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.