¿Es seguro el TAR en pacientes

con filtrado glomerular <90

ml/min?

Félix Gutiérrez

Universidad Miguel Hernández

Hospital General Universitario de Elche

Regimen CrCl (mL/min) Cutoffs

EFV/TDF/FTC ≥ 50

RPV/TDF/FTC ≥ 50

DTG/ABC/3TC ≥ 50

EVG/COBI/TDF/FTC ≥ 50

BIC/TAF/FTC ≥ 50

GFR Cutoffs in most pivotal RCTs with

current ART Regimens

¿Es seguro el TAR en pacientes

con filtrado glomerular

<50ml/min?

¿Es seguro el TAR en pacientes

con filtrado glomerular

<50ml/min?

¿ensayos clínicos?

Estudio GS-US-292-0112:

Diseño del estudio

Estudio fase 3 de 144 semanas, multicéntrico, abierto y de un sólo brazo

ClinicalTrials.gov Identifier: NCT01818596. https://clinicaltrials.gov/ct2/show/study/NCT01818596. Marzo 2016

.

7

Adultos infectados por VIH con supresión virológica* y con insuficiencia renal eGFR

30-69 mL/min

Pozniak A, et al.. J Acquir Immune Defic Syndr 2016 Apr 15;71(5):530-7. Disponible en: http://www.ncbi.nlm.nih.gov/pubmed/26627107. Acceso: 04/16

Apéndice disponible en: http://links.lww.com/QAI/A772 Acceso: 04/16

Semana 24 Semana 48 Semana 96 Semana 144

Endpoint primario: Cambio de la TFGe desde el basal a la semana 24

*Supresión virológica: VIH-1 RNA < 50 copias/ml según snapshot ; FDA; eGFR medido con Cockcroft-Gault f (eGFRCG) en todos los pacientes; DMO: densidad mineral ósea.

Diseño y Procedimientos

• Estudio de un sólo brazo de cambio de regímenes a E/C/F/TAF

• Medición de parámetros inmunovirológicos y metabólicos habituales

• Investigación renal exhaustiva: eGFR, UPCR, UACR, cocientes urinarios RBP:creatinina y B2-microglobulin; mGFR (iohexol) en una muestra.

• CV< 50 c/mL (*); CD4+ ≥ 50 células/µL

• eGFR (CG) 30-69mL/min estable (creatinina

sérica al menos 3 meses no ≥ 25%)

Estudio GS-US-292-0112: Características

basales (*)

7%5%Otros

Ninguno

ITINN

42%

8

ABC

22%

TDF

65%

eGFR<50mL/minn=80

eGFR ≥50 mL/minn=162

Mediana edad (rango) 59 (31-82) 58 (24-76)

Edad≥ 65 años, n (%) 25 (31) 38 (23)

Mujeres, n (%) 21(26) 29(18)

Negra o descendencia africana, % 18 19

VIH-1 RNA <50 copias/ml, % 98 98

Mediana recuento CD4, cells/µL 622 635

Pre cambio TDF, % 58 69

Hipertensión, % 50 34

Diabetes, % 15 13

Mediana eGFRCG medio mL/min 43 60

Mediana eGFRCKD – EPI, SCR medio ml/min/1,73 m2* 45 58

Mediana eGFRCKD – EPI, cysC medio ml/min/1,73 m2† 57 77

Proteinuria por tira reactiva, grado 1 o 2%‡ 44 27

Proteinuria significativa (UPCR> 200 mg/g), %§ 56 35

Albuminuria Significativa (UACR ≥ 30 mg/g), %¶ 64 42

(*) N= 242: median age 58 years (range = 24–82 years), including 63 patients >65 year; 21% of

patients were female; median GFRcg 56; 42% of patients had significant proteinuria (UPCR>200

mg/g), 49% had significant albuminuria (UACR>30 mg/g), 39% had hypertension, and 14% were

diabetic.

CG, Cockroft-Gault.

* Ecuación CKD EPI usando la creatinina sérica (FGe CKD-EPI, creatinina).

†Ecuación CKD-EPI con cistatina C (FGe CKD-EPI, cistatina C).

‡Grado 1 (1+ por tira reactiva), grado 2 (2–3+ por tira reactiva); ninguno tiene grado 3 or 4.

¶ Microalbuminuria ≥ 30 mg/g.

UPCR: cociente creatinina proteína en orinaUACR: cociente creatinina albumina en orina

ITIANs

*Algunas terapias incluían >1 tercer agente;

por lo tanto, el total >100%.

ITINN

42%

INSTI

24%

3%

Antagonista CCR5

IP 44%

Tercer agente*

Pozniak A, et al.. J Acquir Immune Defic Syndr 2016 Apr 15;71(5):530-7. Disponible en: http://www.ncbi.nlm.nih.gov/pubmed/26627107.

