Transcript (DRV).

“Top-Ten” Novedades en el
Tratamiento Antirretroviral.
Dr. MIGUEL GARCÍA DELTORO
Hospital General Universitario Valencia
Unidad Enfermedades Infecciosas
Top Ten Tenis
25 Fármacos antirretrovirales
RAL
DLV
ddC
ZDV
ddI
NVP
d4T
3TC
TFV
ABC
EFV
ETR
FTC
’87 ’88 ’89 ’90 ’91 ’92 ’93 ’94 ’95 ’96 ’97 ’98 ’99 ’00 ’01 ’02 ’03 ’04 ’05 ’06 ’07
NRTI
SQV
NFV
LPV
NNRTI
DRV
FPV
PI
RTV
Inhibidor
entrada
IDV
Ø
INTEGRASA
ATV
APV
TPV
T-20
25 antirretrovirales aprobados por la FDA
MVC
DRV
ETR
MV
C
RAL
Preferred Regimens for Treatment-Naive
Pts: DHHS (12/09)
DHHS guidelines. Available at: http://www.aidsinfo.nih.gov.
Evitar añadir ptes al “carro” de la
Multirresistencia y Lipodistrofia ....
Y entre todos lo estamos consiguiendo, pero
sobre todo por los nuevos fármacos y los “combos”....
Top Ten Novedades Tto ARV….
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.
DRV/r: el último de los IPs y ya casi el más recetado….
 DRV.
– IP/r casi perfecto: el más eficaz, como el más tolerable y benévolo
metabólicamente, el que menos falla y cuando lo hace con menos
mutaciones. Ahora ya datos a medio plazo de ptes naive.
– Ya no necesidad de nevera para el rtv.
– Si no mutaciones de su score se puede dar qd (ODIN).
– Monoterapia no demuestra la no inferioridad a 96 semanas, se
debería de concretar adecuadamente al pte candidato a ella.
La excusa de la nevera se acabó….
(11-11-10: RTV Meltrex aprobado en España y dispobible
desde Enero/2011)
ARTEMIS: Viral load <50 copies/mLICAAC 08
to Week 96 (ITT-TLOVR)a
Patients with VL <50 copies/mL (% [±SE])
Mills A, et al
H-1250c
100
DRV/r QD (N=343)
LPV/r QD or BID (N=346)
80
79%
71%
60
40
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
20
0
0
8
16
24
36
48
60
Time (weeks)
72
aEstimated
84
96
from a logistic regression model
including treatment and stratification factors
(baseline log10 viral load and baseline CD4+ cell
count)
ODIN: study design
• ODIN (TMC114-C229) is a Phase IIIb, randomized, open-label study
– compares efficacy, safety and tolerability at Week 48 in treatmentexperienced adults with no DRV RAMs
• 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
Treatment phase (up to 48 weeks)
590 patients
randomized
Patients stratified by
screening HIV-1
RNA (50,000,
>50,000 copies/mL)
DRV/r 800/100mg qd
+ OBR (2 NRTIs)‡ (N=294)
DRV/r 600/100mg bid
+ OBR (2 NRTIs)‡ (N=296)
*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
Cahn P, et al. 17th CROI 2010. Abstract 57 y AIDS. 2011 Apr 24;25(7):929-939
ODIN: viral load <50 copies/mL
to Week 48 (ITT-TLOVR)
Patients with HIV-1 RNA <50 copies/mL
(% [95% CI])
100
80
72.1%
70.9%
60
DRV/r 800/100mg qd
DRV/r 600/100mg bid
40
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%)
20
0
0
4
8
12
24
Time (weeks)
36
48
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
57 (19.9)
52 (18.4)
0.67
Non-graded lipid-related laboratory
abnormalities, n (%)
