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24 giugno 2014 Roma
Il paziente coinfetto HIV-HCV non più “special population?”La gestione clinica nell’era dei DAA di II generazione
Giustino Parruti
UOC Malattie Infettive - AUSL Pescara
24 giugno 2014 Roma
Agenda
• Interazioni tra cART e DAA - Telaprevir, Boceprevir, Daclatasvir, Simeprevir, Sofosbuvir, Ledipasvir, MK drugs
• Gestione della cART nel paziente candidato a DAA: switch a Inibitori Integrasi o Rilpivirina
• Considerazioni farmaco-economiche e strategiche nel medio-lungo termine
• Possibili scenari futuri nei coinfetti
24 giugno 2014 Roma
French real life cohorts – telaprevir(n=69)
- Patients with relapse, breakthrough and partial non-response to IFN/RBV- Patients with non-response and cirrhosis not permitted
Cotte CROI 2014 abstract 668
24 giugno 2014 Roma
French real life cohorts - boceprevir
- Patients with relapse, breakthrough and partial non-response to IFN/RBV- Patients with non-response and cirrhosis not permitted
Poizot-Martin CROI 2014 abstract LB659
24 giugno 2014 Roma
Drug CYP 3A4 TransportersNon-CYP
metabolism
Telaprevir Substrate Inhibitor
Substrate P-gp Inhibitor P-gp;
OATP1B1/2–
Boceprevir Substrate Inhibitor
Substrate P-gp; BCRP
Inhibitor P-gp; OCT1/2
AKR Substrate
Metabolic pathways of Telaprevir & Boceprevir
P-gp: P-glycoprotein; AKR: aldo-keto reductase
CYP 3A isozymes are The most abundant CYP enzymes in the liver Involved in the metabolism of many drugs
Kessara C et al 18th CROI, Abs 118; Garg V et al 18th CROI, Abs 629; Telaprevir SmPC, 2013; Boceprevir SmPC, 2013; Kiser JJ et al Hepatology 2012; 55: 1620-1628; Kunze A et al Biochem Pharmacol 2012; 84: 1096-1102.
Also note other interaction mechanisms (eg protein binding)
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24 giugno 2014 Roma
24 giugno 2014 Roma
Anemia nella casistica Pescara-Chieti(Pescara: 8 pz - Chieti: 5 pz)
avvio 1° sett
2° sett
3° sett
4° sett
6° sett
8° sett
10° sett
12° sett
16° sett
20° sett
6.0
8.0
10.0
12.0
14.0
16.0
18.0
CEIFMVGMNBAMRAMZAMMPLLADCNRNLPMEDIA
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Iperuricemia nella casistica Pescara-Chieti
avvio 2s 4s 6s 8s 10s 12s0
2
4
6
8
10
12
14
16
CEIFMMNVGBAMRAMMMZAPLLADCNRNLPMEDIA
24 giugno 2014 Roma
24 giugno 2014 Roma
In seconda giornata…
• Un paziente riferisce vomito nella notte e tachicardia notturna non aveva sospeso manidipina
• Riduzione di dose non funziona, controllo PA con modifica terapeutica
24 giugno 2014 Roma
24 giugno 2014 Roma
24 giugno 2014 Roma
Simeprevir in HIV/HCV-coinfection - C212 Study: SVR12 – Primary Endpoint
Dieterich EACS 2013 abstract LBPS9/5
24 giugno 2014 Roma
Simeprevir in HIV/HCV-coinfection - C212 Study: SVR12 – Primary Endpoint
16
SVR1
2, %
78/106 42/53 13/15 7/10 16/28
SVR12, sustained virologic response 12 weeks after end of treatment
Dieterich EACS 2013 abstract LBPS9/5
24 giugno 2014 Roma
Recently Approved DAAs
Drug CYP Activity Transporters Interaction Potential
Simeprevir CYP3A4 substrate Mild inhibition of
intestinal CYP3A4 No hepatic inhibition of
CYP3A4
P-gp substrate Mild inhibition of
intestinal P-gp Inhibits OATP1B1,
MRP2
Moderate
Sofosbuvir Metabolised by cathepsin A; CES1 and is phosphorylated.
