S-Bonora

Switch da regimi NN based –
l’esperienza dei trial e la clinica
Stefano Bonora
Università di Torino
XIV SIMIT8-11 novembre , Catania
STR vs. MTR: US Analysis of Claims Database
Real-World ART Persistence with Single Tablet Regimens: Stribild vs
Eviplera vs Atripla vs. Multi-Tablet Regimens (MTRs)
To evaluate real-world persistence with different backbones (FTC/TDF vs. ABC/3TC) STRs vs. MTRs
as initial ART and between STRs (STB vs. EPA vs. ATR) using data from the US Truven MarketScan®
claims database between 10/2008 and 03/2014
Treatment Persistence Among Different STRs and MTRs
Stribild and Eviplera were associated with the highest
rates of persistence throughout 18 months
Sweet D, et al. HIV12 2014. Glasgow, UK. Poster #P5
Study 111
Study Design
Phase 2b, open-label, multicenter, 48-week study of immediate switch from
EFV/FTC/TDF to RPV/FTC/TDF in stable, virologically controlled subjects
Stable EFV/FTC/TDF for ≥ 3 mos
VL <50 c/mL for ≥ 8 wks
Switch due to EFV intolerance
No resistance to study drugs
(N=50)
EFV/FTC/TDF
STR
RPV/FTC/TDF
STR
12 week
24 week
48 week
Pre-dose PK samples obtained: Wks 1, 2, 4, 6, 8, and 12
Primary endpoint:
• HIV-1 RNA <50c/mL at week 12 after switching
Secondary endpoints:
• Safety and tolerability of RPV/FTC/TDF STR over 24 & 48 wks
• HIV-1 RNA <50 c/mL at week 24 and week 48 post-switch
• Pharmacokinetics of RPV after switching from EFV
Mills A, et al. BHIVA 2012. Birmingham, UK. #P186
3
Study 111
Virologic Outcomes through Week 48 - Snapshot Analysis
Virologic Non-Suppression (4%)
• Maintained in majority of subjects who switched
from EFV/FTC/TDF to RPV/FTC/TDF thru W48
1) Virologic failure* #1
• VL of 330,000 (W48), 1,890 (W51),
and 991 c/mL (W54)
• W48: No detectable RPV
concentrations
• Pan-sensitive virus at W48 & W51
% HIV-1 RNA < 50 c/mL
Virologic Suppression
100
100%
100%
94%
2) Virologic failure #2
• VL of 63 (W36) and 95 c/mL (W48)
• W48: Switched back to
EFV/FTC/TDF
• W51: VL <50 c/mL
80
60
40
No Week 48 Data† (2%)
20
0
3) Lost to follow-up due to incarceration
49/49
49/49
46/49
12
24
48
Weeks
Mills A, et al. HIV Clinical Trials 2013;14(5):216–223
n/N
* Virologic failure defined as confirmed HIV-1 RNA >50
c/mL at least 2 weeks apart
† Wk 48 window spanned 84 days (Days 295 to 379)
4
GS 264-111
Secondary Endpoint: RPV PK after Switching from EFV
Mean (95% CI) Rilpivirine (Ctrough) or Efavirenz Concentrations (anytime)
EFV Concentration
RPV C trough
RPV mean C
trough
in ECHO/THRIVE
2000
100
450
300
150
80
50
60
40
40
30
20
10
RPV IC90 (~12 ng/mL)
EFV IC90 (~10 ng/mL)
0
0 2 4 6
8 12
16
24
Weeks Post-Switch (EFV/FTC/TDF to RPV/FTC/TDF)
20
0
482
RPV Ctrough (ng/ml)
EFV Concentrations (ng/ml)
120
2500
• EFV mean Ctrough
above IC90 (~10
ng/ml*) up to ~4
weeks
• RPV mean Ctrough
within reference
range by 2 weeks
• No subject had RPV
below quantifiable
levels at any visit
except for 1 nonadherent subject at
W48
* Protein-binding adjusted; Corbett JW, et al. J Med. Chem 2000:43;2019-2030
Mills A, et al. HIV Clinical Trials 2013;14(5):216–223
5
 Metabolism of EFV produces a highly neurotoxic metabolite
(8-OH-EFV) that is capable of damaging neurites at very
low concentrations.
