Transcript Titolo

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
Metabolic pathways of Telaprevir &
Boceprevir
Drug
CYP 3A4
Telaprevir
Boceprevir
Transporters
 Inhibitor
 Substrate P-gp
 Inhibitor P-gp;
OATP1B1/2
 Substrate
 Inhibitor
 Substrate P-gp;
BCRP
 Inhibitor P-gp;
OCT1/2
 Substrate
Non-CYP
metabolism
–
AKR
 Substrate
CYP 3A isozymes are
 The most abundant CYP enzymes in the liver
 Involved in the metabolism of many drugs

Also note other interaction mechanisms (eg protein binding)
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.
P-gp: P-glycoprotein; AKR: aldo-keto reductase
24 giugno 2014 Roma
24 giugno 2014 Roma
24 giugno 2014 Roma
Anemia nella casistica Pescara-Chieti
(Pescara: 8 pz - Chieti: 5 pz)
18,0
16,0
14,0
12,0
10,0
8,0
6,0
avvio 1°
2°
3°
4°
6°
8° 10° 12° 16° 20°
sett sett sett sett sett sett sett sett sett sett
CE
IFM
VG
MN
BA
MRA
MZA
MM
PL
LA
DCN
RN
LP
MEDIA
24 giugno 2014 Roma
Iperuricemia
nella casistica Pescara-Chieti
16
CE
IFM
MN
VG
BA
MRA
MM
MZA
PL
LA
DCN
RN
LP
MEDIA
14
12
10
8
6
4
2
0
avvio
2s
4s
6s
8s
10s
12s
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
SVR12, %
Simeprevir in HIV/HCV-coinfection C212 Study: SVR12 – Primary Endpoint
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
16
24 giugno 2014 Roma
Recently Approved DAAs
Drug
CYP Activity
Transporters
Interaction
Potential
Simeprevir  CYP3A4 substrate
 P-gp substrate
 Mild inhibition of
intestinal P-gp
 Inhibits OATP1B1,
MRP2
 Moderate
Sofosbuvir  Metabolised by
 P-gp and BCRP
substrate
 Inhibition (weak) of
intestinal P-gp and
BCRP
 Weak
 Mild inhibition of
intestinal CYP3A4
 No hepatic inhibition of
CYP3A4
cathepsin A; CES1 and
is phosphorylated.
 Not metabolised by
CYPs
 No inhibition of CYP
FDA Antiviral Drugs Advisory Committee Meeting Briefing Document: Simeprevir, October 2013; Simeprevir
USPI; Sekar V et al; EASL 2010; Abstract 1076; Mathias A 14th Int Workshop on Clin Pharm of HIV Ther; April
2013; Sofosbuvir USPI.
24 giugno 2014 Roma
24 giugno 2014 Roma
24 giugno 2014 Roma
24 giugno 2014 Roma
24 giugno 2014 Roma
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.
24 giugno 2014 Roma
24 giugno 2014 Roma
Effect of ARVs on Simeprevir: Victim
Drug
Darunavir/r
Effect on Simeprevir
AUC (exposure)
2.6-fold increase (DRV
increased 18%)
Mechanism/
Recommendation
RTV Inhibits CYP3A4
Not recommended
Rilpivirine
No effect
No dose adjustment
Efavirenz
70% decrease
EFV induces CYP3A4
Not recommended
Raltegravir
11% decrease
Tenofovir
14% decrease (TFV
increased 18%)
No dose adjustment
Intestine or renal transport
No dose adjustment
Ouwerkerk-Mahadevan S et al, IDSA 2012; Abs 1618; Ouwerkerk-Mahadevan S et al, CROI 2012; Abs 49 ; Simeprevir (Olysio) USPI
24 giugno 2014 Roma
Effect of Simeprevir on Statins: Perpetrator
Drug
Effect of Simeprevir on
Statin AUC
Mechanism/
Recommendation
CYP3A & OATP1B1
inhibition
Use lowest dose
Atorvastatin
2.1-fold increase
Rosuvastatin
3.2-fold increase
OATP1B1 inhibition
Initiate with 5mg
40% increase
CYP3A inhibition
Titrate dose carefully
Simvastatin
Simprevir (Olysio) USPi 2013
24 giugno 2014 Roma
Sofosbuvir
Not metabolised by CYP
No inhibition of CYP
Weak interaction with intestinal P-gp
& BCRP
24 giugno 2014 Roma
