prise en charge des co-infectés vih/vhc en 2014 · pas de modification des cd4 ou arn vih osinusi,...
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Prise en charge des co-infectés VIH/VHC en 2014
Valérie Canva, CHRU Lille XXIèmes JRPI 14/10/2014
IFN 6 m. 1989
IFN 12 m. 1994
IFN + Riba 1998
Peg-IFN + Riba 2000
6%
16%
41%
40-45%
75%
Traitements anti VHC
Peg-Riba Sofosbuvir Siméprévir Daclatasvir
2014
90-100%
Peg-IFN + Riba + IP 2011
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
NNRTI, non-nucleoside reverse transcriptase inhibitor
GT 1 GT 2 GT 3 GT 4 GT 1a GT 1b
87
17/19 13/15
89
4/4 1/1 2/2 1/1
100 100 100 100
20
40
60
80
100 HC
V RN
A <L
LOQ
(%)
FTC/TDF + Protease Inhibitor
8/9 7/8 6/6
89 88 100
0
20
40
60
80
100
SVR1
2 (%
)
FTC/TDF + NNRTI
FTC/TDF + Raltegravir
0
Rodriguez-Torres M, IDWeek 2013
Phase 2 Study 1910 : SOF+Peg+RBV HIV/HCV G1-4 Naïfs non cirrhotiques
Photon-1 : SOF+RBV HIV/HCV G1-3 Naïfs/Echecs
Naggie, CROI 2014
Naggie, CROI 2014
Génotype 1
Photon-1 : SOF+RBV HIV/HCV G1-3 Naïfs/Echecs
c c
Photon-1 : SOF+RBV HIV/HCV G1-3 Naïfs/Echecs
Génotype 2 Génotype 3
Naggie, CROI 2014
• Two patients with viral breakthrough had documented study drug non-adherence 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
Resistance Analysis
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.
Safety
Photon-1 : SOF+RBV HIV/HCV G1-3 Naïfs/Echecs
Naggie, CROI 2014
♦ 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
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
Similar response rates in HCV/HIV co-infected patients compared to HCV mono-infected patients
Mono-infected and HCV/HIV Co-infected SOF + RBV ± PegIFN x 12 or 24 weeks
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%
100
28/42
SVR1
2 (%
)
90 89
0
20
40
60
80
100
NEUTRINO1
HCV 19102
HCV/HIV
GT 1 SOF + RBV + PegIFN
12 weeks
GT 1 SOF + RBV 24 weeks
68 76*
0
20
40
60
80
100
SPARE3
HCV PHOTON-14
HCV/HIV
87/114 17/25 95/112
85
PHOTON-26
HCV/HIV
GT 3 SOF + RBV 24 weeks
85 94*
0
20
40
60
80
100
VALENCE5 HCV
PHOTON-14 HCV/HIV
16/17 212/250
PHOTON-26
HCV/HIV
89
94/106
GT 2 SOF + RBV 12 weeks
93 88
0
20
40
60
80
VALENCE5
HCV PHOTON-14
HCV/HIV
68/73 23/26
88
22/25
PHOTON-26
HCV/HIV
262/292 17/19
18
Etude C212 : SMV + Peg-RBV HIV/HCV G1 Naïfs/Echecs
Dieterich, CROI 2014
82% G1a 28% Q80K 27% IL28B CC 13% F4
Etude C212 : SMV + Peg-RBV HIV/HCV G1 Naïfs/Echecs
Dieterich, CROI 2014
RGT (CV S4 <15UI) chez patients naïfs/rechuteurs non F4
Etude C212 : SMV + Peg-RBV HIV/HCV G1 Naïfs/Echecs
Dieterich, CROI 2014
SVR12 selon le score de fibrose
Etude C212 : SMV + Peg-RBV VIH/VHC G1 Naïfs/Echecs
Dieterich, CROI 2014
SVR12 selon polymorphisme NS3 Q80K
Etude C212 : SMV + Peg-RBV VIH/VHC G1 Naïfs/Echecs
Dieterich, CROI 2014
SVR12 selon taux CD4 SVR12 selon ART
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
12 wk (n=100)
8 wk (n=50)
DCV QD + SOF 400 mg QD
DCV QD + SOF 400 mg QD
Study Week 0 12 36 8 24
SVR12
Treatment-naive
24-week Follow-up
24-week Follow-up
DCV QD + SOF 400 mg QD 24-week Follow-up Treatment-experienced
12 wk (n=50)
SVR12
EASL, J Hepatol 2014
SOFOSBUVIR DACLATASVIR
SIMEPREVIR
• 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
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
Résumé : interactions médicamenteuses entre les ARVs et certains anti-VHC
(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)
3 D Asunaprevir Daclatasvir Ledipasvir Simeprevir SofosbuvirABT-450/r Inhibiteur NS3/4A Inhibiteur NS5A Inhibiteur NS5A Inhibiteur NS3/4A Inhibiteur NS5BOmbitasvir (BMS) (BMS) (Gilead) (Janssen) (Gilead)Dasabuvir(Abbvie)
150/100 mg qd 30 mg qd25 mg qd 60 mg qd
400 mg bidATV 300 mg + ABT-450/r NON
ATV/r NON ↓ à 30 mg qd NON ↔DRV/r OUI ? (*) NON ↔LPV/r NON NONEFV NON ↑ à 90 mg qd ↔ NON ↔ETR NONNVP NONRPV NON ↔ ↔ ↔DTG
EVG/Co NONRAL ↔ ↔ ↔ ↔MVCTDF ↔ 60 mg qd OUI ? (**) ↔ ↔
(*) Cmin DRV ↓ ≈ 45% (**) Cmin TDF ↑ 90-160%
Données publiées Pas de données Association CI / Non recommandée / Rsque interactif potentiel
Posologie(s) 90 mg qd 150 mg qd 400 mg qd200 mg bid
IFN 6 m. 1989
IFN 12 m. 1994
IFN + Riba 1998
Peg-IFN + Riba 2000
6%
16%
41%
40-45%
75%
(Futurs) traitements anti VHC
Peg-Riba Sofosbuvir Siméprévir Daclatasvir
2014
90-100%
Peg-IFN + Riba + IP 2011
Tri/Quadri- thérapies IFN-free G 1 à 6
2015-16
90-100%
Le futur… c’est
demain
Sofosbuvir/Lédipasvir : HIV/HCV G1 naïfs non cirrhotiques
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
J0 S12 48 semaines de suivi
SOF / LDV (400/90 mg)
Sans ARV (n = 13) CD4 stable et ARN VIH < 500 cp/ml
ou CD4 > 500 /mm3
Sous ARV (n = 37) CD4 > 100/mm3
ARN VIH < 40 cp/ml ARV stable ≥ 8 semaines
ARV : TDF/FTC, EFV, RPV et RAL
RVS 12 10/10
100 %
RVS 4 22/22
100 %
STARTVerso4 : Faldaprévir+Peg+RBV HIV/HCV G1 Naïfs/Echecs
Dieterich, CROI 2014
C-Worthy : MK5172/MK8742 + RBV VIH/VHC G1 naïfs non cirrhotiques
Sulkowski, EASL 2014
SVR 12 selon statut HIV et RBV+
% Pati
ents
0
20
40
60
80
100100 96.9100 93.596.8
RVR(Week 4)
EOTR(Week 12 or 24)
SVR4 SVR12
96.9 93.5
Phase 2 TURQUOISE-I
12-Week Arm 24-Week Arm
32 Sulkowski MS, et al. IAC 2014. Melbourne, Australia. #MOAB0104LB
SVR12