 Thus, cognitive impairments associated with EFV may
involve synaptic damage mediated by its major metabolite,
8-OH-EFV
6
UK Study - ATR to EPA Switch due to CNS Toxicity
Changes in CNS Adverse Events and Sleep
Open-label, multicenter, 24-week study of 40 virologically suppressed subjects with
ongoing CNS toxicity at least 12 wks of ATR (median 40 mos)2 switching to EPA
45
40
35
30
25
20
15
10
5
0
p<0.001
p<0.001
Baseline
Week 43
Sleep Questionnaire Score
Median total sleep score (%)
Total CNS score (%)
ACTG CNS Toxicity Score
Week 12
p<0.001
35
30
25
p<0.001
20
15
10
5
0
Baseline
Week 43
Week 24
• Switching ATR to EPA led to significant improvement in CNS toxicity and
sleep quality with 100% maintenance of virologic suppression
Identification of individuals with efavirenz toxicity is essential
as alternative agents lead to improvements in tolerability and toxicity
EPA = RPV/FTC/TDF; ATR = EFV/FTC/TDF
1. Rowlands J, et al. ICAAC 2014. Washington, DC. #H1005
2. Rowlands J, et al. BHIVA 2014. Liverpool. Oral #O4
3. Nelson M, et al. ICAAC 2013. Denver, CO. #H-672b
7
UK Study - ATR to EPA Switch due to CNS Toxicity
CNS Adverse Events
 Overall Grade 2-4 CNS adverse events significantly decreased at Week 4, 12 and 24
(p<0.001)
P<0.001
Grade 2-4 CNS Adverse Events
Baseline
Week 4
Week 12
Week 24
100
Proportions (%)
P<0.001
80
60
P=0.001
P=0.020
40
P<0.001
P=0.012
P=0.103
20
P=0.021
P<0.001
P=0.004
P=0.999
0
•
Eight of 10 CNS adverse events showed statistically significant improvement (P<0.05)
Rowlands J, et al. ICAAC 2014. Washington, DC. #H1005
Rowlands J, et al. BHIVA 2014. Liverpool. Oral #O4
8
PRO-STR - Spanish STR Cohort
Switching to STR of Eviplera due to Regimen Intolerance
Prospective, multicenter study of HIV-infected patients on stable ART for ≥ 3 months who switched
to EPA from NNRTI (75%) and PI (25%) due to intolerance of previous regimen (n=122)
 Reasons for switch: CNS (66%), GI (16%), metabolic (13%), other reasons (8%)
 Efficacy: 84% patients remained suppressed (<50 c/mL) at Week 16
 Patient-reported outcomes: Quality of life, number of symptoms, degree of discomfort,
treatment satisfaction (ease and flexibility) were all significantly improved 4 wks post-switch
 After 4 weeks, >80% of patients felt EPA was slightly to much better than their previous ART
ACTG Symptom Index
Satisfaction with Treatment
Health Related
Quality of Life
(EQ-5D)
Baseline
Baseline
Week 4
Week 16
X = P ≤ 0.001 for paired data vs. baseline
Switching to an STR of RPV/FTC/TDF resulted in significant improvements of
symptoms of prior ART intolerance, quality of life, and treatment satisfaction
Podzamczer D, et al. HIV12 2014. Glasgow, UK. Poster #282
‡
EPA in Switch (Italy)
Switch from ATR to EPA Reduces Patient-Reported
Symptoms with Improved Quality of Life and Lipids
Randomized, single centre study evaluating virologically suppressed patients on
stable ATR switching from ATR to EPA immediately (n=44) or after 4 months (n=20)
 All patients maintained virologic suppression (< 50 c/mL)
 Significantly improved quality of life 4 months after switch (EQ5D); p = 0.027
 Majority (28/32) of patient-reported symptoms improved at Month 4
Total Cholesterol
16%
<200 mg/dL
(Grade 1)
200 to 239 mg/dL
(Grade 2)
≥240 mg/dL
(Grade 3)
% of Subjects
“Switching from ATR to EPA is a safe, well tolerated strategy that improves
the overall health status of HIV-treated patients
in terms of QoL and self- reported patient oriented outcomes.”
