SG OBLIGATIONS (C)

Prise en charge des co-infectés
VIH/VHC en 2014
Valérie Canva, CHRU Lille
XXIèmes JRPI 14/10/2014
Traitements anti VHC
90-100%
75%
40-45%
41%
16%
6%
IFN 6 m.
1989
IFN 12 m.
1994
IFN + Riba
1998
Peg-IFN + Riba
2000
Peg-IFN + Riba
+ IP
2011
Peg-Riba
Sofosbuvir
Siméprévir
Daclatasvir
2014
Asselah & Marcellin, Liver Intern 2013
EASL, J Hepatol 2014
EASL, J Hepatol 2014
Avis d’experts – 09/2014
Avis d’experts – 09/2014
Avis d’experts – 09/2014
Phase 2 Study 1910 : SOF+Peg+RBV
HIV/HCV G1-4 Naïfs non cirrhotiques
Rodriguez-Torres, IDWeek 2013
Phase 2 Study 1910 : SOF+Peg+RBV
HIV/HCV G1-4 Naïfs non cirrhotiques
HCV RNA <LLOQ (%)
100
100
100
100
100
89
87
17/19
13/15
4/4
1/1
2/2
1/1
GT 1
GT 1a
GT 1b
GT 2
GT 3
GT 4
80
60
40
20
0
100
100
89
88
8/9
7/8
6/6
FTC/TDF +
Protease Inhibitor
FTC/TDF +
NNRTI
FTC/TDF +
Raltegravir
SVR12 (%)
80
60
40
20
0
NNRTI, non-nucleoside reverse transcriptase inhibitor
Rodriguez-Torres M, IDWeek 2013
Photon-1 : SOF+RBV
HIV/HCV G1-3 Naïfs/Echecs
Naggie, CROI 2014
Photon-1 : SOF+RBV
HIV/HCV G1-3 Naïfs/Echecs
Génotype 1
Naggie, CROI 2014
Photon-1 : SOF+RBV
HIV/HCV G1-3 Naïfs/Echecs
Génotype 2
Génotype 3
c
c
Naggie, CROI 2014
Photon-1 : SOF+RBV
HIV/HCV G1-3 Naïfs/Echecs
Resistance Analysis
• Two patients with viral breakthrough had documented study drug nonadherence with undetectable serum levels of SOF and its metabolite
– No S282T mutations detected
• Deep sequencing (lower limit of detection = 1% prevalence) was
performed on 39 patients following viral relapse*
– No S282T mutations detected
• No change in susceptibility to SOF or RBV observed by phenotypic
analyses of other NS5B polymorphisms
* 2 subjects with relapse failed RNA amplification
Naggie, CROI 2014
Safety
Photon-1 : SOF+RBV
HIV/HCV G1-3 Naïfs/Echecs
*Weight loss, insomnia/agitation,
pneumonia, suicide attempt,
foreign body sensation in throat,
increased anxiety, dyspnea.
†Suicide
9 days after completing
study treatment; patient had history
of depression and was being
treated for ADHD and insomnia
before entering study.
