1

Registrering av antivirala preparat

1960 1970 1980 1990 2000

IFN IDUAra-AAmantadin

ZoviraxPFA

GCV

AZTddIddC

d4T3TC

Ribavirin

FamvirValtrex

Ritonavir

IndinavirSaquinavir

NelfinavirNevirapineCidofovirZanamavirAmprenavir

aringr

Marboran

OseltamivirLopinavir

TenofovirEnfuvirtidAdefovir

Antivirala medeln Behandlingsbara infektioner - Herpes (HSVVZVCMV) - HIV - Influensa AB - RSV - HBV HCV - Enterovirus

n Maringlet aumlr att haumlmma virusfoumlroumlkningen

n Syftet aumlr att mildra symtomen foumlrkortasjukdomstiden bromsa eller foumlrebyggasjukdomsutvecklingen

Development of antiviral drugs - problems

n Toxicityn Development of resistancen Only acute and not latent infectionsn Combination therapy often neededn Maximalhigh levels of viral load when

symptoms appear

2

Time (days)

Viral titers peak early after infection

0 21 3 4 6 75 8

Viral titreSymptom severity

Rapid onsetof symptoms

Peak ofviral replication

Viral titre andsymptom severity

3

Herpes virus morfologi

Humanpatogena herpesvirus

n Herpes simplexvirus typ 1 (HSV-1)n Herpes simplexvirus typ 2 (HSV-2)n Varicella-Zoster virus (VZV)n Cytomegalovirus (CMV)n Epstein-Barr virus (EBV)n Humant herpesvirus 6 (HHV-6)n Humant herpesvirus 7 (HHV-7)n Humant herpesvirus 8 (HHV-8)

4

Herpes ndash antiviral drugs

1 Nucleoside analogues (guanosine analogues) -acyclovir valacyclovir -penciclovir famciclovir -ganciclovir valganciclovir2 Pyrophosphate analogues -Foscarnet3 Acyclic nucleoside-phosphonate analogues -Cidofovir -Adefovir

Nucleoside analogues

Gancilovir Acyclovir Deoxyguanosine

Acyclovir mechanism of action

ACV

HSV coded Tk

ACV-MP ACV-TP

Hostcellenzymes

HSV DNA-pol

dATPdGTPdCTPdTTP

ACV

5

Foscarnet - mechanism ofaction

TTPCTPATPGTP

ppPFA

Herpes DNA-polymerase

PFA

Antiviral therapy for herpes infectionsGuanosine analogues

n Acyc lovir HSV-1 HSV-2 VZVn Valaci clovir (prodrug) HSV-1 HSV-2 VZVn Penciclovir HSV-1 HSV-2 VZVn Famci clovir (prodrug) HSV-1 HSV-2 VZVn Ganciclovir CMVn Valganciclovir (prodrug) CMVn Foscarnet CMVn Cidofovir CMV

Antiviral drugs for HSV-infections

n Acyclovir (Zovirax Geavir) - 200mgx5po suppression - 400mgx2pon Valacyclovir (Valtrex) - 500mgx2po

n Famciclovir (Famvir) - 250mgx2po (Vectavir) creamn (Foscavir) ndash ACV resist inf iv

6

Kliniska effekter av acyclovirbehandling vidHSV-infektion

n Primaumlrinfektion - halvering av tid till utlaumlkning(11 55 dagar)

n Rekurrent infektion - ca 2 dagar foumlrkortad tidtill utlaumlkning (7 5 dagar)

n Suppressionsterapi - enstaka recidiv underbehandling (12 lt 1 recaringr)

n HSV-1 encefalit - Saumlnkt mort (80 21)

Antiviral drugs for VZV-infections

n Acyclovir (Zovirax Geavir) - 800mgx5po

n Valacyklovir (Valtrex) -1000mgx3po

n Famciclovir (Famvir) -250mgx3po

Antiviral drugs for CMV-infection

n Ganciklovir IV PO

n Valganciclovir PO

n Foscarnet IV

n Cidofovir IV

n Fomivirsen intravitreal

7

Resistens herpesvirus nukleosidanaloger

n Ingenmkt laringg frekvens resistensutveckling hosimmunokompetenta (01 ndash 06)

n Rel houmlg frekvens resistenta infektioner hosimmundefekta Cancer AIDS hjaumlrt- lung-transplBMT(43 -29)

n Resistent virus aumlr tymidinkinasnegativt och relavirulent - sprids saumlmre

n Resistens aumlr inget permanent tillstaringndn Resistenta infektioner kan behandlas med Foscavir

eller Cidofovir

CMV-resistens mot antivirala preparat

n Korttidsbehandling (14ndash21dagar) ingenmkt laringgfrekvens

n Laringngtidsbehandling (3-12 maringn) med GCV vid CMVretinit ca 5-30 utvecklade resistent CMV

n Laringngtidsbehandling (3-9 maringnader) CDVPFA vidCMV retinit ca 30 utvecklade resistens

Sammanfattning HSV VZV CMV Faktorerav betydelse foumlr resistensutveckling

n Grad av immunosuppressionn Behandlingstidn Biotillgaumlnglighet vid po administrering ndash houmlg

rdquoviral loadrdquo under paringgaringende terapi

8

HIV som knoppar av fraringn cellytan paring enCD4+ T-cell

Total 332 (306 ndash 361) million

Western ampCentral Europe

760 000[600 000 ndash 11 million]

Middle East amp NorthAfrica

380 000[270 000 ndash 500 000]

Sub-Saharan Africa225 million

[209 ndash 243 million]

Eastern Europeamp Central Asia

16 million[12 ndash 21 million]

South amp South-EastAsia

40 million[33 ndash 51 million]

Oceania75 000

[53 000 ndash 120 000]

North America13 million

[480 000 ndash 19 million]

Latin America16 million

[14 ndash 19 million]

East Asia800 000

[620 000 ndash 960 000]

Caribbean230 000

[210 000 ndash 270 000]

Adults and children estimated to be living with HIV 2007

9

Progression of HIV infection

Viral load(HIV RNA)CD4+ cells

Early stage Intermediate stage Advanced stage

Behandlingsstartlt250 CD4+mm3

1000

500

HIV ndashdroger

Mogen virion

CCR5 haumlmmare ny

Integrashaumlmmare ny

6 klasser av HIV-laumlkemedel

Atazanavir (ATV)Emtricitabine (FTC)

Lopinavir (LPV)Abacavir (ABC)

Fosamprenavir (FPV)Tenofovir (TDF)III Raltegravir

Nelfinavir (NFV)Stavudin (d4T)

Saquinavir(SQV )Etravirin (ETV)Didanosin (ddI)II Maraviroc(CCR5)

Indinavir (IDV)Efavirenz (EFV)Lamuvidin (3TC)

Darunavir (DRV)Tipranavir (TPR)

Nevirapin (NVP)Zidovudin (AZT)I Enfuvirtid (T20)

Protease inhibitors VI(PI)

Non-nucleosideanaloguesV (NNRTI)

Nucleoside analoguesIV (NRTI)

Entry inhibitorsI Fusion (FI)II Co-receptorIntegreringIII Integras

10

HIV reverst transkriptas -NRTINNRTI preparat

Verkningsmekanism proteashaumlmmare

n RNA-virus brukar reglera proteinsyntesen genomatt koda f oumlr ett j aumltteprotein som bryts ned tillmindre funktionella proteinenheter

n Detta sker med ytterst specifika virala proteaser n Dessa proteaser har blivit m aringl fouml r ytterst

verksamma antivirusmedel proteash aumlmmare

Verkningsmekanism -integrashaumlmmare

Raltegravir

11

26dper gen

EuroSIDA Mocroft et al AIDS2003

Months after virolgical suppression

Re

bo

un

de

d

Andel patienter med detekterbart HIV (gt400 kopml)under HAART behandling (PI el NNRTI + 2NRTI)

Incidens ARV resistenta HIV-infektioner (n=7363) i Kanada 1996 ndash 2007 Lima et al

12

SPREAD (transmitted resistance) - Sweden

3 12942007

2 18432006

5 16282005

5 16182004

6 12672003

16 3152002

TotalResistanceYear

J Albert SMI to be published

Faktorer av betydelse foumlrresistensutvecklingn Behandlingsfoumlljsamhetn Virusdynamikvirusnivaringer ndash grad av suppression

med administrerade preparatn Kombination av preparatn Farmakokinetiska foumlrharingllandenn Antal mutationer som ger upphov till resistensn Kvalitativa egenskaper hos virus i samband med

primaumlrinfektion ndash oumlverfoumlrd resistens

Resistensmarkoumlrertester

n ldquoViral loadrdquo - HIV RNAuarrq CD4 cellerdarrθ p24 antigenuarr

ν Genotypisk resistens - PCR +Sekvensering av RT proteasgenenresp integreasgenen

13

Vilka effekter uppnarings med terapi-viralload (HIV-RNA)

n Monoterapica 5 -100 ggr snabb resistensutveckling spec vid 3TC

Icke-nukleosidanalogern Dubbelterapica 10 - 1000 ggr laringngsammare resistensutvecklingn Trippelterapi (tex 2 NRTI + 1 NNRTIalt 1 PI)3 - 5 log mkt laringngsam resistensutveckling

Neuraminidase(9 subtypes)

Haemagglutinin(15 subtypes)

Viral RNA(segmentedgenome)

Orthomyxovirus

Structure of influenza A virus

14

Replication cycle of influenza virus

Attachment

Uncoating

Assemblyamp Budding

Release

Influenza neuraminidase

Surface of influenza virus highly variablebut

n Active site of influenzaneuraminidase is alwayshighly conserved

n Essential for viralreplication

n An ideal target forantiviral intervention

Influenza drugs

n Oseltamivir Tamiflu (A+B) - per oraln Zanamivir Relenza (A+B) - inhalation

15

Neuroaminidase inhibitors Influenza AB

Relenza Tamiflu

Median time to aleviate (days) ofsymptoms (Relenza)

lt000115

n=609

50

n=558

65

Combined

lt000125

n=136

50

n=151

75

NAIB

3002

007810

n=312

50

n=257

60

NAIA

3002

000415

n=161

45

n=160

60

NAIB

3001

P-valueDiff

days

Zanamivir

10 mgx2

PlaceboStudy

Days to normal activity

Oseltamivir

75mg bid

(n=124)

65

55

P value

lt002

lt0001

Difference

28

19

Placebo

(n=129)

94

74

Treanor et al JAMA 2000

Days to normal health

Impact on health outcome measuresOseltamivir (Tamiflu)

16

Influenza Resistance to antiviral drugs

Neuroaminidase treated adult patients ndash slowdevelopment - clinical studies approx 1(limited information) Children 20-30

Behandling av kronisk hepatit Bantivirala preparat och resistens

n Ca ett 100-tal patienter under behandling i Sverige

n Utdragen inflammation leverfibros cirrosca

n Lamuvidin (3TC) 4-5log reduktion HBV-DNA gt50 resistentainf e 3- aringrs behandling

n Adefovir 3-4 log reduktion HBV-DNA lt5 resistentainfektioner e 3- aringrs behandling

n Entecavir gt5log reduktion HBV-DNA frekvens resistenta inf =laringg

n Telbivudin gt5log reduktion HBV-DNA frekvens resistenta inf= l aringg

n ALAT och HBV-DNA 3-4 ggr aringr (gt1 log)

n PCRsekvensering (serum el plasmaprov) av HBV RTpol aa180-240 gt1000-5000 HBV-DNA kopior kr aumlvs (utf oumlrs vHuddinge och Sahlgrenska)

Antiviral drugs for hepatitis C

n Interferon alphan Peg-interferonn Ribavirin

17

Covalent attachment ofbranched 40 kDa PEG to IFN α-2a producesa compound that has sustainedabsorption reduced clearanceand a longer half-life thanunmodified IFN

Standard interferon given tiwFirst week of Dosing

02

46

810

1214

0 25 50 75 100 125 150

Time (hours) over one week

Inte

rfe

ron

(U

mL

)

Mon Tues Wed Thurs Fri Sat Sun

PEG-IFN 180 mcg subcutaneouslygiven once weekly (multiple dosing)

0

5

10

15

20

25

0 25 50 75 100 125 150

Time (hours) over one week

PE

G-I

FN

(ng

mL)

Mon Tues Wed Thurs Fri Sat Sun

168

Effect of pegIFN Vs IFN therapy on HepC infection

n Monotherapy IFN Vs pegIFN 12mo -IFN alpha-2b 12 sustained v response (SVR) -pegIFN 25 (SVR)

n Combined therapy -pegINF+RBV 42 SVR genotype 1 -IFN+RBV 33 SVR genotype 1 -All treatment gr 80 SVR genotypes 2amp3

Enteropicorna infections

n Pleconaril (not FDA approved)compassionate use in enteromeningitis

n Broad spectrum against all enterovirusesincluding rhinoviruses

n Interacts with virus receptor binding to hostcells and uncoating

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu

2

Time (days)

Viral titers peak early after infection

0 21 3 4 6 75 8

Viral titreSymptom severity

Rapid onsetof symptoms

Peak ofviral replication

Viral titre andsymptom severity

3

Herpes virus morfologi

Humanpatogena herpesvirus

n Herpes simplexvirus typ 1 (HSV-1)n Herpes simplexvirus typ 2 (HSV-2)n Varicella-Zoster virus (VZV)n Cytomegalovirus (CMV)n Epstein-Barr virus (EBV)n Humant herpesvirus 6 (HHV-6)n Humant herpesvirus 7 (HHV-7)n Humant herpesvirus 8 (HHV-8)

4

Herpes ndash antiviral drugs

1 Nucleoside analogues (guanosine analogues) -acyclovir valacyclovir -penciclovir famciclovir -ganciclovir valganciclovir2 Pyrophosphate analogues -Foscarnet3 Acyclic nucleoside-phosphonate analogues -Cidofovir -Adefovir

Nucleoside analogues

Gancilovir Acyclovir Deoxyguanosine

Acyclovir mechanism of action

ACV

HSV coded Tk

ACV-MP ACV-TP

Hostcellenzymes

HSV DNA-pol

dATPdGTPdCTPdTTP

ACV

5

Foscarnet - mechanism ofaction

TTPCTPATPGTP

ppPFA

Herpes DNA-polymerase

PFA

Antiviral therapy for herpes infectionsGuanosine analogues

n Acyc lovir HSV-1 HSV-2 VZVn Valaci clovir (prodrug) HSV-1 HSV-2 VZVn Penciclovir HSV-1 HSV-2 VZVn Famci clovir (prodrug) HSV-1 HSV-2 VZVn Ganciclovir CMVn Valganciclovir (prodrug) CMVn Foscarnet CMVn Cidofovir CMV

Antiviral drugs for HSV-infections

n Acyclovir (Zovirax Geavir) - 200mgx5po suppression - 400mgx2pon Valacyclovir (Valtrex) - 500mgx2po

n Famciclovir (Famvir) - 250mgx2po (Vectavir) creamn (Foscavir) ndash ACV resist inf iv

6

Kliniska effekter av acyclovirbehandling vidHSV-infektion

n Primaumlrinfektion - halvering av tid till utlaumlkning(11 55 dagar)

n Rekurrent infektion - ca 2 dagar foumlrkortad tidtill utlaumlkning (7 5 dagar)

n Suppressionsterapi - enstaka recidiv underbehandling (12 lt 1 recaringr)

n HSV-1 encefalit - Saumlnkt mort (80 21)

