Actualidad y tendencia de Actualidad y tendencia de tratamiento ARVtratamiento ARV

Dr. Miguel A Arreola PDr. Miguel A Arreola PHE CMN S XXIHE CMN S XXI

Terapia antirretroviral en 2006Terapia antirretroviral en 2006

Inhibidores de TRInhibidores de TR–– NucleosidosNucleosidos

AZT, AZT, DDI,DDC,D4T, DDI,DDC,D4T, 3TC, ABC3TC, ABCTDF, FTCTDF, FTC

–– No nucleNo nucleóósidossidosEfavirenz,Efavirenz,nevirapinanevirapina

Inhibidores de Inhibidores de ProteasaProteasa–– NelfinavirNelfinavir–– IndinavirIndinavir–– SaquinavirSaquinavir–– FosAmprenavirFosAmprenavir–– Lopinavir/rLopinavir/r–– AtazanavirAtazanavir–– TipranavirTipranavir–– DarunavirDarunavir

Inhibidores de Fusión

Enfuvirtida

Retos y necesidades en el Retos y necesidades en el tratamiento antirretroviral.tratamiento antirretroviral.

RetosRetos–– ApegoApego–– ToxicidadToxicidad–– PotenciaPotencia–– ResistenciaResistencia–– CostoCosto–– CuraciCuracióónn

NecesidadesNecesidades–– SimplificarSimplificar–– mejorar toleranciamejorar tolerancia–– Bajar toxicidadBajar toxicidad–– mayor actividadmayor actividad

virus resistentesvirus resistentes–– ReservoriosReservorios–– Nuevos blancosNuevos blancos–– VacunasVacunas

Selección de un tratamiento ARV y posibles puntos de falla

ARVs

PACIENTE

VIRUS

PotenciaDuraciónPKInteraccionesToleranciaConvenienciaBarrera genética

Tasa de replicación (CV)Tasa de mutación (GT)Reservorios (?)Patogenicidad

ApegoAcceso al medicamentoResistencia primariaAbsorción y metabolismoEtapa de la enfermedad

Dr. Arreola.

Inicio del Tratamiento2 ITRAN + IDV2 ITRAN + SQV2 ITRAN + RTV2 ITRAN + LPV

¿Secuencia?

2 ITRAN + IDV2 ITRAN + SQV2 ITRAN + LPV2 ITRAN + ATV2 ITRAN + TMC2 ITRAN + FosAPV

rtv

Nuevas formulaciones/dosisNuevas formulaciones/dosisNucleNucleóósidossidos–– D4T liberaciD4T liberacióón prolongadan prolongada–– DDI CEDDI CE–– AZT/3TC/AZT/3TC/AbacavirAbacavir

No nucleNo nucleóósidossidos–– Efavirenz 600 mgEfavirenz 600 mg

–– Inhibidores de proteasaInhibidores de proteasa–– Saquinavir Saquinavir gelgel suave/ suave/ SQV tabletas 500 mgSQV tabletas 500 mg–– Nelfinavir BID. Nelfinavir BID. –– PotenciaciPotenciacióón farmacoln farmacolóógica con RTV gica con RTV –– AtazanavirAtazanavir–– ProdrogaProdroga de Amprenavir (FPV).de Amprenavir (FPV).–– LPV/r LPV/r tabstabs 2x2.2x2.

I. Fusión

Enfuvirtida

Nuevos blancos para agentes Nuevos blancos para agentes antirretroviralesantirretrovirales

Inhibidores de Inhibidores de proteinasproteinas reguladorasreguladorasInhibidores de desenvolturaInhibidores de desenvolturaInhibidores de Inhibidores de RNAsaRNAsa IIIIInhibidores de dedos de zincInhibidores de dedos de zincInhibidores de ensamblaje y de Inhibidores de ensamblaje y de formacionformacionde de capsidecapside..

