Uso de los nuevos fármacos en el adulto Jose R Arribas Hospital La Paz

Declining incidence of initial ART failure during 1st year of treatment n Data from 5 observational cohorts from Europe and North America started 3- drug ART between 1996 and 2002 (total n =4,143) Incidence of virologic failure (VL >500 c/mL 6 – 12 months after initiating ART) evaluated by calendar year Incidence of virologic failure (VL >500 c/mL 6 – 12 months after initiating ART) evaluated by calendar year VL failure declined significantly from 1996 to 2002 ( p <0.001) VL failure declined significantly from 1996 to 2002 ( p <0.001) n Risk of VL failure was lower with: l Older age l MSM l Lower baseline VL l Absence of AIDS diagnosis at time of ART initiation Lampe F, et al. 12th CROI, Boston 2005, #593 Patients with virologic failure by year of starting ART

ABC/3TC TFV/FTC NUEVOS NUCLEOSIDOS COMBINADOS

¿Van a reemplazar a otras combinaciones, en especial CBV? ¿Cómo elegir entre ABC/3TC y TFV/FTC?

Estudio 934 Proporción con ARN-VIH <50 c/mL (TLOVR) ITT (n = 509) BL Semanas % Respondedores FTC/TDF 77%* CBV 68%* *IC 95%: (+0.9%, +16.2%) p = Excluyendo NNRTI-R (n=487): FTC/TDF 80%, CBV 70%, p=0.021 (+1.6%,16.6%) Arribas JR et al. 18th International Conference on Antiviral Research; 2005; Barcelona, Spain, Presentation # LB-01..

AIDS: Volume 19(16) 4 November 2005 p ACTG 364

Estudio ABCDE Grasa en miembros 96 sem ABC+3TC+EFV g D4T+3TC+EFV g

Study 934 Total Limb Fat at Week 48 No significant differences in baseline demographics between substudy arms or between the substudy and overall study The substudy participants came from 26 sites in the EU and USFTC+TDF+EFV (n = 50) CBV+EFV (n = 46) p value Mean Median7.25.8

ABC QD vs BID + 3TC + EFV ZODIAC; CNA30021 n Placebo-controlled trial of ABC 600 QD vs 300 BID + 3TC + EFV QD n Baseline characteristics: QDBID n =384 n =386 VL (median) VL > 100K43%44% CD4+ (median) n ABC HSR l 9% in QD; 7% in BID n No difference in AE rates, CD4+ changes Virologic response (VL <50 c/mL ITT and AT) Gazzard BG, et al. 43 rd ICAAC, Chicago, September 2003, #H-1722b % Response Weeks

Genética de la hipersensibilidad a abacavir

Study 934 Glomerular Filtration Rate (Cockcroft-Gault) a.p = for difference between baseline and week 48 b.p < for difference between baseline and week 48FTC+TDF+EFV (n = 257) CBV+EFV (n = 254) Median Baseline GFR (mL/min) Median Change to Week 48 (mL/min) -1.3 a +6.2 b AL Pozniak, et al. 3 rd IAS Conference on HIV Pathogenesis and Treatment, 2005, Poster and Oral #WeOa0202.

Study 934 Mean Change Fasting Total Cholesterol p < mg/dL (0.54 mmol/L) 35 mg/dL (0.91 mmol/L) Baseline: FTC+TDF+EFV 165 mg/dL (4.27 mmol/L), CBV+EFV 161 mg/dL (4.17 mmol/L) FTC+TDF+EFV: CBV+EFV: Study Week Mean Change from Baseline (MG/DL) FTC+TDF+EFV CBV+EFV

Study 934 Mean Change Fasting Triglycerides Study Week Mean Change from Baseline (MG/DL) FTC+TDF+EFV CBV+EFV p = mg/dL (0.03 mmol/L) 31 mg/dL (0.35 mmol/L) Baseline: FTC+TDF+EFV 149 mg/dL (1.68 mmol/L), CBV+EFV 142 mg/dL (1.60 mmol/L) FTC+TDF+EFV: CBV+EFV:

Within-group significant change from baseline: *P<.001, P=.001, P<.05. Error bars indicate 95% confidence intervals. The TC-to-HDL ratio decreased by 1.51 in the abacavir arm (P<.001) but remained stable in the stavudine arm (-0.06); P=.005 for the comparison between arms. ABCDE study. 96-WEEK CHANGES IN LIPID PARAMETERS ACCORDING TO TREATMENT ARMS Podzamczer D, et al. 12th CROI, 2005