ATR - EFV/FTC/TDF, EPA - RPV/FTC/TDF
Maggiolo, F. Glasgow, UK 2014, #P266
Author’s Last Name, Conference Name, Year, Presentation #
11
Study 102 and 103 (STB vs. ATR and ATV+RTV+TVD) – Week 144
Median Changes in Fasting Lipids from Baseline
STB (n=701)
ATR (n=352)
ATV+RTV+TVD (n=355)
Change From BL at Week 144 (mg/dL )
1,2
Study
102
Study
1021,2
P =0.007
P =0.007
Study103
103
3
Study
3
P =0.021
4

4
4
No difference in change in TC to HDL ratio in either treatment groups
TC: total cholesterol; LDL: low density lipoprotein; HDL: high density lipoprotein; TG: triglycerides
1. Wohl D, et al. JAIDS 2014; 65 (3):e119-121
2. Wohl D, et al. ICAAC 2013. Denver, CO. #H-672a
3. Clumeck N, et al. JAIDS 2014;65 (3):e121-124
4. Data on file. Gilead Sciences, Inc.
Study 111
Median Change in Fasting Lipids from Baseline to Wk 48
TC*
Median Change in
Fasting Lipid Values, mg/dL
Baseline (Q1, Q3)†:
177 (159, 210)
LDL*
113 (93, 132)
HDL
TG*
49 (41,58)
114 (86, 147)
-2
-8
-17
-26
• TC:HDL ratio decreased by 0.17 (p=0.14)
* P < 0.05 from Wilcoxon Signed-Rank test
† (Q1, Q3) = 25th percentile, 75th percentile
13
Mills A, et al. HIV Clinical Trials 2013;14(5):216–223
‡
EPA in Switch (Italy)
Switching to EPA in Virologically Suppressed Patients
Improves Lipid Profile
Retrospective, multicentre, cohort study switching from PI or NNRTI (n=508)
• At 6 months, 1.1% VF and 5.5% had discontinued for any reason
• Only the number of pre-switch regimens was associated with VF (HR 1.13,
p=0.001)
• Type of pre-switch regimen was not associated with discontinuation or
failure; with no VFs observed with switching off ATR or RAL regimens
Total Cholesterol
Triglycerides
“Switching to EPA in virologically suppressed patients could be a good
strategy with low risk of virological failure or treatment
discontinuation…with significant improvement in lipid profile.”
Pinnetti C, et al. Glasgow 2014, #P280
‡
NVP to EPA Switch - Netherlands
Switching NVP to EPA:
Efficacy, Safety, Lipids and Cardiovascular Risk
Prospective, open-label, controlled trial in virologically suppressed HIV-1 patients
on NVP+FTC/TDF switched EPA (n=50) or continuing NVP regimen (n=139)
Total Cholesterol at Week 24
Proportion of Subjects, %
Virologic Efficacy (ITT)
19%
<200 mg/dL
(Grade 1)
200 to 239 mg/dL
6%
(Grade 2)
≥240 mg/dL
(Grade 3)
W12
W48
Week 48
 Low VF rate: 6% EPA vs. 8% NVP
 Low discontinuation due to AEs at
Week 48 (n=2)
 1 subject discontinued due to nonadherence
% of Subjects
 Significant  in subjects achieving TC and LDL
goals (+26% & +15%) and ↓ in HDL goal (-19%)*
 Median Framingham risk score did not change
over 24 weeks (-7%, p = 0.029)
 The systolic blood-pressure decreased 6.0 mmHg
(P=.007)
A NVP to EPA switch “could be used in HIV-1 patients at risk for CV diseases”
Rokx C, et al. HIV12 2014. Glasgow, UK. Poster 257
*National Cholesterol Education Project, ATP III Classification
Switching NVP+FTC/TDF to CPA
Virologic Outcomes
Open-label single center study evaluating efficacy after switching
virologically suppressed patients from NVP+FTC/TDF to Complera® (N=32)
• 100%, of subjects switching from NVP+FTC/TDF to the CPA maintained virologic
suppression through 12 weeks
•
Meal Questionnaire
– No impact on virologic outcome was observed despite 17% of cases (33% with