Not metabolised by CYPs
No inhibition of CYP
P-gp and BCRP substrate
Inhibition (weak) of intestinal P-gp and BCRP
Weak
FDA Antiviral Drugs Advisory Committee Meeting Briefing Document: Simeprevir, October 2013; Simeprevir USPI; Sekar V et al; EASL 2010; Abstract 1076; Mathias A 14 th Int Workshop on Clin Pharm of HIV Ther; April 2013; Sofosbuvir USPI.
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Daclatasvir Clinical Pharmacology
Single dose of 60 mg QD; Half life of 12-15h
DDIs
ATV/r – decrease dose to 30 mg QD
EFV – increase dose to 90 mg QD
No effect of gastric acid modifiers
No effect on Midazolam or Oral Contraceptives
Bifano M et al, 2013, 8th Int Workshop on Clin Pharm of Hep Ther, Abs O-15; Bifano M et al AVT 2014; In Press; Bifano M et al 2013; EASL; Abs 794.
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Effect of ARVs on Simeprevir: Victim
Drug Effect on Simeprevir AUC (exposure)
Mechanism/Recommendation
Darunavir/r2.6-fold increase (DRV
increased 18%)
RTV Inhibits CYP3A4Not recommended
Rilpivirine No effect No dose adjustment
Efavirenz 70% decreaseEFV induces CYP3A4
Not recommended
Raltegravir 11% decreaseNo dose adjustment
Tenofovir14% decrease (TFV
increased 18%)
Intestine or renal transportNo dose adjustment
Ouwerkerk-Mahadevan S et al, IDSA 2012; Abs 1618; Ouwerkerk-Mahadevan S et al, CROI 2012; Abs 49 ; Simeprevir (Olysio) USPI
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Effect of Simeprevir on Statins: Perpetrator
DrugEffect of Simeprevir on
Statin AUCMechanism/
Recommendation
Atorvastatin 2.1-fold increase
CYP3A & OATP1B1 inhibition
Use lowest dose
Rosuvastatin 3.2-fold increase OATP1B1 inhibitionInitiate with 5mg
Simvastatin 40% increase CYP3A inhibitionTitrate dose carefully
Simprevir (Olysio) USPi 2013
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Sofosbuvir
Not metabolised by CYPNo inhibition of CYPWeak interaction with intestinal P-gp & BCRP
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Effect of ARVs on Sofosbuvir: Victim
Drug Effect on Sofosbuvir and GS-331007 AUC (exposure)
Recommendation
Darunavir/r SOF increased 34%; GS-331007 – no effect
No dose adjustment
Rilpivirine No effect on SOF or GS-331007 No dose adjustment
Efavirenz No effect on SOF or GS-331007 No dose adjustment
RaltegravirNo effect on SOF or GS-331007:
RAL decreased 27%No dose adjustment
Tenofovir No effect on SOF or GS-331007No dose adjustment
Mathias A 14th Int Workshop on Clin Pharm of HIV Ther Session 5; Kirby B et al 63rd AASLD 2012; Abs 1877. ; Sofosbuvir USPI 2013
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Effect of Co-administered Drugs on Sofosbuvir: Victim
DrugEffect on Sofosbuvir and GS-
331007 AUC (exposure) Recommendation
Methadone(multiple dose)
SOF increased 30%; no effect on GS-331007
No dose adjustment
Cyclosporine SOF increased 4-fold but no effect on GS-331007
No dose adjustment
Tacrolimus No effect on SOF or GS-331007
No dose adjustment
Mathias A 14th Int Workshop on Clin Pharm of HIV Ther Session 5; Kirby B et al 63rd AASLD 2012; Abs 1877. ; Sofosbuvir USPI 2013