Antiviral drugs for VZV-infections

n Acyclovir (Zovirax Geavir) - 800mgx5po

n Valacyklovir (Valtrex) -1000mgx3po

n Famciclovir (Famvir) -250mgx3po

Antiviral drugs for CMV-infection

n Ganciklovir IV PO

n Valganciclovir PO

n Foscarnet IV

n Cidofovir IV

n Fomivirsen intravitreal

7

Resistens herpesvirus nukleosidanaloger

n Ingenmkt laringg frekvens resistensutveckling hosimmunokompetenta (01 ndash 06)

n Rel houmlg frekvens resistenta infektioner hosimmundefekta Cancer AIDS hjaumlrt- lung-transplBMT(43 -29)

n Resistent virus aumlr tymidinkinasnegativt och relavirulent - sprids saumlmre

n Resistens aumlr inget permanent tillstaringndn Resistenta infektioner kan behandlas med Foscavir

eller Cidofovir

CMV-resistens mot antivirala preparat

n Korttidsbehandling (14ndash21dagar) ingenmkt laringgfrekvens

n Laringngtidsbehandling (3-12 maringn) med GCV vid CMVretinit ca 5-30 utvecklade resistent CMV

n Laringngtidsbehandling (3-9 maringnader) CDVPFA vidCMV retinit ca 30 utvecklade resistens

Sammanfattning HSV VZV CMV Faktorerav betydelse foumlr resistensutveckling

n Grad av immunosuppressionn Behandlingstidn Biotillgaumlnglighet vid po administrering ndash houmlg

rdquoviral loadrdquo under paringgaringende terapi

8

HIV som knoppar av fraringn cellytan paring enCD4+ T-cell

Total 332 (306 ndash 361) million

Western ampCentral Europe

760 000[600 000 ndash 11 million]

Middle East amp NorthAfrica

380 000[270 000 ndash 500 000]

Sub-Saharan Africa225 million

[209 ndash 243 million]

Eastern Europeamp Central Asia

16 million[12 ndash 21 million]

South amp South-EastAsia

40 million[33 ndash 51 million]

Oceania75 000

[53 000 ndash 120 000]

North America13 million

[480 000 ndash 19 million]

Latin America16 million

[14 ndash 19 million]

East Asia800 000

[620 000 ndash 960 000]

Caribbean230 000

[210 000 ndash 270 000]

Adults and children estimated to be living with HIV 2007

9

Progression of HIV infection

Viral load(HIV RNA)CD4+ cells

Early stage Intermediate stage Advanced stage

Behandlingsstartlt250 CD4+mm3

1000

500

HIV ndashdroger

Mogen virion

CCR5 haumlmmare ny

Integrashaumlmmare ny

6 klasser av HIV-laumlkemedel

Atazanavir (ATV)Emtricitabine (FTC)

Lopinavir (LPV)Abacavir (ABC)

Fosamprenavir (FPV)Tenofovir (TDF)III Raltegravir

Nelfinavir (NFV)Stavudin (d4T)

Saquinavir(SQV )Etravirin (ETV)Didanosin (ddI)II Maraviroc(CCR5)

Indinavir (IDV)Efavirenz (EFV)Lamuvidin (3TC)

Darunavir (DRV)Tipranavir (TPR)

Nevirapin (NVP)Zidovudin (AZT)I Enfuvirtid (T20)

Protease inhibitors VI(PI)

Non-nucleosideanaloguesV (NNRTI)

Nucleoside analoguesIV (NRTI)

Entry inhibitorsI Fusion (FI)II Co-receptorIntegreringIII Integras

10

HIV reverst transkriptas -NRTINNRTI preparat

Verkningsmekanism proteashaumlmmare

n RNA-virus brukar reglera proteinsyntesen genomatt koda f oumlr ett j aumltteprotein som bryts ned tillmindre funktionella proteinenheter

n Detta sker med ytterst specifika virala proteaser n Dessa proteaser har blivit m aringl fouml r ytterst

verksamma antivirusmedel proteash aumlmmare

Verkningsmekanism -integrashaumlmmare

Raltegravir

11

26dper gen

EuroSIDA Mocroft et al AIDS2003

Months after virolgical suppression

Re

bo

un

de

d

Andel patienter med detekterbart HIV (gt400 kopml)under HAART behandling (PI el NNRTI + 2NRTI)

Incidens ARV resistenta HIV-infektioner (n=7363) i Kanada 1996 ndash 2007 Lima et al

12

SPREAD (transmitted resistance) - Sweden

3 12942007

2 18432006

5 16282005

5 16182004

6 12672003

16 3152002

TotalResistanceYear

J Albert SMI to be published

Faktorer av betydelse foumlrresistensutvecklingn Behandlingsfoumlljsamhetn Virusdynamikvirusnivaringer ndash grad av suppression

med administrerade preparatn Kombination av preparatn Farmakokinetiska foumlrharingllandenn Antal mutationer som ger upphov till resistensn Kvalitativa egenskaper hos virus i samband med

primaumlrinfektion ndash oumlverfoumlrd resistens

Resistensmarkoumlrertester

n ldquoViral loadrdquo - HIV RNAuarrq CD4 cellerdarrθ p24 antigenuarr

ν Genotypisk resistens - PCR +Sekvensering av RT proteasgenenresp integreasgenen

13

Vilka effekter uppnarings med terapi-viralload (HIV-RNA)

n Monoterapica 5 -100 ggr snabb resistensutveckling spec vid 3TC

Icke-nukleosidanalogern Dubbelterapica 10 - 1000 ggr laringngsammare resistensutvecklingn Trippelterapi (tex 2 NRTI + 1 NNRTIalt 1 PI)3 - 5 log mkt laringngsam resistensutveckling

Neuraminidase(9 subtypes)

Haemagglutinin(15 subtypes)

Viral RNA(segmentedgenome)

Orthomyxovirus

Structure of influenza A virus

14

Replication cycle of influenza virus

Attachment

Uncoating

Assemblyamp Budding

Release

Influenza neuraminidase

Surface of influenza virus highly variablebut

n Active site of influenzaneuraminidase is alwayshighly conserved

n Essential for viralreplication

n An ideal target forantiviral intervention

Influenza drugs

n Oseltamivir Tamiflu (A+B) - per oraln Zanamivir Relenza (A+B) - inhalation

15

Neuroaminidase inhibitors Influenza AB

Relenza Tamiflu

Median time to aleviate (days) ofsymptoms (Relenza)

lt000115

n=609

50

n=558

65

Combined

lt000125

n=136

50

n=151

75

NAIB

3002

007810

n=312

50

n=257

60

NAIA

3002

000415

n=161

45

n=160

60

NAIB

3001

P-valueDiff

days

Zanamivir

10 mgx2

PlaceboStudy

Days to normal activity

Oseltamivir

75mg bid

(n=124)

65

55

P value

lt002

lt0001

Difference

28

19

Placebo

(n=129)

94

74

Treanor et al JAMA 2000

Days to normal health

Impact on health outcome measuresOseltamivir (Tamiflu)

16

Influenza Resistance to antiviral drugs

Neuroaminidase treated adult patients ndash slowdevelopment - clinical studies approx 1(limited information) Children 20-30

Behandling av kronisk hepatit Bantivirala preparat och resistens

n Ca ett 100-tal patienter under behandling i Sverige

n Utdragen inflammation leverfibros cirrosca

n Lamuvidin (3TC) 4-5log reduktion HBV-DNA gt50 resistentainf e 3- aringrs behandling

n Adefovir 3-4 log reduktion HBV-DNA lt5 resistentainfektioner e 3- aringrs behandling

n Entecavir gt5log reduktion HBV-DNA frekvens resistenta inf =laringg

n Telbivudin gt5log reduktion HBV-DNA frekvens resistenta inf= l aringg

n ALAT och HBV-DNA 3-4 ggr aringr (gt1 log)

n PCRsekvensering (serum el plasmaprov) av HBV RTpol aa180-240 gt1000-5000 HBV-DNA kopior kr aumlvs (utf oumlrs vHuddinge och Sahlgrenska)

Antiviral drugs for hepatitis C

n Interferon alphan Peg-interferonn Ribavirin

17

Covalent attachment ofbranched 40 kDa PEG to IFN α-2a producesa compound that has sustainedabsorption reduced clearanceand a longer half-life thanunmodified IFN

Standard interferon given tiwFirst week of Dosing

02

46

810

1214

0 25 50 75 100 125 150

Time (hours) over one week

Inte

rfe

ron

(U

mL

)

Mon Tues Wed Thurs Fri Sat Sun

PEG-IFN 180 mcg subcutaneouslygiven once weekly (multiple dosing)

0

5

10

15

20

25

0 25 50 75 100 125 150

Time (hours) over one week

PE

G-I

FN

(ng

mL)

Mon Tues Wed Thurs Fri Sat Sun

168

Effect of pegIFN Vs IFN therapy on HepC infection

n Monotherapy IFN Vs pegIFN 12mo -IFN alpha-2b 12 sustained v response (SVR) -pegIFN 25 (SVR)

n Combined therapy -pegINF+RBV 42 SVR genotype 1 -IFN+RBV 33 SVR genotype 1 -All treatment gr 80 SVR genotypes 2amp3

Enteropicorna infections

n Pleconaril (not FDA approved)compassionate use in enteromeningitis

n Broad spectrum against all enterovirusesincluding rhinoviruses

n Interacts with virus receptor binding to hostcells and uncoating

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu

3

Herpes virus morfologi

Humanpatogena herpesvirus

n Herpes simplexvirus typ 1 (HSV-1)n Herpes simplexvirus typ 2 (HSV-2)n Varicella-Zoster virus (VZV)n Cytomegalovirus (CMV)n Epstein-Barr virus (EBV)n Humant herpesvirus 6 (HHV-6)n Humant herpesvirus 7 (HHV-7)n Humant herpesvirus 8 (HHV-8)

4

Herpes ndash antiviral drugs

1 Nucleoside analogues (guanosine analogues) -acyclovir valacyclovir -penciclovir famciclovir -ganciclovir valganciclovir2 Pyrophosphate analogues -Foscarnet3 Acyclic nucleoside-phosphonate analogues -Cidofovir -Adefovir

Nucleoside analogues

Gancilovir Acyclovir Deoxyguanosine

Acyclovir mechanism of action

ACV

HSV coded Tk

ACV-MP ACV-TP

Hostcellenzymes

HSV DNA-pol

dATPdGTPdCTPdTTP

ACV

5

Foscarnet - mechanism ofaction

TTPCTPATPGTP

ppPFA

Herpes DNA-polymerase

PFA

Antiviral therapy for herpes infectionsGuanosine analogues

n Acyc lovir HSV-1 HSV-2 VZVn Valaci clovir (prodrug) HSV-1 HSV-2 VZVn Penciclovir HSV-1 HSV-2 VZVn Famci clovir (prodrug) HSV-1 HSV-2 VZVn Ganciclovir CMVn Valganciclovir (prodrug) CMVn Foscarnet CMVn Cidofovir CMV

Antiviral drugs for HSV-infections

n Acyclovir (Zovirax Geavir) - 200mgx5po suppression - 400mgx2pon Valacyclovir (Valtrex) - 500mgx2po

n Famciclovir (Famvir) - 250mgx2po (Vectavir) creamn (Foscavir) ndash ACV resist inf iv

6

Kliniska effekter av acyclovirbehandling vidHSV-infektion

n Primaumlrinfektion - halvering av tid till utlaumlkning(11 55 dagar)

n Rekurrent infektion - ca 2 dagar foumlrkortad tidtill utlaumlkning (7 5 dagar)

n Suppressionsterapi - enstaka recidiv underbehandling (12 lt 1 recaringr)

n HSV-1 encefalit - Saumlnkt mort (80 21)

Antiviral drugs for VZV-infections

n Acyclovir (Zovirax Geavir) - 800mgx5po

n Valacyklovir (Valtrex) -1000mgx3po

n Famciclovir (Famvir) -250mgx3po

Antiviral drugs for CMV-infection

n Ganciklovir IV PO

n Valganciclovir PO

n Foscarnet IV

n Cidofovir IV

n Fomivirsen intravitreal

7

Resistens herpesvirus nukleosidanaloger

n Ingenmkt laringg frekvens resistensutveckling hosimmunokompetenta (01 ndash 06)

n Rel houmlg frekvens resistenta infektioner hosimmundefekta Cancer AIDS hjaumlrt- lung-transplBMT(43 -29)

n Resistent virus aumlr tymidinkinasnegativt och relavirulent - sprids saumlmre

n Resistens aumlr inget permanent tillstaringndn Resistenta infektioner kan behandlas med Foscavir

eller Cidofovir

CMV-resistens mot antivirala preparat

n Korttidsbehandling (14ndash21dagar) ingenmkt laringgfrekvens

n Laringngtidsbehandling (3-12 maringn) med GCV vid CMVretinit ca 5-30 utvecklade resistent CMV

n Laringngtidsbehandling (3-9 maringnader) CDVPFA vidCMV retinit ca 30 utvecklade resistens

Sammanfattning HSV VZV CMV Faktorerav betydelse foumlr resistensutveckling

n Grad av immunosuppressionn Behandlingstidn Biotillgaumlnglighet vid po administrering ndash houmlg

rdquoviral loadrdquo under paringgaringende terapi

8

HIV som knoppar av fraringn cellytan paring enCD4+ T-cell

Total 332 (306 ndash 361) million

Western ampCentral Europe

760 000[600 000 ndash 11 million]

Middle East amp NorthAfrica

380 000[270 000 ndash 500 000]

Sub-Saharan Africa225 million

[209 ndash 243 million]

Eastern Europeamp Central Asia

16 million[12 ndash 21 million]

South amp South-EastAsia

40 million[33 ndash 51 million]

Oceania75 000

[53 000 ndash 120 000]

North America13 million

[480 000 ndash 19 million]

Latin America16 million

[14 ndash 19 million]

East Asia800 000

[620 000 ndash 960 000]

Caribbean230 000

[210 000 ndash 270 000]

Adults and children estimated to be living with HIV 2007

9

Progression of HIV infection

Viral load(HIV RNA)CD4+ cells

Early stage Intermediate stage Advanced stage

Behandlingsstartlt250 CD4+mm3

1000

500

HIV ndashdroger

Mogen virion

CCR5 haumlmmare ny

Integrashaumlmmare ny

6 klasser av HIV-laumlkemedel

Atazanavir (ATV)Emtricitabine (FTC)

Lopinavir (LPV)Abacavir (ABC)

Fosamprenavir (FPV)Tenofovir (TDF)III Raltegravir

Nelfinavir (NFV)Stavudin (d4T)

Saquinavir(SQV )Etravirin (ETV)Didanosin (ddI)II Maraviroc(CCR5)

Indinavir (IDV)Efavirenz (EFV)Lamuvidin (3TC)

Darunavir (DRV)Tipranavir (TPR)

Nevirapin (NVP)Zidovudin (AZT)I Enfuvirtid (T20)

Protease inhibitors VI(PI)

Non-nucleosideanaloguesV (NNRTI)

Nucleoside analoguesIV (NRTI)

