terapia del paciente naivecon un régimen de inhibidor de...
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Terapia del paciente naive con un régimen de Inhibidor de la proteasa
Dr. Jose R ArribasIX Curso de avances en
Infección VIH y hepatitis virales
Eficacia en Ensayos Clínicos pivotales en naïves
RAL DTGEVG/c
EFV
ATV/r DRV/r
RPV
Single4
DTG>EFV
Spring-26
DTG=RAL
Flamingo8
DTG>DRV/r
ACTG 52579
DRV/r>ATV/r
ACTG 52579
RAL>ATV/rRAL>DRV/r
ACTG52025
ATV/r=EFV
1037
EVG/C=ATV/r
1022
EVG/C=EFV
Echo/Thrive1
RPV=EFV
Startmrk3
RAL>EFV
1. Cohen CJ et al. JAIDS 2012; 60 (1): 33-42 ; 2. Sax PE et al. Lancet 2012; 379: 2439–48; Rockstroh JK et al. JAIDS 2013; 63 (1); 4. Walmsley SL et al. N Engl J Med 2013; 369:1807-1818; 5. Daar ES, et al. Ann Intern Med 2011;154:445–56; 6. Raffi F et al. Lancet. 2013 Mar 2;381(9868):735-43; 7. DeJesus E, et al. Lancet 2012;379:2429–38; 8. Feinberg J et al. 52 ICAAC, September 9-12, 2012, H-1464a; 9. Landovitz RJ et al. CROI 2014. Abstract 85. 10. Cohen C. AIDS 2014, 28:989–997.
STAR10
RPV=EFV
Study DesignStudy 103
Conducted in parallel with Study 102 comparing STB to ATR
Randomized, double-blind, double dummy, active-controlled, international study
Treatment Naïve HIV-1 RNA ≥ 5000 c/mL
Any CD4 cell count
eGFR ≥70 mL/min
HIV-1 RNA < 50 c/mL by snapshot analysis (ITT)Non-inferiority margin (Wk48): 12%
STB QD
ATV/r+TVD Placebo QD
ATV+RTV+TVD QD
STB Placebo QD
(n=350)
(n=350)
Week 48
1:1*
Week 144
Primary Endpoint Secondary Endpoint
*Randomization stratified by screening HIV-1 RNA
(≤ vs >100,000 c/mL)
Efficacy Endpoint: HIV-1 RNA <50 c/mL Study 103 – Primary (Wk 48) and Secondary (Wk 96 and 144)
Virologic Success * Virologic Failure * No data *
Per
cent
age
of s
ubje
cts
(%)
STB (n=353) ATV+RTV+TVD (n=355)
95% CI for Difference
Favors ATV+RTV+TVD Favors STB
W48
0 -12%
-2.1% 7.5%
2.7%
W96-4.5% 6.7%
1.1%
12%
11
W144-3.2% 9.4%
3.1%11
*Virologic outcome as defined by FDA Snapshot algorithm
A5257 Study Design*
RAL 400 mg BID + FTC/TDF 200/300 mg QD
DRV 800 mg QD + RTV 100 mg QD + FTC/TDF 200/300 mg QD
ATV 300 mg QD + RTV 100mg QD+ FTC/TDF 200/300 mg QD
Study Conclusion 96 weeks after final participant e nrolled
Follow-up continued for 96 weeks after randomization of last subject (range 2-4 years) regardless of status on randomized ART
HIV-infected patients, ≥18 yr, with no previous ART, VL ≥ 1000 c/mL at US Sites
Randomized 1:1:1 to Open Label TherapyStratified by screening HIV-1 RNA level (≥ vs < 100,000 c/mL), A5260s
metabolic substudy participation, cardiovascular risk
*With the exception of RTV, all ART drugs were provided by the study
Cumulative Incidence of Virologic Failure
Difference in 96 wk cumulative incidence (97.5% CI)
-20 0-10 10 20
3.4% (-0.7%, 7.4%)
5.6% (1.3%, 9.9%)
-2.2% (-6.7%, 2.3%)
ATV/r vs RAL
DRV/r vs RAL
ATV/r vs DRV/r
Cumulative Incidence of Tolerability Failure
Difference in 96 wk cumulative incidence (97.5% CI)
-20 0-10 10 20
13% (9.4%, 16%)
3.6% (1.4%, 5.8%)
9.2% (5.5%, 13%)
ATV/r vs RAL
DRV/r vs RAL
ATV/r vs DRV/r
Favors RAL
Favors DRV/r
Cumulative Incidence of Virologic or Tolerability Failure
Difference in 96 wk cumulative incidence (97.5% CI)
-20 0-10 10 20
15% (10%, 20%)
7.5% (3.2%, 12%)
7.5% (2.3%, 13%)
ATV/r vs RAL
DRV/r vs RAL
ATV/r vs DRV/r
Favors RAL
Favors RAL
Favors DRV/r
*Consistent results seen with TLOVR at a 200 copies/ml threshold
Proportion VL ≤50 copies/mLITT, regardless of ART change ITT, off-ART=failure ( SNAPSHOT)
24 48 96 144
ATV/r 83% 90% 88% 90%
RAL 90% 92% 94% 94%
DRV/r 83% 88% 89% 90%
24 48 96 144
ATV/r 70% 73% 63% 62%
RAL 84% 83% 80% 76%
DRV/r 77% 77% 73% 71%
14th European AIDS Conference; October 16-19, 2013; Brussels, Belgium
FLAMINGO (ING114915) Study Design
Clotet et al. EACS 2013; Brussels, Belgium. Abstract LBPS4/6.