Effect of ARVs on Sofosbuvir: Victim
Drug
Effect on Sofosbuvir and
GS-331007 AUC (exposure)
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
Raltegravir
No effect on SOF or GS-331007:
RAL decreased 27%
No dose adjustment
Tenofovir
No effect on SOF or GS-331007
Recommendation
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
24 giugno 2014 Roma
Effect of Co-administered Drugs on
Sofosbuvir: Victim
Drug
Methadone
(multiple dose)
Cyclosporine
Tacrolimus
Effect on Sofosbuvir and
GS-331007 AUC (exposure)
SOF increased 30%; no
effect on GS-331007
Recommendation
No dose adjustment
SOF increased 4-fold but no
effect on GS-331007
No dose adjustment
No effect on SOF or GS331007
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
24 giugno 2014 Roma
PegIFN + RBV + SOF in HIV/HCV Coinfection
SVR12
HCV RNA <LLOQ (%)
100
90
89
87
17/19
13/15
100
100
100
100
4/4
1/1
2/2
1/1
80
70
60
50
40
30
20
10
0
SVR12 (%)
GT 1
100
90
80
70
60
50
40
30
20
10
0
GT 1a
GT 1b
GT 2
GT 3
GT 4
100
89
88
8/9
7/8
6/6
FTC/TDF +
Protease Inhibitor
FTC/TDF
+ NNRTI
FTC/TDF +
Raltegravir
Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714
24 giugno 2014 Roma
Study Design
Wk 0
GT 1
Wk 12
Wk 24
Wk 36
Wk 48
SOF + RBV, n=114
TN
GT 2/3 TN
SOF + RBV, n=68
GT 2/3 TE
SOF + RBV, n=41
SVR 12
SVR 24
 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
24 giugno 2014 Roma
Antiretroviral Regimens
Treatment Naive
Regimen, n (%)
On ART
Tenofovir DF/emtricitabine plus
Efavirenz
Atazanavir/ritonavir
Darunavir/ritonavir
Raltegravir
Rilpivirine
Other
Treatment
Experienced
GT 1
n=114
GT 2/3
n=68
GT 2/3
n=41
112 (98)
61 (90)
39 (95)
42 (37)
24 (21)
15 (13)
21 (18)
7 (6)
3 (3)
20 (33)
7 (11)
17 (28)
8 (13)
5 (8)
4 (7)
16 (41)
8 (21)
2 (5)
7 (18)
2 (5)
4 (10)
24 giugno 2014 Roma
Patient Disposition
Treatment Naive
Treatment
Experienced
GT 1
n=114
GT 2/3
n=68
GT 2/3
n=41
103 (90)
62 (91)
40 (98)
11 (10)
6 (9)
1 (2)
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
0
1 (1)
0
Regimen, n (%)
Completed
Discontinued
Reason for discontinuation
Lost to follow-up
*Three GT1 subjects inadvertently discontinued after 12 weeks; One GT 1 subject did not adhere to study visits
24 giugno 2014 Roma
Virologic Response: Genotype 1
Patients with HCV RNA <LLOQ (%)
100
96
100
76
80
75*
60
40
20
0
110/114
103/103
87/114
86/114
Week 4
EOT
SVR12
SVR24
24 giugno 2014 Roma
Patients with HCV RNA <LLOQ (%)
Virologic Response: Genotype 2
100
96
100
96
88
100
92
88
92
80
60
40
20
25/26
25/26
0
Week 4
22/23 23/26 23/26
22/23 23/26 23/26
EOT SVR12 SVR24
Treatment Naïve
12 Weeks SOF + RBV
24/24 23/23
24/24 23/23
Week 4
22/24 22/24
22/24 22/24
EOT SVR12 SVR24
Treatment Experienced
24 Weeks SOF + RBV
24 giugno 2014 Roma
Patients with HCV RNA <LLOQ (%)
Virologic Response: Genotype 3
100
100
100
98
100
94
88
80
67
67
60
40
20
41/41
41/41
39/40 28/42 28/42
39/40 28/42 28/42
17/17
17/17
17/17
17/17
16/17
16/17
15/17
15/17
0
Week 4
EOT SVR12 SVR24
Treatment Naïve
12 Weeks SOF + RBV
Week 4
EOT SVR12 SVR24
Treatment Experienced
24 Weeks SOF + RBV
24 giugno 2014 Roma
Safety Summary
SOF + RBV
Patients, %
24 Weeks (n=155)
12 Weeks (n=68)
92
84
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†
AEs
AEs in ≥10% of patients
*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.