Combinaciones de nucleósidos n Potencia elevada, muy bajo riesgo de lipoatrofia, perfil lipídico benigno, riesgo bajo de inducción de resistencias n Toxicidad específica manejable l ABC/3TC: RHS. ¿Uso de tests genéticos? l TFV/FTC: Seguimiento CCr n Uso en Coinfección l TFV/FTC: Ideal en coinfección VHB l ABC/3TC: Más datos en insuficiencia hepática l Ambos: Útiles durante el tto anti-VHC n Interacciones l ABC/3TC: muy buen perfil l TFV/FTC: Atazanavir, DDI

LOPc SAQ5 ATV fAMP TPV TMC-114 NUEVOS INHIBIDORES DE LA PROTEASA

NaïveSimplRescate Rescate profundo Atazanavir 400 QD +/? (034) +/? (Swan) - (043) -- Atazanavir/r 300/100 QD ? (138) ? (ATAZIP) + (045) ?/- fAmp 1400 BID +/? (NEAT) ??/-?/-- fAmp/r 1400/200 QD +/? (SOLO) ? - (CONTEXT) -- fAmp/r 700/100 BID ? (KLEAN) ? +/? (CONTEXT) ? (20002) SAQ /100 BID ? ( MaxCmin) SAQ /100 QD -/? ( Focus; Staccato ) ?--

NaïveSimplRescate Rescate profundo Atazanavir 400 QD +/? (034) +/? (Swan) - (043) -- Atazanavir/r 300/100 QD ? (138) ? (ATAZIP) + (045) ?/- (045) fAmp 1400 BID +/? (NEAT) ??/-?/-- fAmp/r 1400/200 QD +/? (SOLO) ? - (CONTEXT) -- fAmp/r 700/100 BID ? (KLEAN) ? +/? (CONTEXT) ? (20002) SAQ /100 BID ? ( MaxCmin) SAQ /100 QD -/? ( Focus ; Staccato ) ?--

NaïveSimplRescate Rescate profundo Atazanavir 400 QD +/? (034) +/? (Swan) - (043) -- Atazanavir/r 300/100 QD ? (138) ? (ATAZIP) + (045) ?/- (045) fAmp 1400 BID +/? (NEAT) ??/-?/-- fAmp/r 1400/200 QD +/? (SOLO) ? - (CONTEXT) -- fAmp/r 700/100 BID ? (KLEAN) ? +/? (CONTEXT) ? (20002) SAQ /100 BID ? ( MaxCmin) SAQ /100 QD -/? ( Focus ; Staccato ) ?--

NaïveSimplRescate Rescate profundo LPV/r Meltrx 800/200 QD ++/? (418; M05-730)???/- LPV/r Meltrx 400/100 BID ++/? (863; M05-730)? + (TORO) Tipra/r 500/200 BID ? ( ) ?/- + (RESIST) ++ (RESIST) Tipra/r 500/100 BID ? ( ) ?/-?/-?/-- TMC /100 BID ??/- + (C-214; POWER) POWER) ++ (POWER) TMC /100 QD ? (ARTEMIS) ???

NaïveSimplRescate Rescate profundo LPV/r Meltrx 800/200 QD ++/? (418; M05-730)???/- LPV/r Meltrx 400/100 BID ++/? (863; M05-730)? + (TORO) Tipra/r 500/200 BID ? ( ) ?/- + (RESIST) ++ (RESIST) Tipra/r 500/100 BID ? ( ) ?/-?/-?/-- TMC /100 BID ??/- + (C-214; POWER) POWER) ++ (POWER) TMC /100 QD ? (ARTEMIS) ???

NaïveSimplRescate Rescate profundo LPV/r Meltrx 800/200 QD ++/? (418; M05-730)???/- LPV/r Meltrx 400/100 BID ++/? (863; M05-730)? + (TORO) Tipra/r 500/200 BID ? ( ) ?/- + (RESIST) ++ (RESIST) Tipra/r 500/100 BID ? ( ) ?/-?/-?/-- TMC /100 BID ??/- + (C-214; POWER) POWER) ++ (POWER) TMC /100 QD ? (ARTEMIS) ???