Acceso: 04/16 Apéndice disponible en: http://links.lww.com/QAI/A772 Acceso: 04/16

0 4 8 1 2 1 6 2 0 2 4 2 8 3 2 3 6 4 0 4 4 4 8

-1 5

-1 0

-5

0

5

1 0

1 5

W e e k s

Me

dia

n (

Q1

,Q3

) e

GF

R C

ha

ng

e

Fr

om

Ba

se

lin

e (

mL

/min

/1.7

3 m

2)

1.81.1

0 4 8 1 2 1 6 2 0 2 4 2 8 3 2 3 6 4 0 4 4 4 8

-1 5

-1 0

-5

0

5

1 0

1 5

W e e k s

Me

dia

n (

Q1

,Q3

) e

GF

R C

ha

ng

e

Fro

m B

as

eli

ne

(m

L/m

in)

0.6

-1.4

Basal eGFRCG 30-49 ml/minBasal eGFRCG 50-69 ml/min

Cambios desde el inicio en eGFR (Cockcroft-Gault)*

Cambios desde el inicio en eGFR (CKD-EPI, Cystatin C)*

No hubo cambios notables en eGFRCG o eGFRCKD-EPI, cystatin C a la semana 48

3.8 (-4.8, 11.2)ml/min/1.73 m2

Endpoint PrimarioCambio en la mediana (IQR) a la semana 24

Cambio en el eGFR a la semana 48

-0.4 (-4.8, 4.5) ml/min

*Estratificación basal basado en eGFR (Cockcroft-Gault)

Gupta, et al. Safety of Tenofovir Alafenamide in Renal Impairment. CROI 2015; Seattle, WA. #795. Disponible en: http://www.croiconference.org/sessions/safety-tenofovir-

alafenamide-renal-impairment Acceso: 03/2016

Gupta SK, et al. Subjects with renal impairment switching from tenofovir disoproxil fumarate to tenofovir alafenamide have improved renal and bone safety through 48 weeks.

IAS 2015; Vancouver, Canada. Oral Presentation TUAB10. Disponible en: http://www.natap.org/2015/IAS/IAS_23.htm Acceso: 04/16

Cam

bio

en la m

edia

na

(Q1, Q

3)

eG

FR

desde

basal(

ml/m

in)

Cam

bio

en la m

edia

na

(Q1, Q

3)

eG

FR

desde

basal(

ml/m

in/1

.73m

3)

Semanas Semanas

Cambios de la proteinuria desde el inicio hasta la

semana 48 en los pacientes que cambiaron a

E/C/F/TAF

1

0

* Todos los ambios de Total y TDF son estadísticamente significativos; † todos los cambios non-TDF son estadísticamente no significativos

Mejorías significativas en la proteinuria, la albuminuria y la proteinuria tubular desde el inicio hasta la semana 48

Proteínas tubulares

Pozniak A, et al. Switching to Tenofovir Alafenamide, Coformulated With Elvitegravir, Cobicistat, and Emtricitabine, in HIV-Infected Patients With Renal Impairment: 48-Week

Results From a Single-Arm, Multicenter, Open-Label Phase 3 Study. J Acquir Immune Defic Syndr 2016 Apr 15;71(5):530-7. Disponible en:

http://www.ncbi.nlm.nih.gov/pubmed/26627107. Acceso: 04/16

Apéndice disponible en: http://links.lww.com/QAI/A772 Acceso: 04/16

Med

ian

a (

mg

/g)

Med

ian

a (

µg

/g)

UPCR: tasa de creatinina proteína en orina; UACR: tasa de creatinina albumina en orina; RBP:Cr: proteína de unión a retinol; β-2-m: Cr: beta-2 microglobulina

No discontinuations

because of renal

adverse effects and no

cases of renal

tubulopathy in either

study group.

657 untreated adults (HIV-1 RNA ≥500 copies per mL)

with eGFR>30 mL/min randomly assigned to

BIC+FTC+TAF or DTG+FTC+TAF.

www.thelancet.com Published online August 31, 2017 http://dx.doi.org/10.1016/S0140-6736(17)32340-1

¿Es seguro el TAR en pacientes

con filtrado glomerular

<50ml/min?

¿?

¿Cómo emplear el TAR con

seguridad en pacientes con

filtrado glomerular <50ml/min?

• Avoid nephrotoxic agents.

• Make dose adjustment as needed according to package inserts• Avoid using co-formulations of ARV in patients with low

GFR

• In patients undergoing dyalisis: consider both drug adjustment and time of administration regarding the dialysis session.

• Do take into account potential drug-drug interactions (more

common and dangereous in this scenario).

