““Top-Ten” Novedades en el Top-Ten” Novedades en el Tratamiento Antirretroviral.Tratamiento Antirretroviral.

Dr. MIGUEL GARCÍA DELTOROHospital General Universitario Valencia

Unidad Enfermedades Infecciosas

Top Ten Tenis

’87 ’91 ’92 ’94 ’95 ’96 ’97 ’98 ’99 ’00’88 ’89 ’90 ’01 ’02 ’03’93 ’05’04 ’06

ddC

3TC

NNRTI

NRTI

PI

Inhibidorentrada

ddI

IDV

SQV LPV

TFVNVP

DRV

TPV

T-20

ZDV d4TABC

DLV

EFV FTC

RTV

NFV ATV

FPV

25 antirretrovirales aprobados por la FDA

’07

MVC

2525 Fármacos antirretrovirales Fármacos antirretrovirales

APV

RAL

Ø INTEGRASA

ETR

DRVDRV MVMVCC

RALRALETRETR

Preferred Regimens for Treatment-Naive Preferred Regimens for Treatment-Naive Pts: DHHS (12/09)Pts: DHHS (12/09)

DHHS guidelines. Available at: http://www.aidsinfo.nih.gov.

Evitar añadir ptes al “carro” de la Evitar añadir ptes al “carro” de la Multirresistencia y Lipodistrofia ....Multirresistencia y Lipodistrofia ....

Y entre todos lo estamos consiguiendo, pero Y entre todos lo estamos consiguiendo, pero sobre todo por los nuevos fármacos y los “combos”....sobre todo por los nuevos fármacos y los “combos”....

1.- DARUNAVIR (DRV).

2.- MARAVIROC (MVC).

3.- RALTEGRAVIR (RAL).

4.- ETRAVIRINA (ETR), Rilpivirina (RPV), Nevirapina (NVP) XR.

5.-MISCELÁNEA (DHHS 2011). . Algunas matizaciones.. Inicio ARV y tto TBC.. Algunas interacciones relevantes.

Top Ten Novedades Tto ARV….Top Ten Novedades Tto ARV….

DRV/r: el último de los IPs y ya casi el más recetado….DRV/r: el último de los IPs y ya casi el más recetado….

DRV.DRV.

– IP/r casi perfecto: el más eficaz, como el más tolerable y benévolo IP/r casi perfecto: el más eficaz, como el más tolerable y benévolo

metabólicamente, el que menos falla y cuando lo hace con menos metabólicamente, el que menos falla y cuando lo hace con menos

mutaciones. mutaciones. Ahora ya datos a medio plazo de ptes naiveAhora ya datos a medio plazo de ptes naive..

– Ya no necesidad de nevera para el rtvYa no necesidad de nevera para el rtv..

– Si no mutaciones de su score se puede dar qd (ODIN).Si no mutaciones de su score se puede dar qd (ODIN).

– Monoterapia no demuestra la no inferioridad a 96 semanas, se Monoterapia no demuestra la no inferioridad a 96 semanas, se

debería de concretar adecuadamente al pte candidato a elladebería de concretar adecuadamente al pte candidato a ella..

La excusa de la nevera se acabó….La excusa de la nevera se acabó….(11-11-10: RTV Meltrex aprobado en España y dispobible (11-11-10: RTV Meltrex aprobado en España y dispobible

desde Enero/2011)desde Enero/2011)

ICAAC 08ARTEMIS: Viral load <50 copies/mLto Week 96 (ITT-TLOVR)a

Estimated difference in response vs LPV/r for non-inferiority:

PP = 8.4% (95% CI: 1.9-14.8) p<0.001

Estimated difference in response vs LPV/r for superiority:

ITT = 8.3% (95% CI: 1.8-14.7) p=0.012

Time (weeks)

79%

71%

LPV/r QD or BID (N=346)

DRV/r QD (N=343)100

80

60

40

20

0

Pat

ien

ts w

ith

VL

<50

co

pie

s/m

L (

% [

±SE

])

0 8 16 24 36 48 60 72 84 96

Mills A, et al H-1250c

aEstimated from a logistic regression model including treatment and stratification factors (baseline log10 viral load and baseline CD4+ cell count)

Cahn P, et al. 17th CROI 2010. Abstract 57 y AIDS. 2011 Apr 24;25(7):929-939

ODIN: study design

• ODIN (TMC114-C229) is a Phase IIIb, randomized, open-label study – compares efficacy, safety and tolerability at Week 48 in treatment-

experienced adults with no DRV RAMs

DRV/r 800/100mg qd + OBR (2 NRTIs)‡ (N=294)

DRV/r 600/100mg bid+ OBR (2 NRTIs)‡ (N=296)

• ARV-experienced patients, aged 18 years

• HIV-1 RNA >1000 copies/mL

• CD4 cell count >50 cells/mm3

• No DRV RAMs at screening*

• Stable HAART for 12 weeks

590 patients randomized

*DRV RAMs include the following mutations: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V; ‡Individualized OBR included 2 N(t)RTIs based on ARV history and resistance testing

