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Estimated 170 Million Persons With HCV
Infection Worldwide
•World Health Organization. Wkly Epid Rec .1999;74:425-427. World Health Organization. Hepatitis C: Global Prevalence: Update. 2003. Farci P, et al. Semin Liver Dis. 2000;20:103-126. Wasley A, et al. Semin Liver Dis. 2000;20:1-16.
•Europe
•8.9 million
•(1.03%)•Americas
•13.1 million
•(1.7%)•Africa
•31.9 million
•(5.3%)
•Western Pacific
•62.2 million
•(3.9%)
•Eastern Mediterranean
•21.3 million
•(4.6%)
•Southeast Asia
•32.3 million
•(2.15%)
Hepatitisweb study
Hepatitisweb study2015
0
20
40
60
80
100
IFN 6m IFN 12m IFN/RBV 6m IFN/RBV 12 m Peg-IFN 12m Peg-IFN/RBV 12m Peg-IFN/RBV/DAA
SV
R (
%)
20011998
2011
StandardInterferon
+ Ribavirin
Peginterferon
1991
+ DAAs
Milestones in Therapy of CHC:Average SVR Rates from Clinical Trials
Adapted from US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring MD.
6%
16%
34%
42%39%
55%
70+%
The Evolution of HCV Therapy
PegIFN/RBVProtease inhibitorNucleos(t)ide polymerase inhibitorNonnucleoside polymerase inhibitorNS5A inhibitorHost targeting agent
2002 2012 Beyond
Current status of HCV…
• Treatment of HCV infection is evolving rapidly.
• The approval in 2013 of two new directacting antivirals—sofosbuvir (a polymerase inhibitor) and simeprevir (a second-generation protease inhibitor)—opens the door for an all-oral regimen, potentially avoiding interferon and its harsh side effects.
• Other direct-acting antivirals are under development.
GOAL OF TREATING HCV:
A SUSTAINED VIROLOGIC RESPONSE
• The aim of HCV treatment is to achieve a sustained virologic response,
- defined as having no detectable viral RNA after completion of antiviral therapy.
• SVR is associated with
1. better clinical outcomes,
2. lower morbidity and all-cause mortality,
3. improvement in liver histology
GOAL OF TREATING HCV:
A SUSTAINED VIROLOGIC RESPONSE
• This end point has traditionally been assessed at 6 months after the end of therapy, but recent data suggest the rates at 12 weeks are essentially equivalent
HCV Life Cycle and DAA Targets
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
Receptor binding
and endocytosis
Fusion
and
uncoating
Transport
and release
(+) RNA
Translation
and
polyprotein
processing
RNA replication
Virion
assembly
Membranous
web
ER lumen
LD
LD
ER lumen
LD
NS3/4
protease
inhibitors
NS5B polymerase
inhibitors
Nucleoside/nucleotide
Nonnucleoside
Each Drug Class Has Unique Features
NS3/4A
Protease
Inhibitors
NS5B Polymerase Inhibitors NS5A
Inhibitors
Cyclophilin A
InhibitorsNucleos(t)ide
Analogue
Non-
nucleos(t)ide
High efficacy
Low genetic
barrier to
resistance
Macrocyclic
or linear
Boceprevir
and
Telaprevir
already
licensed in
the US and
EU
Phase III:
BI 201335,
TMC435
Mimic natural
substrates of the
polymerase
Incorporated into
RNA chain
causing chain
termination
Broad genotypic
coverage
High genetic
barrier to
resistance
Phase III:
PSI-7977
Bind to several
different
allosteric
enzyme sites;
results in
conformational
change
Resistance
more frequent
than nucs
Several agents
in phase II
NS5A has role
in assembly of
replication
complex
Mechanism of
inhibition