Nuevas clases de antirretroviralesNuevas clases de antirretroviralesen desarrolloen desarrollo

Inhibidores de entradaInhibidores de entrada–– uniunióón. n. CD4sCD4s, otros, otros–– inhibidores de inhibidores de coco--receptores. receptores. –– Inhibidores de CXCR4 y de CCR5Inhibidores de CXCR4 y de CCR5–– inhibidores de fusiinhibidores de fusióón. Tn. T--12491249Inhibidores de Inhibidores de integrasaintegrasa. . –– en fases clen fases clíínicas en Mnicas en Mééxicoxico

RT

Provirus

ProteinsRNA

DNA

RNA

DNA

DNA

RT Proteinas reguladorasvirales

Proteasa Viral

Transcriptasaviral

Integrasa viral

RNA

RNA

Unión, fusióny entrada

DNA

DNA

DNA

Proteínas de la nucleocápside

(zinc-finger)

NuevosNuevos objetivosobjetivos del del TxTx

ITRAN/ITRANtITRAN/ITRANtAbacavir Abacavir AlovudinaAlovudinaAmdoxovirAmdoxovirDD--d4FCd4FCDD--FDOCFDOCDidanosinaDidanosina--EC EC FTC FTC LamivudinaLamivudinaSPD754SPD754ReversetReversetStavudinaStavudina--XRXRTenofovir Tenofovir GS 7340GS 7340ZalcitabinaZalcitabinaZidovudinaZidovudina

ITRnANITRnANCalanolidaCalanolida AACapravirinaCapravirinaDelavirdinaDelavirdinaEfavirenzEfavirenz

NevirapinaNevirapinaTMC 125TMC 125

IPsIPsAmprenavirAmprenavirAtazanavirAtazanavir

FosamprenavirFosamprenavirIndinavirIndinavir

Lopinavir/rLopinavir/rNelfinavirNelfinavir

/r/rRoRo--033033--46494649SaquinavirSaquinavirTipranavirTipranavirTMC 114TMC 114

I. FUSIONI. FUSIONBMSBMS--488043488043EnfuvirtidaEnfuvirtidaGW873140GW873140

T 1249T 1249

Nuevo Nuevo EscenarioEscenario ARVARV

I. INTEGRASAL-870810

I. DE CD4BMS 806PRO 542TNX 355

I. CCR5SCH DAK 602

PRO 140TAK 220

UK 427,857

I. CXCR4AMD 070

PRIMERA LINEAPRIMERA LINEA

Arteria hepática

Circulación Sistémica

Intestino

Cmin > EC 50/90SQVSQV HGC

SQV SGC

Porta

Vena Hepática

¿Cómo actúa el refuerzo o booster?

Arteria hepática

Circulación sistémica

Venahepática

PortaIntestino

Cmin > EC50/90SQVSQV HGC

SQV SGC

RTV

SQV

Tiempo (horas)

Concentraciónde fármaco

TerapiaTerapia IP IP reforzadoreforzado: : EvitandoEvitando toxicidadtoxicidad

Drug concentrations below inhibitory levels:viral rebound

00

Umbral de eficacia

Umbral de toxicidad

Concentraciòn del fàrmaco arriba del umbral de toxicidad: Limitante por toxicidad

IP

RefuerzoIP

24

IndividualizaciIndividualizacióónn de los de los tratamientostratamientos reforzadosreforzados con IPcon IP´́ss

Tratamiento con IP´s reforzados QD: Primer esquema, casos sin manejo previo con IP´s, falla a IP´s por toxicidad o mal apego.

Tratamiento con IP´s reforzados BID: Primer esquema, falla a IP´s con resistencia mínima.

Tratamiento con IP´s “doble refuerzo”: Resistencia multiple a IP´s y esquemas de rescate.

Antiviral efficacy of HAARTAntiviral efficacy of HAARTHIV RNA < 50 copies/ml at week 24 (ITT)HIV RNA < 50 copies/ml at week 24 (ITT)

1. Murphy et al. AIDS 2003; 17:2603–14 2. Gathe et al. AIDS 2004; 18:1529–373. Podzamczer et al. 9th EACS 2003. Abstract F1/3 4. Walmsley et al. N Engl J M,ed 2002; 346:2039–465. van Leth et al. Lancet. 2004; 363:1253–63 6. Saag et al. JAMA 2004; 292:180–97. Staszewski et al. 10th CROI 2003. Poster 564b 8. Ananworanich et al. XV IAC 2004. Poster TuPeB4469