HDL below the lower normal limit
*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
DRV/r 800/100 mg OD
+ 2 NRTI (re-optimised at baseline)
n = 129
256 subjects
DRV/r 800/100 mg OD
n = 127
144 weeks
Primary Endpoint: failure at week 48 (TLOVR). Per Protocol, Switch = Failure
The Week 96 analysis was a secondary endpoint.
Rieger et al. Int AIDS Conf July 2010, Vienna [abstr TBLBB209]
MONET: HIV RNA <50 copies/mL at Week 96, TLOVR,
Switch=failure (ITT population)
Switch=failure analysis (TLOVR)
Difference = -5.8% (-16.0%, +4.4%)*
Switch included analysis
Difference = +1.4% (-5.5%, +8.3%)*
100
90
80.6%
80
HIV RNA
<50 by
Week 96
(%)
92.1%
90.7%
74.8%
70
60
50
40
30
20
10
0
DRV/r + 2NRTI
n=129
DRV/r mono
n=127
DRV/r + 2NRTI
DRV/r mono
n=129
* 95% confidence intervals from univariate analysis
n=127
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%.
Annual Spanish Costs of ARV’s
Annual Spanish
cost per person
12000
€11283
€11326
TDF/FTC/DRV/r
TDF/FTC/ATV/r
10000
€8515
8000
6000
€5471
4000
2000
0
DRV/r
TDF/FTC/EFV
MVC: Nuevos datos y posibilidad de utilización qd….
 MVC.
– Mejora parcialmente marcadores de inmunoactivación en ptes suprimidos.
– Disponibilidad de tropismo genotípico rápida y para todos los centros y en
breve posibilidad de tropismo en PBMC para ptes indetectables.
– Datos QD PK (ATV // DRV) y clínicos con ATV disponibles.
– Precio QD muy competitivo.
– Datos QD con DRV “ongoing”.
– Inclusión de QD en ficha técnica por EMEA prevista para Sept-Oct/2011.
Effect of Adding and Removing MVC on Immune Activation in HIV+
Patients on Suppressive ART: Results from ACTG A5256.
Timothy Wilkin et al. CROI 2011 abstract 574.
Mi pequeña contribución al Documento de
Consenso Español de Tropismo….
Estamos en tiempos de crisis….
Coste tratamiento/día
Tratamiento diario (PVL)
Fármaco
Isentress®
Celsentri®
Fuzeon®
Intelence®
Viramune®
Atripla®
Kaletra®
Reyataz®
Prezista®
Dosificación
Coste
Coste RTV
400 mg
Bid
150 mg
Bid
21,00 € (19,00€)
QD
21,76 €
300 mg
Bid
21,76 €
90 mg/ml
Bid
50,85 €
200 mg
Bid
13,00 €
400 mg
QD
13,00 €
400 mg
Bid/QD
8,51 €
600/200/245 mg
QD
23,33 €
400/100 mg
Bid
13,33 €
800/200 mg
QD
13,33 €
300/100 mg
QD
14,55 €
0,75 €
600/100 mg
Bid
21,36 €
1,50 €
800/100 mg
QD
14,24 €
0,75 €
-
10,88 €
-
-
MVC 150 MG QD (+ ATV/R)
All Patients Had Plasma MVC Concentrations Above the in vivo IC50 Across the
Dosing Interval 1
MVC Concentration (ng/mL)
10,000
1000
*
100
10
7.65 ng/mL (in vivo IC50)2
1
0
4
8
12
16
20
24
Hours
* 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
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.
Stephen Taylor et al. CROI 2011 POSTER 636
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 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
ATV/RTV + MVC (n=60)
HIV-1 RNA < 50 copies/mL Overall and by BL VL
100
89
80
Patients (%)
80
ATV/RTV + TDF/FTC
(n=61)
95
81
80
77
60
40
20
0
n=
60
Overall

