édicament conféré par la ou les substitutions amino acidiques

• In vivo “fitness “ des variants viraux sélectionn és

PROVE 2 Trial (Phase II)Naïve, Genotype 1, Europe

��Weeks on therapy480 2412

Placebo + Peg-IFN αααα2a + Ribavirin (RBV)

Telaprevir 750 mg q8h + Peg-IFNαααα2a

+ RBV



+ RBV

Peg-IFNαααα2a + RBV FollowFollow --upup

FollowFollow --upup

FollowFollow --upup

PR48

T12/PR24

T12/PR12

T12/P12

FollowFollow --upup

72

((HHéézode zode et al., N et al., N Engl Engl J Med 2009;360:1839J Med 2009;360:1839 --50)50)

00

2020

4040

6060

8080

100100

1212 --

wee

k S

VR

rat

es (

%)

wee

k S

VR

rat

es (

%)

T12/P12 (no RBV)T12/P12 (no RBV)

3%3%

24%24%

T12/PR12T12/PR12+ T12/PR24+ T12/PR24

PROVE 2 Trial (Phase II)Breakthoughs through week 12


00

2020

4040

6060

8080

100100

SV

R r

ates

(%

)S

VR

rat

es (

%)

T12/P12 (no RBV)T12/P12 (no RBV)((n=78n=78))

48%48%

T12/PR12T12/PR12((n=82n=82))

30%30%

T12/PR24T12/PR24((n=81n=81))

14%14%22%22%

PR48PR48((n=82n=82))

PROVE 2 Trial (Phase II)Relapses after treatment


Boceprevir Boceprevir ((SP/MerckSP/Merck ))

Patterns of Responseto Boceprevir

Patterns of ResponsePatterns of Responseto to BoceprevirBoceprevir

((Susser Susser et al., et al., Hepatology Hepatology 2009;50:17092009;50:1709 --18) 18)

N=22 non-responders to previous standard treatment who were dosed for 14 days with BOC (Phase 1b)

In vitro Resistance toBoceprevir (replicon )IIn vitron vitro Resistance toResistance toBoceprevir Boceprevir ((repliconreplicon ))


Relative in vivo Fitness of Boceprevir -Resistant Variants

Relative Relative in vivoin vivo Fitness of Fitness of BoceprevirBoceprevir --Resistant Resistant VariantsVariants


Dynamics of NS3Protease VariantsDynamics of NS3Dynamics of NS3Protease VariantsProtease Variants


SummarySummarySummary

•• During During telaprevir telaprevir or or boceprevir monotherapyboceprevir monotherapy , pre, pre --existing resistant HCV variants are rapidly selecte d in existing resistant HCV variants are rapidly selecte d in virtually all treated patientsvirtually all treated patients

•• Both single mutants (36, 54, 155 and 156) and doubl e Both single mutants (36, 54, 155 and 156) and doubl e mutants (36/155, 26/156) can be selectedmutants (36/155, 26/156) can be selected

•• The corresponding viral variants generally have The corresponding viral variants generally have reduced fitness compared to wildreduced fitness compared to wild --type HCVtype HCV

•• Most of these amino acid substitutions confer crossMost of these amino acid substitutions confer cross --resistance to all of the NS3/4A protease inhibitors in resistance to all of the NS3/4A protease inhibitors in developmentdevelopment

Summary (cont’d)Summary (cont’d)

•• Failure of the triple combination of Failure of the triple combination of pegylated pegylated IFNIFN--αααααααα, , ribavirin ribavirin and and telaprevir telaprevir to clear HCV is associated with to clear HCV is associated with the selection of the selection of telaprevirtelaprevir --resistant resistant variantsvariants

•• These variants may persist after therapy or be These variants may persist after therapy or be progressively replaced by wildprogressively replaced by wild --type virustype virus

•• Telaprevir Telaprevir resistant variants remain sensitive to resistant variants remain sensitive to pegylated pegylated interferon and interferon and ribavirin ribavirin

Resistance to Inhibitors of HCV Replication

Inhibitors of HCV Replication

• RNA-dependent RNA polymerase (RdRp ) inhibitors

• Nucleoside analogues• Non-nucleoside inhibitors (NNIs)

• NS5A inhibitors

• Cyclophilin inhibitors

• miR122 antagonists

In vitro Resistance

Copyright © 2006 Merck & Co., Inc., Whitehouse Stati on, New Jersey, USA All rights reserved

22’’--methyl nucleosidesmethyl nucleosidesSer Ser 282282

44’’ azidoazido--cytidinecytidineSer Ser 9696

2’C-Me-ATP in the catalytic site

(Migliaccio et al., J Biol Chem 2003;278:49164-70)

HCV Resistance to 2 ’-C-Methyl Nucleoside Inhibitors

7-Deaza-2’-C-Methyl-Adenosine (MK-0608) in Chimpanzees

7-Deaza-2’-C-Methyl-Adenosine (MK-0608) in Chimpanzees

0

1

2

3

4

5

6

7

-15 -10 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70

Days

HC

V R

NA

(Lo

g IU

/mL)