*HIV RNA at 24 weeks estimated from graph †ATV 400 mg results used

Subjects with HIV RNA < 50 copies/ml (%)0 20 40 60 80 100

SQV/r + 2 NRTIs

EFV + ddI + d4TGilead FTC-3016

EFV + TDF + 3TC Gilead 903EFV + ddI + FTC Gilead FTC-301

Staccato 91%

Abbott 418 57%

74%78%

81%

GSK SOLO* 55%

Abbott M98-863* 65%LPV/r (od) + FTC + TDF

FPV/r + ABC + 3TC

LPV/r + d4T + 3TCNVP (bid) + d4T + 3TC 2NN* 65%

ATV/r + d4T + 3TC BMS-008*† 38%

Gilead FTC-301

SQV/r:SQV/r: High percentage of patients with High percentage of patients with < 400 and < 50 copies/ml at 24 weeks (ITT)< 400 and < 50 copies/ml at 24 weeks (ITT)

Time (weeks)

Patie

nts

(%) < 50 copies/ml

< 400 copies/ml

91.0%95.2%

0

20

40

60

80

100

0 8 16 24

Ananworanich et al. XV IAC 2004; Poster TuPeB4469

Time (weeks)

Med

ian

chan

ge in

CD

4 co

unt

from

bas

elin

e (c

ells

/mm

3 )

8 16 240

50

100

150

200

0

p < 0.001 vs. baseline

SQV/r:SQV/r: Change in median CD4 Change in median CD4 count from baseline over 24 weekscount from baseline over 24 weeks

Ananworanich et al. XV IAC 2004; Poster TuPeB4469

MaxCmin1: SQV/r is more potent than IDV/r MaxCmin1: SQV/r is more potent than IDV/r (ITT) due to superior tolerability profile(ITT) due to superior tolerability profile

Patie

nts

(%)

Gerstoft et al. 42nd ICAAC 2002. Abs H-172 Dragsted et al. J Infect Dis 2003; 188:635–42

0

20

40

60

80

100

SQV/r

79%77%

IDV/r

p = ns

On treatment

57%46%

SQV/rIDV/r

p = 0.048

Intent-to-treat/exposed

HIV RNA < 50 copies/ml at 48 weeks

ITT analysis includes all patients who received at least one dose of randomized medication; switch = failure

OT analysis includes all patients who remained on randomized medication at 48 weeks

0

20

40

60

80

100p = ns

On treatment

53 %60 %

Youle et al. 2nd IAS 2003. Poster LB-23

p = nsIntent-to-treat

MaxCmin2 HIV RNA < 50 copies/ml at week 48

SQV/rLPV/r

Patie

nts

(%) 70 %75 %

LPV/r SQV/r

MaxCmin2: MaxCmin2: similar viral load responsesimilar viral load response

ITT analysis includes all patients who received at least one dose of randomized medication; switch = failure

OT analysis includes all patients who remained on randomized medication at 48 weeks

HIV

RN

A (c

opie

s/m

l)

Time (weeks)

10

100

1000

10000

100000

1000000

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

SQV/r 1000/100 mg bid plus

CBV

TZV

QUAD: SQV/r + NRTIs achieved median QUAD: SQV/r + NRTIs achieved median 4 log4 log1010 reduction in HIV RNA (ITT)reduction in HIV RNA (ITT)

Adapted from Staszewski et al. 9th EACS 2003. Oral F1/1

QUAD: impressive virological QUAD: impressive virological response after 48 weeks (OT)response after 48 weeks (OT)

Adapted from Staszewski et al. 9th EACS 2003. Oral F1/1

Time (weeks)

SQV/r + TZV < 400 copies/mlSQV/r + CBV < 400 copies/ml

SQV/r + TZV < 50 copies/mlSQV/r + CBV < 50 copies/ml

Patie

nts

(%)

0

20

40

60

80

100

BL 4 8 12 20 24 28 32 40 4416 36 4829 26 22 23 18 18 18 19 18 1820 18 18CBV n = 29 24 25 21 19 19 20 19 16 1819 19 17TZV n =

SQV/r 1000/100 mg bidplusCBVTZV

Med

ian

CD

4 co

unt*

(c

ells

/mm

³)

0

40

80

120

160

200

BL 4 8 12 16 20 24 28 32 36 40 44 48Time (weeks)