Entry inhibitorsI Fusion (FI)II Co-receptorIntegreringIII Integras

10

HIV reverst transkriptas -NRTINNRTI preparat

Verkningsmekanism proteashaumlmmare

n RNA-virus brukar reglera proteinsyntesen genomatt koda f oumlr ett j aumltteprotein som bryts ned tillmindre funktionella proteinenheter

n Detta sker med ytterst specifika virala proteaser n Dessa proteaser har blivit m aringl fouml r ytterst

verksamma antivirusmedel proteash aumlmmare

Verkningsmekanism -integrashaumlmmare

Raltegravir

11

26dper gen

EuroSIDA Mocroft et al AIDS2003

Months after virolgical suppression

Re

bo

un

de

d

Andel patienter med detekterbart HIV (gt400 kopml)under HAART behandling (PI el NNRTI + 2NRTI)

Incidens ARV resistenta HIV-infektioner (n=7363) i Kanada 1996 ndash 2007 Lima et al

12

SPREAD (transmitted resistance) - Sweden

3 12942007

2 18432006

5 16282005

5 16182004

6 12672003

16 3152002

TotalResistanceYear

J Albert SMI to be published

Faktorer av betydelse foumlrresistensutvecklingn Behandlingsfoumlljsamhetn Virusdynamikvirusnivaringer ndash grad av suppression

med administrerade preparatn Kombination av preparatn Farmakokinetiska foumlrharingllandenn Antal mutationer som ger upphov till resistensn Kvalitativa egenskaper hos virus i samband med

primaumlrinfektion ndash oumlverfoumlrd resistens

Resistensmarkoumlrertester

n ldquoViral loadrdquo - HIV RNAuarrq CD4 cellerdarrθ p24 antigenuarr

ν Genotypisk resistens - PCR +Sekvensering av RT proteasgenenresp integreasgenen

13

Vilka effekter uppnarings med terapi-viralload (HIV-RNA)

n Monoterapica 5 -100 ggr snabb resistensutveckling spec vid 3TC

Icke-nukleosidanalogern Dubbelterapica 10 - 1000 ggr laringngsammare resistensutvecklingn Trippelterapi (tex 2 NRTI + 1 NNRTIalt 1 PI)3 - 5 log mkt laringngsam resistensutveckling

Neuraminidase(9 subtypes)

Haemagglutinin(15 subtypes)

Viral RNA(segmentedgenome)

Orthomyxovirus

Structure of influenza A virus

14

Replication cycle of influenza virus

Attachment

Uncoating

Assemblyamp Budding

Release

Influenza neuraminidase

Surface of influenza virus highly variablebut

n Active site of influenzaneuraminidase is alwayshighly conserved

n Essential for viralreplication

n An ideal target forantiviral intervention

Influenza drugs

n Oseltamivir Tamiflu (A+B) - per oraln Zanamivir Relenza (A+B) - inhalation

15

Neuroaminidase inhibitors Influenza AB

Relenza Tamiflu

Median time to aleviate (days) ofsymptoms (Relenza)

lt000115

n=609

50

n=558

65

Combined

lt000125

n=136

50

n=151

75

NAIB

3002

007810

n=312

50

n=257

60

NAIA

3002

000415

n=161

45

n=160

60

NAIB

3001

P-valueDiff

days

Zanamivir

10 mgx2

PlaceboStudy

Days to normal activity

Oseltamivir

75mg bid

(n=124)

65

55

P value

lt002

lt0001

Difference

28

19

Placebo

(n=129)

94

74

Treanor et al JAMA 2000

Days to normal health

Impact on health outcome measuresOseltamivir (Tamiflu)

16

Influenza Resistance to antiviral drugs

Neuroaminidase treated adult patients ndash slowdevelopment - clinical studies approx 1(limited information) Children 20-30

Behandling av kronisk hepatit Bantivirala preparat och resistens

n Ca ett 100-tal patienter under behandling i Sverige

n Utdragen inflammation leverfibros cirrosca

n Lamuvidin (3TC) 4-5log reduktion HBV-DNA gt50 resistentainf e 3- aringrs behandling

n Adefovir 3-4 log reduktion HBV-DNA lt5 resistentainfektioner e 3- aringrs behandling

n Entecavir gt5log reduktion HBV-DNA frekvens resistenta inf =laringg

n Telbivudin gt5log reduktion HBV-DNA frekvens resistenta inf= l aringg

n ALAT och HBV-DNA 3-4 ggr aringr (gt1 log)

n PCRsekvensering (serum el plasmaprov) av HBV RTpol aa180-240 gt1000-5000 HBV-DNA kopior kr aumlvs (utf oumlrs vHuddinge och Sahlgrenska)

Antiviral drugs for hepatitis C

n Interferon alphan Peg-interferonn Ribavirin

17

Covalent attachment ofbranched 40 kDa PEG to IFN α-2a producesa compound that has sustainedabsorption reduced clearanceand a longer half-life thanunmodified IFN

Standard interferon given tiwFirst week of Dosing

02

46

810

1214

0 25 50 75 100 125 150

Time (hours) over one week

Inte

rfe

ron

(U

mL

)

Mon Tues Wed Thurs Fri Sat Sun

PEG-IFN 180 mcg subcutaneouslygiven once weekly (multiple dosing)

0

5

10

15

20

25

0 25 50 75 100 125 150

Time (hours) over one week

PE

G-I

FN

(ng

mL)

Mon Tues Wed Thurs Fri Sat Sun

168

Effect of pegIFN Vs IFN therapy on HepC infection

n Monotherapy IFN Vs pegIFN 12mo -IFN alpha-2b 12 sustained v response (SVR) -pegIFN 25 (SVR)

n Combined therapy -pegINF+RBV 42 SVR genotype 1 -IFN+RBV 33 SVR genotype 1 -All treatment gr 80 SVR genotypes 2amp3

Enteropicorna infections

n Pleconaril (not FDA approved)compassionate use in enteromeningitis

n Broad spectrum against all enterovirusesincluding rhinoviruses

n Interacts with virus receptor binding to hostcells and uncoating

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu

4

Herpes ndash antiviral drugs

1 Nucleoside analogues (guanosine analogues) -acyclovir valacyclovir -penciclovir famciclovir -ganciclovir valganciclovir2 Pyrophosphate analogues -Foscarnet3 Acyclic nucleoside-phosphonate analogues -Cidofovir -Adefovir

Nucleoside analogues

Gancilovir Acyclovir Deoxyguanosine

Acyclovir mechanism of action

ACV

HSV coded Tk

ACV-MP ACV-TP

Hostcellenzymes

HSV DNA-pol

dATPdGTPdCTPdTTP

ACV

5

Foscarnet - mechanism ofaction

TTPCTPATPGTP

ppPFA

Herpes DNA-polymerase

PFA

Antiviral therapy for herpes infectionsGuanosine analogues

n Acyc lovir HSV-1 HSV-2 VZVn Valaci clovir (prodrug) HSV-1 HSV-2 VZVn Penciclovir HSV-1 HSV-2 VZVn Famci clovir (prodrug) HSV-1 HSV-2 VZVn Ganciclovir CMVn Valganciclovir (prodrug) CMVn Foscarnet CMVn Cidofovir CMV

Antiviral drugs for HSV-infections

n Acyclovir (Zovirax Geavir) - 200mgx5po suppression - 400mgx2pon Valacyclovir (Valtrex) - 500mgx2po

n Famciclovir (Famvir) - 250mgx2po (Vectavir) creamn (Foscavir) ndash ACV resist inf iv

6

Kliniska effekter av acyclovirbehandling vidHSV-infektion

n Primaumlrinfektion - halvering av tid till utlaumlkning(11 55 dagar)

n Rekurrent infektion - ca 2 dagar foumlrkortad tidtill utlaumlkning (7 5 dagar)

n Suppressionsterapi - enstaka recidiv underbehandling (12 lt 1 recaringr)

n HSV-1 encefalit - Saumlnkt mort (80 21)

Antiviral drugs for VZV-infections

n Acyclovir (Zovirax Geavir) - 800mgx5po

n Valacyklovir (Valtrex) -1000mgx3po

n Famciclovir (Famvir) -250mgx3po

Antiviral drugs for CMV-infection

n Ganciklovir IV PO

n Valganciclovir PO

n Foscarnet IV

n Cidofovir IV

n Fomivirsen intravitreal

7

Resistens herpesvirus nukleosidanaloger

n Ingenmkt laringg frekvens resistensutveckling hosimmunokompetenta (01 ndash 06)

n Rel houmlg frekvens resistenta infektioner hosimmundefekta Cancer AIDS hjaumlrt- lung-transplBMT(43 -29)

n Resistent virus aumlr tymidinkinasnegativt och relavirulent - sprids saumlmre

n Resistens aumlr inget permanent tillstaringndn Resistenta infektioner kan behandlas med Foscavir

eller Cidofovir

CMV-resistens mot antivirala preparat

n Korttidsbehandling (14ndash21dagar) ingenmkt laringgfrekvens

n Laringngtidsbehandling (3-12 maringn) med GCV vid CMVretinit ca 5-30 utvecklade resistent CMV

n Laringngtidsbehandling (3-9 maringnader) CDVPFA vidCMV retinit ca 30 utvecklade resistens

Sammanfattning HSV VZV CMV Faktorerav betydelse foumlr resistensutveckling

n Grad av immunosuppressionn Behandlingstidn Biotillgaumlnglighet vid po administrering ndash houmlg

rdquoviral loadrdquo under paringgaringende terapi

8

HIV som knoppar av fraringn cellytan paring enCD4+ T-cell

Total 332 (306 ndash 361) million

Western ampCentral Europe

760 000[600 000 ndash 11 million]

Middle East amp NorthAfrica

380 000[270 000 ndash 500 000]

Sub-Saharan Africa225 million

[209 ndash 243 million]

Eastern Europeamp Central Asia

16 million[12 ndash 21 million]

South amp South-EastAsia

40 million[33 ndash 51 million]

Oceania75 000

[53 000 ndash 120 000]

North America13 million

[480 000 ndash 19 million]

Latin America16 million

[14 ndash 19 million]

East Asia800 000

[620 000 ndash 960 000]

Caribbean230 000

[210 000 ndash 270 000]

Adults and children estimated to be living with HIV 2007

9

Progression of HIV infection

Viral load(HIV RNA)CD4+ cells

Early stage Intermediate stage Advanced stage

Behandlingsstartlt250 CD4+mm3

1000

500

HIV ndashdroger

Mogen virion

CCR5 haumlmmare ny

Integrashaumlmmare ny

6 klasser av HIV-laumlkemedel

Atazanavir (ATV)Emtricitabine (FTC)

Lopinavir (LPV)Abacavir (ABC)

Fosamprenavir (FPV)Tenofovir (TDF)III Raltegravir

Nelfinavir (NFV)Stavudin (d4T)

Saquinavir(SQV )Etravirin (ETV)Didanosin (ddI)II Maraviroc(CCR5)

Indinavir (IDV)Efavirenz (EFV)Lamuvidin (3TC)

Darunavir (DRV)Tipranavir (TPR)

Nevirapin (NVP)Zidovudin (AZT)I Enfuvirtid (T20)

Protease inhibitors VI(PI)

Non-nucleosideanaloguesV (NNRTI)

Nucleoside analoguesIV (NRTI)

Entry inhibitorsI Fusion (FI)II Co-receptorIntegreringIII Integras

10

HIV reverst transkriptas -NRTINNRTI preparat

Verkningsmekanism proteashaumlmmare

n RNA-virus brukar reglera proteinsyntesen genomatt koda f oumlr ett j aumltteprotein som bryts ned tillmindre funktionella proteinenheter

n Detta sker med ytterst specifika virala proteaser n Dessa proteaser har blivit m aringl fouml r ytterst

verksamma antivirusmedel proteash aumlmmare

Verkningsmekanism -integrashaumlmmare

Raltegravir

11

26dper gen

EuroSIDA Mocroft et al AIDS2003

Months after virolgical suppression

Re

bo

un

de

d

Andel patienter med detekterbart HIV (gt400 kopml)under HAART behandling (PI el NNRTI + 2NRTI)

Incidens ARV resistenta HIV-infektioner (n=7363) i Kanada 1996 ndash 2007 Lima et al

12

SPREAD (transmitted resistance) - Sweden

3 12942007

2 18432006

5 16282005

5 16182004

6 12672003

16 3152002

TotalResistanceYear

J Albert SMI to be published

Faktorer av betydelse foumlrresistensutvecklingn Behandlingsfoumlljsamhetn Virusdynamikvirusnivaringer ndash grad av suppression

med administrerade preparatn Kombination av preparatn Farmakokinetiska foumlrharingllandenn Antal mutationer som ger upphov till resistensn Kvalitativa egenskaper hos virus i samband med

primaumlrinfektion ndash oumlverfoumlrd resistens

Resistensmarkoumlrertester

n ldquoViral loadrdquo - HIV RNAuarrq CD4 cellerdarrθ p24 antigenuarr

ν Genotypisk resistens - PCR +Sekvensering av RT proteasgenenresp integreasgenen

13

Vilka effekter uppnarings med terapi-viralload (HIV-RNA)

n Monoterapica 5 -100 ggr snabb resistensutveckling spec vid 3TC

Icke-nukleosidanalogern Dubbelterapica 10 - 1000 ggr laringngsammare resistensutvecklingn Trippelterapi (tex 2 NRTI + 1 NNRTIalt 1 PI)3 - 5 log mkt laringngsam resistensutveckling

Neuraminidase(9 subtypes)

Haemagglutinin(15 subtypes)

Viral RNA(segmentedgenome)

Orthomyxovirus

Structure of influenza A virus

14

Replication cycle of influenza virus

Attachment

Uncoating

Assemblyamp Budding

Release

Influenza neuraminidase

Surface of influenza virus highly variablebut

n Active site of influenzaneuraminidase is alwayshighly conserved

n Essential for viralreplication

n An ideal target forantiviral intervention

Influenza drugs

n Oseltamivir Tamiflu (A+B) - per oraln Zanamivir Relenza (A+B) - inhalation

15

Neuroaminidase inhibitors Influenza AB

Relenza Tamiflu

Median time to aleviate (days) ofsymptoms (Relenza)

lt000115

n=609

50

n=558

65

Combined

lt000125

n=136

50

n=151

75

NAIB

3002

007810

n=312

50

n=257

60

NAIA

3002

000415

n=161

45

n=160

60

NAIB

3001

P-valueDiff

days

Zanamivir

10 mgx2

PlaceboStudy

Days to normal activity

Oseltamivir

75mg bid

(n=124)

65

55

P value

lt002

lt0001

Difference

28

19

Placebo

(n=129)

94

74

Treanor et al JAMA 2000

Days to normal health

Impact on health outcome measuresOseltamivir (Tamiflu)

16

Influenza Resistance to antiviral drugs

Neuroaminidase treated adult patients ndash slowdevelopment - clinical studies approx 1(limited information) Children 20-30

Behandling av kronisk hepatit Bantivirala preparat och resistens

n Ca ett 100-tal patienter under behandling i Sverige

n Utdragen inflammation leverfibros cirrosca

n Lamuvidin (3TC) 4-5log reduktion HBV-DNA gt50 resistentainf e 3- aringrs behandling

n Adefovir 3-4 log reduktion HBV-DNA lt5 resistentainfektioner e 3- aringrs behandling

n Entecavir gt5log reduktion HBV-DNA frekvens resistenta inf =laringg

n Telbivudin gt5log reduktion HBV-DNA frekvens resistenta inf= l aringg

n ALAT och HBV-DNA 3-4 ggr aringr (gt1 log)

n PCRsekvensering (serum el plasmaprov) av HBV RTpol aa180-240 gt1000-5000 HBV-DNA kopior kr aumlvs (utf oumlrs vHuddinge och Sahlgrenska)