under study
Phase III:
Daclatasvir
(BMS-790052)
Supports HCV-
specific RNA
replication,
protein
expression
Interacts with
NS2, NS5A,
NS5B
May regulate
polypeptide
processing,
viral assembly
Phase III:
Alisporivir
On-Treatment Viral Kinetics
HC
V R
NA
0 12 24 36 484
HCV RNA negative in blood
Weeks
First phase
Second phase
Ribavirin
PEG-Interferon
First phase
0 12 24 36 484
HCV RNA negative in blood
Weeks
On-Treatment Viral Kinetics
Improve both first and second phase kinetics
HC
V R
NA Boceprevir /
Telaprevir
1. Increase efficacy
Second
phase
First phase
HC
V R
NA
0 12 24 36 484
HCV RNA negative in blood
Weeks
On-Treatment Viral Kinetics
Improve both first and second phase kinetics
1. Increase efficacy
2. Shorten treatment duration
Boceprevir /
Telaprevir
Nucleoside/tide Analog Polymerase Inhibitors Are Chain-Terminators
AG C
UC GA CGGG
C
RNA chain
cannot be
elongated
NI Chain-terminator
3’
5’
5’
Template strand
Primer strand
NI
Sofosbuvir
• Approval Status: FDA approved December 6, 2013
• Indication for HCV Monoinfection and HCV-HIV Coinfection- GT 1,4: Sofosbuvir + peginterferon + ribavirin (12 weeks)- GT 2: Sofosbuvir + ribavirin (12 weeks) - GT 3: Sofosbuvir + ribavirin (24 weeks)
• Additional Indication for HCV Monoinfection- GT 1 (interferon ineligible): Sofosbuvir + ribavirin (24 weeks)- HCC and awaiting transplant: Sofosbuvir + ribavirin (up to 48 weeks)
• Class & Mechanism- Nucleotide analog inhibitor of NS5B polymerase enzyme
• Dosing: 400 mg PO once daily with or without food
• Adverse Effects (AE) attributable to Sofosbuvir- Fatigue, headache
Sofosbuvir
• Dosing in Renal Impairment
- No dose adjustment is required for patients with mild or moderate
renal impairment.
- No dose recommendation can be given for patients with severe renal
impairment (eGFR <30 mL/min/1.73m2)or with end stage renal disease due
to higher exposures (up to 20 -fold) of the predominant sofosbuvir metabolite
Hepatitisweb study
Hepatitisweb study
Hepatitisweb study
Sofosbuvir: Details of Key Phase 2/3 Studies
Source: Kowdley K, et al. Lancet. 2013;381:2100-7.
Sofosbuvir + Peginterferon + Ribavirin in Genotypes 1,4,6
ATOMIC Trial: Design
N =14
Drug DosingSofosbuvir (SOF): 400 mg once dailyRibavirin (RBV) weight-based and divided bid: 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kgPeginterferon alfa-2a (PEG): 180 µg once weekly
Cohort An = 52
GT 1
GT4
GT6
SOF + PEG + RBV
SOF + PEG + RBV
SOF + PEG + RBV SVR24
SVR24
SVR24
Cohort Bn = 125
Cohort Cn = 155
SOF
SOF + RBV
0 12 48Week 24 36
Sofosbuvir + Peginterferon + Ribavirin in Genotypes 1,4,6
ATOMIC Trial: Results, by Cohort (Regimen)
ATOMIC: SVR 24 by Cohort (Regimen)
Source: Kowdley K, et al. Lancet. 2013;381:2100-7.
89 89 87
0
20
40
60
80
100
Cohort A Cohort B Cohort C
Pati
en
ts (
%)
wit
h S
VR
24
46/52 97/109 135/155
Patients with Genotype 1, 4, or 6
The rates of sustained virologic response were very high
and were not significantly different among the three groups:
89%, 89%, and 87%, respectively
Sofosbuvir + Peginterferon + Ribavirin in Genotypes 1,4,6
ATOMIC Trial: Results, by Cohort (Regimen)
ATOMIC: SVR 24 by Genotype
Source: Kowdley K, et al. Lancet. 2013;381:2100-7.