QUAD: rapid CD4 recovery reducing risk of opportunistic infection

Staszewski et al. 9th EACS 2003. Oral F1/1

*ITT–LOCF

EnfuvirtidaEnfuvirtidaFuzeonFuzeonTMTM

Aproximación de la partícula viral a los receptores CD4

Adhesión de la gp 120 a los receptores CD4 Unión de la proteína gp 120 a los co-receptores CD4+

Desprendimiento de laproteína gp 120

Inserción de la gp 41 Retracción de la partícula viralhacia la célula

Aparece FUZEON Inhibe la fusión

Mecanismo de Acción

Enfuvirtida + TO Enfuvirtida + TO cambiocambio promediopromedio de CV y CD4 de CV y CD4 desde el desde el inicioinicio (On(On--Treatment)Treatment)

-2.0

-1.0

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

RN

A m

ean

chan

gefr

om B

LC

D4

mea

n ch

ange

from

BL

Viral load

0

50

100

150

CD4

119

166

- 2.07- 1.90

661 495 352661 478 337

VLCD4

ConclusionesConclusiones

La carga viral disminuye considerablemente La carga viral disminuye considerablemente desde el inicio de la terapiadesde el inicio de la terapiaLa respuesta de La respuesta de CD4sCD4s y CV se mantiene y CV se mantiene durante 96 semanasdurante 96 semanasFUZEON fue bien tolerado y en general no FUZEON fue bien tolerado y en general no se relaciono con toxicidad sistse relaciono con toxicidad sistéémicamica

–– No se presentaron eventos adversos adicionales No se presentaron eventos adversos adicionales entre la semana 48 y la 96.entre la semana 48 y la 96.

–– La reacciLa reaccióón en el sitio de la inyeccin en el sitio de la inyeccióón fue el n fue el evento adverso presente.evento adverso presente.

Otros estudios con nuevos Otros estudios con nuevos ffáármacosrmacos

2006 Update of IAS2006 Update of IAS--USA USA Guidelines for Initial TherapyGuidelines for Initial Therapy

SQV/RTVSQV/RTVFPV/RTVFPV/RTVABC/3TCABC/3TC‡‡

ATV/RTVATV/RTV(NVP)(NVP)ZDV/3TCZDV/3TC‡‡

LPV/RTVLPV/RTVEFVEFVTDF/FTCTDF/FTC††

PIsPIsNNRTIsNNRTIsNRTIsNRTIs

Recommended Components of Initial Antiretroviral Recommended Components of Initial Antiretroviral Therapy*Therapy*

*Therapy should consist of 2 NRTIs + either an NNRTI or PI.†Or 3TC. ‡Or FTC.Hammer S, et al. JAMA. 2006;296:827-843.

ACTG 5142: Change in CD4+ ACTG 5142: Change in CD4+ Cell Count at Week 96Cell Count at Week 96

Riddler S, et al. IAC 2006. Abstract THLB0204.

P = .01

P = .96

P = .01

268285

241

0

50

100

150

200

250

300

Med

ian

CD

4+ C

hang

e,

cells

/mm

3

LPV/RTV + EFVEFV + 2 NRTIsLPV/RTV + 2 NRTI

KLEAN: FPV/RTV vs LPV/RTV as KLEAN: FPV/RTV vs LPV/RTV as Initial TherapyInitial Therapy

Phase IIIb, randomized, Phase IIIb, randomized, openopen--label, 48label, 48--week study week study FPV/RTV 700/100 mg BID FPV/RTV 700/100 mg BID (n = 434) vs LPV/RTV SGC (n = 434) vs LPV/RTV SGC (400/100 mg BID) (n = 444)(400/100 mg BID) (n = 444)–– + ABC/3TC (600/300 mg) QD+ ABC/3TC (600/300 mg) QD

No difference in virologic No difference in virologic outcome overall or stratified outcome overall or stratified by baseline VL or CD4+ by baseline VL or CD4+ countcountCD4+ gain: +176 (FPV/RTV) CD4+ gain: +176 (FPV/RTV) vs +191 (LPV/RTV) (ITTvs +191 (LPV/RTV) (ITT--E)E)

VL S

uppr

essi

on a

t Wk

48 (%

)

0

20

40

60

80

100

FPV/RTV

LPV/RTV

65%66%

TLOVR Analysis

Eron JJ Jr, et al. Lancet. 2006;368:476-482.