Antiviral drugs for hepatitis C

n Interferon alphan Peg-interferonn Ribavirin

17

Covalent attachment ofbranched 40 kDa PEG to IFN α-2a producesa compound that has sustainedabsorption reduced clearanceand a longer half-life thanunmodified IFN

Standard interferon given tiwFirst week of Dosing

02

46

810

1214

0 25 50 75 100 125 150

Time (hours) over one week

Inte

rfe

ron

(U

mL

)

Mon Tues Wed Thurs Fri Sat Sun

PEG-IFN 180 mcg subcutaneouslygiven once weekly (multiple dosing)

0

5

10

15

20

25

0 25 50 75 100 125 150

Time (hours) over one week

PE

G-I

FN

(ng

mL)

Mon Tues Wed Thurs Fri Sat Sun

168

Effect of pegIFN Vs IFN therapy on HepC infection

n Monotherapy IFN Vs pegIFN 12mo -IFN alpha-2b 12 sustained v response (SVR) -pegIFN 25 (SVR)

n Combined therapy -pegINF+RBV 42 SVR genotype 1 -IFN+RBV 33 SVR genotype 1 -All treatment gr 80 SVR genotypes 2amp3

Enteropicorna infections

n Pleconaril (not FDA approved)compassionate use in enteromeningitis

n Broad spectrum against all enterovirusesincluding rhinoviruses

n Interacts with virus receptor binding to hostcells and uncoating

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu

5

Foscarnet - mechanism ofaction

TTPCTPATPGTP

ppPFA

Herpes DNA-polymerase

PFA

Antiviral therapy for herpes infectionsGuanosine analogues

n Acyc lovir HSV-1 HSV-2 VZVn Valaci clovir (prodrug) HSV-1 HSV-2 VZVn Penciclovir HSV-1 HSV-2 VZVn Famci clovir (prodrug) HSV-1 HSV-2 VZVn Ganciclovir CMVn Valganciclovir (prodrug) CMVn Foscarnet CMVn Cidofovir CMV

Antiviral drugs for HSV-infections

n Acyclovir (Zovirax Geavir) - 200mgx5po suppression - 400mgx2pon Valacyclovir (Valtrex) - 500mgx2po

n Famciclovir (Famvir) - 250mgx2po (Vectavir) creamn (Foscavir) ndash ACV resist inf iv

6

Kliniska effekter av acyclovirbehandling vidHSV-infektion

n Primaumlrinfektion - halvering av tid till utlaumlkning(11 55 dagar)

n Rekurrent infektion - ca 2 dagar foumlrkortad tidtill utlaumlkning (7 5 dagar)

n Suppressionsterapi - enstaka recidiv underbehandling (12 lt 1 recaringr)

n HSV-1 encefalit - Saumlnkt mort (80 21)

Antiviral drugs for VZV-infections

n Acyclovir (Zovirax Geavir) - 800mgx5po

n Valacyklovir (Valtrex) -1000mgx3po

n Famciclovir (Famvir) -250mgx3po

Antiviral drugs for CMV-infection

n Ganciklovir IV PO

n Valganciclovir PO

n Foscarnet IV

n Cidofovir IV

n Fomivirsen intravitreal

7

Resistens herpesvirus nukleosidanaloger

n Ingenmkt laringg frekvens resistensutveckling hosimmunokompetenta (01 ndash 06)

n Rel houmlg frekvens resistenta infektioner hosimmundefekta Cancer AIDS hjaumlrt- lung-transplBMT(43 -29)

n Resistent virus aumlr tymidinkinasnegativt och relavirulent - sprids saumlmre

n Resistens aumlr inget permanent tillstaringndn Resistenta infektioner kan behandlas med Foscavir

eller Cidofovir

CMV-resistens mot antivirala preparat

n Korttidsbehandling (14ndash21dagar) ingenmkt laringgfrekvens

n Laringngtidsbehandling (3-12 maringn) med GCV vid CMVretinit ca 5-30 utvecklade resistent CMV

n Laringngtidsbehandling (3-9 maringnader) CDVPFA vidCMV retinit ca 30 utvecklade resistens

Sammanfattning HSV VZV CMV Faktorerav betydelse foumlr resistensutveckling

n Grad av immunosuppressionn Behandlingstidn Biotillgaumlnglighet vid po administrering ndash houmlg

rdquoviral loadrdquo under paringgaringende terapi

8

HIV som knoppar av fraringn cellytan paring enCD4+ T-cell

Total 332 (306 ndash 361) million

Western ampCentral Europe

760 000[600 000 ndash 11 million]

Middle East amp NorthAfrica

380 000[270 000 ndash 500 000]

Sub-Saharan Africa225 million

[209 ndash 243 million]

Eastern Europeamp Central Asia

16 million[12 ndash 21 million]

South amp South-EastAsia

40 million[33 ndash 51 million]

Oceania75 000

[53 000 ndash 120 000]

North America13 million

[480 000 ndash 19 million]

Latin America16 million

[14 ndash 19 million]

East Asia800 000

[620 000 ndash 960 000]

Caribbean230 000

[210 000 ndash 270 000]

Adults and children estimated to be living with HIV 2007

9

Progression of HIV infection

Viral load(HIV RNA)CD4+ cells

Early stage Intermediate stage Advanced stage

Behandlingsstartlt250 CD4+mm3

1000

500

HIV ndashdroger

Mogen virion

CCR5 haumlmmare ny

Integrashaumlmmare ny

6 klasser av HIV-laumlkemedel

Atazanavir (ATV)Emtricitabine (FTC)

Lopinavir (LPV)Abacavir (ABC)

Fosamprenavir (FPV)Tenofovir (TDF)III Raltegravir

Nelfinavir (NFV)Stavudin (d4T)

Saquinavir(SQV )Etravirin (ETV)Didanosin (ddI)II Maraviroc(CCR5)

Indinavir (IDV)Efavirenz (EFV)Lamuvidin (3TC)

Darunavir (DRV)Tipranavir (TPR)

Nevirapin (NVP)Zidovudin (AZT)I Enfuvirtid (T20)

Protease inhibitors VI(PI)

Non-nucleosideanaloguesV (NNRTI)

Nucleoside analoguesIV (NRTI)

Entry inhibitorsI Fusion (FI)II Co-receptorIntegreringIII Integras

10

HIV reverst transkriptas -NRTINNRTI preparat

Verkningsmekanism proteashaumlmmare

n RNA-virus brukar reglera proteinsyntesen genomatt koda f oumlr ett j aumltteprotein som bryts ned tillmindre funktionella proteinenheter

n Detta sker med ytterst specifika virala proteaser n Dessa proteaser har blivit m aringl fouml r ytterst

verksamma antivirusmedel proteash aumlmmare

Verkningsmekanism -integrashaumlmmare

Raltegravir

11

26dper gen

EuroSIDA Mocroft et al AIDS2003

Months after virolgical suppression

Re

bo

un

de

d

Andel patienter med detekterbart HIV (gt400 kopml)under HAART behandling (PI el NNRTI + 2NRTI)

Incidens ARV resistenta HIV-infektioner (n=7363) i Kanada 1996 ndash 2007 Lima et al

12

SPREAD (transmitted resistance) - Sweden

3 12942007

2 18432006

5 16282005

5 16182004

6 12672003

16 3152002

TotalResistanceYear

J Albert SMI to be published

Faktorer av betydelse foumlrresistensutvecklingn Behandlingsfoumlljsamhetn Virusdynamikvirusnivaringer ndash grad av suppression

med administrerade preparatn Kombination av preparatn Farmakokinetiska foumlrharingllandenn Antal mutationer som ger upphov till resistensn Kvalitativa egenskaper hos virus i samband med

primaumlrinfektion ndash oumlverfoumlrd resistens

Resistensmarkoumlrertester

n ldquoViral loadrdquo - HIV RNAuarrq CD4 cellerdarrθ p24 antigenuarr

ν Genotypisk resistens - PCR +Sekvensering av RT proteasgenenresp integreasgenen

13

Vilka effekter uppnarings med terapi-viralload (HIV-RNA)

n Monoterapica 5 -100 ggr snabb resistensutveckling spec vid 3TC

Icke-nukleosidanalogern Dubbelterapica 10 - 1000 ggr laringngsammare resistensutvecklingn Trippelterapi (tex 2 NRTI + 1 NNRTIalt 1 PI)3 - 5 log mkt laringngsam resistensutveckling

Neuraminidase(9 subtypes)

Haemagglutinin(15 subtypes)

Viral RNA(segmentedgenome)

Orthomyxovirus

Structure of influenza A virus

14

Replication cycle of influenza virus

Attachment

Uncoating

Assemblyamp Budding

Release

Influenza neuraminidase

Surface of influenza virus highly variablebut

n Active site of influenzaneuraminidase is alwayshighly conserved

n Essential for viralreplication

n An ideal target forantiviral intervention

Influenza drugs

n Oseltamivir Tamiflu (A+B) - per oraln Zanamivir Relenza (A+B) - inhalation

15

Neuroaminidase inhibitors Influenza AB

Relenza Tamiflu

Median time to aleviate (days) ofsymptoms (Relenza)

lt000115

n=609

50

n=558

65

Combined

lt000125

n=136

50

n=151

75

NAIB

3002

007810

n=312

50

n=257

60

NAIA

3002

000415

n=161

45

n=160

60

NAIB

3001

P-valueDiff

days

Zanamivir

10 mgx2

PlaceboStudy

Days to normal activity

Oseltamivir

75mg bid

(n=124)

65

55

P value

lt002

lt0001

Difference

28

19

Placebo

(n=129)

94

74

Treanor et al JAMA 2000

Days to normal health

Impact on health outcome measuresOseltamivir (Tamiflu)

16

Influenza Resistance to antiviral drugs

Neuroaminidase treated adult patients ndash slowdevelopment - clinical studies approx 1(limited information) Children 20-30

Behandling av kronisk hepatit Bantivirala preparat och resistens

n Ca ett 100-tal patienter under behandling i Sverige

n Utdragen inflammation leverfibros cirrosca

n Lamuvidin (3TC) 4-5log reduktion HBV-DNA gt50 resistentainf e 3- aringrs behandling

n Adefovir 3-4 log reduktion HBV-DNA lt5 resistentainfektioner e 3- aringrs behandling

n Entecavir gt5log reduktion HBV-DNA frekvens resistenta inf =laringg

n Telbivudin gt5log reduktion HBV-DNA frekvens resistenta inf= l aringg

n ALAT och HBV-DNA 3-4 ggr aringr (gt1 log)

n PCRsekvensering (serum el plasmaprov) av HBV RTpol aa180-240 gt1000-5000 HBV-DNA kopior kr aumlvs (utf oumlrs vHuddinge och Sahlgrenska)

Antiviral drugs for hepatitis C

n Interferon alphan Peg-interferonn Ribavirin

17

Covalent attachment ofbranched 40 kDa PEG to IFN α-2a producesa compound that has sustainedabsorption reduced clearanceand a longer half-life thanunmodified IFN

Standard interferon given tiwFirst week of Dosing

02

46

810

1214

0 25 50 75 100 125 150

Time (hours) over one week

Inte

rfe

ron

(U

mL

)

Mon Tues Wed Thurs Fri Sat Sun

PEG-IFN 180 mcg subcutaneouslygiven once weekly (multiple dosing)

0

5

10

15

20

25

0 25 50 75 100 125 150

Time (hours) over one week

PE

G-I

FN

(ng

mL)

Mon Tues Wed Thurs Fri Sat Sun

168

Effect of pegIFN Vs IFN therapy on HepC infection

n Monotherapy IFN Vs pegIFN 12mo -IFN alpha-2b 12 sustained v response (SVR) -pegIFN 25 (SVR)

n Combined therapy -pegINF+RBV 42 SVR genotype 1 -IFN+RBV 33 SVR genotype 1 -All treatment gr 80 SVR genotypes 2amp3

Enteropicorna infections

n Pleconaril (not FDA approved)compassionate use in enteromeningitis

n Broad spectrum against all enterovirusesincluding rhinoviruses

n Interacts with virus receptor binding to hostcells and uncoating

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu

6

Kliniska effekter av acyclovirbehandling vidHSV-infektion

n Primaumlrinfektion - halvering av tid till utlaumlkning(11 55 dagar)

n Rekurrent infektion - ca 2 dagar foumlrkortad tidtill utlaumlkning (7 5 dagar)

n Suppressionsterapi - enstaka recidiv underbehandling (12 lt 1 recaringr)

n HSV-1 encefalit - Saumlnkt mort (80 21)

Antiviral drugs for VZV-infections

n Acyclovir (Zovirax Geavir) - 800mgx5po

n Valacyklovir (Valtrex) -1000mgx3po

n Famciclovir (Famvir) -250mgx3po

Antiviral drugs for CMV-infection

n Ganciklovir IV PO

n Valganciclovir PO

n Foscarnet IV

n Cidofovir IV

n Fomivirsen intravitreal

7

Resistens herpesvirus nukleosidanaloger

n Ingenmkt laringg frekvens resistensutveckling hosimmunokompetenta (01 ndash 06)

n Rel houmlg frekvens resistenta infektioner hosimmundefekta Cancer AIDS hjaumlrt- lung-transplBMT(43 -29)

n Resistent virus aumlr tymidinkinasnegativt och relavirulent - sprids saumlmre

n Resistens aumlr inget permanent tillstaringndn Resistenta infektioner kan behandlas med Foscavir

eller Cidofovir

CMV-resistens mot antivirala preparat

n Korttidsbehandling (14ndash21dagar) ingenmkt laringgfrekvens

n Laringngtidsbehandling (3-12 maringn) med GCV vid CMVretinit ca 5-30 utvecklade resistent CMV

n Laringngtidsbehandling (3-9 maringnader) CDVPFA vidCMV retinit ca 30 utvecklade resistens

Sammanfattning HSV VZV CMV Faktorerav betydelse foumlr resistensutveckling

n Grad av immunosuppressionn Behandlingstidn Biotillgaumlnglighet vid po administrering ndash houmlg

rdquoviral loadrdquo under paringgaringende terapi

8

HIV som knoppar av fraringn cellytan paring enCD4+ T-cell

Total 332 (306 ndash 361) million

Western ampCentral Europe

760 000[600 000 ndash 11 million]

Middle East amp NorthAfrica

380 000[270 000 ndash 500 000]

Sub-Saharan Africa225 million

[209 ndash 243 million]

Eastern Europeamp Central Asia

16 million[12 ndash 21 million]

South amp South-EastAsia

40 million[33 ndash 51 million]

Oceania75 000

[53 000 ndash 120 000]

North America13 million

[480 000 ndash 19 million]

Latin America16 million

[14 ndash 19 million]

East Asia800 000

[620 000 ndash 960 000]

Caribbean230 000

[210 000 ndash 270 000]

Adults and children estimated to be living with HIV 2007

9

Progression of HIV infection

Viral load(HIV RNA)CD4+ cells

Early stage Intermediate stage Advanced stage

Behandlingsstartlt250 CD4+mm3

1000

500

HIV ndashdroger

Mogen virion

CCR5 haumlmmare ny

Integrashaumlmmare ny

6 klasser av HIV-laumlkemedel

Atazanavir (ATV)Emtricitabine (FTC)

Lopinavir (LPV)Abacavir (ABC)