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PegIFN + RBV + SOF in HIV/HCV CoinfectionSVR12
Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714
GT 1 GT 2 GT 3 GT 4GT 1a GT 1b
87
17/19 13/15
89
4/4 1/1 2/2 1/1
100100100100
0
10
20
30
40
50
60
70
80
90
100
HC
V R
NA
<L
LO
Q (
%)
FTC/TDF + Protease Inhibitor
8/9 7/8 6/6
89 88100
0
1020
3040
50
6070
8090
100
SV
R12
(%
)
FTC/TDF + NNRTI
FTC/TDF + Raltegravir
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Study Design
¨ Broad inclusion criteria– Cirrhosis permitted with no platelet cutoff
– Hemoglobin: ≥12 mg/dL (males); ≥11 mg/dL (females)
¨ Wide range of ART regimens allowed – Undetectable HIV RNA for >8 weeks on stable ART regimen
¨ Baseline CD4 count– ART treated: CD4 T-cell count >200 cells/mm3 and HIV RNA < 50 c/mL
– ART untreated: CD4 T-cell count >500 cells/mm3
Wk 0 Wk 12 Wk 24 Wk 36
SOF + RBV, n=114 GT 1 TN
SOF + RBV, n=41GT 2/3 TE
SOF + RBV, n=68 GT 2/3 TN
Wk 48
SVR 12SVR 24
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Antiretroviral Regimens
Regimen, n (%)
Treatment Naive Treatment Experienced
GT 1 n=114
GT 2/3n=68
GT 2/3n=41
On ART 112 (98) 61 (90) 39 (95)
Tenofovir DF/emtricitabine plus
Efavirenz 42 (37) 20 (33) 16 (41)
Atazanavir/ritonavir 24 (21) 7 (11) 8 (21)
Darunavir/ritonavir 15 (13) 17 (28) 2 (5)
Raltegravir 21 (18) 8 (13) 7 (18)
Rilpivirine 7 (6) 5 (8) 2 (5)
Other 3 (3) 4 (7) 4 (10)
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Patient Disposition
*Three GT1 subjects inadvertently discontinued after 12 weeks; One GT 1 subject did not adhere to study visits
Regimen, n (%)
Treatment Naive Treatment Experienced
GT 1 n=114
GT 2/3n=68
GT 2/3n=41
Completed 103 (90) 62 (91) 40 (98)
Discontinued 11 (10) 6 (9) 1 (2)
Reason for discontinuation
AE 3 (3) 3 (4) 1 (2)
Withdrew consent 2 (2) 1 (1) 0
Protocol violation* 4 (4) 0 0
Investigator decision 1 (<1) 1 (1) 0
Efficacy failure 1 (<1) 0 0
Lost to follow-up 0 1 (1) 0
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Virologic Response: Genotype 1P
atie
nts
with
HC
V R
NA
<LL
OQ
(%
)
Series10
20
40
60
80
100 96 100
76 75*
86/114110/114 103/103 87/114
Week 4 EOT SVR12 SVR24
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Virologic Response: Genotype 2P
atie
nts
with
HC
V R
NA
<LL
OQ
(%
)
Series10
20
40
60
80
100 96100
96100
8892
8892
25/26 22/23
Week 4 EOT SVR12 SVR24 Week 4 EOT SVR12 SVR24
Treatment Naïve12 Weeks SOF + RBV
Treatment Experienced24 Weeks SOF + RBV
23/26 23/26 24/24 23/23 22/24 22/2425/26 22/23 23/26 23/26 24/24 23/23 22/24 22/24
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Virologic Response: Genotype 3P
atie
nts
with
HC
V R
NA
<LL
OQ
(%
)
Series10
20
40
60
80
100100 10098 100
67
94
67
88
41/41 39/40
Week 4 EOT SVR12 SVR24 Week 4 EOT SVR12 SVR24
Treatment Naïve12 Weeks SOF + RBV
Treatment Experienced24 Weeks SOF + RBV
28/42 28/42 17/17 17/17 16/17 15/1741/41 39/40 28/42 28/42 17/17 17/17 16/17 15/17
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Safety Summary
*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.