♦ 11 pts were not on ARVs during the study, none had clinically significant variation in HIV
RNA occurred during HCV treatment dosing
♦ 2 pts had transient HIV viral breakthrough, both with documented nonadherence to ART
♦ No decrease in CD4 T-cell % with treatment
Naggie, CROI 2014
Mono-infected and HCV/HIV Co-infected
SOF + RBV ± PegIFN x 12 or 24 weeks
GT 1
SOF + RBV + PegIFN
12 weeks
SVR12 (%)
100
90
100
100
89
76*
GT 3
SOF + RBV
24 weeks
GT 2
SOF + RBV
12 weeks
GT 1
SOF + RBV
24 weeks
85
93
88
88
100
80
80
60
60
60
40
40
40
40
20
20
20
20
80
80
60
262/292
17/19
0
0
NEUTRINO1
HCV
19102
HCV/HIV
68
17/25
87/114
SPARE3
PHOTON-14
HCV
HCV/HIV
95/112
PHOTON-26
HCV/HIV
68/73
23/26
VALENCE5
PHOTON-14
22/25
0
28/42
85
212/250
94*
16/17
89
94/106
0
HCV
HCV/HIV
PHOTON-26
HCV/HIV
VALENCE5
HCV
PHOTON-14 PHOTON-26
HCV/HIV
HCV/HIV
Similar response rates in HCV/HIV co-infected patients
compared to HCV mono-infected patients
SVR12 from VALENCE includes pooled analysis from all patients (treatment-naïve and –experienced) by genotype and duration of therapy
*GT1 SVR24 of 75%; GT3 TE SVR24 of 88%
1. Lawitz E, et al. APASL 2013. Singapore. Oral #LB-02. 2. Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster 714. 3. Osinusi A, et al. JAMA. 2013;310(8):804-811.
4. Naggie S, et al. CROI 2014. Boston, MA. Oral #26. 5. Zeuzem S, et al. AASLD 2013. Washington, DC. #1085. 6. Molina JM, et al. IAS Melbourne Abstract MOAB0105LB
1
8
Etude C212 : SMV + Peg-RBV
HIV/HCV G1 Naïfs/Echecs
82% G1a
28% Q80K
27% IL28B CC
13% F4
Dieterich, CROI 2014
Etude C212 : SMV + Peg-RBV
HIV/HCV G1 Naïfs/Echecs
RGT (CV S4 <15UI) chez patients naïfs/rechuteurs non F4
Dieterich, CROI 2014
Etude C212 : SMV + Peg-RBV
HIV/HCV G1 Naïfs/Echecs
SVR12 selon le score de fibrose
Dieterich, CROI 2014
Etude C212 : SMV + Peg-RBV
VIH/VHC G1 Naïfs/Echecs
SVR12 selon polymorphisme NS3 Q80K
Dieterich, CROI 2014
Etude C212 : SMV + Peg-RBV
VIH/VHC G1 Naïfs/Echecs
SVR12 selon ART
SVR12 selon taux CD4
Dieterich, CROI 2014
DCV + SOF: ALLY 2
HIV CoInfection Study Design
• Objective: Assess the efficacy and safety of DCV 30, 60, or 90 mg/day
dependent upon concomitant HIV dosing regimen in treatment-naive
or -experienced GT1–6 HIV-coinfected patients
• Primary endpoint: SVR12
Study Week
0
8
12
12 wk DCV QD + SOF
Treatment-naive
(n=100) 400 mg QD
8 wk
(n=50)
DCV QD +
SOF 400 mg
QD
SVR12
24
24-week Follow-up
24-week Follow-up
SVR12
Treatment-experienced
12 wk DCV QD + SOF
(n=50) 400 mg QD
24-week Follow-up
36
SOFOSBUVIR
DACLATASVIR
EASL, J Hepatol 2014
SIMEPREVIR
Co-administration non recommandée avec inducteurs ou inhibiteurs
modérés à forts du cytochrome P450 3A (CYP3A)
•
Raltegravir, maraviroc, rilpivirine,
tenofovir, emtricitabine,
lamivudine, abacavir n’ont pas
d’interactions avec le Siméprévir
•
Pas d’adaptation de doses avec les