24 giugno 2014 Roma
Laboratory Abnormalities
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)
26 (17)
4 (6)
2 (1)
0
3 (2)
0
<10 mg/dL
27 (17)
7 (10)
<8.5 mg/dL
2 (1)
1 (1)
n (%)
Taking atazanavir*
Not taking atazanavir
Grade ≥3 elevated lipase†
Hemoglobin††
*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.
24 giugno 2014 Roma
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
24 giugno 2014 Roma
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 Roma
C-WORTHY
HCV-PI + NS5A for HIV/HCV coinfection
Sulkowski et al, EASL 2014 abstract O63
24 giugno 2014 Roma
C-WORTHY
HCV-PI + NS5A for HIV/HCV co-infection
Sulkowski et al, EASL 2014 abstract O63
24 giugno 2014 Roma
DAAs in Development
Drug
CYP Activity
Asunaprevir  CYP3A4 substrate
 Inducer of CYP3A4
(weak)
 Inhibition of
CYP2D6 (weak)
Ledipasvir
Transporters
 P-gp, OATP1B1/3
substrate
 Inhibition of P-gp
(weak), OATP1B1/3
 Little metabolism
 P-gp substrate (likely)
 Not Inhibitor of CYP  Inhibition of intestinal
or UGT
P-gp (weak)
 Not Inducer of CYP  Inhibition of
or UGT
OATP1B1/3 (weak)
Interaction
Potential
 Moderate
 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, 8th 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
SOF/Ledipasvir for HIV/HCV-coinfection
ERADICATE
 Fifty HIV/HCV genotype 1, treatment-naive subjects
 HAI fibrosis stage 0 – 3
Wk 12
Wk 0
48 week follow up
ARV Untreated (n=13)
CD4 count stable + HIV RNA <500 copies
OR
- CD4 count > 500 cells/mm3
SVR 12
SOF/LDV (400/90mg)
ARV Treated (n=37)
- CD4 count > 100 cells/mm3
- HIV RNA < 40 copies
SVR 4
- Current ARVs ≥ 8 weeks
ARVs: tenofovir, emtricitabine, efavirenz, rilpivirine
and raltegravir
Osinusi A, EASL, 2014, O14
24 giugno 2014 Roma
SOF/Ledipasvir for HIV/HCV-coinfection
ARV Untreated
ARV Treated
ERADICATE
n = 13
n = 37
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)
6.07
(4.05 – 7.29)
5.97
(4.80 – 7.05)
5 (38)
8 (22)
687
(319 – 1287)
576
(113 – 1612)
Median age (range)
Median HCV RNA log10 IU/mL
(range)
HAI Fibrosis Stage 3 , n (%)
Median CD4 T-cell count (range)
Osinusi A, EASL, 2014, O14
24 giugno 2014 Roma
SOF/Ledipasvir for HIV/HCV-coinfection
ERADICATE
Regimen
ARVs n (%)
ARV Treated
n = 37
37 (100)
Tenofovir/Emtricitabine plus
Efavirenz (EFV)
15 (41)
Raltegravir (RAL)
10 (27)
Rilpivirine (RPV)
8 (21)
Osinusi A, EASL, 2014, O14
RPV/RAL
3 (8)
EFV/RAL
1 (3)
24 giugno 2014 Roma
SOF/Ledipasvir for HIV/HCV-coinfection
ERADICATE
Median HCV Viral Decay
106
104
Clearance of infectious
virus (c)
ARV
Untreated
ARV
Treated
9.05/day
10.3/day
p=0.68
102
Osinusi A, EASL, 2014, O14
24 giugno 2014 Roma
SOF/Ledipasvir for HIV/HCV-coinfection
ERADICATE
ARV Untreated
ARV Treated
% of patients with
HCV RNA < LLOQ (ITT)
100
80
60
40
20
0
12
13
Wk 4
Wk 8
EOT
SVR4
SVR8
SVR12
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
24 giugno 2014 Roma
24 giugno 2014 Roma
24 giugno 2014 Roma
24 giugno 2014 Roma
24 giugno 2014 Roma
24 giugno 2014 Roma
24 giugno 2014 Roma
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)
24 giugno 2014 Roma
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.