FPV/RTV

LPV/RTV

71%73%

< 400 c/mL < 50 c/mL

GS934: HIV RNA < 400 and GS934: HIV RNA < 400 and < 50 copies/mL at Week 96 (TLOVR)< 50 copies/mL at Week 96 (TLOVR)

WeeksGallant J, et al. IAC 2006. Abstract TUPE0064.

20

40

60

80

100

8 16 24 32 40 48 60 72 84 96

Res

pond

ers

(%)

0BL

ZDV/3TC < 400: 62%

FTC/TDF < 400: 75%P (< 400) = .004FTC/TDF < 50: 67%

ZDV/3TC < 50: 61%P (< 50) = .19

MONARK: LPV/RTV Monotherapy vs MONARK: LPV/RTV Monotherapy vs LPV/RTV + 2 NRTIs in Naive PatientsLPV/RTV + 2 NRTIs in Naive Patients

LPV/RTV SGC 400/100 mg BID+ ZDV/3TC 300/150 mg BID

(n = 53)

LPV/RTV monotherapySGC 400/100 mg BID

(n = 83)

Week 24 Week 48

Antiretroviral naive; VL < 100,000; CD4+ > 100

(N = 138)

Delfraissy JF, et al. IAC 2006. Abstract THLB0202.

Week 96

Primary efficacy analysisProportion of subjects with HIV-1 RNA < 400 copies/mL at Week 24 AND < 50 copies/mL at Week 48

MONARK: MONARK: HIV RNA < 400 and < 50 HIV RNA < 400 and < 50 copies/mL at Week 48 (ITT Analysis)copies/mL at Week 48 (ITT Analysis)

Sample SizeLPV/r Arm: 83Triple Arm: 53

Delfraissy JF, et al. IAC 2006. Abstract THLB0202.

*3 intensified with ZDV/3TC

LPV/RTV < 400 82%

0

20

40

60

80

100

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

% P

atie

nts

(ITT,

95%

CI)

LPV/RTV < 50 71%*

Triple < 400 75%Triple < 50 75%

< 400 copies/mL< 50 copies/mL

Monotherapy Strategy

LPV/RTV SGC 400/100 mg BIDReintroduction of NRTIs permitted

for virologic rebound(n = 100)

Triple Therapy Strategy

LPV/RTV SGC 400/100 mg BID + 2 NRTIs(n = 98)

HIV-infected patientswith VL < 50 copies/mL

for ≥ 6 months on LPV/RTV + 2 NRTIs for ≥ 1 month;

no history of virologic failure on a PI

(N = 198)

Primary endpoint Week 48

OK04 Study: LPV/r Maintenance OK04 Study: LPV/r Maintenance Monotherapy vs Continued HAARTMonotherapy vs Continued HAART

Arribas J, et al. IAC 2006. Abstract THLB0203.

Randomized 1:1

OK04 Study: LPV/RTV Maintenance OK04 Study: LPV/RTV Maintenance Monotherapy vs Continued HAARTMonotherapy vs Continued HAART

Similar median time < 50 copies/mL at baseline in both Similar median time < 50 copies/mL at baseline in both groups (17groups (17--19 19 mosmos))Proportion without therapeutic failureProportion without therapeutic failure–– 94.0% vs 89.8% for monotherapy vs triple therapy94.0% vs 89.8% for monotherapy vs triple therapy

Time to virologic failure not significantly differentTime to virologic failure not significantly different–– 4 LPV/RTV monotherapy pts required intensification with NRTIs fo4 LPV/RTV monotherapy pts required intensification with NRTIs for r

virologic rebound > 500 copies/mLvirologic rebound > 500 copies/mL

Sensitivity (ITT) analysis (Sensitivity (ITT) analysis (reintensificationreintensification = failure)= failure)–– 85.0% vs 89.8% for monotherapy vs triple therapy85.0% vs 89.8% for monotherapy vs triple therapy

Primary PI resistance mutationsPrimary PI resistance mutations–– 2 pts on monotherapy vs 1 on triple therapy 2 pts on monotherapy vs 1 on triple therapy

Arribas J et al. IAC 2006. Abstract THLB0203.