Primary endpoint: proportion with HIV-1 RNA <50 c/mL at Week 48, FDA Snapshot
analysis, -12% non-inferiority (NI) margin
Secondary endpoints: antiviral activity, safety, tolerability, health outcomes and viral
resistance
HIV+ ART-naiveVL ≥1,000 c/mL
Stratified by screening plasma HIV-1 RNA
(≤ vs >100,000 c/mL) and background dual NRTI (ABC/3TC or TDF/FTC*)
Week 96 analysis
Randomization Week 48
analysis
DRV/r 800 mg/100 mg QD
+ 2 NRTIs
DTG + ART
Open-label randomized phase
DTG 50 mg QD +
2 NRTIs
Extension phase
*Investigator selected backbone of choice
Orkin C et al HIV Med 2012; 14:49–59.
PI Resistance Rare at VF in First-line Studies of Boosted PIsStudy n PI Wk Genotypes Major PI Mutations
CASTLE[1] 440443
ATV/RTVLPV/RTV
962626
10
ACTG 5202[2] 463465
ATV/RTV 968357
10
Study 103[3] 355 ATV/RTV 144 NR 0
ARTEMIS[4] 343346
DRV/RTVLPV/RTV
963146
00
FLAMINGO[5] 242 DRV/RTV 48 NR 0
ACTG 5257[6] 605601
ATV/RTVDRV/RTV
967599
00
1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Daar ES, et al. Ann Intern Med. 2011;154:445-456.3. Clumeck N, et al. EACS 2013. Abstract LBPS7/2. 4. Mills A, et al. AIDS. 2009;23:1679-1688. 5. Clotet B, et al. Lancet. 2014;[Epub ahead of print]. 6. Landovitz R, et al. CROI 2014. Abstract 85.
� Among 4303 pts in these trials, only 2 pts developed major PI mutations at initial VF
Patient with bad adherence
Dual therapy with Lopinavir/ Ritonavir (LPV/r) and Lamivudine (3TC) is
non-inferior to standard triple drug therapy in Naïve HIV-1 infected
subjects : 48-week results of the GARDEL Study.
ClinicalTrials.gov : # NCT01237444
Pedro Cahn on behalf of the GARDEL study group
Study design
Phase III, randomized, international , controlled, open-label study
• Study included adult patients from Argentina, Chile, Mexico, Peru, Spain, US.
DT:
LPV/r 400/100mg BID
+ 3TC 150 mg BID
(n=217)
TT:LPV/r 400/100mg BID
+ 3TC or FTC and a third investigator-selected NRTI in
fixed-dose combination(n=209)
ARV- naive patients,
≥18 years
HIV-1 RNA >1000 copies/ml
No IAS-USA defined NRTI or PI resistance at screening*
HB(s)Ag negative
(N = 426)
Stratified by screening
HIV-1 RNA
(≤ or > 100,000 copies/mL)
Wk 48
primary endpoint
*Defined as > 1 major or > 2 minor LPV/r mutations)
LPV major mutations include the following mutations: V32I; I47V/A; L76V; V82A/F/T/S
Wk 24
interim analysis
Viral load <50 copies/mL
at week 48 (ITTe)
88.3%
83.7%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
BSL W4 W8 W12 W24 W36 W48
DT TT
(p= 0.171, difference +4.6%
[CI95%:-2.2% to +11.8%])
Viral load <50 copies/mL
at week 48 (ITTe), baseline VL
> 100.000 copies/mL
87.2%
77.9%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
BSL W4 W8 W12 W24 W36 W48
DT TT
(p= 0.145, difference +9.3%
[CI95%:-2.8% to +21.5%])
Protocol-Defined Virologic Failure and
Emergent Resistance Mutations
Number of patients, n (%)DT
(N=214)
TT
(N=202)
Confirmed virological failures 10 (4.6 %) 12 (5.9 %)*
HIV-1 RNA at failure (copies/ml) (median-
IQR)
236
(183-17,687)
1027
(123-4,880)
Never suppressed 2 8
Rebounders 8 4
Primary PI RAMs 0 0
NRTI RAMs (M184V) 2 0
*p=0.72
PDVF: 2 measurements of HIV-1 RNA at least 1 week apart
>400 copies/mL at week 24
> 50 copies/mL at week 48
Emergent resistance mutations, in samples successfully amplified:
DT: 2 out of 5 both M184V
TT: 0 out of 8
Milestones in the Evolution of the PI Class
PAST PRESENT(Not-too-distant)
FUTURE
Many pills per day Multiple doses necessary
Improved tolerabilitySome boosted
1 pill per day (+ RTV & NRTIs)Boosting gold standard
Manageable toxicity
More coformulations Single-tablet regimens
High toxicity
Once-daily dosingCoformulation
Some treatment-limiting toxicity
SQVRTVIDV
APVNFV
FPV/RTVLPV/RTV
ATVATV/RTVDRV/RTV
ATV/COBIDRV/COBI
DRV/COBI/TAF/FTC
SQV/RTVIDV/RTV
8000
DRV/COBI FDC Bioequivalent to DRV + RTV and to DRV + COBI� PK analyses in healthy subjects
DRV Concentration When DRV and COBI Administered as Single Agents or as
Coformulation [2]
DRV Concentration When Administered as DRV + RTV or as DRV/COBI Coformulation [1]