Patients, %
SOF + RBV
24 Weeks (n=155) 12 Weeks (n=68)
AEs 92 84
AEs in ≥10% of patients
Fatigue 39 35
Insomnia 15 21
Headache 14 13
Nausea 15 18
Diarrhea 11 9
Irritability 10 10
URI 12 12
Grade 3-4 AEs 12 10
Serious AEs 6 7
Treatment D/C due to AEs* 3 4
Death 0 1†
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Laboratory Abnormalities
n (%)
SOF + RBV
24 Weeks (n=155)
12 Weeks (n=68)
Any Grade ≥3 33 (21) 8 (12)
Grade ≥3 hyperbilirubinemia (indirect) 28 (18) 4 (6)
Taking atazanavir* 26 (17) 4 (6)
Not taking atazanavir 2 (1) 0
Grade ≥3 elevated lipase† 3 (2) 0
Hemoglobin††
<10 mg/dL 27 (17) 7 (10)
<8.5 mg/dL 2 (1) 1 (1)
*4 patients changed ARV regimens from atazanavir to darunavir due to hyperbilirubinemia;
†Lipase elevations were not associated with clinical signs/symptoms and resolved ††43 (19%) required ribavirin dose reduction during study; epoetin alfa was not permitted.
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HIV Safety
¨ Eleven patients were not on ARVs during the study¨ No clinically significant variation in HIV RNA occurred
during HCV treatment dosing
¨ Two patients with transient HIV viral breakthrough– Both with documented nonadherance to ART
• No decrease in CD4 T-cell % with treatment– Decrease in absolute CD4 T-cells consistent with
known ribavirin-mediated decrease in lymphocytes
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Conclusions• The interferon-free regimen of SOF + RBV resulted in high SVR12 and
SVR24 rates in HIV-infected patients with HCV genotype 1, 2 and 3 co-infection– SVR12 rates were similar to those observed in patients with HCV
monoinfection • SOF + RBV was effectively co-administered with multiple antiretroviral
regimens including inhibitors of HIV-1 protease, reverse transcriptase (non-nucleoside/nucleoside) and integrase– HIV viral breakthrough seen exclusively in the setting of poor ART
adherence– No effect on CD4 T-cell percent
• No resistance (deep sequencing) was observed in virologic failures
• SOF was well tolerated, with a low rate of treatment discontinuations due to adverse events
24 giugno 2014 RomaSulkowski et al, EASL 2014 abstract O63
C-WORTHY HCV-PI + NS5A for HIV/HCV coinfection
24 giugno 2014 RomaSulkowski et al, EASL 2014 abstract O63
C-WORTHY HCV-PI + NS5A for HIV/HCV co-infection
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DAAs in Development
Drug CYP Activity Transporters Interaction Potential
Asunaprevir CYP3A4 substrate Inducer of CYP3A4
(weak) Inhibition of
CYP2D6 (weak)
P-gp, OATP1B1/3 substrate
Inhibition of P-gp (weak), OATP1B1/3
Moderate