breakfast) meal intake below 399 kcal
240
6000
100
4000
160
120
2000
80
Lower limit of RPV phase 3
mean trough level (50µg/L)
40
0
0
0
1
2
4
Weeks Post Switch
NVP plasma
concentration (μg/L)
RPV plasma
concentration (μg/L)
RPV and NVP mean plasma concentration after switching from NVP
12
NVP had only a short and limited inductive effect on RPV metabolism, which is not
clinically significant
CPA = RPV/FTC/TDF
Allavena C, et al. ICAAC 2013. Denver, CO. #H-657
16
17
Background
•
In patients treated with tenofovir-disoproxil fumarate renal tubular toxicity
have been reported.
•
Among risk factors, a role has been recognized for:

High TFV plasma concentrations;
Impairment in kidney tubular function in patients receiving tenofovir is
associated with higher tenofovir plasma concentrations
Rodríguez-Nóvoa et al. AIDS 2010; 24: 1064–1066

Boosted PIs use (associated with higher TFV exposure trough
intestinal CYP3A4 and p-glycoprotein and tubular MRP4
inhibition)
Background
•The suggested mechanism is TFV reduced urinary excretion, followed by
“entrapment” in proximal tubular cells with consequent mitochondrial toxicity
PI/R
pTFV
TFV
MRP2?
MRP2
hOAT3
OAT3?
?
X
CNT2?
?
TFV
MRP4
MRP4
[TFV]
[TFV]
Pgp?
PROXIMAL
TUBULAR CELL
MRP7?
MRP7
Pgp?
Pgp?
URINE
URINE
BLOOD
BLOOD
hOAT1
OAT1
u/p TFV ratio
uTFV
Reduced TFV urinary output (low urinary-to-plasma concentration ratio) is
associated with signs of tubular damage (Marinaro, ICAR 2014)
Background
Data on tenofovir plasma exposure when associated with rilpivirine are scarced
but it has been reported to be higher than with other NNRTIs
Ramanathan CROI 2013
No study has so far investigated tenofovir pharmacokinetics and tubular
safety are unknown in patients switching to
tenofovir/emtricitabine/rilpivirine.
MATERIALI E METODI
 Studio prospettico di coorte non interventistico presso la Clinica Universitaria Amedeo di
Savoia.
 Pazienti adulti HIV positivi che passavano sia da regimi contenenti tenofovir che tenofovir-
free al STR rilpivirina, tenofovir, emtrcitabina con HIV RNA < 50 copie/mL
 Sono state analizzate le resistenze genotipiche cumulative in quei pazienti che avevano
eseguito un test del genotipo virale.
 Alle settimane 0,12 e 48 abbiamo valutato:
– HIV RNA
– [TFV] urinarie e plasmatiche a 12 ore dalla somministrazione
– Esame completo urine 24 h e creatinina plasmatica
– [RBP] U/creatininuria su campione spot ( alle settimane 0 e 12)
– Predittori indiretti di danno tubulare (PTH, vitamina D, bALP) (alle settimane 0 e 12)
 Abbiamo suddiviso i risultati in sottogruppi sulla base del regime assunto prima dello
switch
CARATTERISTICHE DELLA POPOLAZIONE
VARIABILE
N assoluto (%)
NUMERO DI PAZIENTI ARRUOLATI per EFFICACIA
153 (100)
NUMERO DI PAZIENTI ARRUOLATI per SICUREZZA RENALE
92 (100)
SESSO
RAZZA
M
123 (80,4)
F
30 (19,6)
Caucasica
143 (93,5)
Africana
6 (3,9)
Latina
4 (2,6)
Coinfezione HCV
28 (18,3)
Precedente HAART con NNRTI
81 (52,9)
Precedente HAART con PI
63 (41,2)
Precedente HAART con altre classi
9 (5,9)
Resistenze maggiori
11 (7,2)
VARIABILE
Mediana (IQR)
Età
47 (40,4-52,4)
BMI
23,44 (20,8225,82)
560 (437-717)
Linfociti CD4
49% da
ATRIPLA
RISULTATI
[TFV plasma]
Ratio Urine/plasma
P>0.05
TDF_plasma da
NNRTI 56 vs.77
ng/mL p= 0.009
Ratio U/pl da
NNRTI 419 vs.