RESIST 1 RESIST 1

TPV/r TPV/r vsvs Otros Otros IP/rIP/rEn presencia de En presencia de mutaciones a IPmutaciones a IPEn ausencia de En ausencia de mutaciones a IP mutaciones a IP (1(1--2)2)AnAnáálisis a 24 lisis a 24 semanassemanas

05

10152025303540

TPV/r IP/r

Por

cent

aje

de p

acie

ntes

con

ef

icac

ia (>

1 lo

g)

Schapiro

RESIST 2RESIST 2TPV/r TPV/r vsvs LPV/rLPV/rTerapia optimizada por genotipoTerapia optimizada por genotipoDos medicamentos activosDos medicamentos activosPacientes pretratadosPacientes pretratados

0 6 12 18 24 semanas

Car

ga v

iral

(log

prom

edio

)

1

2

LPV/r

TPV/r

0.5

1.5

Cooper

Booster de TMC (Booster de TMC (powerpower))

Estudio en pacientes conEstudio en pacientes conexperiencia triple claseexperiencia triple clase

Seguimiento a 24 semanas Seguimiento a 24 semanas (multic(multicééntrico)ntrico)

TO+ENF+TMC 114/r TO+ENF+TMC 114/r (600/100mg BID) (600/100mg BID) vsvs Otro IP/rOtro IP/r

La dosis ya fue seleccionadaLa dosis ya fue seleccionadaTolerancia adecuada y Tolerancia adecuada y comparable a otros comparable a otros esquemas boosteresquemas booster

Haubrich

0

10

20

30

40

50

<50 copias CV Log (-)

TMC 114/r IP/r

0

1

2

% p

ts C

V <

50

copi

as

RN

A C

V lo

g(-

)

-1.85

-0.72TMC

IP/r

¿¿QuQuéé pasa con las pasa con las resistencias en la actualidad?resistencias en la actualidad?

SPREAD: Transmitted Drug SPREAD: Transmitted Drug Resistance in Europe, 2002Resistance in Europe, 2002--200320031717--nation study in Europe nation study in Europe and Israeland Israel1083 newly diagnosed 1083 newly diagnosed patients in 2002patients in 2002--20032003Overall prevalence of any Overall prevalence of any resistance: 9%resistance: 9%71% of pts with drug 71% of pts with drug resistance had single resistance had single mutationmutation

–– Implies little loss of Implies little loss of susceptibility to boosted PIssusceptibility to boosted PIs

Wensing AMJ, et al. IAC 2006. Abstract TUAB00101.

Prev

alen

ce o

f Mut

atio

ns,

2002

-200

3, %

Any

10

8

6

4

2

0

5.4

3.02.6

9.1

NRTI NNRTI PI ≥ 2 Classes

0.7

Transmitted Drug Resistance Transmitted Drug Resistance Over Time: SPREAD and CATCHOver Time: SPREAD and CATCH

Comparison of 2002Comparison of 2002--2003 data from SPREAD (Europe and 2003 data from SPREAD (Europe and Israel) with earlier retrospective data from CATCH (Europe)Israel) with earlier retrospective data from CATCH (Europe)

Wensing AMJ, et al. IAC 2006. Abstract TUAB00101.

Prev

alen

ce o

f Mut

atio

ns, %

96-97 98-99 2000-01 02-03

NRTINNRTIPI

1412

10

8

6

4

2

0

SPREADCATCH

Nuevo enfoqueNuevo enfoqueSEGURIDADSEGURIDAD

Lo mLo máás s nuevonuevo……A los mA los méédicos nos interesan dicos nos interesan

los pacientes!!!los pacientes!!!

Why do patients stop therapy?Why do patients stop therapy?