Ledipasvir Little metabolism Not Inhibitor of CYP
or UGT Not Inducer of CYP
or UGT
P-gp substrate (likely) Inhibition of intestinal
P-gp (weak) Inhibition of
OATP1B1/3 (weak)
Weak
Eley T et al, 2013, 8th Int Workshop on Clin Pharm of Hep Ther; Abs O-13; Eley T et al, 2011, 62nd AASLD Abs 381; Eley T et al 2012, 7th Int Workshop on Clin Pharm of Hep Ther; Abs O-4; Kirby B et al 2013, 8 th Int Workshop on Clin Pharm of Hep Ther; Abs O-20; Mathias A, 14th Int Workshop on Clin Pharm of HIV Ther, Session 5
24 giugno 2014 Roma
ARV Treated (n=37)- CD4 count > 100 cells/mm3
- HIV RNA < 40 copies
- Current ARVs ≥ 8 weeks
Fifty HIV/HCV genotype 1, treatment-naive subjects HAI fibrosis stage 0 – 3
SOF/Ledipasvir for HIV/HCV-coinfectionERADICATE
SVR 12
SVR 4
ARV Untreated (n=13)CD4 count stable + HIV RNA <500 copies
OR- CD4 count > 500 cells/mm3
ARVs: tenofovir, emtricitabine, efavirenz, rilpivirine and raltegravir
Wk 0 Wk 1248 week follow up
SOF/LDV (400/90mg)
Osinusi A, EASL, 2014, O14
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ARV Untreatedn = 13
ARV Treatedn = 37
Median age (range) 59 (48 - 63) 58 (34 - 75)
Male, n (%) 7 (54) 30 (81)
African American, n (%) 10 (77) 32 (86)
Median BMI (range) 26 (22 - 35) 26 (19 - 41)
Genotype 1a, n (%) 9 (75) 30 (81)
Median HCV RNA log10 IU/mL (range)
6.07 (4.05 – 7.29)
5.97(4.80 – 7.05)
HAI Fibrosis Stage 3 , n (%) 5 (38) 8 (22)
Median CD4 T-cell count (range) 687 (319 – 1287)
576 (113 – 1612)
Osinusi A, EASL, 2014, O14
SOF/Ledipasvir for HIV/HCV-coinfection ERADICATE
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RegimenARV Treated
n = 37
ARVs n (%) 37 (100)
Tenofovir/Emtricitabine plus
Efavirenz (EFV) 15 (41)
Raltegravir (RAL) 10 (27)
Rilpivirine (RPV) 8 (21)
RPV/RAL 3 (8)
EFV/RAL 1 (3)
Osinusi A, EASL, 2014, O14
SOF/Ledipasvir for HIV/HCV-coinfection ERADICATE
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Med
ian
HC
V V
iral D
ecay
106
104
102
ARVUntreated
Clearance of infectiousvirus (c)
9.05/day 10.3/day p=0.68
ARVTreated
Osinusi A, EASL, 2014, O14
SOF/Ledipasvir for HIV/HCV-coinfection ERADICATE
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ARV - 13/ 13 13/13 13/ 13 12/12 10/10 10/10
ARV + 37/37 37/37 30/30 22/22
Osinusi A, EASL, 2014, O14
SOF/Ledipasvir for HIV/HCV-coinfectionERADICATE
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SOFOSBUVIR/LEDIPASVIR IN RETREATMENT OF HCV GENOTYPE-1 PATIENTS WHO PREVIOUSLY FAILED SOFOSBUVIR/RIBAVIRIN THERAPY
Anu Osinusi1,2, Miriam Marti1, Anita Kohli3,4, Eric Meissner 1, Kerry Townsend1, Amy Nelson1, Rachel Silk3, Xiaozhen Zhang 1, William T.
