Regímenes STR: Análisis Crítico · 2018-10-04 · Raltegravir Aluminium and magnesium containing...
Transcript of Regímenes STR: Análisis Crítico · 2018-10-04 · Raltegravir Aluminium and magnesium containing...
Regímenes STR:Análisis Crítico
XXI Curso VIH
SOCHINF
Agosto 2018
Conflictos de interés
Speaker/ Congresos
• MSD
• Pfizer
• Abbott
• Novartis
Actividad laboral
• Fundación Arturo López Pérez
• Consulta privada pacientes VIH
Regímenes de tableta única disponibles (STR)
Agent Type Yr of FDA
Approval
Efavirenz/tenofovir DF/emtricitabine
(EFV/TDF/FTC)
NNRTI + dual NRTI 2006
Rilpivirine/tenofovir DF/emtricitabine
(RPV/TDF/FTC)
NNRTI + dual NRTI 2011
Elvitegravir/cobicistat/tenofovir DF/emtricitabine
(EVG/COBI/TDF/FTC)*
INSTI + booster + dual NRTI 2012
Dolutegravir/abacavir/lamivudine
(DTG/ABC/3TC)*
INSTI + dual NRTI 2014
Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine
(EVG/COBI/TAF/FTC)*
INSTI + booster + dual NRTI 2015
Rilpivirine/tenofovir alafenamide/emtricitabine
(RPV/TAF/FTC)
NNRTI + dual NRTI 2016
Bictegravir /tenofovir alafenamide/emtricitabine * INSTI + dual NRTI 2018 (BIC/ FTC /TAF)
*DHHS recommended regimen for initial ART.
Class DHHS[1] IAS-USA[2]
INSTI BIC/TAF/FTC DTG/ABC/3TC DTG + (TAF or TDF)/FTC EVG/COBI/(TAF or
TDF)/FTC RAL + (TAF or TDF)/FTC
BIC/TAF/FTC DTG/ABC/3TC DTG + TAF/FTC
DHHS, IAS-USA Guidelines: Recommended Regimens for First-line ART
• Recommendations may differ based on baseline HIV-1 RNA, CD4+ cell count, CrCl, eGFR, HLA-B*5701 status, HBsAg status, osteoporosis status, and pregnancy status
• Data are lacking for women of child-bearing age not using contraception
• IAS-USA now lists EVG/COBI/TAF/FTC and RAL + TAF/FTC as alternative regimens owing to their lower resistance barriers and, respectively, more drug interactions and higher pill burden[2]
1. DHHS Guidelines. May 2018. 2. Saag MS, et al. JAMA. 2018;320:379-396.
Potenciales Ventajas y desventajas de Regímenesde tableta única (STR)
VENTAJAS DESVENTAJAS
Simplicity
Conveniencia
Reduce la no adherencia
selectiva a componentes del
regimen terapeútico
Imposibilidad de ajuste de
dosis de sus componentes
individuales si se requiere:
-interacciones
medicamentosas , tolerancia ,
insuficiencia renal
No disponible para todos los
regímenes de TARV.
No disponible para todos los
backbone de NRTI.
ATHENA and Swiss HIV Cohort Studies: Polifarmacia enPacientes Among VIH + en terapia antiretroviral
5.2% of pts 50-64 yrs of age and 14.2% of pts ≥ 65 yrs of age received ≥ 4 meds other than ART comedications
• Predicts that 20% of pts will be receiving ≥ 3 meds other than ART in 2030
1. Smit M, et al. Lancet Infect Dis. 2015;15:810-818. 2. Hasse B, et al. Clin Infect Dis.
2011:53;1130-1139.
ATHENA Modeling Study[1]
16,0
0014,0
0012,0
0010,0
00800
600
0400
0200
00P
eop
le (
n)
+ comedications2 comedications1 comedicationNo comedication
201
0
201
5
2020 202
5
203
0
Swiss HIV Cohort
Study (N = 8444)[2]
Prospective Observational
Study
< 50 Yrs 50-64 Yrs ≥ 65 Yrs
10
0
80
60
40
20
0
Part
icip
ants
(%
)
n5761 2233 450
No
comedication
1 comedication
2 comedication
3 comedications
4+
Una variedad de interaccionesfarmacocinéticas afectan absorción de drogas
El grado de absorción oral de antiretrovirales pueden ser afectados por :• Ambiente Gástrico• Agentes que disminuyen la producción de ácido (ej. PPIs,
antagonistas H2, antiácidos) pueden reducir la absorción de ARVs que requieren acidez gástrica (ej. ATV -RPV)
• Cationes Polivalentes en algunos productos (ej. Al3+-, Ca2+-, Mg2+ en antiácidos/suplementos/ productos con fierro) pueden unirse a inhibidores de integrasa y reducir suabsorción.