44
61
39
HIV-1 RNA < 100K
CD4 + cell count increases similar

16
22
HIV-1 RNA  100K
Grade 3/4 hyperbilirubinemia
–
ATV/RTV + MVC: 195 cells/mm³
–
ATV/RTV + MVC: 59.3%
–
ATV/RTV + TDF/FTC: 173 cells/mm³
–
ATV/RTV + TDF/FTC: 49.2%

Mills A, et al. Int AIDS Conf 2010. Abstract THLBB203.
5 patients in MVC arm, 1 patient in
TDF/FTC arm switched to DRV/RTV per
protocol for jaundice or scleral icterus
RAL y otros inhibidores de la integrasa….
 RAL.
– Eficacia y Tolerancia perfectas ya con datos a medio plazo de pacientes naive.
– RAL/LPV posible como tto libre de NRTI.
– Esperanza en 1 comp en combo QD con elvitegravir.
– Esperanza en rescate con dolutegravir.
– Dosis QD es inferior a la BID.
J.K. Rockstroh, et al. CROI 2010 Abstract # K-135
Raltegravir (RAL): 156 Week (Wk) Results from STARTMRK
 Design
– Multicenter, double-blind, randomized (1:1),
active-controlled study
• RAL 400mg BID vs. EFV 600mg qhs.
• Both given with co-formulated tenofovir
Main Objectives
/ emtricitabine
(FTC) efficacy
–RAL +(TDF)
TDF/FTC
will have non-inferior
compared 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 156
Enrolled Patients
Randomized 1:1
To RAL:EFV Arms
281 Patients
Treated with
RAL
282 Patients
Treated with
EFV
54 Patients (19.2%)
Discontinued
71 Patients (25.2%)
Discontinued
5 – lack of efficacy
12 – AEs
8 – lost to follow-up
29 – miscellaneous*
7 – lack of efficacy
22 – AEs
14 – lost to follow-up
28 – miscellaneous*
227 Patients
(80.8%)
Completed
156 Weeks
211 Patients
(74.8%)
Completed
156 Weeks
*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
<50 c/mL through 156 Weeks (NC = F)
Percent of Patients with
HIV RNA <50 Copies/mL
100
86
81
75
80
82
79
60
68
Δ (RAL-EFV) [95% CI] = +7.3 [-0.2, +14.7]
40
Non-Inferiority p-Value <0.001
20
0
0
16
32
48
60
72
84
96 108 120 132 144 156
Weeks
Number of Contributing Patients
Raltegravir group
Efavirenz group
281
282
281
281
278
280
280 281 281 280 281 281 277 279 280 281
281 282 282 281 282 279 281 281 281 282
llmk518p21CROI50wk156 Jan. 11, 2011
Mean Change from Baseline in Metabolic
Parameters at Week 144
Mean Change (mg/dL)
50
40
Raltegravir
Efavirenz
‡
‡
p<0.001
* p=0.137
‡
30
‡
20
‡
10
*
0
T CHOL

HDL-C
LDL-C
TG
Glucose
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)
Lipoatrophy

Due to attrition in Patients participating in the DEXA substudy it
is difficult to interpret the data in a comparative fashion

The majority of patients in both groups experienced modest fat
gain
– “Return to health” phenomenon

1/25 patients on RAL and 2/32 patients on EFV had at least 20%
appendicular fat loss (lipoatrophy) at Week 156
– There was no discordance between appendicular and trunk
fat loss among these few patients
– None of the patients with lipoatrophy identified by DEXA
scanning had investigator-reported lipodystrophy as an
adverse event
CROI 2011 150LB
QDMRK (P071)
Study Design
 Multicenter, double-blind, randomized, active-controlled study
 Non-inferiority design (10% margin)
Primary endpoint
Week 48
Secondary endpoint
Week 96
Raltegravir 800 mg QD + TDF/FTC FDC
n=382
HIV-1-infected
Treatment naive
HIV-1 RNA >5000 copies/mL
No CD4 cell cut-off
No documented resistance to
tenofovir or emtricitabine
1:1
Raltegravir 400 mg BID + TDF/FTC FDC
n=388
J Eron et al. CROI 2011, 150 LB.
CROI 2011 150LB
QDMRK
% of Patients with HIV RNA < 50 copies/mL (NC=F†)
BID
88.9%
Percent of Patients with
HIV RNA <50 Copies/mL
100
80
QD
83.2%
60
40
Δ (QD-BID) [95% CI] = -5.7 [-10.7, -0.83]
20
0
0
4
8
12
16
24
36
48
381
386
382
386
Study Week
Number of Contributing Patients
RAL 800 mg QD
RAL 400 mg BID
382 382 377 381 379
388 388 386 387 386
380
387
*All patients received TDF/FTC FDC
† Non-completer equals failure (NC=F) approach treats all discontinuations as failures
CROI 2011 150LB
QDMRK
Time 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
100
Percent of Event Free
Percent of Event Free
100
80
HR 0.489 (0.276, 0.867)
P-value 0.0145
60
40
HR 0.572 (0.250,1.308)
p-value 0.1856
60
40
20
20
0
0
0
8
16
24
36
48
60
72
84
0
96
Week
152
152
126
138
126
137
125
135
122
132
112
122
8
16 24
36
48
60
72
84
96
144
147
65
71
34
32
13
15
Week
Number of Patients at Risk
Number of Patients at Risk
RAL 800 mg QD
RAL 400 mg BID
80
79
88
31
39
17
23
5
10
RAL 800 mg QD
RAL 400 mg BID.
230
236
224
231
219
230
216
229
215
226
199
212
CROI 2011 150LB
QDMRK - 48 Week Summary of Virologic
Failures & Resistance Data
Virologic
Failures
VF >400 c/mL,
(data available)
No Evidence of
Resistance
Raltegravir
QD
Raltegravir
BID
53/382 (13.9%)
35/388 (9.0%)
30
(27 with IN data)
16
(12 with IN data)
7
7
Number of VF by Baseline HIV RNA
Raltegravir
QD
Raltegravir
BID
≤ 100,000
16
8
> 100,000
37
27
BL VL (cp/mL)
Definition Of Virologic Failure
Integrase
Resistance and
FTC Resistance
9
2
FTC Resistance
Alone
11
4
1. HIV RNA >50 copies/mL at Week 24
(confirmed at least 1 week apart),
OR
2. 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)
NOTE: No Patient in Either Arm Failed with Evidence of TDF Resistance
CROI 2011 150LB
QDMRK - Summary of Intense and Sparse
PK Parameters
RAL QD
RAL BID
Ratio
RAL QD /
RAL BID
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)
245
83 (140)
304
380 (126)
0.22 (0.19, 0.25)
PK Parameter
GM Ctrough* (nM)
†
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.
||AUC
0-12hr for BID arm and AUC0-24hr for QD arm. Ratio is for 24-hour exposure: (AUC0-24hr QD / 2*AUC0-12hr BID)
§C
trough = C12hr for BID and C24hr for QD
*GM C
trough = 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 150LB
QDMRK
Histograms for GM Ctrough and % with HIV RNA <50 copies/mL
(Observed Failure)
GM C12hr (nM)
Range
Median
GM C24hr (nM)
Range
Median
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
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.
HIV-1 RNA < 40 copies/mL (ITT-TLOVR)
LPV/RTV + RAL
100
80
Patients (%)