1. Kakuda TN, et al. Clin Pharmacol. 2012. Abstract O_20. 2. Kakuda TN, et al. IAS 2013. Abstract MOPE029.
HrsPla
sma
Con
cent
ratio
n of
DR
V
(ng/
mL;
Mea
n ±± ±±
SD
)
Hrs
DRV/RTV 800/100 mg QD as single agents (n = 32)DRV/COBI 800/150 mg QD as FDC (n = 33)DRV/COBI 800/150 mg QD as FDC (n = 33)
Single agents; fed (n = 38)FDC; fed (n = 40)Single agents; fasted (n = 72)FDC; fasted (n = 74)
6000
4000
2000
0240 6 12 18
8000
6000
4000
2000
00 4 8 12 16 20 24
Ongoing Studies of COBI-Boosted DRV Plus 2 NRTIs� Phase IIIb study in tx-naive tx-exp’d pts
with no DRV RAMs[1]
– Primary endpoint: grade 3 or grade 4 AEs by Wk 24
– Secondary endpoints: HIV-1 RNA at Wk 24 and Wk 48
� Randomized, double-blind phase II trial[2]
– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 24
Pts with HIV-1 RNA≥ 500; naive or on stable
ART for 12 wks and sensitive to
2 NRTIs with no DRV RAMS
(N = 300)
DRV + COBI + 2 NRTIs
Wk 48
1. ClinicalTrials.gov. NCT01440569. 2. ClinicalTria ls.gov. NCT01565850.
ART-naive pts, HIV-1 RNA ≥ 5000 c/mL,
eGFR ≥ 70 mL/min(N = 150)
DRV/COBI/TAF/FTC QD(n = 75)
DRV/COBI + TDF/FTC(n = 75)
Wk 48Wk 24
Wk 24
� Coformulation of DRV and COBI being considered for approval by FDA
EIMC . En prensa
Lennox JL et al. Annals of internal medicine 2014
Conclusiones
� Los IPs potenciados son apropiados para muchos pacientes naïve
� Gran experiencia clínica
� Prácticamente no hay resistencia primara
� Alto grado de supresión virológico en terapia de inicio.
� No selección de resistencias tras fracaso.
� Buen perfil metabólico (ATV y DRV)
� Cobicistat puede ofrecer una nueva oportunida de coformulación
� FLEXIBILIDAD
– Terapias duales
Emergent Resistance Through Week 144Study 102/103 – Week 144
STB(n=701)
EFV/TVD(n=352)
ATV/r + TVD (n=355)
n (%) W96 W144 W96 W144 W96 W144
Population Analyzed
36 (5.1%) +6 (0.9%) 23 (6.5%) +5 (1.4%) 16 (4.5%) +3 (0.8%)
EmergentResistance
16 (1.9%) +2 (+0.3%) 10 (2.8%) +4 (+1.1%) 0 +2 (+0.6%)
Primary INSTI-R
14 (2.0%) +1 (+0.1%) 10 (2.8%) +4 (+1.1%) 0 0
or NNRTI-R E92Q 9 0 K103N 9 +4 I50L 0 0
or PI-R N155H 5 0 K101E 3 +2 I84V 0 0
Q148R 3 0 V108I 2 +2 N88S 0 0
T66I 2 0 Y188F/H/L 2 +1
T97A 0 +1 M230L 2 +0
V90I 1 +0
G190A/S 1 +0
P225H 1 +0
Primary NRTI-R
15 (2.1%) +2 (+0.3%) 3 (0.9%) +1 (+0.3%) 0 +2 (+0.6%)
M184V/I 15 +2 M184V/I 3 +1 M184V/I 0 +2
K65R 5 0 K65R 3 +0 K65R 0 0