simplificación del tratamiento antirretroviraljornadesvih.org/pdf/2017_santigo_moreno.pdf ·...
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Simplificación del Tratamiento Antirretroviral
Dr. Santiago Moreno
Servicio de Enfermedades Infecciosas
Hospital Universitario Ramón y Cajal
Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)
Universidad de Alcalá de Henares
Madrid
Definition: Treatment Simplification
• US Department of Health and Human Services
• Defined broadly as a change in established effective therapy to
reduce pill burden and dosing frequency, to enhance tolerability, or
to decrease specific food and fluid requirement
• GeSIDA
• A switch from a suppressive therapy regimen to a more simple one
that can maintain virological suppression
El término OPTIMIZACION es preferible
Estrategias de Optimización (Simplificación)
• Reducir el número de dosis
• Reducir el número de pastillas
• Reducir el número de fármacos
• Mejorar las condiciones de las tomas
• Interrumpir el tratamiento
• Disminuir los días de administración de fármacos
Estrategias de Optimización (Simplificación)
• Reducir el número de fármacos
• Disminuir los día de administración de fármacos
Número de Fármacos: Evolución del TAR
Dual NRTIs
1987 • First NRTI
1991–2 Two new NRTIs approved
1994 Dual NRTIs better than monotherapy
Triple combination
therapy
Sequential monotherapy
PI/r monotherapy
• NNRTI + 2NRTIs • PI/r + 2NRTIs • II + 2NRTIs • CCR5a + 2 NRTIs
Dual therapy
• PI/r + NRTI • PI/r + NNRTI • PI/r + CCR5 inh • PI/r + II • II + 3TC
75,2% 69,3%
10,1% 16,5%
2,3%
7,9%
11,6%
6,3%
0,8%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
DRV/r + 2NRTI (ITT) DRV/r mono (ITT)
difference=-5.9%,
95% C.I.-16.9%, +5.1%).
HIV RNA <50
Switch NRTI
VF
d/c - AE
d/c - other
Perc
enta
ge o
f patients
DRV-r en monoterapia no cumplió criterios de no inferioridad frente a DRV/r + 2 ITIAN (Monet, 144 sem)
HIV Med. 2012 Aug;13(7):398-405. doi: 10.1111/j.1468-1293.2012.00989.x. Epub 2012 Mar 14.
Estudio PROTEA. HIV-1 RNA in CSF samples at Week 48
Clarke A. HIV Drug Therapy Conference, Glasgow, UK, November 2014 [oral presentation: O423A]
7
%<
50cp
s/m
l
• 8/77 Monotherapy >50 by week 48
• 6/8 Genotype amplified
• 3/6 INI resistance
• 1 each 155H, 263K, 230R
• DSMB stopped study
• Authors recommend against DTG monotherapy
• Combined analysis of 3 cohorts*
• 11/178 (6.1%) VF
• 3.9% INI resistance
• 148R/H (3), 155H (2), 118R (2)
DTG Monotherapy RCT Stopped Due to Failures
Wijting l, et al. 24th CROI; Seattle, WA; February 13-16, 2017. Abst. 451LB. *Blanco Jl, et al. 24th CROI; Seattle, WA; February 13-16, 2017. Abst. 42
SALT Trial Switching to ATV/r+3TC vs. Standard ATV/r+2NRTIs is safe and effective
Pérez Molina JA. Lancet Infectious Diseases 2016 9
10
Metanalysis of bPI-based dual therapy: clinical trials identified
Study (n) DT group TT group
ATLAS-M1 (266) ATV/r+3TC ATV/r+2N(t)RTIs
SALT2 (286) ATV/r+3TC ATV/r+2N(t)RTIs
OLE3 (250) LPV/r+3TC LPV/r+2N(t)RTIs
DUAL4 (249) DRV/r+3TC DRV/r+2N(t)RTIs
Source: 1Di Giambenedetto S. et al. Journal of Antimicrobial Chemotherapy. 2017;72:1163-1171 2Perez-Molina JA. et al. The Lancet Infectious Diseases. 2015;15:775–84 3Arribas JR. et al. The Lancet Infectious Diseases. 2015;15:785–92 4Pulido F. et al. Clinical Infectious Diseases 2017; Aug 17. doi: 10.1093/cid/cix734
Estrategias en pacientes experimentados
11
Primary endpoint
HIV-RNA ≥50 cop/mL at week 48 Dual therapy – triple therapy (%)
SALT
ATLAS
DUAL
OLE
POOLED
1.40 (-2.80, 5.60)
-0.70 (-5.90, 4.40)
1.50 (-2.20, 5.30)
1.70 (-2.60, 6.00)
0.90 (-1.30, 3.20)
0 0%
Absolute risk difference, (95% CI) Non-inferiority margin: 4%
4% Favours DT
At 48w, 4% of patients on DT vs. 3.04% on TT had HIV-RNA ≥50 cop/mL
Difference 0.9% (95%CI, -1.3% to 3.2%)
Estrategias en pacientes experimentados
Treatment difference (DT vs. TT) was not affected by Sex, HCV infection status or type of PI
• 110 Subjects
• No Hx of failure, No Hep B
• 8 week Switch to 2NRTI+DTG
• 40 Weeks FU on DTG/3TC
• 1 x VF (no resistance)
• 4 SAE
• Suicidal ideation
• CK elevation post exercise
• Grade 4 Depression
• Acute Hep C
ANRS 167 LamiDol Study DTG/3TC Maintenance
Joly V, et al. 24th CROI; Seattle, WA; February 13-16, 2017. Abst. 458.