Toxicity58.3%

Non-adherence19.6%

Virological failure 14.1%

Other8.0%

d’Arminio Monforte et al. AIDS 2000; 14:499–507

Reasons for discontinuation of a first HAART regimen by 45 weeks in ICONA cohort (n = 862)

Tolerability and convenience drive Tolerability and convenience drive adherence, which drives efficacyadherence, which drives efficacy

Tolerability and convenience

Tolerability and convenience drive Tolerability and convenience drive adherence, which drives efficacyadherence, which drives efficacy

Adherence

Tolerability and convenience

Adherence

Efficacy

Tolerability and convenience

Tolerability and convenience drive Tolerability and convenience drive adherence, which drives efficacyadherence, which drives efficacy

HyperlipidaemiaHyperlipidaemia

0

5

10

15

0 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.50

5

10

15

20

Total Cholesterol to HDL-Cholesterol Ratio

Incidence of coronary events in 8 years of follow-up (%)

Prevalence (%)

Munster heart study

0

2

4

6

8

None

Inci

denc

e of

MI P

er 1

000

PY

10

< 1 1-2 2-3 3-4 4-5 5-6 > 6Exposure to HAART (Yrs)

EventsPYFU

14 16 22 34 56 55 39 4110103 6324 8165 10846 13060 12254 9073 6751

D:A:DD:A:D——Prolonged Antiretroviral Prolonged Antiretroviral Exposure and Myocardial InfarctionExposure and Myocardial Infarction

El-Sadr W, et al. Abstract 42.

All subjects

Updated analysis shows Updated analysis shows continuing increase in risk continuing increase in risk with longer durationwith longer duration[1][1]

Increased risk partially but Increased risk partially but not completely explained not completely explained by dyslipidemiaby dyslipidemia

However, trend for However, trend for decreasingdecreasing MI incidence MI incidence from 2000from 2000--2003 after 2003 after adjusting for adjusting for ↓↓ smoking, smoking, ↑↑lipidlipid--lowering therapylowering therapy[2][2] 10

Relative rate of MI (95% Cl)Multivariate model; adjusted for family history,

BMI, HIV risk, cohort, year and race

10

HAART per add’l year

Age per 5 yrs older

Male sex

Previous CVD

Smoking

Family history

Adjusted RR, 1.17 (95% Cl, 1.08–1.26)

D:A:DD:A:D——Prolonged Antiretroviral Prolonged Antiretroviral Exposure and Myocardial InfarctionExposure and Myocardial Infarction

1. El-Sadr W, et al. Abstract 42. 2. Sabin C, et al. Abstract 866.

Gerstoft et al. 42nd ICAAC 2002. Abstract H-172Walmsley et al. 11th CROI 2004. Poster N-90

Med

ian

chan

ge in

fast

ing

lipid

s fr

om b

asel

ine

to w

eek

48 (%

)

IDV/r SQV/r

Totalcholesterol

LDLcholesterol Triglycerides

20

15

10

25

n = 121

0

5 n = 128

n = n = 6060

n = 73

n = 129

n = 132

p < 0.05p < 0.05

p < 0.05

MaxCmin1 & 2: MaxCmin1 & 2: SQV/r exhibited a superior lipid profileSQV/r exhibited a superior lipid profile

MaxCmin1

Total cholesterol Triglycerides

SQV/r LPV/r

MaxCmin2

-10

-5

0

5

10

15

20

25

30

35

n = 145

n = 148

p = nsp = 0.001

n = 135

n = 139

Mea

n se

rum

lipi

d le

vels

(m

mol

/l)

FOCUS trial: saquinavir/r* and efavirenzhave similar impact on lipids

Montaner, et al. 42nd ICAAC. San Diego, USA, 2002. H-167

Total cholesterol

Triglycerides

Saquinavir/r n = 81 75 72 65 59 57 60 53 53 53

Efavirenz n = 80 78 71 73 72 70 70 65 64 60

0

1

2

3

4

5

6

0 4 8 12 16 20 24 32 40 48 Time (weeks)

*Investigational saquinavir/r 1600/100 mg od dosage.The licensed dosage of saquinavir/r is 1000/100 mg bid.

FOCUS trial: saquinavir/r* and efavirenz have similar impact on triglycerides

Walmsley et al. 4th Int Wkshop ADE & Lipo 2002. Abstract 52.

0

0.5

1

1.5

2

2.5

Mea

n ch

ange

in tr

igly

cerid

e le

vels

to

wee

k 48

(mm

ol/l)

Saquinavir/r without d4T

Efavirenz without d4T

Saquinavir/r with d4T

Efavirenz with d4T

53 56 27 23n =

p = ns

p = ns

No d4T vs d4Tp = 0.0014

*Investigational saquinavir/r 1600/100 mg od dosage.The licensed dosage of saquinavir/r is 1000/100 mg bid.