Symonds5, John McHutchison5, Michael Polis 1, Henry Masur4, Shyam Kottilil 1 for the NIAID/CC Hepatitis C SYNERGY team1,3,4
1Laboratory of Immunoregulation, NIAID, NIH, Bethesda, Maryland, 2Dept of Infectious Diseases, University of Maryland, Baltimore, 3CMRP, SAIC–Frederick Inc, Frederick National Laboratory for Cancer Research,
Frederick, Maryland , 4Critical Care Medicine Department, NIH, Bethesda, Maryland , 5Gilead Sciences, Foster City, California
24 giugno 2014 Roma
Disclosures No financial disclosures
Investigator initiated study conducted by NIAID/CC, NIH
This presentation includes discussion of investigational use of Sofosbuvir (SOF)/Ledipasvir (LDV) fixed dose combination
Fuding Statement: This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
This research was supported by the National Institute of Allergy and Infectious Diseases
24 giugno 2014 Roma
Background The IFN-free regimen of sofosbuvir (SOF) + RBV for
24 weeks has recently been approved for use in GT-1 IFN ineligible subjects (SVR12 rates: 68 – 76%)
The ideal regimen for retreatment of SOF failures in GT-1 infections is unclear
Single reported case of a GT-1 patient who failed 8 weeks of SOF/LDV therapy and was successfully retreated with SOF/LDV/RBV for 24 weeks (Lonestar, AASLD 2013)
Lawitz E et al AASLD 2013 #215, Osinusi A et al JAMA 2013 (310)
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Background
Sofosbuvir (HCV NS5B RNA polymerase inhibitor)
- Potent antiviral activity against HCV GT 1 - 6
Ledipasvir (HCV NS5A inhibitor)
- Activity against HCV GT1a and 1b, 4 - 6
- Effective against variants with the NS5B resistance mutation S282T
Sofosbuvir/Ledipasvir Fixed dose combination- Once daily, oral (400/90mg) combination pill
24 giugno 2014 Roma
Objective
To evaluate the efficacy of SOF/LDV in HCV monoinfected, GT- 1 patients who relapsed with prior SOF/RBV therapy.
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Sofosbuvir 400mg + RBV 600mgn = 25
Sofosbuvir 400mg + RBV 1000 -1200mg n = 25
Sofosbuvir 400mg + RBV 1000 -1200mg n = 10
Part 1
Sixty HCV genotype 1, treatment-naive subjects Part 1: HAI fibrosis stage 0-2 Part 2: HAI fibrosis stage 0-4
Design: NIAID SPARE Study (SOF/RBV)
Part 2
SVR 48 : 90%
24 weeks
SVR 48 : 68%
SVR 48: 48%
Osinusi A, et al JAMA 2013, 310
ITT analysis
24 giugno 2014 Roma
Despite Rapid and Prolonged Viral Suppression, 17 of 55 Patients Relapsed After the End of Treatment
Vir
al L
oad
(lo
g 10)
Relapse is the cause of treatment failure in other DAA trials using sofosbuvir and ribavirin, although mechanisms are unknown
Gane EJ et al, NEJM 2013 (368), Osinusi A et al, JAMA 2013 (310)Jacobson IM et al, NEJM 2013 (368), Lawitz E et al, NEJM 2013 (368).
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SOF/LDV (400/90mg) NIAID SYNERGY STUDY
Study Design: SOF/LDV
n = 14 SVR 12
Wk 0 Wk 1248 week follow up
Hypothesis: combining SOF with a second DAA may effectively suppress HCV replication and improve odds of achieving SVR
3 participants did not participate- 1 developed hepatocellular cancer- 1 opted for telaprevir triple therapy- 1 declined participation
SOF/RBV (SPARE Study)
17 relapsers
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Study Endpoints Primary endpoint: Efficacy (SVR 12)
- All patients who received one dose of study drug (ITT analysis)