Treatment phase (up to 48 weeks)

Patients stratified by screening HIV-1

RNA (50,000, >50,000 copies/mL)

ODIN: viral load <50 copies/mL to Week 48 (ITT-TLOVR)

72.1%

70.9%

0

20

40

60

80

100

0 4 8 12 24 36 48

Time (weeks)

Pat

ien

ts w

ith

HIV

-1 R

NA

<50

co

pie

s/m

L

(% [

95%

CI]

)

DRV/r 800/100mg qd

DRV/r 600/100mg bid

Difference in response qd vs bid: ITT: 72.1–70.9 = 1.2% (95% CI = –6.1%, 8.5%)PP: 73.4–72.5 = 0.9% (95% CI = –6.7%, 8.4%)

CI = confidence interval; PP = per protocol

ODIN: laboratory abnormalities

Treatment-emergent grade 2–4 lipid and liver-related laboratory abnormalities (≥2% incidence), n (%)*

Once-daily DRV/r

800/100mg (N=294)

Twice-daily DRV/r

600/100mg (N=296)

P value

Triglycerides 15 (5.2) 31 (11.0) <0.014

Total cholesterol* 29 (10.1) 58 (20.6) <0.0007

LDLc cholesterol* 28 (9.8) 47 (16.7) <0.019

ALT 5 (1.7) 10 (3.5) 0.20

AST 6 (2.1) 10 (3.5) 0.32

Non-graded lipid-related laboratory abnormalities, n (%)

HDL below the lower normal limit 57 (19.9) 52 (18.4) 0.67

*Based on the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Paediatric Adverse Events 2004, which does not have a grade 1 classification for triglycerides and grade 4 for total cholesterol and LDL

MONET - Trial Design

Inclusion: Taking 2 NRTI + either NNRTI or boosted PI at screening (stratified) HIV RNA <50 copies/mL for at least 6 months, no prior use of darunavir (DRV) No history of virological failure

144 weeks

256 subjects

DRV/r 800/100 mg OD+ 2 NRTI (re-optimised at baseline)

n = 129

DRV/r 800/100 mg ODn = 127

Rieger et al. Int AIDS Conf July 2010, Vienna [abstr TBLBB209]Rieger et al. Int AIDS Conf July 2010, Vienna [abstr TBLBB209]

Primary Endpoint: failure at week 48 (TLOVR). Per Protocol, Switch = FailureThe Week 96 analysis was a secondary endpoint.

0

10

20

30

40

50

60

70

80

90

100

DRV/r + 2NRTI DRV/r mono DRV/r + 2NRTI DRV/r mono

MONET: HIV RNA <50 copies/mL at Week 96, TLOVR, Switch=failure (ITT population)

HIV RNA<50 byWeek 96(%)

Switch=failure analysis (TLOVR) Switch included analysisDifference = -5.8% (-16.0%, +4.4%)* Difference = +1.4% (-5.5%, +8.3%)*

n=129 n=127 n=129 n=127

80.6%74.8%

90.7% 92.1%

* 95% confidence intervals from univariate analysis

CONCLUSIONES

La monoterapia con IPs es ligeramente inferior a la triple terapia, pero es semejante si se reintroducen los NRTI.

Darunavir/r en monoterapia es no inferior a su triple terapia a las 48 semanas, y es ligeramente inferior a su triple terapia a las 96 semanas.

En pacientes seleccionados, como los pacientes con toxicidad a NRTI puede ser una alternativa razonable (GESIDA, EACS, etc…).

Crea escasas mutaciones. La monoterapia es coste-efectiva, suponiendo un

ahorro del 40%.

0

2000

4000

6000

8000

10000

12000

DRV/r TDF/FTC/EFV TDF/FTC/DRV/r TDF/FTC/ATV/r

Annual Spanish cost per person

€5471

€8515

€11283 €11326

Annual Spanish Costs of ARV’s

MVC: Nuevos datos y posibilidad de utilización qd….MVC: Nuevos datos y posibilidad de utilización qd….

MVC.MVC.

– Mejora parcialmente Mejora parcialmente marcadores de inmunoactivaciónmarcadores de inmunoactivación en ptes suprimidos. en ptes suprimidos.

– Disponibilidad de Disponibilidad de tropismo genotípicotropismo genotípico rápida y para todos los centros y en rápida y para todos los centros y en

breve breve posibilidad de tropismo en PBMCposibilidad de tropismo en PBMC para ptes indetectables. para ptes indetectables.

– Datos Datos QD PK (ATV // DRVQD PK (ATV // DRV) y ) y clínicos con ATVclínicos con ATV disponibles. disponibles.

– Precio QDPrecio QD muy competitivo. muy competitivo.

– Datos Datos QD con DRV “ongoingQD con DRV “ongoing”.”.

– Inclusión de Inclusión de QD en ficha técnica por EMEA prevista para Sept-Oct/2011QD en ficha técnica por EMEA prevista para Sept-Oct/2011..

Effect of Adding and Removing MVC on Immune Activation in HIVEffect of Adding and Removing MVC on Immune Activation in HIV++ Patients on Suppressive ART: Results from ACTG A5256.Patients on Suppressive ART: Results from ACTG A5256.

