Ekonomiska effekter och marknadsföringsvärden av filmproduktion
Schema pdf VT 07 - pharmguse.netpharmguse.net/pharm/fsl/t6-antiviral-terapi.pdf · ”viral load”...
Transcript of Schema pdf VT 07 - pharmguse.netpharmguse.net/pharm/fsl/t6-antiviral-terapi.pdf · ”viral load”...
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