24 giugno 2014 Roma
Design: NIAID SPARE Study (SOF/RBV)

Sixty HCV genotype 1, treatment-naive subjects

Part 1: HAI fibrosis stage 0-2

Part 2: HAI fibrosis stage 0-4
24 weeks
ITT analysis
Part 1
Sofosbuvir 400mg + RBV 1000 -1200mg
n = 10
SVR 48 : 90%
Sofosbuvir 400mg + RBV 1000 -1200mg
n = 25
SVR 48 : 68%
Sofosbuvir 400mg + RBV 600mg
n = 25
SVR 48: 48%
Part 2
Osinusi A, et al JAMA 2013, 310
24 giugno 2014 Roma
Viral Load (log10)
Despite Rapid and Prolonged Viral Suppression, 17
of 55 Patients Relapsed After the End of Treatment
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).
24 giugno 2014 Roma
Study Design: SOF/LDV
SOF/RBV
17 relapsers
(SPARE Study)
Wk 0
n = 14
Hypothesis: combining SOF with
a second DAA may effectively
suppress HCV replication and
improve odds of achieving SVR
Wk 12
SOF/LDV (400/90mg)
NIAID SYNERGY STUDY
48 week follow up
SVR 12
3 participants did not participate
- 1 developed hepatocellular cancer
- 1 opted for telaprevir triple therapy
- 1 declined participation
24 giugno 2014 Roma
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%
24 giugno 2014 Roma
Profile of Participants
SOF/LDV
n= 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 (%)
Median HCV RNA log10 IU/mL
(range)
HAI Stage 3 - 4 Fibrosis, n (%) *
8 (57)
6.45 (5.5 - 6.8)
7 (50)
* Fibrosis staging prior to enrollment in NIAID SPARE study
24 giugno 2014 Roma
Population Sequencing For S282T Mutation
PT
1
2
3
4
5
6
7
8
9
10
11
12
13
14
SOF/RBV
Day 0
WT
WT
WT
WT
WT
WT
WT
WT
WT
WT
WT
WT
WT
WT
EOT
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
Wk 26 Wk 28
SVR2 SVR4
ND
WT
ND
ND
ND
WT
WT
WT
ND
WT
WT
ND
ND
WT
ND
WT
WT
WT
S282T
WT
WT
WT
ND
WT
WT
Wk 32
SVR8
WT
WT
Wk 36
SVR12
WT
WT
WT
WT
WT
WT
WT
ND
WT
WT
WT
WT
WT
WT
WT
WT
WT
Weeks
between
regimens
53
57
53
59
53
57
57
57
54
56
59
59
60
61
24 giugno 2014 Roma
Treatment Response On SOF/LDV
% of patients with HCV
RNA < LLOQ
100
80
60
40
20
0
n/N
WK 4
14/14
WK 8
14/14
EOT
14/14
SVR 4
14/14
SVR8
14/14
SVR12
14/14
24 giugno 2014 Roma
No Significant Hemoglobin Decline
Occurred During Treatment With SOF/LDV
HgB Decline Sem
Hgb Decline (g/dL)
Mean (SEM)
3
SOF/LDV
SOF/RBV
2
1
* p= < 0.05
0
*
*
*
-1
-2
12
W
K
8
W
K
4
K
W
D
AY
0
-3
Mean hemoglobin drop from baseline at 12 weeks with SOF/LDV was
0.3g/dL vs. 1.2 g/dL with SOF/RBV
24 giugno 2014 Roma
Adverse events
All Adverse events
SOF/LDV
n = 14
Deaths, grade 3 or 4 AEs or
discontinuations
0
Headache
1
Myalgia
2
Congestion
1
Constipation
1
Diarrhea
1
Rash
1
24 giugno 2014 Roma
Laboratory Abnormalities (≥ Grade 2)
Laboratory
Abnormalities
≥ Grade 2
SOF/LDV
n = 14
Elevated creatinine
1
Hypophosphatemia
2
Hypoglycemia
1
Neutropenia
1
Hyperbilirubinemia
1
4 Grade 3 events: hypophosphatemia (2),
hypercholesterolemia (1), elevated creatinine (1)
24 giugno 2014 Roma
No Changes Observed In Renal Parameters
On Treatment
cr decline sem
GFR decline sem
Estimated Glomerular