Timothy WilkinTimothy Wilkin et al. CROI 2011 abstract 574. et al. CROI 2011 abstract 574.

Mi pequeña contribución al Documento de Mi pequeña contribución al Documento de Consenso Español de Tropismo….Consenso Español de Tropismo….

Estamos en tiempos de crisis….Estamos en tiempos de crisis….Coste tratamiento/díaCoste tratamiento/día

Tratamiento diario (PVL)Tratamiento diario (PVL)

Fármaco Fármaco Dosificación Dosificación Coste Coste Coste RTV Coste RTV

IsentressIsentress® ® 400 mg400 mg BidBid 21,00 € 21,00 € (19,00(19,00€€)) --

CelsentriCelsentri®®150 mg150 mg

300 mg300 mg

BidBid

BidBid

21,76 €21,76 €

21,76 €21,76 €

FuzeonFuzeon®® 90 mg/ml90 mg/ml BidBid 50,85 €50,85 € --

IntelenceIntelence®®200 mg200 mg

400 mg400 mg

BidBid

QDQD

13,00 €13,00 €

13,00 €13,00 €--

ViramuneViramune® ® 400 mg400 mg Bid/QDBid/QD 8,51 €8,51 €

AtriplaAtripla®® 600/200/245 mg600/200/245 mg QDQD 23,33 €23,33 € --

KaletraKaletra®®400/100 mg400/100 mg

800/200 mg800/200 mg

BidBid

QDQD

13,33 €13,33 €

13,33 €13,33 €--

ReyatazReyataz®® 300/100 mg300/100 mg QDQD 14,55 €14,55 € 0,75 €0,75 €

PrezistaPrezista®®600/100 mg600/100 mg

800/100 mg800/100 mg

BidBid

QDQD

21,36 €21,36 €

14,24 €14,24 €

1,50 €1,50 €

0,75 €0,75 €

QD QD

10,88 €10,88 €

MVC 150 MG QD (+ ATV/R)MVC 150 MG QD (+ ATV/R)All Patients Had Plasma MVC Concentrations Above the All Patients Had Plasma MVC Concentrations Above the in vivo in vivo ICIC5050 Across the Across the

Dosing Interval Dosing Interval 11

Hours

MVC

Con

cent

ratio

n (n

g/m

L)

* One patient accidentally dosed with MVC prior to the 24-hour sample draw

1. Vourvahis et al ICWPHIV 2010 2. Rosario MC, et al. J Acquir Immune Defic Syndr. 2006;42:183-191

0 4 8 12 16 20 24

*

7.65 ng/mL (in vivo IC50)2

1

10

100

1000

10,000

Stephen Taylor et al. CROI 2011 POSTER 636

Maraviroc 300mg Once Daily + Darunavir/Ritonavir 800/100mg Once Daily Provides Maraviroc Trough

Concentrations Comparable to Trough Concentrations in HIV1 Patients Taking Maraviroc 300mg Twice Daily +

Truvada: Implications for Phase 3 Studies.

Estudio PK de MVC. Conclusiones relevantes.Estudio PK de MVC. Conclusiones relevantes.

•300mg MVC OD with DRV/r 800/100 OD achieved comparable MVC Cpeak and higher Ctrough compared to 300 mg BD dosed with NRTIs (no bPIs)

• Limited data on MVC 150mg OD with DRV/r 800/100 OD achieved comparable Ctrough compared to 300 mg BD dosed with NRTIs (no bPIs)

• All regimens were well tolerated with no cases of symptomatic postural hypotension identified

• The planned phase 3 study (A4001095) is using a dose of 150 mg of MVC

OD with DRV/r 800/100

• Higher [MVC]s in Black subjects was observed and needs to be

investigated further

Stephen Taylor et al. CROI 2011 POSTER 636

MOTIVATE 1 y 2MOTIVATE 1 y 2

Gulick R, et al. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Sydney, Australia, 22–25 July 2007. Poster WEPEB116LB

A4001078: ATV/RTV + MVC vs ATV/RTV + TDF/FTC—Wk 24 Interim Analysis

CD4 + cell count increases similar

– ATV/RTV + MVC: 195 cells/mm³

– ATV/RTV + TDF/FTC: 173 cells/mm³

Grade 3/4 hyperbilirubinemia

– ATV/RTV + MVC: 59.3%

– ATV/RTV + TDF/FTC: 49.2%

5 patients in MVC arm, 1 patient in TDF/FTC arm switched to DRV/RTV per protocol for jaundice or scleral icterus

Mills A, et al. Int AIDS Conf 2010. Abstract THLBB203.

40

0

100

20

80

HIV-1 RNA < 100K

95

80

60

7781

HIV-1 RNA 100K

HIV-1 RNA < 50 copies/mL Overall and by BL VL

22163944

Overall

8980

6160

Pat

ien

ts (

%)

n =

ATV/RTV + MVC (n=60)

ATV/RTV + TDF/FTC(n=61)

RAL y otros inhibidores de la integrasa….RAL y otros inhibidores de la integrasa….