immunosuppresseurs (cyclosporine
et tacrolimus)
•
Ajustements de dose nécessaires
avec
– Certains antiarythmiques (warfarin,
calcium bloqueurs),
– Inh HMG Co-A reductase
– Sédatifs/anxiolytiques
• Sont contre-indiqués :
– Antiépileptiques (carbamazepine,
oxcarbazepine, phenobarbital,
phenytoin)
– Antibiotiques (erythromycin,
clarithromycin, telithromycin,
rifampin, rifabutin, rifapentine)
– Antifongiques sytémiques
(itroconazole, ketoconazole,
posaconazole, fluconazole,
voriconazole)
– Dexamethasone IV, cisapride,
millepertuis
– ARVs (cobicistat, efavirenz,
delavirdine, etravirine, nevirapine,
ritonavir, IP+/- ritonavir)
EASL, J Hepatol 2014
Résumé : interactions médicamenteuses entre les ARVs et certains anti-VHC
3D
Asunaprevir
Daclatasvir
Ledipasvir
Simeprevir
Sofosbuvir
ABT-450/r
Ombitasvir
Dasabuvir
Inhibiteur NS3/4A
(BMS)
Inhibiteur NS5A
(BMS)
Inhibiteur NS5A
(Gilead)
Inhibiteur NS3/4A
(Janssen)
Inhibiteur NS5B
(Gilead)
200 mg bid
30 mg qd
60 mg qd
90 mg qd
150 mg qd
400 mg qd
(Abbvie)
Posologie(s)
ATV
ATV/r
DRV/r
LPV/r
EFV
ETR
NVP
RPV
DTG
EVG/Co
RAL
MVC
TDF
150/100 mg qd
25 mg qd
400 mg bid
300 mg + ABT-450/r
NON
OUI ? (*)
NON
NON
NON
↔
NON
NON
NON
NON
NON
NON
NON
↔
↔
↔
NON
↔
↔
OUI ? (**)
↔
↔
↔
↓ à 30 mg qd
↑ à 90 mg qd
↔
60 mg qd
(*) Cmin DRV ↓ ≈ 45%
(**) Cmin TDF ↑ 90-160%
Données publiées
Pas de données
Association CI / Non recommandée / Rsque interactif potentiel
(Rockstroh JK, IWCPHHT 2014 ; Karageorgopoulos DE et al. Curr Opin Infect Dis
2014; Khatri A et al., ICAAC 2014 ; RCP Sofosbuvir version US 12/2013 ; RCP
Simeprevir version US 05/2013)
↔
↔
↔
↔
(Futurs) traitements anti VHC
90-100%
90-100%
75%
Le
futur…
c’est
demain
40-45%
41%
16%
6%
IFN 6 m.
1989
IFN 12 m.
1994
IFN + Riba
1998
Peg-IFN + Riba
2000
Peg-IFN + Riba
+ IP
2011
Peg-Riba
Sofosbuvir
Siméprévir
Daclatasvir
2014
Tri/Quadrithérapies
IFN-free
G1à6
2015-16
Sofosbuvir/Lédipasvir :
HIV/HCV G1 naïfs non cirrhotiques
J0
S12
Sans ARV (n = 13)
CD4 stable et ARN VIH < 500 cp/ml
ou
CD4 > 500 /mm3
48 semaines de suivi
RVS 12
10/10
100 %
SOF / LDV (400/90 mg)
Sous ARV (n = 37)
CD4 > 100/mm3
ARN VIH < 40 cp/ml
ARV stable ≥ 8 semaines
RVS 4
22/22
100 %
ARV : TDF/FTC, EFV, RPV et RAL
 L’association SOF/LDV pendant 12 semaines est efficace chez les patients
co-infectés de génotype1
 Pas de modification des CD4 ou ARN VIH
Osinusi, EASL 2014
STARTVerso4 : Faldaprévir+Peg+RBV
HIV/HCV G1 Naïfs/Echecs
Dieterich, CROI 2014
C-Worthy : MK5172/MK8742 + RBV
VIH/VHC G1 naïfs non cirrhotiques
SVR 12 selon statut HIV et RBV+
Sulkowski, EASL 2014
Phase 2 TURQUOISE-I
SVR12
100
100
100
96.8
96.9
93.5
96.9
93.5
% Patients
80
12-Week Arm
60
24-Week Arm
40
20
0
RVR
(Week 4)
EOTR
(Week 12 or 24)
SVR4
SVR12
32
Sulkowski MS, et al. IAC 2014. Melbourne, Australia. #MOAB0104LB

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