Table 2. Adverse Events in the Study Groups

++++++FosamprenavirFosamprenavir

++++++++++++++Tipranavir/ritonavirTipranavir/ritonavir[[1]1]

————SaquinavirSaquinavir[[2]2]

++++——NevirapineNevirapine++++++++++++RitonavirRitonavir

++++++NelfinavirNelfinavir

++++++++++++Lopinavir/ritonavirLopinavir/ritonavir[[1]1]

——++++IndinavirIndinavir

++++++++EfavirenzEfavirenz——++++DelavirdineDelavirdine——++++AtazanavirAtazanavir

Enzyme InductionEnzyme InductionEnzyme InhibitionEnzyme InhibitionDrugDrug

1. Assessment also reflects the effects of ritonavir.2. Saquinavir can inhibit P450 3A4 in vitro, but this is not generally manifested clinically.

Modified from: Flexner CW. http://clinicaloptions.com/2004PK

InhibiciInhibicióónn e e inducciinduccióónn enzimenzimááticaticaInfluenciaInfluencia en en interaccionesinteracciones medicamentosasmedicamentosas y y

eventoseventos adversosadversos

SQV/r SQV/r Sin Sin toxicidadtoxicidad caractercaracteríísticastica

= = ToxicidadToxicidadprincipalprincipal

DiarrhoeaDiarrhoea

HyperlipidaemiaHyperlipidaemia

RashRashScleral icterus, JaundiceScleral icterus, JaundiceHyperbilirubinaemiaHyperbilirubinaemia

Signature toxicitiesSignature toxicities

LipodystrophyLipodystrophy

GastrointestinalGastrointestinal

Class toxicitiesClass toxicitiesSQVSQVNFVNFVLPV/rLPV/rFPVFPVATVATV

EfectosEfectos metabmetabóólicoslicos de de loslos IPIP´́ss

no no ΔΔ insulin sensitivityinsulin sensitivitylittle little ΔΔATV/(r)ATV/(r)no no ΔΔ insulin sensitivityinsulin sensitivitylittle little ΔΔSQV/(r)SQV/(r)

??↑↑ TC/TGTC/TGTMCTMC--114/r114/r??↑↑ TC/TGTC/TGTPV/rTPV/r

no no ΔΔ insulin sensitivityinsulin sensitivity↑↑ TC/TGTC/TGAPV/(r) or APV/(r) or FPV/(r)FPV/(r)

LipidsLipids

no no ΔΔ insulin sensitivityinsulin sensitivity↑↑ LDL/TG, LDL/TG, ↑↑ HDL(?)HDL(?)NFVNFV

GlucoseGlucose

↑↑ insulin resistanceinsulin resistance↑↑ TC/TGTC/TGIDV/(r)IDV/(r)↑↑ insulin resistanceinsulin resistance↑↑ TC/TGTC/TGLPV/rLPV/r↑↑ insulin resistanceinsulin resistance↑↑ ↑↑ TC/TGTC/TGRTV (full dose)RTV (full dose)

ConclusiConclusióónn: : PerfilPerfil MetabMetabóólicolico de de saquinavir/r en saquinavir/r en pacientespacientes VIH+: VIH+:

Saquinavir/r Saquinavir/r muestranmuestran un un ligeroligero y y limitadolimitado efectoefecto en en llíípidospidos comparadocomparado con con loslos demdemááss IP IP reforzadosreforzados..–– ParticularmenteParticularmente sisi se se usanusan RTV 100 mg QDRTV 100 mg QD

CombinaciCombinacióónn garantizadagarantizada: saquinavir/r y ATV/r : saquinavir/r y ATV/r ((EsAsEsAs) ) BenBenééficofico cuandocuando eses usadousado en en combinacicombinacióónn con con ITRN con ITRN con pocopoco o o nulonulo efectoefecto esperadoesperado en en tejidotejidoadiposoadiposo perifperifééricorico y y sensibiidadsensibiidad a la a la insulinainsulina((evitandoevitando d4T)d4T)EfectoEfecto en la en la distribucidistribucióónn de de tejidotejido adiposoadiposo motivarmotivarááinvestigaciinvestigacióónn futurafutura..

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