RAL.RAL.

– Eficacia y Tolerancia perfectas ya con Eficacia y Tolerancia perfectas ya con datos a medio plazo de pacientes naivedatos a medio plazo de pacientes naive..

– RAL/LPV RAL/LPV posible como tto libre de NRTI.posible como tto libre de NRTI.

– Esperanza en 1 comp en Esperanza en 1 comp en combo QD con elvitegravircombo QD con elvitegravir..

– Esperanza en rescate con Esperanza en rescate con dolutegravirdolutegravir..

– Dosis QD es inferior a la BIDDosis QD es inferior a la BID..

Raltegravir (RAL): 156 Week (Wk) Results from STARTMRKRaltegravir (RAL): 156 Week (Wk) Results from STARTMRK

DesignDesign

– Multicenter, Multicenter, double-blinddouble-blind, randomized (1:1), , randomized (1:1), active-controlled studyactive-controlled study• RAL 400mg BID vs. EFV 600mg qhs.• Both given with co-formulated tenofovir

(TDF) / emtricitabine (FTC)

J.K. Rockstroh, et al.J.K. Rockstroh, et al. CROI 2010 Abstract # K-135

Main ObjectivesMain Objectives

–RAL + TDF/FTC will have non-inferior efficacy RAL + TDF/FTC will have non-inferior efficacy compared to EFV + TDF/FTCcompared to EFV + TDF/FTC

•Primary hypothesis time point: 48 weeks•Secondary hypothesis time point: 96 weeks•Long term follow-up planned through 5 years•Primary outcome: vRNA <50 c/mL•Secondary outcomes: vRNA <400 c/mL, CD4 change from baseline

Patient Disposition at Week 156Patient Disposition at Week 156

281 Patients 281 Patients Treated with Treated with

RALRAL

282 Patients 282 Patients Treated with Treated with

EFVEFV

Enrolled Patients Enrolled Patients Randomized 1:1 Randomized 1:1

To RAL:EFV ArmsTo RAL:EFV Arms

227 Patients 227 Patients (80.8%) (80.8%)

CompletedCompleted156 Weeks156 Weeks

211 Patients 211 Patients (74.8%) (74.8%)

CompletedCompleted156 Weeks156 Weeks

54 Patients (19.2%)54 Patients (19.2%)DiscontinuedDiscontinued5 – lack of efficacy5 – lack of efficacy

12 – AEs12 – AEs8 – lost to follow-up8 – lost to follow-up29 – miscellaneous*29 – miscellaneous*

71 Patients (25.2%)71 Patients (25.2%)DiscontinuedDiscontinued7 – lack of efficacy7 – lack of efficacy

22 – AEs22 – AEs14 – lost to follow-up14 – lost to follow-up28 – miscellaneous*28 – miscellaneous*

*Miscellaneous includes consent withdrawn, protocol deviation, and patients who completed the base protocol but who did not enter the extension as well as other

Proportion (%) of Patients (95% CI) with HIV RNA Proportion (%) of Patients (95% CI) with HIV RNA <50 c/mL through 156 Weeks (NC = F)<50 c/mL through 156 Weeks (NC = F)

281 281 278 280 281 281 280 281 281 277 279 280 281282 281 280 281 282 282 281 282 279 281 281 281 282

llmk518p21CROI50wk156 Jan. 11, 2011

Raltegravir groupEfavirenz group

0 16 32 48 60 72 84 96 108 120 132 144 156

Weeks

0

20

40

60

80

100

Per

cent

of P

atie

nts

with

HIV

RN

A <

50 C

opie

s/m

L

Number of Contributing Patients

86

82

81

79

75

68

Δ (RAL-EFV) [95% CI] = +7.3 [-0.2, +14.7]

Non-Inferiority p-Value <0.001

The change from baseline in the T CHOL:HDL-C ratio was -0.20 for the RAL group The change from baseline in the T CHOL:HDL-C ratio was -0.20 for the RAL group and 0.04 for EFV group (p=0.061)and 0.04 for EFV group (p=0.061)

Mean Change from Baseline in Metabolic Mean Change from Baseline in Metabolic Parameters at Week 144Parameters at Week 144

‡ p<0.001

* p=0.137

Raltegravir

Efavirenz

T CHOL HDL-C LDL-C TG Glucose

0

10

20

30

40

50M

ean

Ch

an

ge

(mg

/dL

)

‡

‡

‡

‡

*

LipoatrophyLipoatrophy

Due to attrition in Patients participating in the DEXA substudy it Due to attrition in Patients participating in the DEXA substudy it is difficult to interpret the data in a comparative fashionis difficult to interpret the data in a comparative fashion

The majority of patients in both groups experienced modest fat The majority of patients in both groups experienced modest fat gaingain

– ““Return to healthReturn to health”” phenomenon phenomenon

1/25 patients on RAL and 2/32 patients on EFV had at least 20% 1/25 patients on RAL and 2/32 patients on EFV had at least 20% appendicular fat loss (lipoatrophy) at Week 156appendicular fat loss (lipoatrophy) at Week 156