Nuevos IPs n Ausencia de resistencias en pacientes naïve l Lop/r (c), Famp/r, Saq500/r?, Ata/r? n nº comp/día y QD posible l ATA & ATA/r, Lop/r (c), Saq500/r, Famp/r n Mejor tolerancia digestiva l ATA & ATA/r, Lop/r ©?, Saq500/r, Famp/r n Mejor perfíl lipídico l ATA & ATA/r, Saq5/r, Famp/r n Interacciones problemáticas l ATA, TPV/r n Menor resistencia cruzada. Tercera línea eficaz l TPV/r, TMC-114

Absence of PI resistance in ART-naïve patients treated with SQV + RTV n ART-naïve Thai adults (n=258) l Part of induction phase of the Staccato trial l CD4+ 200–350 cells/mm3 l Most SQV + RTV 1600/100 mg QD + d4T + ddI-EC for 6 months n 10 patients (3.9%) had virologic failure l No major PI-resistance mutations reported l 3 had RT mutations n Preliminary evidence that SQV resistance is not observed when used as RTV-boosted QD agent in ARV-naïve subjects Ananworanich J, et al. 3 rd IAS, Rio de Janeiro 2005, #WePe4.4C12

Nuevos IPs n Ausencia de resistencias en pacientes naïve l Lop/r (c), Famp/r, Saq500/r?, Ata/r? n nº comp/día y QD posible l ATA & ATA/r, Lop/r (c), Saq500/r, Famp/r n Mejor tolerancia digestiva l ATA & ATA/r, Lop/r ©?, Saq500/r, Famp/r n Mejor perfíl lipídico l ATA & ATA/r, Saq5/r, Famp/r n Interacciones problemáticas l ATA, TPV/r n Menor resistencia cruzada. Tercera línea eficaz l TPV/r, TMC-114

Eficacia. Figura 3: Estimaciones Globales del riesgo relativo* del tiempo transcurrido hasta el rebote virológico y el tiempo transcurrido hasta el fracaso. 012 Tiempo transcurrido hasta Vreb Tiempo transcurrido hasta fracaso Favorable a ATV Favorable al IP comparador Riesgo relativo (Intervalo de confianza del 95%) ESTUDIO SWAN

Nuevos IPs n Ausencia de resistencias en pacientes naïve l Lop/r (c), Famp/r, Saq500/r?, Ata/r? n nº comp/día y QD posible l ATA & ATA/r, Lop/r (c), Saq500/r, Famp/r n Mejor tolerancia digestiva l ATA & ATA/r, Saq500/r, Famp/r, Lop/r (c)?, n Mejor perfíl lipídico l ATA & ATA/r, Saq5/r, Famp/r n Interacciones problemáticas l ATA, TPV/r n Menor resistencia cruzada. Tercera línea eficaz l TPV/r, TMC-114

1 (1) 3 (2) DebilidadDebilidad 1 (1) 3 (2) InsomnioInsomnio 2 (2) 3 (2) CefaleaCefalea 1 (1) 4 (2) AsteniaAstenia 3 (4) 3 (2) VómitosVómitos 3 (4) 9 (5) NauseasNauseas 2 (2) 12 (7) Erupción cutánea 4 (5) 15 (9) R. Hipersensibilidad 15 (18)* 8 (5) Diarrea Diarrea NFV BID N=83 N=83 FPV BID N=166 N=166 Nº (%) de pacientes con efectos adversos Estudio NEAT Efectos adversos de al menos moderada intensidad * p=0,002 Interrupción del TAR por EEAA: 5% FPV vs 6% NFV Interrupción del TAR por EEAA: 5% FPV vs 6% NFV NEAT

Nuevos IPs n Ausencia de resistencias en pacientes naïve l Lop/r (c), Famp/r, Saq500/r?, Ata/r? n nº comp/día y QD posible l ATA & ATA/r, Lop/r (c), Saq500/r, Famp/r n Mejor tolerancia digestiva l ATA & ATA/r, Saq500/r, Famp/r, Lop/r (c)?, n Mejor perfíl lipídico l ATA & ATA/r, Saq5/r, Famp/r n Interacciones problemáticas l ATA, TPV/r n Menor resistencia cruzada. Tercera línea eficaz l TPV/r, TMC-114