Recommendations for safe use of ART in patients

with moderate to severe renal impairment (<50

ml/min)

• Avoid nephrotoxic agents.

• Make dose adjustment as needed accordingto package inserts• Avoid using co-formulations of ARV in patients with low

GFR

• In patients undergoing dyalisis: consider both drugadjustment and time of administration regarding the dialysis session.

• Do take into account potential drug-drug interactions (more

common and dangereous in this scenario).

Recommendations for safe use of ART in patients

with moderate to severe renal impairment (<50

ml/min)

Current ARV and their effects on the

kidneyAntiretroviral drug(s) Alteration of renal function

[(generally) not treatment-limiting]Treatment-limiting renal disease

Tenofovir disoproxilfumarate

Renal tubular dysfunction; eGFR decline >3 ml/min per year; Proteinuria (non-glomerular origin); Chronic kidney disease

Acute kidney injury (rare); Tubulo-interstitial nephritis (rare); Renal tubular disease/Fanconi syndrome (uncommon); CKD with progressive eGFR decline

Atazanavir/r Inhibition of tubular creatinine secretion; Renal tubular dysfunction; Crytalluria; eGFR decline >3 ml/min per year; CKD

Acute kidney injury (rare); Tubulo-interstitial nephritis (rare); Nephrolithiasis (uncommon)

Lopinavir/r Chronic kidney disease Nephrolithiasis (rare)

Cobi/atazanavir(+TDF/FTC)

Inhibition of tubular creatinine secretion AKI; Renal tubular disease/Fanconisyndrome (uncommon)

Cobi/elvitegravir(+TDF/FTC)

Inhibition of tubular creatinine secretion AKI (uncommon); Renal tubular disease/Fanconi syndrome (uncommon)

Cobi/elvitegravir(+TAF/FTC)

Inhibition of tubular creatinine secretion None reported

Rilpivirine/Dolutegravir Inhibition of tubular creatinine secretion None reported

Darunavir/r Crystalluria Nephrolithiasis (rare)

Current ARV and their effects on the

kidneyAntiretroviral drug(s) Alteration of renal function

[(generally) not treatment-limiting]Treatment-limiting renal disease

Tenofovir disoproxilfumarate

Renal tubular dysfunction; eGFR decline >3 ml/min per year; Proteinuria (non-glomerular origin); Chronic kidney disease

Acute kidney injury (rare); Tubulo-interstitial nephritis (rare); Renal tubular disease/Fanconi syndrome (uncommon); CKD with progressive eGFR decline

Atazanavir/r Inhibition of tubular creatinine secretion; Renal tubular dysfunction; Crytalluria; eGFR decline >3 ml/min per year; CKD

Acute kidney injury (rare); Tubulo-interstitial nephritis (rare); Nephrolithiasis (uncommon)

Lopinavir/r Chronic kidney disease Nephrolithiasis (rare)

Cobi/atazanavir(+TDF/FTC)

Inhibition of tubular creatinine secretion AKI; Renal tubular disease/Fanconisyndrome (uncommon)

Cobi/elvitegravir(+TDF/FTC)

Inhibition of tubular creatinine secretion AKI (uncommon); Renal tubular disease/Fanconi syndrome (uncommon)

Cobi/elvitegravir(+TAF/FTC)

Inhibition of tubular creatinine secretion None reported

Rilpivirine/Dolutegravir Inhibition of tubular creatinine secretion None reported

Darunavir/r Crystalluria Nephrolithiasis (rare)

Tenofovir alafenamida (TAF)

Diferencias PK entre TAF y TDF

1.-TAF más estable en plasma que TDF2.-Mayores (x4) concentraciones intracelulares del metabolito activo de TFV (TFV difosfato), lo que permite emplear dosis más bajas 3.- Debido a 1 y 2, la exposición plasmática a TFV es 90% menor, lo que reduce el riesgo de toxicidad renal y ósea.4.- En los ensayos de fase 2 y 3 de TAF+FTC (coadministrado con EVG-c/BIC/DTG/DRV-c/RPV) ha mostrado un “perfil renal” más favorable que TDF y comparable a ABC.

† T1/2 basado en estudios in vitro.

11 randomised head-to-head trials (8111 patients) of TDF versus TAF.

11 randomised head-to-head trials (8111 patients) of TDF versus TAF.

• Avoid nephrotoxic agents.

• Make dose adjustment as needed accordingto package inserts• Avoid using co-formulations of ARV in patients with low

GFR

• In patients undergoing dyalisis: consider both drugadjustment and time of administration regarding the dialysis session.

• Do take into account potential drug-drug interactions (more

common and dangereous in this scenario).