TMA + + + + - - - - - - - - + +

LOQ (20 IU/mL)

MK-0608 at 1mg.kg -1 orally

- 4,6 - 4,1

wt S282R/T/I wt S282

(Carroll et al., (Carroll et al., Antimicrob Antimicrob Agents Agents Chemother Chemother 2009;53:9262009;53:926 --934) 934)

((Afdhal Afdhal et al, EASL 2006)et al, EASL 2006)

Valopicitabine (NM283)Phase IIb , IFN Nonresponders

Weeks

Week 24 n=7

-0.27

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

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

NM283 800 mg monotherapy

HC

V R

NA

red

uctio

n

Antiviral Efficacy of NNIs

-1.52 days600 mg bidIIABT-333

-3.73 days750 mg bidIbVX-222

-1.710 days400 mg tidIIVCH-759

Ib

II

II

II

II

Phase

-1.3 (1a), -3.8 (1b)7 days800 mg bidMK-3281

-3.13 days800 mg q8hBI207127

-2.93 days800 mg bidANA598

-2.18 days300 mg bidFilibuvir

-1.4 8 days40 mg bidGS-9190

Median/mean logHCV RNA reduction

DurationDoseDrug

In vitro Resistance

Copyright © 2006 Merck & Co., Inc., Whitehouse Stati on, New Jersey, USA All rights reserved

AA

NNI site ANNI site AIndolesIndoles, , BenzimidazolesBenzimidazoles

Pro 495, Pro 496, Val 499Pro 495, Pro 496, Val 499

NNI site BNNI site BThiopheneThiophene--COOHCOOH

Met 423Met 423

BB

NNI site CNNI site CBenzothiadiazineBenzothiadiazine

Asn Asn 411, Met 414, 411, Met 414, Tyr Tyr 448448

Allosteric Allosteric GTPGTP

CC

NNI site DNNI site DBenzofuransBenzofurans

Cys Cys 316, Val 201316, Val 201

AA

BBCC

DD

EE

NNI siteNNI site E (hypothetical)E (hypothetical)Cys Cys 445, 445, Tyr Tyr 448, 448, Tyr Tyr 452452

HCV 796 (ViroPharma & Wyeth )Antiviral efficacy

(Chandra et al, DDW 2006)(Chandra et al, DDW 2006)

--11 22 55 88 1111 1144 1177 2200 2233 2266 2299--33

--22

--11

00

11

PPllaacceebboo5500 mmgg110000 mmgg225500 mmgg550000 mmgg11000000 mmgg11550000 mmgg

SSttuuddyy DDaayy

Log

HC

V R

NA

cha

nge

Log

HC

V R

NA

cha

nge

TreatmentTreatment FollowFollow --upup

Prevention of Resistance

Prevention of Resistance to HCV Inhibitors

• Exclude use as a monotherapy

• Combine with one or several other antivirals with :

• At least additive antiviral effect• No cross-resistance

R7128/R7227 CombinationINFORM Trial

Day0 2 4 6 8 10 12 14

-7

-6

-5

-3

-2

-1

0

1

Mea

n lo

g10

HC

V R

NA

cha

nge

from

-4

Placebo

R7128 500b D1-7/R7227 100t D4-7-Na

R7227 100t D1-7/R7128 500b D4-7-Na

500b/200t 1000b/200t

500b/100t

1000b/100t

(Gane et al., EASL 2009)

R7128/R7227 CombinationINFORM Trial

Day0 2 4 6 8 10 12 14

-7

-6

-5

-3

-2

-1

0

1

Mea

n lo

g10

HC

V R

NA

cha

nge

from

-4

Placebo

1000b/900b-TE

1000b/600b-TE

(Gane et al., AASLD 2009)

1000b/900b-Na

Cure with IFN -Free Regimens ?

Combination of MK -7009 andMK-608 (Merck ) in vitro

Synergy in the genotype 1bSynergy in the genotype 1breplicon replicon at low MKat low MK --0608,0608,

high MKhigh MK --7009 doses7009 doses

--55

00

55

1010

0.020.020.150.15

1.201.201212

0.30.3

MKMK--608 608 pol pol inhibitor (inhibitor ( mMmM))

MKMK--7009 NS3 7009 NS3 inhibitor (inhibitor ( nMnM))

55--1010

00--55

--55--00

(Olsen et al., APASL 2008)(Olsen et al., APASL 2008)

MK 7009monotherapy

0

1

2

3

4

5

6

0 50 90 130 170 210 250

Day

log

IU/m

L

LOQLOQ

Combination of MK -7009 andMK-608 (Merck ) in vivo

MK 7009+ MK-608 Chimp AChimp A

Chimp BChimp B

Chimp CChimp C

SVR

(Olsen et al., APASL 2008)(Olsen et al., APASL 2008)

Health & Medicine

Pawlotsky Hcv RéSistance