– There was no discordance between appendicular and trunk There was no discordance between appendicular and trunk fat loss among these few patientsfat loss among these few patients

– None of the patients with lipoatrophy identified by DEXA None of the patients with lipoatrophy identified by DEXA scanning had investigator-reported lipodystrophy as an scanning had investigator-reported lipodystrophy as an adverse eventadverse event

CROI 2011 150LB

QDMRK (P071)Study Design

QDMRK (P071)Study Design

Multicenter, double-blind, randomized, active-controlled study Non-inferiority design (10% margin)

Multicenter, double-blind, randomized, active-controlled study Non-inferiority design (10% margin)

Raltegravir 800 mg QD + TDF/FTC FDCRaltegravir 800 mg QD + TDF/FTC FDCn=382n=382

Raltegravir 800 mg QD + TDF/FTC FDCRaltegravir 800 mg QD + TDF/FTC FDCn=382n=382

Raltegravir 400 mg BIDRaltegravir 400 mg BID + TDF/FTC FDC+ TDF/FTC FDCn=388n=388

Raltegravir 400 mg BIDRaltegravir 400 mg BID + TDF/FTC FDC+ TDF/FTC FDCn=388n=388

HIV-1-infectedTreatment naive

HIV-1 RNA >5000 copies/mLNo CD4 cell cut-off

No documented resistance to tenofovir or emtricitabine

HIV-1-infectedTreatment naive

HIV-1 RNA >5000 copies/mLNo CD4 cell cut-off

No documented resistance to tenofovir or emtricitabine

Primary endpointWeek 48

Primary endpointWeek 48

Secondary endpointWeek 96

Secondary endpointWeek 96

1:11:1

J Eron et al. CROI 2011, 150 LB.

CROI 2011 150LB

*All patients received TDF/FTC FDC† Non-completer equals failure (NC=F) approach treats all discontinuations as failures

QDMRK% of Patients with HIV RNA < 50 copies/mL (NC=F†)

QDMRK% of Patients with HIV RNA < 50 copies/mL (NC=F†)

BID BID 88.9%88.9%

QD QD 83.2%83.2%

ΔΔ (QD-BID) [95% CI] = -5.7 [-10.7, -0.83] (QD-BID) [95% CI] = -5.7 [-10.7, -0.83]

382 382 377 381 379 380 381 382388 388 386 387 386 387 386 386

RAL 800 mg QDRAL 400 mg BID

0 4 8 12 16 24 36 48

Study Week

0

20

40

60

80

100P

erc

en

t o

f P

atie

nts

with

HIV

RN

A <

50

Co

pie

s/m

L

Number of Contributing Patients

CROI 2011 150LBQDMRKTime to Loss of Virologic Response

(TLOVR)

QDMRKTime to Loss of Virologic Response

(TLOVR)

TLOVR (OF)Patients With BL vRNA >100,000 cp/mL

TLOVR (OF)Patients With BL vRNA <=100,000 cp/mL

HR 0.489 (0.276, 0.867)P-value 0.0145

HR 0.572 (0.250,1.308)p-value 0.1856

0 8 16 24 36 48 60 72 84 96

Week

0

20

40

60

80

100

Per

cen

t of

Eve

nt F

ree

Number of Patients at Risk

152 138 137 135 132 122 88 39 23 10152 126 126 125 122 112 79 31 17 5RAL 800 mg QD

RAL 400 mg BID

0 8 16 24 36 48 60 72 84 96

Week

0

20

40

60

80

100

Per

cen

t of

Eve

nt F

ree

Number of Patients at Risk

236 231 230 229 226 212 147 71 32 15230 224 219 216 215 199 144 65 34 13RAL 800 mg QD

RAL 400 mg BID.

CROI 2011 150LB

QDMRK - 48 Week Summary of Virologic Failures & Resistance Data

QDMRK - 48 Week Summary of Virologic Failures & Resistance Data

Raltegravir Raltegravir

QDQDRaltegravir Raltegravir

BIDBID

Virologic Virologic FailuresFailures 53/382 (13.9%)53/382 (13.9%) 35/388 (9.0%)35/388 (9.0%)

VF >400 c/mL, VF >400 c/mL, (data available)(data available)

30 30 (27 with IN data)(27 with IN data)

16 16 (12 with IN data)(12 with IN data)

No Evidence of No Evidence of ResistanceResistance 77 77

Integrase Integrase Resistance and Resistance and FTC ResistanceFTC Resistance

99 22

FTC Resistance FTC Resistance AloneAlone 1111 44

NOTE: No Patient in Either Arm Failed with Evidence of TDF Resistance

Number of VF by Baseline HIV RNA

RaltegravirRaltegravirQDQD

RaltegravirRaltegravirBIDBID

BL VL (cp/mL)BL VL (cp/mL)

≤ ≤ 100,000 100,000 16 16

8 8

> 100,000 > 100,000 37 37

27 27

Definition Of Virologic Failure1. HIV RNA >50 copies/mL at Week 24 (confirmed at least 1 week apart), OR2. virologic relapse after initial response:HIV RNA>50 copies/mL (on 2 consecutive measurements at least 1 week apart) after initial response with HIV RNA <50 copies/mL