8882
100
0
20
40
60
80
100
GT 1 GT 4 GT 6
Pati
en
ts (
%)
wit
h S
VR
24
264/300 9/11 5/5
Notes: (1) No patients with Genotype 5 enrolled in study
(2) All patients with Genotype 4 or 6 received 24 weeks of SOF + PEG + RBV
(3) The 2 patients with Genotype 4 and failure resulted from lost to follow-up at end of treatment
Sofosbuvir + Peginterferon + Ribavirin in Genotypes 1,4,6
ATOMIC Trial: Implications
1. There is no benefit in prolonging treatment with sofosbuvir beyond 12 weeks,
since adverse events increased without any improvement in the rate of
sustained virologic response
2. There is a very low likelihood of developing viral resistance or mutation when
using sofosbuvir.
3. There is no role for response-guided therapy, a concept used with protease
inhibitor-based regimens in which patients who have complete clearance of
the virus within the first 4 weeks of treatment (a rapid virologic response) and
remain clear through 12 weeks of treatment (an extended rapid viral
response) can be treated for a shorter duration without decreasing the
likelihood of a sustained virologic response
• .
Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6
NEUTRINO Trial: Design
Sofosbuvir + PEG + RBVN=327
Drug Dosing
Sofosbuvir: 400 mg once daily
Peginterferon alfa-2a: 180 µg once weekly
Ribavirin (weight-based and in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg
0 12 24Week
SVR12
Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6
NEUTRINO Trial: Results
NEUTRINO: HCV RNA <25 IU/ml by Study Timepoint
Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
99 99
90
0
20
40
60
80
100
Week 4 Week 12 (End of Tx) SVR12
Pa
tie
nts
(%
) w
ith
HC
V R
NA
< 2
5 I
U/m
l
SVR = sustained virologic response
321/325 326/327 295/327
Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6
NEUTRINO Trial: Results
NEUTRINO: SVR 12 by Liver Disease
Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
92
80
0
20
40
60
80
100
No Cirrhosis Cirrhosis
Pati
en
ts w
ith
SV
R12 (
%)
252/273 43/54
Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6
NEUTRINO Trial: Conclusions
Conclusions: “In the open-label, single-group study, 12
weeks of treatment with sofosbuvir plus peginterferon-
ribavirin had high efficacy in previously untreated patients
with genotype 1 or 4 infection, with apparent reductions in
adverse effects.”
*Note: This conclusion pertains to both the NEUTRINO and FISSION trials, which were published in tandem
HEPATITIS WEB STUDY HEPATITIS C ONLINE
Treatment NaïvePhase 2 Study – Genotype 1, 2 & 3 (Sof + Peg + RBV)
Source: Lawitz E, et al. Lancet Infect Dis. 2013;13:401-8.
Sofosbuvir + Peginterferon + Ribavirin in Genotypes 1-3
PROTON Trial: Design
N =14Drug DosingSofosbuvir (SOF): 400 mg once daily, except as designated in arm that received 200 mg once dailyRibavirin (RBV) weight-based and divided bid: 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kgPeginterferferon alfa-2a (PEG): 180 µg once weekly
n = 48
SOF + PEG + RBVn = 25GT 2, 3
GT 1
SOF (200 mg) +
PEG + RBV
+ RVRPEG + RBV
- RVR PEG + RBV
n = 47 SOF (400 mg) +
PEG + RBV
+ RVRPEG + RBV
- RVR PEG + RBV
SOF + PEG + RBVn = 26
0 24 4812 72Week
Sofosbuvir + Ribavirin + Peginterferon in Genotypes 1-3
PROTON Trial: Results, by Genotype
PROTON: SVR 24
Source: Lawitz E, et al. Lancet Infect Dis. 2013;13:401-8.
90 91
58
92
0
20
40
60
80
100
SOF 200 mg + PR SOF 400 mg + PR PR SOF 400 mg + PR
Pati
en
ts (
%)
wit
h S
VR
24
41/48 42/47 15/26 23/25
Genotype 1 Genotype 2 or 3
Source: Lawitz E, et al. Lancet Infect Dis. 2013;13:401-8.