13
ASPIRE: cambio a 3TC+ Dolutegravir
en pacientes con CV indetectable
Taiwo BO, et al. EACS 2017. Abstract PE 8/5.
Open-label, randomized, multicenter investigator-initiated clinical trial
1:1 Randomization
Week 24
Primary Endpoint Week 48
14 ASPIRE: Virologic outcomes at week
48
(FDA Snapshot)
Taiwo BO, et al. EACS 2017. Abstract PE 8/5.
N 41 41 1 0 2 4
On Study 44 45 44 45 44 45
Continue on the same cART (CONTROL)
Switch to DTG + 3TC dual therapy
Open-label
Randomisation
1 : 1 : 1
Stratifying by 3rd agent HIV+ ≥ 18 years
On triple cART
HIV RNA < 50 c/mL > 12
months
No prior VF to 3TC/FTC or
INSTI
Nadir CD4 >200 cells/mm3
HBsAg negative
W24
Switch to DTG monotherapy
W48
DOLAM: Dolutegravir-based
simplification strategies
Blanco JL, et al. EACS 2017. Abstract PE .
Dolutegravir + Rilpivirine for Maintenance of Suppression: : Snapshot Outcomes at Week 48.
Llibre J, et al. 24th CROI; Seattle, WA; February 13-16, 2017. Abst. 44LB.
DTG+RPV is non-inferior to CAR with respect to snapshot in the ITT-E population (<50 c/mL) at Week 48
Adjusted Treatment Difference (95% CI)
DTG + RPV CAR
-3.0
-0.2
2.5
Percentage-Point Difference
Virologic Outcomes
Fletcher CV. PNAS 2014.
17
Existe replicación vírica persistente en tejidos
Variable penetration of ARV in tissue
Fletcher, 19th CROI, Seattle 2012
CD
14
+C
D1
6-C
D1
63
+ c
ell
s (
%)
c A R T M P I
0
2 0
4 0
6 0
8 0
1 0 0
p = 0 .0 3 1
sC
D1
4 (
ng
/ml)
c A R T M P I
1 0 0 0
1 5 0 0
2 0 0 0
2 5 0 0
3 0 0 0
3 5 0 0
p = 0 .0 0 4
sC
D1
63
(n
g/m
l)
c A R T M P I
0
2 5 0
5 0 0
7 5 0
1 0 0 0
p = 0 .0 0 2
LB
P (
ng
/ml)
c A R T M P I
5 0 0 0
7 5 0 0
1 0 0 0 0
1 2 5 0 0
1 5 0 0 0
p = 0 .0 7
A B
C D
La monoterapia con IP/r se asocia con una mayor replicación vírica persistente
García F. CROI 2013; JIAS 2014.
T-cell immune activation levels in mART-treated and cART-treated patients
2
0
Petrara. PLoS One. 2017.
2
1
CD4/CD8 ratio in patients who switch cART therapy: triple drug regimen could be better than mono/dual?
Mussini C. IAS 2017. Paris. Abstract MOPEB0323
Porcentaje de diferencia en la concentración sérica de los biomarcadores (ajustado por edad, VHC, hipertensión, raza y tabaquismo).
Castillo-Mancilla JR et al. Clin Infect Dis 2016. pii: ciw650. [Epub ahead of print]
Abreviaturas: BAFF, factor activador de las células B; CCL, quimioquinas C-C ligando; CXCL
quimioquinas CXC ligando; GM-CSF, factor estimulante de granulocitos y macrófagos ; IFN- ,
interferón gamma; IL, interleucina; sCD14, CD14 soluble; sCD27, CD27 soluble; sgp130,
glicoproteína soluble 130; sIL-2R , receptor soluble IL-2; sIL-6R, receptor soluble IL-6; sTNF-R2,
receptor soluble del factor de necrosis tumoral; TNF- , factor de necrosis tumoral lpha; CRP,
proteína C reactiva.