Most Pts failed with 2 or more mutations known to be associated with RAL resistance.  Signature mutations included N155H (4 pts in QD), Y143C/R (3 pts in QD, 1 pt in BID)

CROI 2011 150LBQDMRK - Summary of Intense and Sparse

PK Parameters

QDMRK - Summary of Intense and Sparse

PK Parameters 

RAL QD RAL BIDRatio

RAL QD /RAL BID

PK Parameter N LS Mean† (% CV‡) N LS Mean† (% CV‡) GMR (90% CI)

AUC || (µM·hr) 22 30.87 (70) 20 13.14 (99) 1.17 (0.80, 1.72)

Cmax (µM) 22 13.46 (69) 20 3.38 (135) 3.98 (2.58, 6.16)

Ctrough§ (nM) 22 40 (111) 20 257 (167) 0.15 (0.09, 0.26)

GM Ctrough* (nM)  245 83 (140) 304 380 (126) 0.22 (0.19, 0.25)

† Back-transformed from log scale; LS Mean = Geometric Least-Squares Mean.‡ %CV = 100 x sqrt(exp(s2) - 1), where s2 is the observed variance on the natural log-scale.||AUC0-12hr for BID arm and AUC0-24hr for QD arm. Ratio is for 24-hour exposure: (AUC0-24hr QD / 2*AUC0-12hr BID)§Ctrough = C12hr for BID and C24hr for QD*GM Ctrough = Ctrough calculated from sparse PK samples; for each patient, GM Ctrough represents the geometric mean of all concentration values measured between 11 and 13 hours postdose (for BID arm) or 22 and 26 hours postdose (for QD arm)

CROI 2011 150LBQDMRKHistograms for GM Ctrough and % with HIV RNA <50

copies/mL (Observed Failure)

QDMRKHistograms for GM Ctrough and % with HIV RNA <50

copies/mL (Observed Failure)

GM C12hr (nM) GM C24hr (nM)

Overall Responses:400 mg BID – 92%800 mg QD – 87%

In 800 mg QD dataset, there is a drop-off in efficacy for patients in lowest Ctrough quartile

RangeMedian

RangeMedian

PROGRESS: LPV/RTV + RAL vs LPV/RTV + NRTIs in Treatment-Naive Patients Randomized, open-label,

multicenter phase III trial in treatment-naive patients with HIV-1 RNA > 1000 copies/mL

– LPV/RTV 400 mg BID + RAL 400 mg BID (n = 101) vs

– LPV/RTV 400 mg BID + TDF/FTC 300/200 mg QD (n = 105)

Relatively low mean baseline HIV-1 RNA

– 4.25 log10 copies/mL

Reynes J, et al. Int AIDS Conf 2010. Abstract MOAB0101. Graphic used with permission.

Similar CD4+ cell count gain at Wk 48

– LPV/RTV + RAL: 215 cells/mm³

– LPV/RTV + NRTIs: 245 cells/mm³

0

20

40

60

80

100

Wks

0

HIV-1 RNA < 40 copies/mL (ITT-TLOVR)

8 16 24 32 40 48

83.2%

84.8%

Difference: -1.6% (95% CI: -12.0% to 8.8%)

*Statistically significant difference between arms:Wks 2, 4, 8 P < .002Wk 16 P = .038

**

*

*

Pat

ien

ts (

%)

LPV/RTV + RAL

Dolutegravir (DTG).

VIKING: Second-Generation INSTI S/GSK1349572 in RAL-Resistant Patients International, multicenter, single-arm,

phase II study in 27 patients with RAL resistance

– S/GSK572 50 mg QD to replace RAL in failing regimen (or added if RAL already d/c) for 10 days of functional monotherapy

– Day 11-Wk 24: S/GSK572 50 mg QD continued and regimen optimized

– Median fold-change in RAL susceptibility at BL: 161 (range: 0.6 - > 166)

– Median S/GSK572 FC at BL: 1.5 (range: 0.6-35)

Stratified by BL integrase genotype

– Group 1: Q148 + ≥ 1 secondary resistance mutations (n = 9)

– Group 2: All others (N155H and Y143H pathways) and single mutations at Q148 (n = 18)

HIV-1 RNA Response at Day 11

Group 1(n = 9)

Group 2(n = 18)

< 400 c/mL or ≥ 0.7 log10 c/mL decline, % 33 100

Change from baseline, log10 c/mL -0.72 -1.82

Day 1 FC to S/GSK572 highly predictive of Day 11 virologic response (r = 0.79; P < .001)

Among 18 paired isolates evaluated on Day 1 and Day 11, no evidence of emergent RAL mutations

– In 17 subjects, < 2 FC in susceptibility

– In 1 subject, ~ 6 FC in susceptibility

Eron J, et al. Int AIDS Conf 2010. Abstract MOAB0105.

Dolutegravir (DTG). (50 mg qd para naive y vía 155 y 50 mg bid para vía 148).