Sofosbuvir + Ribavirin + Peginterferon in Genotypes 1-3
PROTON Trial: Conclusions
Interpretation: “Our findings lend support to the further assessment, in
phase 2 and 3 trials, of sofosbuvir 400 mg plus peginterferon and
ribavirin for 12 weeks in treatment-naive patients with HCV genotype-1.”
HEPATITIS WEB STUDY HEPATITIS C ONLINE
Treatment Naïve & ExperiencedPhase 2 Study – Genotype 1, 2 & 3 (Sof + Peg + RBV)
Source: Gane EJ, et al. N Engl J Med. 2013;368:34-44.
Sofosbuvir and Ribavirin +/- Peginterferon in GT 1-3
ELECTRON Trial (Arms 1-8): Design
SOF + RBV
N =14Drug DosingSofosbuvir (SOF): 400 mg once dailyRibavirin (RBV) weight-based and divided bid: 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kgPeginterferon alfa-2a (PEG): 180 µg once weekly
n = 9
n = 10
SOF + RBV + PEG (week 1-4)
n = 10 SOF + RBV + PEG (week 1-8)
n = 11 SOF + RBV + PEG
SOF
SOF + RBV + PEG
SOF + RBV
SOF + RBV SVR12
n = 10
n = 10
n = 10
n = 25
SVR12
SVR12
SVR12
SVR12
SVR12
SVR12
SVR12GT 1 Null
GT 2,3
Naïve
GT 1 Naive
0 20 24Week 8 12
Sofosbuvir and Ribavirin +/- Peginterferon in GT 1-3
ELECTRON Trial (Arms 1-8): Results
ELECTRON: SVR 12, by Treatment Regimen
Source: Gane EJ, et al. N Engl J Med. 2013;368:34-44.
100 100 100 100
60
100
10
84
0
20
40
60
80
100
SOF 12 wksRBV 12 wks
SOF 12 wksRBV 12 wksPEG wk 1-4
SOF 12 wksRBV 12 wksPEG wk 1-8
SOF 12 wksRBV 12 wksPEG 12 wks
SOF 12 wks SOF 8 wksRBV 8 wksPEG 8 wks
SOF 12 wksRBV 12 wks
SOF 12 wksRBV 12 wks
Pa
tie
nts
wit
h S
VR
(%
)
10/10
Genotype 2 or 3 (all treatment naïve)Genotype 1
Exp-Null Naive
9/9 10/10 11/11 6/10 10/10 21/25
1/10
Source: Gane EJ, et al. N Engl J Med. 2013;368:34-44.
Sofosbuvir + RBV in Treatment-Experienced HCV GT 2 or 3
ELECTRON Trial (Arms 1-8): Conclusions
Conclusions: “Sofosbuvir plus ribavirin for 12 weeks may be effective in previously untreated patients with HCV genotype 1, 2, or 3 infection.”
HEPATITIS WEB STUDY HEPATITIS C ONLINE
Treatment NaïvePhase 3 Study - Genotype 2 & 3 ((Sof + RBV) & (Peg + RBV))
Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
N=243
N=256 SVR12
SVR12
Sofosbuvir + Ribavirin for Treatment-Naïve HCV GT 2 or 3
FISSION Trial: Design
Peginterferon + RBV (fixed-dose)
Sofosbuvir +
RBV (weight-based)
Drug Dosing
Sofosbuvir: 400 mg once daily
Peginterferon alfa-2a: 180 µg once weekly
Weight-based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg
Fixed-dose Ribavirin (in 2 divided doses): 800 mg/day
Week 0 12 3624
Sofosbuvir + Ribavirin for Treatment-Naïve HCV GT 2 or 3
FISSION Trial: Results
FISSION: SVR12 by Genotype
Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
67
97
56
67
78
63
0
20
40
60
80
100
GT 2 and 3(n=496)
GT 2(n=137)
GT 3(n=359)
Pati
en
ts (
%)
wit
h S
VR
12
Sofosbuvir + RBV PEG + RBV
RBV = Ribavirin; PEG = Peginterferon
68/70 52/67 102/183 110/176170/253 162/243
Sofosbuvir + Ribavirin for Treatment-Naïve HCV GT 2 or 3
FISSION Trial: Results
FISSION: SVR12 by Presence of Cirrhosis
Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
72
47
74
38
0
20
40
60
80
100
No Cirrhosis(n=397)
Cirrhosis(n=99)
Pati
en
ts (
%)
wit
h S
VR
12
Sofosbuvir + RBV PEG + RBV
RBV = Ribavirin; PEG = Peginterferon
147/204 23/49 19/50143/193
Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
Sofosbuvir + Ribavirin for Treatment-Naïve HCV GT 2 or 3
FISSION Trial: Conclusions
Conclusions: “In the randomized trial of previously untreated patients
with genotype 2 or 3 infection, the efficacy of the all-oral regimen of
sofosbuvir plus ribavirin was similar to that of peginterferon–ribavirin, but
response rates among patients with genotype 3 infection were lower than
the rates among those with genotype 2 infection.”
