Prise en charge des co-infectés VIH/VHC en 2014 · 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 =

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


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


c c


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


*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


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


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


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



RGT (CV S4 <15UI) chez patients naïfs/rechuteurs non F4



SVR12 selon le score de fibrose

Etude C212 : SMV + Peg-RBV VIH/VHC G1 Naïfs/Echecs


SVR12 selon polymorphisme NS3 Q80K

Etude C212 : SMV + Peg-RBV VIH/VHC G1 Naïfs/Echecs


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


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)


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


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

Documents

Prise en charge des co-infectés VIH/VHC en 2014 · 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 =