234 p= 0.015
[TFV urine]
RISULTATI
 Nel sottogruppo dei pazienti da NN non sono state riscontrate variazioni
significative nei valori delle urine nelle 24 ore (p> 0.05).
BL mediana (IQR)
W12 mediana (IQR)
W48 mediana (IQR)
Creatinina mg/dL
0.93 (0.85-1.05)
1 (0.89-1.08)
0.94 (0.6-1.36)
Clearance
100.9 (85.8-127.1)
108.3 (80.3-134.8)
115.8 (51.4-241.6)
Glicosuria g/24h
0.06 (0.02-0.08)
0.05 (0.02-0.08)
0.05 (0-0.08)
Fosfaturia g/24h
0.89 (0.66-1.17)
0.95 (0.74-1.17)
0.98(0.20-1.70)
Calciuria g/24h
0.20 (0.11-0.28)
0.21 (0.13-0.28)
0.21 (0.03-0.58)
165 (118-200)
150 (50-425)
0.620 (0.49-0.77)
0.67 (0.17-1.74)
creatinina ml/min
Proteinuria mg/ 24h 155 (110-202)
Uricuria g/24h
0.635 (0.52-0.79)
 Escrezione frazionata di acido urico e frazione riassorbita di
fosfato entro i range di normalità alla settimana 48 (<0.15 e >0.82)
RISULTATI
Non variazioni significative di Retinol Binding Protein (RBP)/creatinina
su urine nei pazienti provenienti da Atripla
25
DISCUSSIONE
RPV
pTFV
TFV
hOAT1
OAT1
MRP2?
MRP2
hOAT3
OAT3?
?
MRP4
MRP4
Pgp?
[TFV]
[TFV]
=
PROXIMAL
TUBULAR CELL
MRP7?
MRP7
Pgp?
Pgp?
URINE
URINE
BLOOD
BLOOD
CNT2?
?
TFV
=
u/p TFV ratio
uTFV
RPV rispetto a EFV aumenta l’assorbimento intestinale di TFV attraverso la
glicoproteina-P, ma non agisce sui trasportatori del tubulo renale deputati alla
clearance del farmaco.
CONCLUSIONI - Lo switch da ATRIPLA® a EVIPLERA®
• Mantenimento della soppressione virologica
• Miglioramento del profilo di tollerabilità neuropsichico
• Miglioramento dei patient-reported outcomes
(soddisfazione, quality of life)
• Miglioramento del profilo lipidico
• Non impatto significativo sul profilo di tollerabilità renale
(tubulopatia) malgrado incremento delle concentrazioni
plasmatiche di TFV
27
PK lab
Antonio D’Avolio
Jessica Cusato
Marco Simiele
ID Unit
Andrea Calcagno
Letizia Marinaro
Lorena Baietto
Alessandra Arialdo
Amedeo De Nicolò
Laura Trentini
Sarah Allegra
MCristina Tettoni
Debora Pensi
Chiara Alcantarini
Mauro Sciandra
Micol Ferrara
Francesca Patti
Chiara Montrucchio
Ilaria Motta
Filippo Lipani
Prof Giovanni Di Perri
Viro lab
Tiziano Allice
Maria Grazia Milia
Valeria Ghisetti