• Drogas que inducen/inhiben enzima CYP3A4 o la glicoproteína P intestinal (efflux transporter) puedereducir/promover la absorción de otras drogas.
DHHS guidelines. Updated October 2017. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf
Antiácidos disminuyen concentraciones plasmáticasde Elvitegravir
Ramanathan S, et al. J Acquir Immune Defic Syndr 2013;64:45–50
0 6 12 18 24
1000
100
EVG/r alone
EVG/r + antacid (Al/Mg)
Mea
n (
SD)
pla
sma
con
cen
trat
ion
(n
g/m
L)
Time (hours)
Patel et al 2011
Dolutegravir Quelación de Inhibidores de Integrasa por cationes
polivalentes
0 10 20 30 40 50 8060 70
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
Mea
n D
TG c
on
cen
trat
ion
(µ
g/m
L)
Time (h)
DTG + antacid 2 hours later
DTG alone
DTG + antacid
Mg2+
Mg2+
InSTI
Inhibidores de Integrasa y Antiácidos que contienenCationes : Recommendaciones
Inhibidores de Integrasa
Recomendación
RaltegravirAluminium and magnesium containing antacids reduce RAL plasma levels. Co- or staggered administration of RAL with these antacids is NOT recommended.RAL 600 and Ca++ (altas dosis) - NOT recommendedRAL 400 with Ca++ no dose adjustment
DolutegravirMagnesium/ aluminium-containing antacid should be taken well separated in time from the administration of DTG (minimum 2 hours after or 6 hours before). Applies also to Ca++ and Fe++ supplements.
Elvitegravir/cobicistat
It is recommended to separate Stribild and antacid administration by at least 4 hours.No specific recommendation for Ca++ and Fe++.
Tivicay SPC; Isentress SPC; Stribild SPC
*Recommended TDF/FTC dose in pts with CrCl 30-49 mL/min: 1 tablet q48h. †Caution needed in INSTI-experienced pts (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with severe renal impairment.
ARVFDA Approved for Pts
With CrCl, mL/min
EVG/COBI/FTC/TDF[1] ≥ 70
DRV/COBI[2] + FTC/TDF*[3] ≥ 70
EFV/FTC/TDF[4] ≥ 50
RPV/FTC/TDF[5] ≥ 50
DTG/ABC/3TC[6] ≥ 50
DRV/RTV, DTG,† or RAL + FTC/TDF*[3] ≥ 50
EVG/COBI/FTC/TAF[7] ≥ 30
RPV/FTC/TAF[8] ≥ 30
DRV/COBI, DRV/RTV, DTG†, or RAL +
FTC/TAF[9]
≥ 30
Consideraciones para Pacientes con InsuficienciaRenal
Potenciales Interaciones para Cobicistat y Ritonavir
• Ambos inhiben CYP3A y gp-P; RTV es un inductor de CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, y UGT1A1
Marzolini C, et al. J Antimicrob Chemother. 2016;71:1755-1758.
COBI [package insert]. RTV [package insert].
Agents That Have Interactions With RTV and/or COBI
Analgesics Contraceptives
Antiarrhythmics Digoxin
Anticancer agents Glucocorticoids
Anticoagulants Methamphetamine
Anticonvulsants PDE5 inhibitors
Antidepressants Rifabutin
Beta-blockers Sedatives/hypnotics
Clarithromycin Statins
Selección de Inhibidor de Integrasa
Agent Advantages Disadvantages
RAL Longest experience
Fewer DDIs vs EVG, DTG
No coformulation
Relatively low barrier to resistance
EVG STR with TAF
Once-daily dosing
EVG/COBI/FTC/TAF STR
approved for use in pts with CrCl
> 30 mL/min
Requires COBI boosting with
associated DDIs
Relatively low barrier to resistance
DTG Only non-tenofovir–containing
STR
Once-daily dosing
Higher barrier to resistance
Few DDIs
Active against some RAL- and
EVG-resistant virus
Only coformulated with ABC/3TC
Increases metformin levels
DTG/ABC/3TC STR not
recommended for pts with CrCl < 50
mL/min
EVG/COBI/FTC/TAF [package insert]. DTG/ABC/3TC [package insert]. RAL
[package insert].