Filtration Rate
0.9
SOF/LDV
SOF/RBV
GFR change (mL/min)
Mean (SEM)
Creatinine change (mg/dL)
Mean (SEM)
Serum Creatinine
0.6
0.3
0.0
-0.3
-0.6
40
SOF/LDV
SOF/RBV
20
0
-20
-40
-0.9
Day Wk
4
0
Wk
8
Wk SVR
4
12
Day Wk
0
4
Wk
8
Wk SVR
12
4
24 giugno 2014 Roma
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
24 giugno 2014 Roma
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 Diseases
National Institutes of Health
Department of Health and Human Services
Bethesda, MD
24 giugno 2014 Roma
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
Week
0
6
Treatment naïve
All stages Sofosbuvir + Ledipasvir (n=20)
fibrosis
Treatment naïve
Cirrhosis
excluded
Sofosbuvir +
Ledipasvir
+ GS-9669 (n=20)
SVR12
Treatment naïve
Cirrhosis
excluded
Sofosbuvir +
Ledipasvir
+ GS-9451 (n=20)
SVR12
12
SVR12
24 giugno 2014 Roma
Profile of Participants
Sofosbuvir +
Ledipasvir
Sofosbuvir +
Ledipasvir +
GS-9451
6 weeks
(n=20)
p-value
12 weeks
(n=20)
Sofosbuvir +
Ledipasvir +
GS-9669
6 weeks
(n=20)
Age – mean ± standard deviation
57 ± 8
54 ± 7
54 ± 9
0.28
Male – n (%)
14 (70)
13 (65)
16 (80)
0.56
Black
16 (80)
19 (95)
18 (90)
White
4 (20)
1 (5)
2 (10)
1a
11 (55)
14 (70)
17 (85)
1b
9 (45)
6 (30)
3 (15)
15 (75)
13 (65)
14 (70)
CC
5 (25)
2 (10)
5 (25)
CT/TT
15 (75)
18 (90)
15 (75)
0–2
12 (60)
15 (75)
15 (75)
3
5 (25)
5 (25)
5 (25)
4
3 (15)
0
0
Race – n (%)
0.32
HCV genotype – n (%)
HCV RNA >800,000 IU/mL – n (%)
0.12
0.79
IL28B genotype – n (%)
0.66
Knodell HAI Fibrosis Score – n (%)
0.16
24 giugno 2014 Roma
Treatment Response (ITT)
% of patients with
HCV RNA <LLOQ (ITT)
Sofosbuvir + Ledipasvir (n=20)
Sofosbuvir + Ledipasvir + GS-9669( n=20)
Sofosbuvir + Ledipasvir + GS-9451 (n=20)
100
90
100 100
100 100 100
90
100
95
100
100
95
100
80
70
60
50
40
30
20
10
0
Week 4
EOT
SVR 4
SVR 12
24 giugno 2014 Roma
HCV Viral Kinetic Fitted Model
Median HCV RNA decline
107
Sofosbuvir + Ledipasvir
Sofosbuvir + Ledipasvir + GS-9669
Sofosbuvir + Ledipasvir + GS-9451
106
105
104
103
102
0
7
14
21
28
Time (days)
24 giugno 2014 Roma
Early Normalization of ALT and AST
Sofosbuvir + Ledipasvir
(n=20)
Sofosbuvir + Ledipasvir +
GS-9669 (n=20)
Sofosbuvir + Ledipasvir +
GS-9451 (n=20)
100
Aspartate aminotransferase (U/L)
Alanine aminotransferase (U/L)
100
80
60
40
20
0
80
60
40
20
0
0
7
Day
2
3
4
6
8 10 12 14 16 18 20 24
Week
0
7
Day
2
3
4
6
8 10 12 14 16 18 20 24
Week
● 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 + GS9451, respectively
24 giugno 2014 Roma
Safety Profiles
Sofosbuvir +
Ledipasvir
12 weeks
(n=20)
Sofosbuvir +
Ledipasvir +
GS-9669
6 weeks
(n=20)
Sofosbuvir +
Ledipasvir +
GS-9451
6 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
* From Day 0 to 30 days post-treatment
• Elevated creatinine occurred in two patients with baseline
renal insufficiency and in third patient who initiated
1600 mg/day ibuprofen
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
24 giugno 2014 Roma