Fosamprenavir (FPV)Tenofovir (TDF)III Raltegravir

Nelfinavir (NFV)Stavudin (d4T)

Saquinavir(SQV )Etravirin (ETV)Didanosin (ddI)II Maraviroc(CCR5)

Indinavir (IDV)Efavirenz (EFV)Lamuvidin (3TC)

Darunavir (DRV)Tipranavir (TPR)

Nevirapin (NVP)Zidovudin (AZT)I Enfuvirtid (T20)

Protease inhibitors VI(PI)

Non-nucleosideanaloguesV (NNRTI)

Nucleoside analoguesIV (NRTI)

Entry inhibitorsI Fusion (FI)II Co-receptorIntegreringIII Integras

10

HIV reverst transkriptas -NRTINNRTI preparat

Verkningsmekanism proteashaumlmmare

n RNA-virus brukar reglera proteinsyntesen genomatt koda f oumlr ett j aumltteprotein som bryts ned tillmindre funktionella proteinenheter

n Detta sker med ytterst specifika virala proteaser n Dessa proteaser har blivit m aringl fouml r ytterst

verksamma antivirusmedel proteash aumlmmare

Verkningsmekanism -integrashaumlmmare

Raltegravir

11

26dper gen

EuroSIDA Mocroft et al AIDS2003

Months after virolgical suppression

Re

bo

un

de

d

Andel patienter med detekterbart HIV (gt400 kopml)under HAART behandling (PI el NNRTI + 2NRTI)

Incidens ARV resistenta HIV-infektioner (n=7363) i Kanada 1996 ndash 2007 Lima et al

12

SPREAD (transmitted resistance) - Sweden

3 12942007

2 18432006

5 16282005

5 16182004

6 12672003

16 3152002

TotalResistanceYear

J Albert SMI to be published

Faktorer av betydelse foumlrresistensutvecklingn Behandlingsfoumlljsamhetn Virusdynamikvirusnivaringer ndash grad av suppression

med administrerade preparatn Kombination av preparatn Farmakokinetiska foumlrharingllandenn Antal mutationer som ger upphov till resistensn Kvalitativa egenskaper hos virus i samband med

primaumlrinfektion ndash oumlverfoumlrd resistens

Resistensmarkoumlrertester

n ldquoViral loadrdquo - HIV RNAuarrq CD4 cellerdarrθ p24 antigenuarr

ν Genotypisk resistens - PCR +Sekvensering av RT proteasgenenresp integreasgenen

13

Vilka effekter uppnarings med terapi-viralload (HIV-RNA)

n Monoterapica 5 -100 ggr snabb resistensutveckling spec vid 3TC

Icke-nukleosidanalogern Dubbelterapica 10 - 1000 ggr laringngsammare resistensutvecklingn Trippelterapi (tex 2 NRTI + 1 NNRTIalt 1 PI)3 - 5 log mkt laringngsam resistensutveckling

Neuraminidase(9 subtypes)

Haemagglutinin(15 subtypes)

Viral RNA(segmentedgenome)

Orthomyxovirus

Structure of influenza A virus

14

Replication cycle of influenza virus

Attachment

Uncoating

Assemblyamp Budding

Release

Influenza neuraminidase

Surface of influenza virus highly variablebut

n Active site of influenzaneuraminidase is alwayshighly conserved

n Essential for viralreplication

n An ideal target forantiviral intervention

Influenza drugs

n Oseltamivir Tamiflu (A+B) - per oraln Zanamivir Relenza (A+B) - inhalation

15

Neuroaminidase inhibitors Influenza AB

Relenza Tamiflu

Median time to aleviate (days) ofsymptoms (Relenza)

lt000115

n=609

50

n=558

65

Combined

lt000125

n=136

50

n=151

75

NAIB

3002

007810

n=312

50

n=257

60

NAIA

3002

000415

n=161

45

n=160

60

NAIB

3001

P-valueDiff

days

Zanamivir

10 mgx2

PlaceboStudy

Days to normal activity

Oseltamivir

75mg bid

(n=124)

65

55

P value

lt002

lt0001

Difference

28

19

Placebo

(n=129)

94

74

Treanor et al JAMA 2000

Days to normal health

Impact on health outcome measuresOseltamivir (Tamiflu)

16

Influenza Resistance to antiviral drugs

Neuroaminidase treated adult patients ndash slowdevelopment - clinical studies approx 1(limited information) Children 20-30

Behandling av kronisk hepatit Bantivirala preparat och resistens

n Ca ett 100-tal patienter under behandling i Sverige

n Utdragen inflammation leverfibros cirrosca

n Lamuvidin (3TC) 4-5log reduktion HBV-DNA gt50 resistentainf e 3- aringrs behandling

n Adefovir 3-4 log reduktion HBV-DNA lt5 resistentainfektioner e 3- aringrs behandling

n Entecavir gt5log reduktion HBV-DNA frekvens resistenta inf =laringg

n Telbivudin gt5log reduktion HBV-DNA frekvens resistenta inf= l aringg

n ALAT och HBV-DNA 3-4 ggr aringr (gt1 log)

n PCRsekvensering (serum el plasmaprov) av HBV RTpol aa180-240 gt1000-5000 HBV-DNA kopior kr aumlvs (utf oumlrs vHuddinge och Sahlgrenska)

Antiviral drugs for hepatitis C

n Interferon alphan Peg-interferonn Ribavirin

17

Covalent attachment ofbranched 40 kDa PEG to IFN α-2a producesa compound that has sustainedabsorption reduced clearanceand a longer half-life thanunmodified IFN

Standard interferon given tiwFirst week of Dosing

02

46

810

1214

0 25 50 75 100 125 150

Time (hours) over one week

Inte

rfe

ron

(U

mL

)

Mon Tues Wed Thurs Fri Sat Sun

PEG-IFN 180 mcg subcutaneouslygiven once weekly (multiple dosing)

0

5

10

15

20

25

0 25 50 75 100 125 150

Time (hours) over one week

PE

G-I

FN

(ng

mL)

Mon Tues Wed Thurs Fri Sat Sun

168

Effect of pegIFN Vs IFN therapy on HepC infection

n Monotherapy IFN Vs pegIFN 12mo -IFN alpha-2b 12 sustained v response (SVR) -pegIFN 25 (SVR)

n Combined therapy -pegINF+RBV 42 SVR genotype 1 -IFN+RBV 33 SVR genotype 1 -All treatment gr 80 SVR genotypes 2amp3

Enteropicorna infections

n Pleconaril (not FDA approved)compassionate use in enteromeningitis

n Broad spectrum against all enterovirusesincluding rhinoviruses

n Interacts with virus receptor binding to hostcells and uncoating

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu

7

Resistens herpesvirus nukleosidanaloger

n Ingenmkt laringg frekvens resistensutveckling hosimmunokompetenta (01 ndash 06)

n Rel houmlg frekvens resistenta infektioner hosimmundefekta Cancer AIDS hjaumlrt- lung-transplBMT(43 -29)

n Resistent virus aumlr tymidinkinasnegativt och relavirulent - sprids saumlmre

n Resistens aumlr inget permanent tillstaringndn Resistenta infektioner kan behandlas med Foscavir

eller Cidofovir

CMV-resistens mot antivirala preparat

n Korttidsbehandling (14ndash21dagar) ingenmkt laringgfrekvens

n Laringngtidsbehandling (3-12 maringn) med GCV vid CMVretinit ca 5-30 utvecklade resistent CMV

n Laringngtidsbehandling (3-9 maringnader) CDVPFA vidCMV retinit ca 30 utvecklade resistens

Sammanfattning HSV VZV CMV Faktorerav betydelse foumlr resistensutveckling

n Grad av immunosuppressionn Behandlingstidn Biotillgaumlnglighet vid po administrering ndash houmlg

rdquoviral loadrdquo under paringgaringende terapi

8

HIV som knoppar av fraringn cellytan paring enCD4+ T-cell

Total 332 (306 ndash 361) million

Western ampCentral Europe

760 000[600 000 ndash 11 million]

Middle East amp NorthAfrica

380 000[270 000 ndash 500 000]

Sub-Saharan Africa225 million

[209 ndash 243 million]

Eastern Europeamp Central Asia

16 million[12 ndash 21 million]

South amp South-EastAsia

40 million[33 ndash 51 million]

Oceania75 000

[53 000 ndash 120 000]

North America13 million

[480 000 ndash 19 million]

Latin America16 million

[14 ndash 19 million]

East Asia800 000

[620 000 ndash 960 000]

Caribbean230 000

[210 000 ndash 270 000]

Adults and children estimated to be living with HIV 2007

9

Progression of HIV infection

Viral load(HIV RNA)CD4+ cells

Early stage Intermediate stage Advanced stage

Behandlingsstartlt250 CD4+mm3

1000

500

HIV ndashdroger

Mogen virion

CCR5 haumlmmare ny

Integrashaumlmmare ny

6 klasser av HIV-laumlkemedel

Atazanavir (ATV)Emtricitabine (FTC)

Lopinavir (LPV)Abacavir (ABC)

Fosamprenavir (FPV)Tenofovir (TDF)III Raltegravir

Nelfinavir (NFV)Stavudin (d4T)

Saquinavir(SQV )Etravirin (ETV)Didanosin (ddI)II Maraviroc(CCR5)

Indinavir (IDV)Efavirenz (EFV)Lamuvidin (3TC)

Darunavir (DRV)Tipranavir (TPR)

Nevirapin (NVP)Zidovudin (AZT)I Enfuvirtid (T20)

Protease inhibitors VI(PI)

Non-nucleosideanaloguesV (NNRTI)

Nucleoside analoguesIV (NRTI)

Entry inhibitorsI Fusion (FI)II Co-receptorIntegreringIII Integras

10

HIV reverst transkriptas -NRTINNRTI preparat

Verkningsmekanism proteashaumlmmare

n RNA-virus brukar reglera proteinsyntesen genomatt koda f oumlr ett j aumltteprotein som bryts ned tillmindre funktionella proteinenheter

n Detta sker med ytterst specifika virala proteaser n Dessa proteaser har blivit m aringl fouml r ytterst

verksamma antivirusmedel proteash aumlmmare

Verkningsmekanism -integrashaumlmmare

Raltegravir

11

26dper gen

EuroSIDA Mocroft et al AIDS2003

Months after virolgical suppression

Re

bo

un

de

d

Andel patienter med detekterbart HIV (gt400 kopml)under HAART behandling (PI el NNRTI + 2NRTI)

Incidens ARV resistenta HIV-infektioner (n=7363) i Kanada 1996 ndash 2007 Lima et al

12

SPREAD (transmitted resistance) - Sweden

3 12942007

2 18432006

5 16282005

5 16182004

6 12672003

16 3152002

TotalResistanceYear

J Albert SMI to be published

Faktorer av betydelse foumlrresistensutvecklingn Behandlingsfoumlljsamhetn Virusdynamikvirusnivaringer ndash grad av suppression

med administrerade preparatn Kombination av preparatn Farmakokinetiska foumlrharingllandenn Antal mutationer som ger upphov till resistensn Kvalitativa egenskaper hos virus i samband med

primaumlrinfektion ndash oumlverfoumlrd resistens

Resistensmarkoumlrertester

n ldquoViral loadrdquo - HIV RNAuarrq CD4 cellerdarrθ p24 antigenuarr

ν Genotypisk resistens - PCR +Sekvensering av RT proteasgenenresp integreasgenen

13

Vilka effekter uppnarings med terapi-viralload (HIV-RNA)

n Monoterapica 5 -100 ggr snabb resistensutveckling spec vid 3TC

Icke-nukleosidanalogern Dubbelterapica 10 - 1000 ggr laringngsammare resistensutvecklingn Trippelterapi (tex 2 NRTI + 1 NNRTIalt 1 PI)3 - 5 log mkt laringngsam resistensutveckling

Neuraminidase(9 subtypes)

Haemagglutinin(15 subtypes)

Viral RNA(segmentedgenome)

Orthomyxovirus

Structure of influenza A virus

14

Replication cycle of influenza virus

Attachment

Uncoating

Assemblyamp Budding

Release

Influenza neuraminidase

Surface of influenza virus highly variablebut

n Active site of influenzaneuraminidase is alwayshighly conserved

n Essential for viralreplication

n An ideal target forantiviral intervention

Influenza drugs

n Oseltamivir Tamiflu (A+B) - per oraln Zanamivir Relenza (A+B) - inhalation

15

Neuroaminidase inhibitors Influenza AB

Relenza Tamiflu

Median time to aleviate (days) ofsymptoms (Relenza)

lt000115

n=609

50

n=558

65

Combined

lt000125

n=136

50

n=151

75

NAIB

3002

007810

n=312

50

n=257

60

NAIA

3002

000415

n=161

45

n=160

60

NAIB

3001

P-valueDiff

days

Zanamivir

10 mgx2

PlaceboStudy

Days to normal activity

Oseltamivir

75mg bid

(n=124)

65

55

P value

lt002

lt0001

Difference

28

19

Placebo

(n=129)

94

74

Treanor et al JAMA 2000

Days to normal health

Impact on health outcome measuresOseltamivir (Tamiflu)

16

Influenza Resistance to antiviral drugs

Neuroaminidase treated adult patients ndash slowdevelopment - clinical studies approx 1(limited information) Children 20-30

Behandling av kronisk hepatit Bantivirala preparat och resistens

n Ca ett 100-tal patienter under behandling i Sverige

n Utdragen inflammation leverfibros cirrosca

n Lamuvidin (3TC) 4-5log reduktion HBV-DNA gt50 resistentainf e 3- aringrs behandling

n Adefovir 3-4 log reduktion HBV-DNA lt5 resistentainfektioner e 3- aringrs behandling

n Entecavir gt5log reduktion HBV-DNA frekvens resistenta inf =laringg

n Telbivudin gt5log reduktion HBV-DNA frekvens resistenta inf= l aringg

n ALAT och HBV-DNA 3-4 ggr aringr (gt1 log)

n PCRsekvensering (serum el plasmaprov) av HBV RTpol aa180-240 gt1000-5000 HBV-DNA kopior kr aumlvs (utf oumlrs vHuddinge och Sahlgrenska)

Antiviral drugs for hepatitis C

n Interferon alphan Peg-interferonn Ribavirin

17

Covalent attachment ofbranched 40 kDa PEG to IFN α-2a producesa compound that has sustainedabsorption reduced clearanceand a longer half-life thanunmodified IFN

Standard interferon given tiwFirst week of Dosing

02

46

810

1214

0 25 50 75 100 125 150

Time (hours) over one week

Inte

rfe

ron

(U

mL

)

Mon Tues Wed Thurs Fri Sat Sun

PEG-IFN 180 mcg subcutaneouslygiven once weekly (multiple dosing)

0

5

10

15

20

25

0 25 50 75 100 125 150

Time (hours) over one week

PE

G-I

FN

(ng

mL)

Mon Tues Wed Thurs Fri Sat Sun

168

Effect of pegIFN Vs IFN therapy on HepC infection

n Monotherapy IFN Vs pegIFN 12mo -IFN alpha-2b 12 sustained v response (SVR) -pegIFN 25 (SVR)

n Combined therapy -pegINF+RBV 42 SVR genotype 1 -IFN+RBV 33 SVR genotype 1 -All treatment gr 80 SVR genotypes 2amp3