84.8%
*
*
83.2%
*
60
Difference: -1.6%
(95% CI: -12.0% to 8.8%)
40
*
*Statistically significant difference between arms:
Wks 2, 4, 8 P < .002
Wk 16 P = .038
20
0
0

8
16
24 32
Wks
40
48
Similar CD4+ cell count gain at Wk 48
–
LPV/RTV + RAL: 215 cells/mm³
–
LPV/RTV + NRTIs: 245 cells/mm³
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
–
–

HIV-1 RNA Response
at Day 11
< 400 c/mL or ≥ 0.7
log10 c/mL decline, %
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)
Eron J, et al. Int AIDS Conf 2010. Abstract MOAB0105.
Change from baseline,
log10 c/mL
Group 1
(n = 9)
Group 2
(n = 18)
33
100
-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
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.
– Vida media “casi infinita” (41 horas).
– Primeros datos SENSE QD a 12 S, en este año los de 48 S (IAS).
– Algún estudio piloto QD pequeño en simplificación.
– NVP XR, más de lo mismo (?).
– Esperanza con RPV de nuevo combo de 1 comp (TRU + RPV), pendiente dictamen
FDA en Mayo/2011.
– Formulación mejorable (aunque “bebible”), posible para Sept-Oct/2011 comps 200
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 treatmentemergent neuropsychiatric AEs
at Wk 12

More drug-related neuropsychiatric
AEs in EFV arm vs ETR arm
100
Patients (%)

Mean change in HIV-1 RNA at Wk 12 
similar between arms (-2.9 log10
copies/mL)
80
Drug-Related Neuropsychiatric AEs
Grade 1-4
P < .001
60
Grade 2-4
P = .02
46
40
20
0
17
ETR EFV
5
ETR
17
EFV
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.
Switching to dual therapy with
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, doubleblind, 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
HIV-1 RNA < 50 copies/mL (TLOVR)
100
Inclusion criteria
–
HIV-1 RNA > 1000 copies/mL
–
CD4+ cell count
< 400 cells/mm3 if male or
< 250 cells/mm3 if female
Adjusted difference 4.92%
(95% CI: -0.11 to 9.96)
81.0
Patients (%)

80
75.9
60
40
20
0
NVP IR


NVP XR
Similar safety and tolerability for
both arms
AEs included
– Stevens-Johnson (n = 5)
– Hepatitis (n = 14)
Gathe J, et al. Int AIDS Conf 2010. Abstract THLBB202.
– Rash (n = 21)
ECHO, THRIVE: Rilpivirine vs EFV in
Treatment-Naive Patients