Recommendations for safe use of ART in patients

with moderate to severe renal impairment (<50

ml/min)

• NRTIs

– Require dose adjustment except abacavir

– Eliminated by renal route: should be given

after dyalisis

• Not required for NNRTIs, PIs, InSTI

Recommendations for safe use of ART in patients

with moderate to severe renal impairment (<50

ml/min)

• NRTIs

– Require dose adjustment except abacavir

– Eliminated by renal route: should be given

after dyalisis

• Not required for NNRTIs, PIs, raltegravirnor DTG

Recommendations for safe use of ART in patients

with moderate to severe renal impairment (<50

ml/min)

Generic

nameDosage form CrCl 50-30 ml/min CrCl 29-10 ml/min CrCl <10 ml/min

Abacavir

(ABC)

ABC 300 mg

tabletStandard dose

KIVEXA Not recommended

Emtricitabine

(FTC)

FTC 200 mg200 mg every 48

hours

200 mg every 72

hours

200 mg every 96

hours; administer after

dialysis

TRUVADA Not recommended

FTC 200 mg +

TAF 25 mgStandard dose Not recommended

Lamivudine

(3TC)

3TC, 100, 150,

300 mg tablet, 5

mg/ml solution

150 mg daily150 mg stat then 100

mg/d

150 mg stat then 50

mg/d

KIVEXA Not recommended

Tenofovir

Disoproxil

Fumarate

(TDF)

TDF 300 mg

tablet300 mg every 48

hours300 mg 2 days/week 300 mg every 7 days

TRUVADA Not recommended

Tenofovir

Alafenamide

(TAF)

TAF 10 or 25

mg + FTC 200

mg

Standard dose Not recommended

Antiretroviral dose adjustments of NRTIs in

chronic kidney disease according to CrCl

¿Es seguro el TAR en pacientes

con filtrado glomerular

<30ml/min?

¿Es seguro el TAR en pacientes con

filtrado glomerular <30 ml/min?

Generic

nameDosage form

Standard adult

dose

CrCl 50-30

ml/minCrCl 29-10 ml/min

CrCl <10

ml/min

Abacavir

(ABC)

ABC 300 mg

tablet600 mg daily Standard dose

ABC 600 mg

+3TC 300 mg1 tablet daily Not recommended

Emtricitabine

(FTC)

FTC 200 mg 200 mg daily200 mg every

48 hours200 mg every 72 hours

200 mg every

96 hours;

administer after

dialysis

FTC 200 mg +

TDF 300 mg1 tablet daily Not recommended

FTC 200 mg +

TAF 25 mg1 tablet daily 1 tablet daily Not recommended

Lamivudine

(3TC)

3TC, 100, 150,

300 mg tablet, 5

mg/ml solution

300 mg/day 150 mg daily 150 mg stat then 100 mg/d150 mg stat

then 50 mg/d

3TC 300 mg +

ABC 600 mg1 tablet daily Not recommended

Tenofovir

Disoproxil

Fumarate

(TDF)

TDF 300 mg

tablet300 mg daily

300 mg every

48 hours300 mg 2 days/week

300 mg every 7

days

TDF 300 mg +

FTC 200 mg1 tablet daily Not recommended

Tenofovir

Alafenamide

(TAF)

TAF 10 or 25

mg + FTC 200

mg

1 tablet daily Standard dose Not recommended

Antiretroviral dose adjustments of NRTIs in

chronic kidney disease according to CrCl

¿TAF en pacientes con filtrado

glomerular <30ml/min?

TFV Cmax and AUC 2.8-and 5.7-fold

higher in subjects with severe RI

than the controls, but lower than

exposures in nonrenally impaired

subjects on TDF-based regimens

(historical)

Custodio JM et al. AAC 2016; 60: 135-140.

Entonces, ¿qué pautas de TAR

podemos utilizar con “seguridad”

en pacientes con insuficiencia

renal moderada-severa ?

ARV regimens in patients with moderate

to severe renal impairment/dyalisis

Recommended Regimens• [ABC]+[3TC (adjusted to eGFR)]+[DTG or RAL or BIC]

• [TAF]+[FTC (do not use with severe renal impairment: eGFR<30 mL/min)]+[DTG or RAL or BIC]

Alternative Regimens• The same NRTIs as above+[boosted DRV or EFV or RPV]*

• TFV/ABC sparing regimens:

– DRV/r+RAL* (if CD4 count >200 cells/mm3, HIV RNA <100,000 copies/mL)

– DTG+RPV*

– DRV/r *+3TC (adjusted to eGFR)

– DTG+3TC (adjusted to eGFR)

*When using PIs and NNRTIs in trasplant recipients dose adjustment of immunosuppresive

agents is needed.

In patients with severe renal impairment or end-stage renal disease, all drugs

should be used with caution and with increased monitoring for adverse effects

Muchas gracias!!!