Enteropicorna infections

n Pleconaril (not FDA approved)compassionate use in enteromeningitis

n Broad spectrum against all enterovirusesincluding rhinoviruses

n Interacts with virus receptor binding to hostcells and uncoating

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu

8

HIV som knoppar av fraringn cellytan paring enCD4+ T-cell

Total 332 (306 ndash 361) million

Western ampCentral Europe

760 000[600 000 ndash 11 million]

Middle East amp NorthAfrica

380 000[270 000 ndash 500 000]

Sub-Saharan Africa225 million

[209 ndash 243 million]

Eastern Europeamp Central Asia

16 million[12 ndash 21 million]

South amp South-EastAsia

40 million[33 ndash 51 million]

Oceania75 000

[53 000 ndash 120 000]

North America13 million

[480 000 ndash 19 million]

Latin America16 million

[14 ndash 19 million]

East Asia800 000

[620 000 ndash 960 000]

Caribbean230 000

[210 000 ndash 270 000]

Adults and children estimated to be living with HIV 2007

9

Progression of HIV infection

Viral load(HIV RNA)CD4+ cells

Early stage Intermediate stage Advanced stage

Behandlingsstartlt250 CD4+mm3

1000

500

HIV ndashdroger

Mogen virion

CCR5 haumlmmare ny

Integrashaumlmmare ny

6 klasser av HIV-laumlkemedel

Atazanavir (ATV)Emtricitabine (FTC)

Lopinavir (LPV)Abacavir (ABC)

Fosamprenavir (FPV)Tenofovir (TDF)III Raltegravir

Nelfinavir (NFV)Stavudin (d4T)

Saquinavir(SQV )Etravirin (ETV)Didanosin (ddI)II Maraviroc(CCR5)

Indinavir (IDV)Efavirenz (EFV)Lamuvidin (3TC)

Darunavir (DRV)Tipranavir (TPR)

Nevirapin (NVP)Zidovudin (AZT)I Enfuvirtid (T20)

Protease inhibitors VI(PI)

Non-nucleosideanaloguesV (NNRTI)

Nucleoside analoguesIV (NRTI)

Entry inhibitorsI Fusion (FI)II Co-receptorIntegreringIII Integras

10

HIV reverst transkriptas -NRTINNRTI preparat

Verkningsmekanism proteashaumlmmare

n RNA-virus brukar reglera proteinsyntesen genomatt koda f oumlr ett j aumltteprotein som bryts ned tillmindre funktionella proteinenheter

n Detta sker med ytterst specifika virala proteaser n Dessa proteaser har blivit m aringl fouml r ytterst

verksamma antivirusmedel proteash aumlmmare

Verkningsmekanism -integrashaumlmmare

Raltegravir

11

26dper gen

EuroSIDA Mocroft et al AIDS2003

Months after virolgical suppression

Re

bo

un

de

d

Andel patienter med detekterbart HIV (gt400 kopml)under HAART behandling (PI el NNRTI + 2NRTI)

Incidens ARV resistenta HIV-infektioner (n=7363) i Kanada 1996 ndash 2007 Lima et al

12

SPREAD (transmitted resistance) - Sweden

3 12942007

2 18432006

5 16282005

5 16182004

6 12672003

16 3152002

TotalResistanceYear

J Albert SMI to be published

Faktorer av betydelse foumlrresistensutvecklingn Behandlingsfoumlljsamhetn Virusdynamikvirusnivaringer ndash grad av suppression

med administrerade preparatn Kombination av preparatn Farmakokinetiska foumlrharingllandenn Antal mutationer som ger upphov till resistensn Kvalitativa egenskaper hos virus i samband med

primaumlrinfektion ndash oumlverfoumlrd resistens

Resistensmarkoumlrertester

n ldquoViral loadrdquo - HIV RNAuarrq CD4 cellerdarrθ p24 antigenuarr

ν Genotypisk resistens - PCR +Sekvensering av RT proteasgenenresp integreasgenen

13

Vilka effekter uppnarings med terapi-viralload (HIV-RNA)

n Monoterapica 5 -100 ggr snabb resistensutveckling spec vid 3TC

Icke-nukleosidanalogern Dubbelterapica 10 - 1000 ggr laringngsammare resistensutvecklingn Trippelterapi (tex 2 NRTI + 1 NNRTIalt 1 PI)3 - 5 log mkt laringngsam resistensutveckling

Neuraminidase(9 subtypes)

Haemagglutinin(15 subtypes)

Viral RNA(segmentedgenome)

Orthomyxovirus

Structure of influenza A virus

14

Replication cycle of influenza virus

Attachment

Uncoating

Assemblyamp Budding

Release

Influenza neuraminidase

Surface of influenza virus highly variablebut

n Active site of influenzaneuraminidase is alwayshighly conserved

n Essential for viralreplication

n An ideal target forantiviral intervention

Influenza drugs

n Oseltamivir Tamiflu (A+B) - per oraln Zanamivir Relenza (A+B) - inhalation

15

Neuroaminidase inhibitors Influenza AB

Relenza Tamiflu

Median time to aleviate (days) ofsymptoms (Relenza)

lt000115

n=609

50

n=558

65

Combined

lt000125

n=136

50

n=151

75

NAIB

3002

007810

n=312

50

n=257

60

NAIA

3002

000415

n=161

45

n=160

60

NAIB

3001

P-valueDiff

days

Zanamivir

10 mgx2

PlaceboStudy

Days to normal activity

Oseltamivir

75mg bid

(n=124)

65

55

P value

lt002

lt0001

Difference

28

19

Placebo

(n=129)

94

74

Treanor et al JAMA 2000

Days to normal health

Impact on health outcome measuresOseltamivir (Tamiflu)

16

Influenza Resistance to antiviral drugs

Neuroaminidase treated adult patients ndash slowdevelopment - clinical studies approx 1(limited information) Children 20-30

Behandling av kronisk hepatit Bantivirala preparat och resistens

n Ca ett 100-tal patienter under behandling i Sverige

n Utdragen inflammation leverfibros cirrosca

n Lamuvidin (3TC) 4-5log reduktion HBV-DNA gt50 resistentainf e 3- aringrs behandling

n Adefovir 3-4 log reduktion HBV-DNA lt5 resistentainfektioner e 3- aringrs behandling

n Entecavir gt5log reduktion HBV-DNA frekvens resistenta inf =laringg

n Telbivudin gt5log reduktion HBV-DNA frekvens resistenta inf= l aringg

n ALAT och HBV-DNA 3-4 ggr aringr (gt1 log)

n PCRsekvensering (serum el plasmaprov) av HBV RTpol aa180-240 gt1000-5000 HBV-DNA kopior kr aumlvs (utf oumlrs vHuddinge och Sahlgrenska)

Antiviral drugs for hepatitis C

n Interferon alphan Peg-interferonn Ribavirin

17

Covalent attachment ofbranched 40 kDa PEG to IFN α-2a producesa compound that has sustainedabsorption reduced clearanceand a longer half-life thanunmodified IFN

Standard interferon given tiwFirst week of Dosing

02

46

810

1214

0 25 50 75 100 125 150

Time (hours) over one week

Inte

rfe

ron

(U

mL

)

Mon Tues Wed Thurs Fri Sat Sun

PEG-IFN 180 mcg subcutaneouslygiven once weekly (multiple dosing)

0

5

10

15

20

25

0 25 50 75 100 125 150

Time (hours) over one week

PE

G-I

FN

(ng

mL)

Mon Tues Wed Thurs Fri Sat Sun

168

Effect of pegIFN Vs IFN therapy on HepC infection

n Monotherapy IFN Vs pegIFN 12mo -IFN alpha-2b 12 sustained v response (SVR) -pegIFN 25 (SVR)

n Combined therapy -pegINF+RBV 42 SVR genotype 1 -IFN+RBV 33 SVR genotype 1 -All treatment gr 80 SVR genotypes 2amp3

Enteropicorna infections

n Pleconaril (not FDA approved)compassionate use in enteromeningitis

n Broad spectrum against all enterovirusesincluding rhinoviruses

n Interacts with virus receptor binding to hostcells and uncoating

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu

9

Progression of HIV infection

Viral load(HIV RNA)CD4+ cells

Early stage Intermediate stage Advanced stage

Behandlingsstartlt250 CD4+mm3

1000

500

HIV ndashdroger

Mogen virion

CCR5 haumlmmare ny

Integrashaumlmmare ny

6 klasser av HIV-laumlkemedel

Atazanavir (ATV)Emtricitabine (FTC)

Lopinavir (LPV)Abacavir (ABC)

Fosamprenavir (FPV)Tenofovir (TDF)III Raltegravir

Nelfinavir (NFV)Stavudin (d4T)

Saquinavir(SQV )Etravirin (ETV)Didanosin (ddI)II Maraviroc(CCR5)

Indinavir (IDV)Efavirenz (EFV)Lamuvidin (3TC)

Darunavir (DRV)Tipranavir (TPR)

Nevirapin (NVP)Zidovudin (AZT)I Enfuvirtid (T20)

Protease inhibitors VI(PI)

Non-nucleosideanaloguesV (NNRTI)

Nucleoside analoguesIV (NRTI)

Entry inhibitorsI Fusion (FI)II Co-receptorIntegreringIII Integras

10

HIV reverst transkriptas -NRTINNRTI preparat

Verkningsmekanism proteashaumlmmare

n RNA-virus brukar reglera proteinsyntesen genomatt koda f oumlr ett j aumltteprotein som bryts ned tillmindre funktionella proteinenheter

n Detta sker med ytterst specifika virala proteaser n Dessa proteaser har blivit m aringl fouml r ytterst

verksamma antivirusmedel proteash aumlmmare

Verkningsmekanism -integrashaumlmmare

Raltegravir

11

26dper gen

EuroSIDA Mocroft et al AIDS2003

Months after virolgical suppression

Re

bo

un

de

d

Andel patienter med detekterbart HIV (gt400 kopml)under HAART behandling (PI el NNRTI + 2NRTI)

Incidens ARV resistenta HIV-infektioner (n=7363) i Kanada 1996 ndash 2007 Lima et al

12

SPREAD (transmitted resistance) - Sweden

3 12942007

2 18432006

5 16282005

5 16182004

6 12672003

16 3152002

TotalResistanceYear

J Albert SMI to be published

Faktorer av betydelse foumlrresistensutvecklingn Behandlingsfoumlljsamhetn Virusdynamikvirusnivaringer ndash grad av suppression

med administrerade preparatn Kombination av preparatn Farmakokinetiska foumlrharingllandenn Antal mutationer som ger upphov till resistensn Kvalitativa egenskaper hos virus i samband med

primaumlrinfektion ndash oumlverfoumlrd resistens

Resistensmarkoumlrertester

n ldquoViral loadrdquo - HIV RNAuarrq CD4 cellerdarrθ p24 antigenuarr

ν Genotypisk resistens - PCR +Sekvensering av RT proteasgenenresp integreasgenen

13

Vilka effekter uppnarings med terapi-viralload (HIV-RNA)

n Monoterapica 5 -100 ggr snabb resistensutveckling spec vid 3TC

Icke-nukleosidanalogern Dubbelterapica 10 - 1000 ggr laringngsammare resistensutvecklingn Trippelterapi (tex 2 NRTI + 1 NNRTIalt 1 PI)3 - 5 log mkt laringngsam resistensutveckling

Neuraminidase(9 subtypes)

Haemagglutinin(15 subtypes)

Viral RNA(segmentedgenome)

Orthomyxovirus

Structure of influenza A virus

14

Replication cycle of influenza virus

Attachment

Uncoating

Assemblyamp Budding

Release

Influenza neuraminidase

Surface of influenza virus highly variablebut

n Active site of influenzaneuraminidase is alwayshighly conserved

n Essential for viralreplication

n An ideal target forantiviral intervention

Influenza drugs

n Oseltamivir Tamiflu (A+B) - per oraln Zanamivir Relenza (A+B) - inhalation

15

Neuroaminidase inhibitors Influenza AB

Relenza Tamiflu

Median time to aleviate (days) ofsymptoms (Relenza)

lt000115

n=609

50

n=558

65

Combined

lt000125

n=136

50

n=151

75

NAIB

3002

007810

n=312

50

n=257

60

NAIA

3002

000415

n=161

45

n=160

60

NAIB

3001

P-valueDiff

days

Zanamivir

10 mgx2

PlaceboStudy

Days to normal activity

Oseltamivir

75mg bid

(n=124)

65

55

P value

lt002

lt0001

Difference

28

19

Placebo

(n=129)

94

74

Treanor et al JAMA 2000

Days to normal health

Impact on health outcome measuresOseltamivir (Tamiflu)

16

Influenza Resistance to antiviral drugs

Neuroaminidase treated adult patients ndash slowdevelopment - clinical studies approx 1(limited information) Children 20-30

Behandling av kronisk hepatit Bantivirala preparat och resistens

n Ca ett 100-tal patienter under behandling i Sverige

n Utdragen inflammation leverfibros cirrosca

n Lamuvidin (3TC) 4-5log reduktion HBV-DNA gt50 resistentainf e 3- aringrs behandling

n Adefovir 3-4 log reduktion HBV-DNA lt5 resistentainfektioner e 3- aringrs behandling

n Entecavir gt5log reduktion HBV-DNA frekvens resistenta inf =laringg

n Telbivudin gt5log reduktion HBV-DNA frekvens resistenta inf= l aringg

n ALAT och HBV-DNA 3-4 ggr aringr (gt1 log)

n PCRsekvensering (serum el plasmaprov) av HBV RTpol aa180-240 gt1000-5000 HBV-DNA kopior kr aumlvs (utf oumlrs vHuddinge och Sahlgrenska)

Antiviral drugs for hepatitis C

n Interferon alphan Peg-interferonn Ribavirin

17

Covalent attachment ofbranched 40 kDa PEG to IFN α-2a producesa compound that has sustainedabsorption reduced clearanceand a longer half-life thanunmodified IFN

Standard interferon given tiwFirst week of Dosing

02

46

810

1214

0 25 50 75 100 125 150

Time (hours) over one week

Inte

rfe

ron

(U

mL

)

Mon Tues Wed Thurs Fri Sat Sun

PEG-IFN 180 mcg subcutaneouslygiven once weekly (multiple dosing)

0

5

10

15

20

25

0 25 50 75 100 125 150

Time (hours) over one week

PE

G-I

FN

(ng

mL)

Mon Tues Wed Thurs Fri Sat Sun

168

Effect of pegIFN Vs IFN therapy on HepC infection

n Monotherapy IFN Vs pegIFN 12mo -IFN alpha-2b 12 sustained v response (SVR) -pegIFN 25 (SVR)

n Combined therapy -pegINF+RBV 42 SVR genotype 1 -IFN+RBV 33 SVR genotype 1 -All treatment gr 80 SVR genotypes 2amp3

Enteropicorna infections

n Pleconaril (not FDA approved)compassionate use in enteromeningitis

n Broad spectrum against all enterovirusesincluding rhinoviruses

n Interacts with virus receptor binding to hostcells and uncoating

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu

10

HIV reverst transkriptas -NRTINNRTI preparat

Verkningsmekanism proteashaumlmmare

n RNA-virus brukar reglera proteinsyntesen genomatt koda f oumlr ett j aumltteprotein som bryts ned tillmindre funktionella proteinenheter

n Detta sker med ytterst specifika virala proteaser n Dessa proteaser har blivit m aringl fouml r ytterst

verksamma antivirusmedel proteash aumlmmare

Verkningsmekanism -integrashaumlmmare

Raltegravir

11

26dper gen

EuroSIDA Mocroft et al AIDS2003

Months after virolgical suppression

Re

bo

un

de

d

Andel patienter med detekterbart HIV (gt400 kopml)under HAART behandling (PI el NNRTI + 2NRTI)