CROI 2011. Paper 151LB.

ETR: Utilización QD. NVP XR. RPV, un nuevo combo para el 2012.ETR: Utilización QD. NVP XR. RPV, un nuevo combo para el 2012.

ETR.ETR.

– Vida media “casi infinita” (41 horas). Vida media “casi infinita” (41 horas).

– Primeros datos Primeros datos SENSE QD a 12 SSENSE QD a 12 S, en este año los de 48 , en este año los de 48 SS (IAS). (IAS).

– Algún Algún estudio piloto QDestudio piloto QD pequeño en pequeño en simplificaciónsimplificación..

– NVP XRNVP XR, más de lo mismo (?)., más de lo mismo (?).

– Esperanza con Esperanza con RPVRPV de nuevo combo de 1 comp (TRU + RPV), pendiente dictamen de nuevo combo de 1 comp (TRU + RPV), pendiente dictamen

FDA en Mayo/2011.FDA en Mayo/2011.

– Formulación mejorable (aunque “bebible”), Formulación mejorable (aunque “bebible”), posible para Sept-Oct/2011 comps 200posible para Sept-Oct/2011 comps 200

mg (aprovados por FDA en Dic/2010).mg (aprovados por FDA en Dic/2010).

SENSE: EFV vs ETR in Treatment-Naive Patients Randomized, double-blind trial of

treatment-naive patients with HIV-1 RNA > 5000 copies/mL

– EFV 600 mg QD (n = 78) vs

– ETR 400 mg QD (n = 79)

– Each with investigator-selected NRTIs (TDF/FTC, ABC/3TC, or ZDV/3TC)

Primary endpoint: % of patients with grade 1-4 drug-related treatment-emergent neuropsychiatric AEs at Wk 12

Mean change in HIV-1 RNA at Wk 12 similar between arms (-2.9 log10 copies/mL)

More drug-related neuropsychiatric AEs in EFV arm vs ETR arm

40

0

100

20

80

46

17

60

175

Grade 1-4 Grade 2-4

EFV ETR EFVETR

10 patients discontinued in ETR and 8 in EFV arm by Wk 12

Gazzard B, et al. Int AIDS Conf 2010. Abstract LBPE19. Nelson M, et al. AIDS 2011 Jan 28; 25 (3): 335-40.

Drug-Related Neuropsychiatric AEs

Pat

ien

ts (

%)

P < .001 P = .02

Switching to dual therapy with Switching to dual therapy with rtv/DRV/ETR (qd)rtv/DRV/ETR (qd)

• Estudio retrospectivo. N 21 ptes.– Cambio por simplificación de 2 IPS (N=13),

toxicidad NRTI (N=7), fallo CBV/NVP (N=1)

• Al cambio 19 de 21 ptes (90%) CV< 50 cop/ml.

– A 24 S todos CV < 50 cop/ml.– A 48S (9 ptes) CV< 50 cop/ml.

Marshall NJ, et al. HIV10 Conference, Glasgow, November 2010; P51.

VERxVE: Extended-Release NVP vs Standard NVP in Naive Patients at Wk 48 Multicenter, randomized, double-

blind, noninferiority study in treatment-naive patients

– NVP XR 400 mg QD (n = 508) vs

– NVP IR 200 mg BID (n = 505)

– Both combined with TDF/FTC

Inclusion criteria

– HIV-1 RNA > 1000 copies/mL

– CD4+ cell count < 400 cells/mm3 if male or < 250 cells/mm3 if female

Similar safety and tolerability for both arms

AEs included– Stevens-Johnson (n = 5)

– Hepatitis (n = 14)

– Rash (n = 21)

0

20

40

60

80

100

NVP IR NVP XR

81.075.9

HIV-1 RNA < 50 copies/mL (TLOVR)

Gathe J, et al. Int AIDS Conf 2010. Abstract THLBB202.

Adjusted difference 4.92% (95% CI: -0.11 to 9.96)

Rilpivirine 25 mg QD+ TDF/FTC 300/200 mg QD

(n = 346)

EFV 600 mg QD+ TDF/FTC 300/200 mg QD

(n = 344)

*THRIVE only. †Selected by investigator from ABC/3TC, TDF/FTC, ZDV/3TC.

Stratification by BL HIV-1 RNA < 100,000

vs ≥ 100,000 copies/mL, NRTI use*

Wk 96final analysis

Wk 48primary analysis

Rilpivirine 25 mg QD+ 2 NRTIs†

(n = 340)

EFV 600 mg QD+ 2 NRTIs†

(n = 338)

ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients Randomized, double-blind phase III trials

Cohen C, et al. Int AIDS Conf 2010. Abstract THLBB206.

ECHO(N = 690)

THRIVE(N = 678)

Treatment-naive, HIV-1 RNA ≥ 5000 copies/mL

no NNRTI RAMs,susceptible to NRTIs

ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients

HIV-1 RNA < 50 copies/mL (ITT-TLOVR) at Wk 48

*P < .0001 for noninferiority at -12% margin.