Randomized, double-blind phase III trials
Stratification by BL
HIV-1 RNA < 100,000
vs ≥ 100,000 copies/mL,
NRTI use*
ECHO
(N = 690)
Treatment-naive,
HIV-1 RNA ≥ 5000 copies/mL
no NNRTI RAMs,
susceptible to NRTIs
THRIVE
(N = 678)
Wk 48
primary analysis
Rilpivirine 25 mg QD
+ TDF/FTC 300/200 mg QD
(n = 346)
EFV 600 mg QD
+ TDF/FTC 300/200 mg QD
(n = 344)
Rilpivirine 25 mg QD
+ 2 NRTIs†
(n = 340)
EFV 600 mg QD
+ 2 NRTIs†
(n = 338)
*THRIVE only. †Selected by investigator from ABC/3TC, TDF/FTC, ZDV/3TC.
Cohen C, et al. Int AIDS Conf 2010. Abstract THLBB206.
Wk 96
final analysis
ECHO, THRIVE: Rilpivirine vs EFV in
Treatment-Naive Patients
Rilpivirine
EFV
100
84.3
82.3
Patients (%)
80
85.6
82.9
82.8
81.7
Patients (%)
HIV-1 RNA < 50 copies/mL (ITT-TLOVR) at Wk 48
60
HIV-1 RNA < 50 copies/mL at Wk 48 by BL VL
6.6 (1.6-11.5)
100
91
90
90
84
83
84
80
60
40
20
0
40
100
0
n = 686
682
Pooled
346
344
ECHO
340
338
THRIVE
*P < .0001 for noninferiority at -12% margin.
Patients (%)
20
80
162/ 136/
181 163
170/ 140/
187 167
Pooled
ECHO
THRIVE
≤100,000 copies/mL
-3.6 (-9.8 to +2.5)
77
81
76
82
79
80
60
40
20
0
Cohen C, et al. Int AIDS Conf 2010. Abstract THLBB206.
Graphics used with permission.
332/ 276/
368 330
246/ 285/
318 352
Pooled
125/ 149/
165 181
121/ 136/
153 171
THRIVE
ECHO
> 100,000 copies/mL
ECHO, THRIVE: Treatment Failure,
Resistance, and Adverse Events
Patients (%)
Treatment Failure in ECHO and THRIVE
15
Rilpivirine
12
9
EFV
9.0
6.7
3
0
Wk 48 Outcome,
%
4.8
6
686 682
n = 346
VF
DC for AE
2.0
686 682
AE
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
E138K
K103N
68
32
M184I
M184V
 Most frequent NNRTI RAM
 1 Emergent NRTI RAMs, %
 Most frequent NRTI RAM
Rilpivirine
(n = 686)
Efavirenz
(n = 682)
P Value
3
8
.0005
Most Common AEs of Interest, %
Resistance at Virologic Failure
Wk 48 Outcome
Adverse Events and Discontinuation
Any neurologic AE
17
38
< .0001
Any psychiatric AE
15
23
.0002
Any rash
3
14
< .0001
Cohen C, et al. Int AIDS Conf 2010. Abstract THLBB206.
Miscelánea (DHHS 2011).
Recuento de céls CD4
Fallo virológico: > 200 cop/ml.
(en práctica clínica diaria)
PR/QT e IP/r
PR/QT e IP/r y metadona
ARV con potenciales ventajas en
interacciones prácticas:
FPV ó DRV/rtv; ETR; RAL; MVC.
Y cuidado que hay interacciones que matan….
TBC/VIH e inicio tto ARV.
Probability of Survival
CAMELIA: Survival With Early (2 S) vs Late (8 S) Therapy
(D4T + 3TC + EFV) in TB-Coinfected Patients
Survival Probability, Early vs Late Therapy
1.00
Early arm
Late arm
0.90
Factors Independently Associated With Mortality
Multivariate
Adjusted HR (95% CI)
P
Late therapy
1.52 (1.12-2.05)
.007
0.80
BMI ≤ 16
1.68 (1.07-2.63)
.01
0.70
Karnofsky score
≤ 40
4.96 (2.42-10.16)
< .001`
Log rank P = .0042
0.60
0
Wk
50
100
150
200
250
Wks From TB Treatment Initiation
Survival Probability, % (95% CI)
P
Early 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
Blanc FX, et al. AIDS 2010. Abstract THLBB206.
Factor
Pulmonary +
extrapulmonary
TB
2.26 (1.62-3.16)
NTM
2.84 (1.13-7.13)
< .001
MDR-TB
8.02 (4.00-16.07)
< .001

< .001
Significantly higher incidence of IRIS
with early vs late HAART
– 4.03 vs 1.44 per 100 person-mos,
respectively (P < .0001)
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….
La ficha (técnica) , el ficha y los fichajes….