Incidens ARV resistenta HIV-infektioner (n=7363) i Kanada 1996 ndash 2007 Lima et al

12

SPREAD (transmitted resistance) - Sweden

3 12942007

2 18432006

5 16282005

5 16182004

6 12672003

16 3152002

TotalResistanceYear

J Albert SMI to be published

Faktorer av betydelse foumlrresistensutvecklingn Behandlingsfoumlljsamhetn Virusdynamikvirusnivaringer ndash grad av suppression

med administrerade preparatn Kombination av preparatn Farmakokinetiska foumlrharingllandenn Antal mutationer som ger upphov till resistensn Kvalitativa egenskaper hos virus i samband med

primaumlrinfektion ndash oumlverfoumlrd resistens

Resistensmarkoumlrertester

n ldquoViral loadrdquo - HIV RNAuarrq CD4 cellerdarrθ p24 antigenuarr

ν Genotypisk resistens - PCR +Sekvensering av RT proteasgenenresp integreasgenen

13

Vilka effekter uppnarings med terapi-viralload (HIV-RNA)

n Monoterapica 5 -100 ggr snabb resistensutveckling spec vid 3TC

Icke-nukleosidanalogern Dubbelterapica 10 - 1000 ggr laringngsammare resistensutvecklingn Trippelterapi (tex 2 NRTI + 1 NNRTIalt 1 PI)3 - 5 log mkt laringngsam resistensutveckling

Neuraminidase(9 subtypes)

Haemagglutinin(15 subtypes)

Viral RNA(segmentedgenome)

Orthomyxovirus

Structure of influenza A virus

14

Replication cycle of influenza virus

Attachment

Uncoating

Assemblyamp Budding

Release

Influenza neuraminidase

Surface of influenza virus highly variablebut

n Active site of influenzaneuraminidase is alwayshighly conserved

n Essential for viralreplication

n An ideal target forantiviral intervention

Influenza drugs

n Oseltamivir Tamiflu (A+B) - per oraln Zanamivir Relenza (A+B) - inhalation

15

Neuroaminidase inhibitors Influenza AB

Relenza Tamiflu

Median time to aleviate (days) ofsymptoms (Relenza)

lt000115

n=609

50

n=558

65

Combined

lt000125

n=136

50

n=151

75

NAIB

3002

007810

n=312

50

n=257

60

NAIA

3002

000415

n=161

45

n=160

60

NAIB

3001

P-valueDiff

days

Zanamivir

10 mgx2

PlaceboStudy

Days to normal activity

Oseltamivir

75mg bid

(n=124)

65

55

P value

lt002

lt0001

Difference

28

19

Placebo

(n=129)

94

74

Treanor et al JAMA 2000

Days to normal health

Impact on health outcome measuresOseltamivir (Tamiflu)

16

Influenza Resistance to antiviral drugs

Neuroaminidase treated adult patients ndash slowdevelopment - clinical studies approx 1(limited information) Children 20-30

Behandling av kronisk hepatit Bantivirala preparat och resistens

n Ca ett 100-tal patienter under behandling i Sverige

n Utdragen inflammation leverfibros cirrosca

n Lamuvidin (3TC) 4-5log reduktion HBV-DNA gt50 resistentainf e 3- aringrs behandling

n Adefovir 3-4 log reduktion HBV-DNA lt5 resistentainfektioner e 3- aringrs behandling

n Entecavir gt5log reduktion HBV-DNA frekvens resistenta inf =laringg

n Telbivudin gt5log reduktion HBV-DNA frekvens resistenta inf= l aringg

n ALAT och HBV-DNA 3-4 ggr aringr (gt1 log)

n PCRsekvensering (serum el plasmaprov) av HBV RTpol aa180-240 gt1000-5000 HBV-DNA kopior kr aumlvs (utf oumlrs vHuddinge och Sahlgrenska)

Antiviral drugs for hepatitis C

n Interferon alphan Peg-interferonn Ribavirin

17

Covalent attachment ofbranched 40 kDa PEG to IFN α-2a producesa compound that has sustainedabsorption reduced clearanceand a longer half-life thanunmodified IFN

Standard interferon given tiwFirst week of Dosing

02

46

810

1214

0 25 50 75 100 125 150

Time (hours) over one week

Inte

rfe

ron

(U

mL

)

Mon Tues Wed Thurs Fri Sat Sun

PEG-IFN 180 mcg subcutaneouslygiven once weekly (multiple dosing)

0

5

10

15

20

25

0 25 50 75 100 125 150

Time (hours) over one week

PE

G-I

FN

(ng

mL)

Mon Tues Wed Thurs Fri Sat Sun

168

Effect of pegIFN Vs IFN therapy on HepC infection

n Monotherapy IFN Vs pegIFN 12mo -IFN alpha-2b 12 sustained v response (SVR) -pegIFN 25 (SVR)

n Combined therapy -pegINF+RBV 42 SVR genotype 1 -IFN+RBV 33 SVR genotype 1 -All treatment gr 80 SVR genotypes 2amp3

Enteropicorna infections

n Pleconaril (not FDA approved)compassionate use in enteromeningitis

n Broad spectrum against all enterovirusesincluding rhinoviruses

n Interacts with virus receptor binding to hostcells and uncoating

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu

11

26dper gen

EuroSIDA Mocroft et al AIDS2003

Months after virolgical suppression

Re

bo

un

de

d

Andel patienter med detekterbart HIV (gt400 kopml)under HAART behandling (PI el NNRTI + 2NRTI)

Incidens ARV resistenta HIV-infektioner (n=7363) i Kanada 1996 ndash 2007 Lima et al

12

SPREAD (transmitted resistance) - Sweden

3 12942007

2 18432006

5 16282005

5 16182004

6 12672003

16 3152002

TotalResistanceYear

J Albert SMI to be published

Faktorer av betydelse foumlrresistensutvecklingn Behandlingsfoumlljsamhetn Virusdynamikvirusnivaringer ndash grad av suppression

med administrerade preparatn Kombination av preparatn Farmakokinetiska foumlrharingllandenn Antal mutationer som ger upphov till resistensn Kvalitativa egenskaper hos virus i samband med

primaumlrinfektion ndash oumlverfoumlrd resistens

Resistensmarkoumlrertester

n ldquoViral loadrdquo - HIV RNAuarrq CD4 cellerdarrθ p24 antigenuarr

ν Genotypisk resistens - PCR +Sekvensering av RT proteasgenenresp integreasgenen

13

Vilka effekter uppnarings med terapi-viralload (HIV-RNA)

n Monoterapica 5 -100 ggr snabb resistensutveckling spec vid 3TC

Icke-nukleosidanalogern Dubbelterapica 10 - 1000 ggr laringngsammare resistensutvecklingn Trippelterapi (tex 2 NRTI + 1 NNRTIalt 1 PI)3 - 5 log mkt laringngsam resistensutveckling

Neuraminidase(9 subtypes)

Haemagglutinin(15 subtypes)

Viral RNA(segmentedgenome)

Orthomyxovirus

Structure of influenza A virus

14

Replication cycle of influenza virus

Attachment

Uncoating

Assemblyamp Budding

Release

Influenza neuraminidase

Surface of influenza virus highly variablebut

n Active site of influenzaneuraminidase is alwayshighly conserved

n Essential for viralreplication

n An ideal target forantiviral intervention

Influenza drugs

n Oseltamivir Tamiflu (A+B) - per oraln Zanamivir Relenza (A+B) - inhalation

15

Neuroaminidase inhibitors Influenza AB

Relenza Tamiflu

Median time to aleviate (days) ofsymptoms (Relenza)

lt000115

n=609

50

n=558

65

Combined

lt000125

n=136

50

n=151

75

NAIB

3002

007810

n=312

50

n=257

60

NAIA

3002

000415

n=161

45

n=160

60

NAIB

3001

P-valueDiff

days

Zanamivir

10 mgx2

PlaceboStudy

Days to normal activity

Oseltamivir

75mg bid

(n=124)

65

55

P value

lt002

lt0001

Difference

28

19

Placebo

(n=129)

94

74

Treanor et al JAMA 2000

Days to normal health

Impact on health outcome measuresOseltamivir (Tamiflu)

16

Influenza Resistance to antiviral drugs

Neuroaminidase treated adult patients ndash slowdevelopment - clinical studies approx 1(limited information) Children 20-30

Behandling av kronisk hepatit Bantivirala preparat och resistens

n Ca ett 100-tal patienter under behandling i Sverige

n Utdragen inflammation leverfibros cirrosca

n Lamuvidin (3TC) 4-5log reduktion HBV-DNA gt50 resistentainf e 3- aringrs behandling

n Adefovir 3-4 log reduktion HBV-DNA lt5 resistentainfektioner e 3- aringrs behandling

n Entecavir gt5log reduktion HBV-DNA frekvens resistenta inf =laringg

n Telbivudin gt5log reduktion HBV-DNA frekvens resistenta inf= l aringg

n ALAT och HBV-DNA 3-4 ggr aringr (gt1 log)

n PCRsekvensering (serum el plasmaprov) av HBV RTpol aa180-240 gt1000-5000 HBV-DNA kopior kr aumlvs (utf oumlrs vHuddinge och Sahlgrenska)

Antiviral drugs for hepatitis C

n Interferon alphan Peg-interferonn Ribavirin

17

Covalent attachment ofbranched 40 kDa PEG to IFN α-2a producesa compound that has sustainedabsorption reduced clearanceand a longer half-life thanunmodified IFN

Standard interferon given tiwFirst week of Dosing

02

46

810

1214

0 25 50 75 100 125 150

Time (hours) over one week

Inte

rfe

ron

(U

mL

)

Mon Tues Wed Thurs Fri Sat Sun

PEG-IFN 180 mcg subcutaneouslygiven once weekly (multiple dosing)

0

5

10

15

20

25

0 25 50 75 100 125 150

Time (hours) over one week

PE

G-I

FN

(ng

mL)

Mon Tues Wed Thurs Fri Sat Sun

168

Effect of pegIFN Vs IFN therapy on HepC infection

n Monotherapy IFN Vs pegIFN 12mo -IFN alpha-2b 12 sustained v response (SVR) -pegIFN 25 (SVR)

n Combined therapy -pegINF+RBV 42 SVR genotype 1 -IFN+RBV 33 SVR genotype 1 -All treatment gr 80 SVR genotypes 2amp3

Enteropicorna infections

n Pleconaril (not FDA approved)compassionate use in enteromeningitis

n Broad spectrum against all enterovirusesincluding rhinoviruses

n Interacts with virus receptor binding to hostcells and uncoating

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu

12

SPREAD (transmitted resistance) - Sweden

3 12942007

2 18432006

5 16282005

5 16182004

6 12672003

16 3152002

TotalResistanceYear

J Albert SMI to be published

Faktorer av betydelse foumlrresistensutvecklingn Behandlingsfoumlljsamhetn Virusdynamikvirusnivaringer ndash grad av suppression

med administrerade preparatn Kombination av preparatn Farmakokinetiska foumlrharingllandenn Antal mutationer som ger upphov till resistensn Kvalitativa egenskaper hos virus i samband med

primaumlrinfektion ndash oumlverfoumlrd resistens

Resistensmarkoumlrertester

n ldquoViral loadrdquo - HIV RNAuarrq CD4 cellerdarrθ p24 antigenuarr

ν Genotypisk resistens - PCR +Sekvensering av RT proteasgenenresp integreasgenen

13

Vilka effekter uppnarings med terapi-viralload (HIV-RNA)

n Monoterapica 5 -100 ggr snabb resistensutveckling spec vid 3TC

Icke-nukleosidanalogern Dubbelterapica 10 - 1000 ggr laringngsammare resistensutvecklingn Trippelterapi (tex 2 NRTI + 1 NNRTIalt 1 PI)3 - 5 log mkt laringngsam resistensutveckling

Neuraminidase(9 subtypes)

Haemagglutinin(15 subtypes)

Viral RNA(segmentedgenome)

Orthomyxovirus

Structure of influenza A virus

14

Replication cycle of influenza virus

Attachment

Uncoating

Assemblyamp Budding

Release

Influenza neuraminidase

Surface of influenza virus highly variablebut

n Active site of influenzaneuraminidase is alwayshighly conserved

n Essential for viralreplication

n An ideal target forantiviral intervention

Influenza drugs

n Oseltamivir Tamiflu (A+B) - per oraln Zanamivir Relenza (A+B) - inhalation

15

Neuroaminidase inhibitors Influenza AB

Relenza Tamiflu

Median time to aleviate (days) ofsymptoms (Relenza)

lt000115

n=609

50

n=558

65

Combined

lt000125

n=136

50

n=151

75

NAIB

3002

007810

n=312

50

n=257

60

NAIA

3002

000415

n=161

45

n=160

60

NAIB

3001

P-valueDiff

days

Zanamivir

10 mgx2

PlaceboStudy

Days to normal activity

Oseltamivir

75mg bid

(n=124)

65

55

P value

lt002

lt0001

Difference

28

19

Placebo

(n=129)

94

74

Treanor et al JAMA 2000

Days to normal health

Impact on health outcome measuresOseltamivir (Tamiflu)

16

Influenza Resistance to antiviral drugs

Neuroaminidase treated adult patients ndash slowdevelopment - clinical studies approx 1(limited information) Children 20-30

Behandling av kronisk hepatit Bantivirala preparat och resistens

n Ca ett 100-tal patienter under behandling i Sverige

n Utdragen inflammation leverfibros cirrosca

n Lamuvidin (3TC) 4-5log reduktion HBV-DNA gt50 resistentainf e 3- aringrs behandling

n Adefovir 3-4 log reduktion HBV-DNA lt5 resistentainfektioner e 3- aringrs behandling

n Entecavir gt5log reduktion HBV-DNA frekvens resistenta inf =laringg

n Telbivudin gt5log reduktion HBV-DNA frekvens resistenta inf= l aringg

n ALAT och HBV-DNA 3-4 ggr aringr (gt1 log)

n PCRsekvensering (serum el plasmaprov) av HBV RTpol aa180-240 gt1000-5000 HBV-DNA kopior kr aumlvs (utf oumlrs vHuddinge och Sahlgrenska)

Antiviral drugs for hepatitis C

n Interferon alphan Peg-interferonn Ribavirin

17

Covalent attachment ofbranched 40 kDa PEG to IFN α-2a producesa compound that has sustainedabsorption reduced clearanceand a longer half-life thanunmodified IFN

Standard interferon given tiwFirst week of Dosing

02

46

810

1214

0 25 50 75 100 125 150

Time (hours) over one week

Inte

rfe

ron

(U

mL

)

Mon Tues Wed Thurs Fri Sat Sun

PEG-IFN 180 mcg subcutaneouslygiven once weekly (multiple dosing)

0

5

10

15

20

25

0 25 50 75 100 125 150

Time (hours) over one week

PE

G-I

FN

(ng

mL)

Mon Tues Wed Thurs Fri Sat Sun

168

Effect of pegIFN Vs IFN therapy on HepC infection

n Monotherapy IFN Vs pegIFN 12mo -IFN alpha-2b 12 sustained v response (SVR) -pegIFN 25 (SVR)

n Combined therapy -pegINF+RBV 42 SVR genotype 1 -IFN+RBV 33 SVR genotype 1 -All treatment gr 80 SVR genotypes 2amp3