Safety and tolerability
- Adverse events and discontinuations
NS5B S282T resistance mutations- Population sequencing (Sanger methodology)
- Sensitivity cut-off: 20% - 25%
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SOF/LDVn= 14
Median age (range) 59.5 (48-70)
Male, n (%) 13 (93)
African American, n (%) 13 (93)
IL28B CT/TT, n (%) 12 (86)
Median BMI (range) 28.5 (20 - 41)
Genotype 1a, n (%) 8 (57)Median HCV RNA log10 IU/mL (range)
6.45 (5.5 - 6.8)
HAI Stage 3 - 4 Fibrosis, n (%) * 7 (50)
Profile of Participants
* Fibrosis staging prior to enrollment in NIAID SPARE study
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Population Sequencing For S282T Mutation
PTSOF/RBV
Day 0 EOTWk 26SVR2
Wk 28SVR4
Wk 32SVR8
Wk 36SVR12
Weeks between regimens
1 WT ND ND WT WT 532 WT ND ND ND WT WT 573 WT ND WT 534 WT ND ND ND WT WT 595 WT ND WT WT 536 WT ND WT WT 577 WT ND WT WT 578 WT ND S282T WT 579 WT ND ND WT WT WT 54
10 WT ND WT WT WT WT 5611 WT ND WT WT WT WT 5912 WT ND ND ND ND WT 5913 WT ND ND WT WT WT 6014 WT ND WT WT WT WT 61
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Treatment Response On SOF/LDV
n / N 14/14 14/14 14/14 14/14 14/14 14/14
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No Significant Hemoglobin Decline Occurred During Treatment With SOF/LDV
Mean hemoglobin drop from baseline at 12 weeks with SOF/LDV was 0.3g/dL vs. 1.2 g/dL with SOF/RBV
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Adverse events All Adverse events SOF/LDV
n = 14Deaths, grade 3 or 4 AEs or discontinuations 0
Headache 1
Myalgia 2
Congestion 1
Constipation 1
Diarrhea 1
Rash 1
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Laboratory Abnormalities (≥ Grade 2)
4 Grade 3 events: hypophosphatemia (2), hypercholesterolemia (1), elevated creatinine (1)
Laboratory Abnormalities ≥ Grade 2
SOF/LDV n = 14
Elevated creatinine 1
Hypophosphatemia 2
Hypoglycemia 1
Neutropenia 1
Hyperbilirubinemia 1
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No Changes Observed In Renal Parameters On Treatment
Serum Creatinine Estimated Glomerular Filtration Rate
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Conclusions
The IFN/RBV free regimen of SOF/LDV resulted in 100% SVR12 rates in patients who had relapsed post completion of SOF/RBV 24 week therapy
One patient with detectable S282T mutation after relapse to SOF/RBV achieved SVR
SOF/LDV was well tolerated with no discontinuations
These results suggest that patients who fail SOF/RBV therapy can be successfully retreated with SOF/LDV for 12 weeks
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Combination Oral, Hepatitis C Antiviral Therapy for 6 or 12
Weeks:Results of the SYNERGY Trial
Anita Kohli, Zayani Sims, Miriam Marti, Amy Nelson, Anu Osinusi, Dimitra Bon, Eva Hermann, Colleen Kotb, Rachel
Silk, Gebeyehu Teferi, William T. Symonds, Phil S Pang, John McHutchison, G. Mani Subramanian, Michael A. Polis,
Henry Masur, Shyam Kottilil
National Institute of Allergy and Infectious DiseasesNational Institutes of Health
Department of Health and Human ServicesBethesda, MD
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Study Design• Sofosbuvir (nucleotide NS5B inhibitor) 400 mg / ledipasvir (NS5A
inhibitor) 90 mg once daily
• GS-9669 (non-nucleoside NS5B inhibitor) 500 mg once daily