Rilpivirine EFV

Cohen C, et al. Int AIDS Conf 2010. Abstract THLBB206. Graphics used with permission.

HIV-1 RNA < 50 copies/mL at Wk 48 by BL VL

40

0

100

20

8082.384.3

60

682686n =

ECHO THRIVEPooled

Pa

tie

nts

(%

)

82.882.9 81.785.6

338340344346

-3.6 (-9.8 to +2.5)-3.6 (-9.8 to +2.5)

6.6 (1.6-11.5)6.6 (1.6-11.5)

> 100,000 copies/mL

125/165

121/153

246/318

149/181

136/171

285/352

7781 79 8076 82

Pa

tie

nts

(%

)

40

0

100

20

80

60

Pooled THRIVEECHO

≤100,000 copies/mL

162/181

170/187

332/368

136/163

140/167

276/330

9083

9184

9084

Pa

tie

nts

(%

)

40

0

100

20

80

60

ECHO THRIVEPooled

ECHO, THRIVE: Treatment Failure, Resistance, and Adverse Events

Wk 48 Outcome Rilpivirine(n = 686)

Efavirenz(n = 682)

VF with resistance data, n 62 28

No NNRTI or NRTI RAMs,% 29 43

1 Emergent NNRTI RAM,% 63 54

Most frequent NNRTI RAM E138K K103N

1 Emergent NRTI RAMs, % 68 32

Most frequent NRTI RAM M184I M184V

Cohen C, et al. Int AIDS Conf 2010. Abstract THLBB206.

Treatment Failure in ECHO and THRIVE

Adverse Events and Discontinuation

Resistance at Virologic Failure

6

0

15

3

12

94.8

346n =

VF

9.0

682686

6.7

AE

2.0

682686

Pat

ien

ts (

%)

Wk 48 Outcome, %

Rilpivirine(n = 686)

Efavirenz(n = 682)

P Value

DC for AE 3 8 .0005

Most Common AEs of Interest, %

Any neurologic AE 17 38 < .0001Any psychiatric

AE 15 23 .0002

Any rash 3 14 < .0001

Rilpivirine

EFV

Miscelánea (DHHS 2011).Miscelánea (DHHS 2011).

Recuento de céls CD4Recuento de céls CD4

Fallo virológico: > 200 cop/ml.Fallo virológico: > 200 cop/ml.(en práctica clínica diaria)(en práctica clínica diaria)

PR/QT e IP/rPR/QT e IP/r

PR/QT e IP/r y metadonaPR/QT e IP/r y metadona

ARV con potenciales ventajas en ARV con potenciales ventajas en interacciones prácticas:interacciones prácticas:

FPV ó DRV/rtv; ETR; RAL; MVC.FPV ó DRV/rtv; ETR; RAL; MVC.

Y cuidado que hay interacciones que matan….

TBC/VIH e inicio tto ARV.TBC/VIH e inicio tto ARV.

CAMELIA: Survival With Early (2 S) vs Late (8 S) Therapy (D4T + 3TC + EFV) in TB-Coinfected Patients

Significantly higher incidence of IRIS with early vs late HAART

– 4.03 vs 1.44 per 100 person-mos, respectively (P < .0001)

Blanc FX, et al. AIDS 2010. Abstract THLBB206.

WkSurvival Probability, % (95% CI)

PEarly Arm Late Arm

50 86.1 (81.8-89.4)

80.7 (76.0-84.6) .07

100 82.6 (78.0-86.4)

73.0 (67.7-77.6) .006

150 82.0 (77.2-85.9)

70.2 (64.5-75.2) .002

Factor Multivariate Adjusted HR (95% CI)

P

Late therapy 1.52 (1.12-2.05) .007

BMI ≤ 16 1.68 (1.07-2.63) .01

Karnofsky score ≤ 40 4.96 (2.42-10.16) < .001`

Pulmonary + extrapulmonary TB

2.26 (1.62-3.16)< .001

NTM 2.84 (1.13-7.13) < .001

MDR-TB 8.02 (4.00-16.07) < .001

Factors Independently Associated With MortalitySurvival Probability, Early vs Late Therapy

Log rank P = .0042

Wks From TB Treatment Initiation

Pro

bab

ilit

y o

f S

urv

ival 1.00

0.90

0.80

0.70

0.60

Early armLate arm

0 50 100 150 200 250

Interacciones tto ARV.Interacciones tto ARV.

Interacciones tto ARV.Interacciones tto ARV.

Interacciones tto ARV.Interacciones tto ARV.

Bosentan (tracleer®) Dosis: Inicial 62.5 mg 1 comp/12 horas 4 semanas y después 125 mg 1 comp/12 horas.Comps de 62.5 y 125 mg (ambos PVL 2230 € envase 56 comps).

Nuestra Cohorte: 6 PTES todos con LPV/ATV y Bosentan estables, antes llevaban 125 mg/12 horas, ahora 62,5 mg QOD= AHORRO ANUAL DE 120. 000 €

Conclusiones….Conclusiones….

La ficha (técnica) , el ficha y los fichajes….La ficha (técnica) , el ficha y los fichajes….