Enteropicorna infections

n Pleconaril (not FDA approved)compassionate use in enteromeningitis

n Broad spectrum against all enterovirusesincluding rhinoviruses

n Interacts with virus receptor binding to hostcells and uncoating

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu

13

Vilka effekter uppnarings med terapi-viralload (HIV-RNA)

n Monoterapica 5 -100 ggr snabb resistensutveckling spec vid 3TC

Icke-nukleosidanalogern Dubbelterapica 10 - 1000 ggr laringngsammare resistensutvecklingn Trippelterapi (tex 2 NRTI + 1 NNRTIalt 1 PI)3 - 5 log mkt laringngsam resistensutveckling

Neuraminidase(9 subtypes)

Haemagglutinin(15 subtypes)

Viral RNA(segmentedgenome)

Orthomyxovirus

Structure of influenza A virus

14

Replication cycle of influenza virus

Attachment

Uncoating

Assemblyamp Budding

Release

Influenza neuraminidase

Surface of influenza virus highly variablebut

n Active site of influenzaneuraminidase is alwayshighly conserved

n Essential for viralreplication

n An ideal target forantiviral intervention

Influenza drugs

n Oseltamivir Tamiflu (A+B) - per oraln Zanamivir Relenza (A+B) - inhalation

15

Neuroaminidase inhibitors Influenza AB

Relenza Tamiflu

Median time to aleviate (days) ofsymptoms (Relenza)

lt000115

n=609

50

n=558

65

Combined

lt000125

n=136

50

n=151

75

NAIB

3002

007810

n=312

50

n=257

60

NAIA

3002

000415

n=161

45

n=160

60

NAIB

3001

P-valueDiff

days

Zanamivir

10 mgx2

PlaceboStudy

Days to normal activity

Oseltamivir

75mg bid

(n=124)

65

55

P value

lt002

lt0001

Difference

28

19

Placebo

(n=129)

94

74

Treanor et al JAMA 2000

Days to normal health

Impact on health outcome measuresOseltamivir (Tamiflu)

16

Influenza Resistance to antiviral drugs

Neuroaminidase treated adult patients ndash slowdevelopment - clinical studies approx 1(limited information) Children 20-30

Behandling av kronisk hepatit Bantivirala preparat och resistens

n Ca ett 100-tal patienter under behandling i Sverige

n Utdragen inflammation leverfibros cirrosca

n Lamuvidin (3TC) 4-5log reduktion HBV-DNA gt50 resistentainf e 3- aringrs behandling

n Adefovir 3-4 log reduktion HBV-DNA lt5 resistentainfektioner e 3- aringrs behandling

n Entecavir gt5log reduktion HBV-DNA frekvens resistenta inf =laringg

n Telbivudin gt5log reduktion HBV-DNA frekvens resistenta inf= l aringg

n ALAT och HBV-DNA 3-4 ggr aringr (gt1 log)

n PCRsekvensering (serum el plasmaprov) av HBV RTpol aa180-240 gt1000-5000 HBV-DNA kopior kr aumlvs (utf oumlrs vHuddinge och Sahlgrenska)

Antiviral drugs for hepatitis C

n Interferon alphan Peg-interferonn Ribavirin

17

Covalent attachment ofbranched 40 kDa PEG to IFN α-2a producesa compound that has sustainedabsorption reduced clearanceand a longer half-life thanunmodified IFN

Standard interferon given tiwFirst week of Dosing

02

46

810

1214

0 25 50 75 100 125 150

Time (hours) over one week

Inte

rfe

ron

(U

mL

)

Mon Tues Wed Thurs Fri Sat Sun

PEG-IFN 180 mcg subcutaneouslygiven once weekly (multiple dosing)

0

5

10

15

20

25

0 25 50 75 100 125 150

Time (hours) over one week

PE

G-I

FN

(ng

mL)

Mon Tues Wed Thurs Fri Sat Sun

168

Effect of pegIFN Vs IFN therapy on HepC infection

n Monotherapy IFN Vs pegIFN 12mo -IFN alpha-2b 12 sustained v response (SVR) -pegIFN 25 (SVR)

n Combined therapy -pegINF+RBV 42 SVR genotype 1 -IFN+RBV 33 SVR genotype 1 -All treatment gr 80 SVR genotypes 2amp3

Enteropicorna infections

n Pleconaril (not FDA approved)compassionate use in enteromeningitis

n Broad spectrum against all enterovirusesincluding rhinoviruses

n Interacts with virus receptor binding to hostcells and uncoating

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu

14

Replication cycle of influenza virus

Attachment

Uncoating

Assemblyamp Budding

Release

Influenza neuraminidase

Surface of influenza virus highly variablebut

n Active site of influenzaneuraminidase is alwayshighly conserved

n Essential for viralreplication

n An ideal target forantiviral intervention

Influenza drugs

n Oseltamivir Tamiflu (A+B) - per oraln Zanamivir Relenza (A+B) - inhalation

15

Neuroaminidase inhibitors Influenza AB

Relenza Tamiflu

Median time to aleviate (days) ofsymptoms (Relenza)

lt000115

n=609

50

n=558

65

Combined

lt000125

n=136

50

n=151

75

NAIB

3002

007810

n=312

50

n=257

60

NAIA

3002

000415

n=161

45

n=160

60

NAIB

3001

P-valueDiff

days

Zanamivir

10 mgx2

PlaceboStudy

Days to normal activity

Oseltamivir

75mg bid

(n=124)

65

55

P value

lt002

lt0001

Difference

28

19

Placebo

(n=129)

94

74

Treanor et al JAMA 2000

Days to normal health

Impact on health outcome measuresOseltamivir (Tamiflu)

16

Influenza Resistance to antiviral drugs

Neuroaminidase treated adult patients ndash slowdevelopment - clinical studies approx 1(limited information) Children 20-30

Behandling av kronisk hepatit Bantivirala preparat och resistens

n Ca ett 100-tal patienter under behandling i Sverige

n Utdragen inflammation leverfibros cirrosca

n Lamuvidin (3TC) 4-5log reduktion HBV-DNA gt50 resistentainf e 3- aringrs behandling

n Adefovir 3-4 log reduktion HBV-DNA lt5 resistentainfektioner e 3- aringrs behandling

n Entecavir gt5log reduktion HBV-DNA frekvens resistenta inf =laringg

n Telbivudin gt5log reduktion HBV-DNA frekvens resistenta inf= l aringg

n ALAT och HBV-DNA 3-4 ggr aringr (gt1 log)

n PCRsekvensering (serum el plasmaprov) av HBV RTpol aa180-240 gt1000-5000 HBV-DNA kopior kr aumlvs (utf oumlrs vHuddinge och Sahlgrenska)

Antiviral drugs for hepatitis C

n Interferon alphan Peg-interferonn Ribavirin

17

Covalent attachment ofbranched 40 kDa PEG to IFN α-2a producesa compound that has sustainedabsorption reduced clearanceand a longer half-life thanunmodified IFN

Standard interferon given tiwFirst week of Dosing

02

46

810

1214

0 25 50 75 100 125 150

Time (hours) over one week

Inte

rfe

ron

(U

mL

)

Mon Tues Wed Thurs Fri Sat Sun

PEG-IFN 180 mcg subcutaneouslygiven once weekly (multiple dosing)

0

5

10

15

20

25

0 25 50 75 100 125 150

Time (hours) over one week

PE

G-I

FN

(ng

mL)

Mon Tues Wed Thurs Fri Sat Sun

168

Effect of pegIFN Vs IFN therapy on HepC infection

n Monotherapy IFN Vs pegIFN 12mo -IFN alpha-2b 12 sustained v response (SVR) -pegIFN 25 (SVR)

n Combined therapy -pegINF+RBV 42 SVR genotype 1 -IFN+RBV 33 SVR genotype 1 -All treatment gr 80 SVR genotypes 2amp3

Enteropicorna infections

n Pleconaril (not FDA approved)compassionate use in enteromeningitis

n Broad spectrum against all enterovirusesincluding rhinoviruses

n Interacts with virus receptor binding to hostcells and uncoating

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu

15

Neuroaminidase inhibitors Influenza AB

Relenza Tamiflu

Median time to aleviate (days) ofsymptoms (Relenza)

lt000115

n=609

50

n=558

65

Combined

lt000125

n=136

50

n=151

75

NAIB

3002

007810

n=312

50

n=257

60

NAIA

3002

000415

n=161

45

n=160

60

NAIB

3001

P-valueDiff

days

Zanamivir

10 mgx2

PlaceboStudy

Days to normal activity

Oseltamivir

75mg bid

(n=124)

65

55

P value

lt002

lt0001

Difference

28

19

Placebo

(n=129)

94

74

Treanor et al JAMA 2000

Days to normal health

Impact on health outcome measuresOseltamivir (Tamiflu)

16

Influenza Resistance to antiviral drugs

Neuroaminidase treated adult patients ndash slowdevelopment - clinical studies approx 1(limited information) Children 20-30

Behandling av kronisk hepatit Bantivirala preparat och resistens

n Ca ett 100-tal patienter under behandling i Sverige

n Utdragen inflammation leverfibros cirrosca

n Lamuvidin (3TC) 4-5log reduktion HBV-DNA gt50 resistentainf e 3- aringrs behandling

n Adefovir 3-4 log reduktion HBV-DNA lt5 resistentainfektioner e 3- aringrs behandling

n Entecavir gt5log reduktion HBV-DNA frekvens resistenta inf =laringg

n Telbivudin gt5log reduktion HBV-DNA frekvens resistenta inf= l aringg

n ALAT och HBV-DNA 3-4 ggr aringr (gt1 log)

n PCRsekvensering (serum el plasmaprov) av HBV RTpol aa180-240 gt1000-5000 HBV-DNA kopior kr aumlvs (utf oumlrs vHuddinge och Sahlgrenska)

Antiviral drugs for hepatitis C

n Interferon alphan Peg-interferonn Ribavirin

17

Covalent attachment ofbranched 40 kDa PEG to IFN α-2a producesa compound that has sustainedabsorption reduced clearanceand a longer half-life thanunmodified IFN

Standard interferon given tiwFirst week of Dosing

02

46

810

1214

0 25 50 75 100 125 150

Time (hours) over one week

Inte

rfe

ron

(U

mL

)

Mon Tues Wed Thurs Fri Sat Sun

PEG-IFN 180 mcg subcutaneouslygiven once weekly (multiple dosing)

0

5

10

15

20

25

0 25 50 75 100 125 150

Time (hours) over one week

PE

G-I

FN

(ng

mL)

Mon Tues Wed Thurs Fri Sat Sun

168

Effect of pegIFN Vs IFN therapy on HepC infection

n Monotherapy IFN Vs pegIFN 12mo -IFN alpha-2b 12 sustained v response (SVR) -pegIFN 25 (SVR)

n Combined therapy -pegINF+RBV 42 SVR genotype 1 -IFN+RBV 33 SVR genotype 1 -All treatment gr 80 SVR genotypes 2amp3

Enteropicorna infections

n Pleconaril (not FDA approved)compassionate use in enteromeningitis

n Broad spectrum against all enterovirusesincluding rhinoviruses

n Interacts with virus receptor binding to hostcells and uncoating

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu

16

Influenza Resistance to antiviral drugs

Neuroaminidase treated adult patients ndash slowdevelopment - clinical studies approx 1(limited information) Children 20-30

Behandling av kronisk hepatit Bantivirala preparat och resistens

n Ca ett 100-tal patienter under behandling i Sverige

n Utdragen inflammation leverfibros cirrosca

n Lamuvidin (3TC) 4-5log reduktion HBV-DNA gt50 resistentainf e 3- aringrs behandling

n Adefovir 3-4 log reduktion HBV-DNA lt5 resistentainfektioner e 3- aringrs behandling

n Entecavir gt5log reduktion HBV-DNA frekvens resistenta inf =laringg

n Telbivudin gt5log reduktion HBV-DNA frekvens resistenta inf= l aringg

n ALAT och HBV-DNA 3-4 ggr aringr (gt1 log)

n PCRsekvensering (serum el plasmaprov) av HBV RTpol aa180-240 gt1000-5000 HBV-DNA kopior kr aumlvs (utf oumlrs vHuddinge och Sahlgrenska)

Antiviral drugs for hepatitis C

n Interferon alphan Peg-interferonn Ribavirin

17

Covalent attachment ofbranched 40 kDa PEG to IFN α-2a producesa compound that has sustainedabsorption reduced clearanceand a longer half-life thanunmodified IFN

Standard interferon given tiwFirst week of Dosing

02

46

810

1214

0 25 50 75 100 125 150

Time (hours) over one week

Inte

rfe

ron

(U

mL

)

Mon Tues Wed Thurs Fri Sat Sun

PEG-IFN 180 mcg subcutaneouslygiven once weekly (multiple dosing)

0

5

10

15

20

25

0 25 50 75 100 125 150

Time (hours) over one week

PE

G-I

FN

(ng

mL)

Mon Tues Wed Thurs Fri Sat Sun

168

Effect of pegIFN Vs IFN therapy on HepC infection

n Monotherapy IFN Vs pegIFN 12mo -IFN alpha-2b 12 sustained v response (SVR) -pegIFN 25 (SVR)

n Combined therapy -pegINF+RBV 42 SVR genotype 1 -IFN+RBV 33 SVR genotype 1 -All treatment gr 80 SVR genotypes 2amp3

Enteropicorna infections

n Pleconaril (not FDA approved)compassionate use in enteromeningitis

n Broad spectrum against all enterovirusesincluding rhinoviruses

n Interacts with virus receptor binding to hostcells and uncoating

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu

17

Covalent attachment ofbranched 40 kDa PEG to IFN α-2a producesa compound that has sustainedabsorption reduced clearanceand a longer half-life thanunmodified IFN

Standard interferon given tiwFirst week of Dosing

02

46

810

1214

0 25 50 75 100 125 150

Time (hours) over one week

Inte

rfe

ron

(U

mL

)

Mon Tues Wed Thurs Fri Sat Sun

PEG-IFN 180 mcg subcutaneouslygiven once weekly (multiple dosing)

0

5

10

15

20

25

0 25 50 75 100 125 150

Time (hours) over one week

PE

G-I

FN

(ng

mL)

Mon Tues Wed Thurs Fri Sat Sun

168

Effect of pegIFN Vs IFN therapy on HepC infection

n Monotherapy IFN Vs pegIFN 12mo -IFN alpha-2b 12 sustained v response (SVR) -pegIFN 25 (SVR)

n Combined therapy -pegINF+RBV 42 SVR genotype 1 -IFN+RBV 33 SVR genotype 1 -All treatment gr 80 SVR genotypes 2amp3

Enteropicorna infections

n Pleconaril (not FDA approved)compassionate use in enteromeningitis

n Broad spectrum against all enterovirusesincluding rhinoviruses

n Interacts with virus receptor binding to hostcells and uncoating

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu

18

The Swedish Reference Group for Antiviral Therapy

(RAV)

RAV is an independent expert group whose members are appointed by the

Swedish Society of Medicine (Svenska Laumlkaresaumlllskapet) and the SwedishInstitute for Infectious Disease Control (Smittskyddsinstitutet) RAV was

founded in September 1997

httpwwwravnu