<100% vs 100% (6-m)
Estimado p
TNF-α 11,2% <0,001
IFN-γ 14,8% 0,008
CRP 21,1% 0,006
IL-2 14,4% 0,022
IL-10 11,1% 0,023
IL-6 11,6% 0,014
Abreviaturas: IFN- , interferón gamma; IL, interleucina; TNF- , factor de necrosis tumoral lpha; CRP, proteína C reactiva.
Suboptimal cART Adherence is Associated with
Higher Levels of Inflammation Despite HIV Suppression.
LATTE-2: Cabotegravir IM + Rilpivirine IM for
Long-Acting Maintenance ART
• Multicenter, open-label phase IIb study
• Cabotegravir: integrase inhibitor
Margolis DA, et al. CROI 2016. Abstract 31LB.
CAB 400 mg IM + RPV 600 mg IM Q4W†
(n = 115)
CAB 600 mg IM + RPV 900 mg IM Q8W‡
(n = 115)
6 pts discontinued for AEs or death in induction analysis. *Pts with HIV-1 RNA < 50 c/mL from Wk 16 to Wk 20 continued to
maintenance phase. †Loading dose: Day 1, CAB 800 mg + RPV 600 mg. ‡Loading dose: Day 1, CAB 800 mg + RPV 900
mg; Wk 4, CAB 600 mg.
ART-naive HIV-
infected pts with
CD4+ cell count >
200 cells/mm3
(N = 309) CAB 30 mg PO + ABC/3TC PO QD
(n = 56)
CAB 30 mg PO QD + ABC/3TC
Wk 32
primary analysis
Wk 20
Induction Phase* Maintenance Phase
Wk 1 Wk 96 Wk 16: RPV
PO added
CAB loading doses at Day 1 (800 mg) and Week 4 (600 mg)
Induction period
LATTE-2 Study Design
Week 32
Primary analysis
Dosing regimen
selection
Day 1
Randomization
2:2:1
Week 48
Analysis
Dosing regimen
confirmation
Week 96b
CAB loading dose at Day 1 (800 mg)
CAB 30 mg + ABC/3TC PO QD (n=56)
Maintenance perioda
CAB 400 mg IM + RPV 600 mg IM Q4W (n=115)
CAB 600 mg IM + RPV 900 mg IM Q8W (n=115)
CAB 30 mg +
ABC/3TC for
20 weeks
Add RPV
PO QD
4 weeks
Eron et al. IAS 2017; Paris, France. Slides MOAX0205LB.
ABC/3TC, abacavir/lamivudine; ALT, alanine aminotransferase; IM, intramuscular; PO, orally; QD, once daily;
Q4W, every 4 weeks; Q8W, every 8 weeks; ULN, upper limit of normal. aSubjects who withdrew after at least 1 IM dose entered the long-term follow-up period. bSubjects can elect to enter
Q4W and Q8W LA extension phase beyond Week 96.
Inclusion criteria • ≥18 years old
• Naive to antiretroviral therapy
• CD4+ ≥200 cells/mm3
Exclusion criteria • Positive for hepatitis B
• ALT ≥5 × ULN
• Creatinine clearance <50 mL/min
Qualification for
maintenance • HIV-1 RNA <50 c/mL between Week -4 and
Day 1
Comparable Response Across Arms Week 96 HIV-1 RNA <50 c/mL by Snapshot (ITT-ME)
• CAB, cabotegravir; CI, confidence interval; IM, intramuscular; ITT-ME, intent-to-treat maintenance exposed; LA, long acting; NRTI, nucleoside reverse transcriptase inhibitor;
PO, orally; Q4W, every 4 weeks; Q8W, every 8 weeks; RPV, rilpivirine.
Virologic outcomes Treatment differences (95% CI)
Oral IM
Q8W IM
−8.4% 14.4%
Q4W IM
− 0.6% 20.5%
Eron et al. IAS 2017; Paris, France. Slides MOAX0205LB.
Conclusiones • El tratamiento antirretroviral actual se encuentra en un avanzado estado de
simplificación y optimización
• En cuanto a potenciales estrategias futuras de optimización:
• Parece descartada la monoterapia con los fármacos actualmente disponibles
• Buenos datos clínicos con la disminución del número de fármacos en el régimen
• Fármacos de administración prolongada
• Cualquier estrategia futura de optimización del tratamiento antirretroviral debe tener las garantías razonables de no someter a un daño innecesario a los pacientes
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