• GS-9451 (a protease/ NS3/4 inhibitor) 80 mg once daily
Treatment naïveAll stages
fibrosisTreatment naïve
Cirrhosisexcluded
Treatment naïveCirrhosisexcluded
0 6 12Week
SVR12
SVR12
SVR12
Sofosbuvir + Ledipasvir (n=20)
Sofosbuvir + Ledipasvir+ GS-9669 (n=20)
Sofosbuvir + Ledipasvir+ GS-9451 (n=20)
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Profile of ParticipantsSofosbuvir +Ledipasvir
12 weeks(n=20)
Sofosbuvir +Ledipasvir +
GS-96696 weeks(n=20)
Sofosbuvir +Ledipasvir +
GS-94516 weeks(n=20)
p-value
Age – mean ± standard deviation 57 ± 8 54 ± 7 54 ± 9 0.28
Male – n (%) 14 (70) 13 (65) 16 (80) 0.56
Race – n (%)
Black 16 (80) 19 (95) 18 (90)0.32
White 4 (20) 1 (5) 2 (10)
HCV genotype – n (%)
1a 11 (55) 14 (70) 17 (85)0.12
1b 9 (45) 6 (30) 3 (15)
HCV RNA >800,000 IU/mL – n (%) 15 (75) 13 (65) 14 (70) 0.79
IL28B genotype – n (%)
CC 5 (25) 2 (10) 5 (25)0.66
CT/TT 15 (75) 18 (90) 15 (75)
Knodell HAI Fibrosis Score – n (%)
0–2 12 (60) 15 (75) 15 (75)
0.163 5 (25) 5 (25) 5 (25)
4 3 (15) 0 0
24 giugno 2014 Roma
Treatment Response (ITT)Sofosbuvir + Ledipasvir (n=20)Sofosbuvir + Ledipasvir + GS-9669( n=20)Sofosbuvir + Ledipasvir + GS-9451 (n=20)
0
Week 4
10
20
30
40
50
60
70
80
90
100
EOT SVR 4 SVR 12
% o
f p
atie
nts
wit
hH
CV
RN
A <
LL
OQ
(IT
T)
90
100 100 100 100 100 10095
100 10095
100
24 giugno 2014 Roma
HCV Viral Kinetic Fitted Model
0
Med
ian
HC
V R
NA
dec
lin
e
102
103
104
105
106
107
Time (days)7 14 21 28
Sofosbuvir + LedipasvirSofosbuvir + Ledipasvir + GS-9669Sofosbuvir + Ledipasvir + GS-9451
24 giugno 2014 Roma
Early Normalization of ALT and AST
● Alanine aminotransferase (ALT) levels declined to normal by day 14 in 90%, 100% and 95% of patients treated with sofosbuvir + ledipasvir, sofosbuvir + ledipasvir + GS-9669 and sofosbuvir + ledipasvir + GS-9451, respectively
0
Ala
nin
e am
inot
ran
sfer
ase
(U/L
)
0
Day
Sofosbuvir + Ledipasvir(n=20)Sofosbuvir + Ledipasvir +GS-9669 (n=20)Sofosbuvir + Ledipasvir +GS-9451 (n=20)
20
40
60
80
100
7 2 3 4 6 8 10 12 14 16 18 20 24
Week
00
Day
20
40
60
80
100
7 2 3 4 6 8 10 12 14 16 18 20 24
Week
Asp
arta
te a
min
otra
nsf
eras
e (U
/L)
24 giugno 2014 Roma
Sofosbuvir +Ledipasvir
12 weeks(n=20)
Sofosbuvir +Ledipasvir +
GS-96696 weeks(n=20)
Sofosbuvir +Ledipasvir +
GS-94516 weeks(n=20)
Any Grade 4 abnormality during treatment* – n (%) 0 0 0
Any Grade 3 abnormality during treatment* – n (%) 3 (15) 2 (10) 4 (20)
Hypophosphatemia 0 2 (10) 0
Elevated serum creatinine 0 0 3 (15)
Decreased hemoglobin 0 0 1 (5)
Elevated ALT 1 (5) 0 0
Elevated AST 1 (5) 0 0
Elevated LDL 1 (5) 0 0
Hyperglycemia 1 (5) 0 0
Hypoglycemia 1 (5) 0 0
Safety Profiles
• Elevated creatinine occurred in two patients with baseline renal insufficiency and in third patient who initiated 1600 mg/day ibuprofen
* From Day 0 to 30 days post-treatment
24 giugno 2014 Roma
Conclusions
• Hepatitis C can be successfully and safely treated in six weeks using three direct acting agents with different mechanisms of acting
• Addition of a third DAA enabled a shorter duration of therapy
• This short duration, simple therapy for HCV may prove relevant for the global elimination of hepatitis C, where uncomplicated, well-tolerated therapy is required to ensure adherence and minimize health care expenditures
24 giugno 2014 Roma
Recommended