*Note: This conclusion pertains to both the FISSION and NEUTRINO trials, which were published in tandem
HEPATITIS WEB STUDY HEPATITIS C ONLINE
Treatment Naïve & ExperiencedPhase 3 Study - Genotype 2 & 3 (Sof + RBV)
Source: Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001.
Sofosbuvir and Ribavirin for HCV GT 2 or 3
VALENCE Trial: Study Features
VALENCE Trial: Features
Design: Randomized, phase 3, using sofosbuvir + ribavirin in treatment naive or experienced, chronic HCV GT 2 or 3
Setting: Europe
Entry Criteria - Chronic HCV Genotype 2 or 3- Treatment naïve or treatment experienced- Platelet ≥ 50,000
Patient Characteristics (range in different treatment arms)- N = 419 - Sex: male (55-62%)- Race: white (89-100%)- Cirrhosis: (14-23%)- IL28B Genotype: non-CC (64-74%)
End-Points: Primary = SVR12; Secondary = safety
Source: Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001.
Sofosbuvir and Ribavirin for HCV GT 2 or 3
VALENCE: Treatment Arms
Sofosbuvir + RBV(n = 73)
Sofosbuvir + RBV(n = 250)
GT 2
GT 3
Drug Dosing
Sofosbuvir 400 mg once daily
Ribavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg
Original Study Protocol: Placebo versus 12 weeks treatment for GT 2 and 3.
Amended Protocol: GT3 treatment extended from 12 to 24 weeks; Placebo arm offered alternative treatment
Note: 85 patients enrolled in placebo arm
0 24 36Week 12
SVR12
SVR12
Sofosbuvir and Ribavirin for HCV GT 2 or 3
VALENCE: Results for Treatment Naïve and Experienced
VALENCE: SVR12 by Genotype
Source: Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001.
93
85
0
20
40
60
80
100
Genotype 2 Genotype 3
Pati
en
t (%
) w
ith
SV
R 1
2
12-week Treatment 24-week Treatment
68/73 213/250
Sofosbuvir and Ribavirin for HCV GT 2 or 3
VALENCE: Results
VALENCE: SVR12 by Genotype and Prior Treatment Experience
Source: Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001.
93
85
97 9490
79
0
20
40
60
80
100
Genotype 2 Genotype 3
Pati
en
ts (
%)
wit
h S
VR
12
All Treatment-Naïve Treatment-Experienced
68/73 213/25031/32 37/41 99/105 114/145
HEPATITIS WEB STUDY HEPATITIS C ONLINE
Treatment NaïvePhase 2 Study - Genotype 1 (Peg not an option)
Source: Osinusi A, et al. JAMA. 2013;310:804-11.