Clutter DS, et al. Infect Genet Evol. 2016
Tsepamo: Defectos Tubo Neural y Exposición a Dolutegravir
• At latest analysis on July 15, 2018[2]
– NTD prevalence with DTG exposure at conception: 4/596(0.67%; 95% CI: 0.26% to 1.7%)
– NTD prevalence with DTG started during pregnancy: 1/3104(0.03%; 95% CI: 0.01% to 0.18%)
• Next formal analysis to occur after March 31, 2019, which will include 72% of national births
Zash R, et al. N Engl J Med. 2018;[Epub ahead of print]. 2. Zash R, et al. AIDS 2018. Session TUSY15.
Estudios Clínicos STR
STARTMARK 156 semanas RAL vs EFV
Boosted EVG-Based Regimens Noninferior in Treatment-Naive Pts at Wk 48
1. Sax PE, et al. Lancet. 2012;379:2439-2448.
2. DeJesus E, et al. Lancet. 2012;379:2429-2438.
3. Sax PE, et al. Lancet. 2015;385:2606-2615.
Study Regimens Wk 48 HIV-1 RNA
< 50 c/mL, %
Adjusted
Treatment
Difference, %
(95% CI)
GS-102[1]
EVG/COBI/FTC/TDF
(n = 348)
EFV/FTC/TDF (n =
352)
87.6
84.13.6 (-1.6 to 8.8)
GS-103[2]
EVG/COBI/FTC/TDF
(n = 353)
ATV/RTV + FTC/TDF
(n =355)
89.5
86.83.0 (-1.9 to 7.8)
GS-
104/111[3]
EVG/COBI/FTC/TAF
(n = 866)
EVG/COBI/FTC/TDF
(n = 867)
92.4
90.42.0 (-0.7 to 4.7)
Estudio SINGLE
Resultado virológico semana 48-96-144
Fracaso virológico
Estudio SPRING 2
Resultado virológico semana 96
Fracaso virológico
Eventos adversos
Bictegravir
CROI 2018
DRV/COBI/FTC/TAF: Primer STR basadoen Inhibidores de la Proteasa
• Once-daily single-tablet regimen approved by FDA in July 2018
DRV/COBI/FTC/TAF [package insert]. July 2018.
Key US Label Information
Indications For treatment-naive patients For patients with virologic suppression (ie, HIV-1 RNA < 50 copies/mL)
for ≥ 6 mos with no known resistance to DRV or tenofovir
Administration requirements
Take with food
Key DDIs
Contraindicated with: alfuzosin, ranolazine, dronedarone, carbamazepine, phenobarbital, phenytoin, colchicine (if renal/hepatic impairment), rifampin, lurasidone, pimozide, ergot derivatives, cisapride, St John’s wort, elbasvir/grazoprevir, lovastatin, simvastatin, sildenafil (when used for pulmonary arterial hypertension), oral midazolam, oral triazolam
Dose adjustments
None for mild/moderate renal or hepatic impairment; not recommended if CrCl < 30 mL/min or Child-Pugh C
Encuesta de TARV
• 48 pacientes con TARV no STR
• 46 hombres 2 mujeres
• 4 (8,3%) responden que mantendrían su actual TARV.
• 44 (91,7 %) cambiarían a STR.
• 35 (73%) cambiarían a antiretrovirales de depósito inyectables cada 8 semanas.
Conclusiones
• Terapias STR se consideran como de primera Línea en Guías Clínicas nacionales e internacionales.
• Considerar y monitorizar sus diversas interacciones medicamentosas.
• No olvidar seguimiento de función renal.
• Se necesita más evidencia de eficacia en pacientes que debutan con enfermedad avanzada.