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““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….