ATV en inicioIP comparador en inicioATV en semana 24IP comparador en semana 24 ESTUDIO SWAN Lípidos. Figura 4: Niveles de lípidos clasificados por las guías NCEP ATP III (1). InicioSemana Porcentaje TC 240 mg/dL 7 36 p < InicioSemana Porcentaje LDL-C 130 mg/dL p <

n = 153 Gerstoft et al. 42 nd ICAAC Abstract H-172. Walmsley et al. 11th CROI Poster N-90 Median change in fasting lipids from baseline to week 48 (%) IDV/rSQV/r Total cholesterol LDL cholesterol Triglycerides n = n = 128 n = 60 n = 73 n = 129 n = 132 p<.05 MaxCmin1 & 2: SQV/r exhibited a superior lipid profile MaxCmin1 Total cholesterolTriglycerides SQV/rLPV/r MaxCmin n = 139 n = 153 n = 140

Nuevos IPs n Ausencia de resistencias en pacientes naïve l Lop/r (c), Famp/r, Saq500/r?, Ata/r? n nº comp/día y QD posible l ATA & ATA/r, Lop/r (c), Saq500/r, Famp/r n Mejor tolerancia digestiva l ATA & ATA/r, Saq500/r, Famp/r, Lop/r (c)?, n Mejor perfíl lipídico l ATA & ATA/r, Saq5/r, Famp/r n Interacciones problemáticas l ATA, TPV/r n Menor resistencia cruzada. Tercera línea eficaz l TPV/r, TMC-114

Drugs Affecting ATV Concentrations ATV Trough (ng/mL) 400 QD300 QD +100 RTV + RIF+ OMP+ TDF w/o RTV + TDF w/RTV Atazanavir Dose and Combination Abbreviations: ATV, atazanavir; RIF, rifampin; OMP, omeprazole; TDF, tenofovir. RIF and OMP given in combination with ATV/r 300/100 QD.

BI : Use of Tipranavir in Double-Boosted PI Regimens TPV/rTPV/APV/r TPV/SQV/rTPV/LPV/r Change in HIV-1 RNA (log 10 copies/mL) MonotherapyTPV added to boosted LPV, APV, SQV Weeks of Treatment Median VL change from baseline APV LPV SQV Geometric Mean Ratio (+/- 90% Confidence Interval ) AUC C max C min Ratio of PI concentrations with TPV: without TPV Walmsley, et al. IAC Abstract WeOrB1236.

Nuevos IPs n Ausencia de resistencias en pacientes naïve l Lop/r (c), Famp/r, Saq500/r?, Ata/r? n nº comp/día y QD posible l ATA & ATA/r, Lop/r (c), Saq500/r, Famp/r n Mejor tolerancia digestiva l ATA & ATA/r, Saq500/r, Famp/r, Lop/r (c)?, n Mejor perfíl lipídico l ATA & ATA/r, Saq5/r, Famp/r n Interacciones problemáticas l ATA, TPV/r n Menor resistencia cruzada. Tercera línea eficaz l TPV/r, TMC-114

POWER-1 and -2: Response to TMC114/r Katlama C, et al. CROI Abstract 164LB. * Mean Change in HIV-1 RNA (log 10 copies/mL) * 400 QD (n = 66) -1.43* 800 QD (n = 61) -1.47* 400 BID (n = 64) -1.85* 600 BID (n = 64) Control (n = 74) Weeks * P <.0001 vs control P <.05 vs TMC BID 0 ITT : NC=F

NaïveSimplRescate Rescate profundo Ata QD Ata/r QD fAmp BID fAmp/r QD fAmp/r BID SAQ500 BID SAQ500 QD LPV/r C QD LPV/r C BID TPV/r BID TMC-114 BID

T-20 INHIBIDORES DE LA FUSION

DHHS GUIDELINES OCT-05 Extensive prior treatment and drug resistance: In patients with active antiretroviral agents available (e.g. an active ritonavir- boosted PI and enfuvirtide), THE GOAL OF THERAPY IS SUPPRESSION OF VIREMIA. In patients without active antiretroviral agent available and with ongoing viremia, the goal of therapy is preservation of immune responses and delay of clinical progression.

T-20 n Debe utilizarse con el objetivo de suprimir la replicación viral (< 50 copias/mL) n Excelente perfil de seguridad sistémica. n Ausencia de interacciones. n Reacciones locales y uso parenteral principal limitación para su uso.