Sofosbuvir and Ribavirin for Treatment-Naïve HCV GT 1
NIH SPARE Trial: Features
NIAID/NIH Trial: Features
Design- Randomized, open-label, 2-part, phase 2 study of sofosbuvir and ribavirin- Part 1: “proof of concept”- Part 2: low dose versus weight-based dose of ribavirin in GT-1
Setting: Single center: NIAID
Entry Criteria: HCV genotype 1; treatment-naïve
Patient Characteristics- N = 60 HCV-monoinfected patients- HCV Genotype: 1A (70%), 1B (30%) - IL28B Genotype: 81% non-CC - Age and Sex: median 54 (range 48-57); 62% male- Race: 83% black; 13% white- Liver disease: 23% had advanced fibrosis (F3-F4 by Knodell-HAI scoring)
Primary end-points: Efficacy (SVR24) and safety
Source: Osinusi A, et al. JAMA. 2013;310:804-11.
Part 2
N =50
Sofosbuvir + RBV (low-dose)
24 weeks
Sofosbuvir + RBV (wt-based)24 weeks
Part 1
N =10
Sofosbuvir and Ribavirin for Treatment-Naïve HCV GT 1
NIH SPARE Trial: Design
SVR24
Sofosbuvir + RBV (wt-based)
24 weeksSVR24
N =25
N =25
Drug Dosing
Sofosbuvir: 400 mg once daily
Low-dose Ribavirin (divided bid): 800 mg/day
Weight-based Ribavirin (divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg
SVR24
0 24 48Week
Sofosbuvir and Ribavirin for Treatment-Naïve HCV GT 1
NIH SPARE Trial: Part 1 Results
NIH SPARE Part 1: HCV <12 IU/ml by Study Timepoint
Source: Osinusi A, et al. JAMA. 2013;310:804-11.
80
90 90
0
20
40
60
80
100
Week 4 Week 24 (End of Tx) SVR24
Pa
tie
nts
(%
) w
ith
HC
V R
NA
< 1
2 IU
/ml
All 10 patients in Part 1 received sofosbuvir plus weight-based ribavirin
8/10 9/10 9/10
Sofosbuvir and Ribavirin for Treatment-Naïve HCV GT 1
NIH SPARE Trial: Part 2 Results
NIAID/NIH Part 2: HCV RNA <12 IU/ml by Study Timepoint
Source: Osinusi A, et al. JAMA. 2013;310:804-11.
9688
48
96 96
68
0
20
40
60
80
100
Week 4 Week 24 (End of Tx) SVR24
Pa
tie
nts
(%
) w
ith
HC
V R
NA
< 1
2 IU
/ml
SOF + RBV (low dose) SOF + RBV (weight based)
SOF = Sofosbuvir; RBV = Ribavirin
24/25 24/25 22/25 24/25 12/25 17/25
Sofosbuvir and Ribavirin for Treatment-Naïve HCV GT 1
NIH SPARE Trial: Part 2 Results
NIH SPARE Part 2: SVR24 by Fibrosis Stage
Source: Osinusi A, et al. JAMA. 2013;310:804-11.
56
29
74
50
0
20
40
60
80
100
Early Stage (0-1*) Advanced (3-4*)
Pa
tie
nts
(%
) w
ith
SV
R24
Fibrosis Stage (Knodell Histology Activity Index Scoring System)
SOF +RBV (Low Dose) SOF +RBV (Wt-Based)
SOF = Sofosbuvir; RBV = Ribavirin
3/62/714/1910/18
21
82
63
78
0
20
40
60
80
100
>800,000 IU/ml <800,000 IU/ml
Pati
en
ts (
%)
wit
h S
VR
24
HCV RNA Level
SOF +RBV (Low Dose) SOF +RBV (Wt-Based)
Sofosbuvir and Ribavirin for Treatment-Naïve HCV GT 1
NIH SPARE Trial: Part 2 Results
NIH SPARE Part 2: SVR24 by Baseline HCV RNA Level
Source: Osinusi A, et al. JAMA. 2013;310:804-11.
SOF= Sofosbuvir; RBV = Ribavirin
7/99/1110/163/14
Source: Osinusi A, et al. JAMA. 2013;310:804-11.
Sofosbuvir and Ribavirin for Treatment-Naïve HCV GT 1
NIH SPARE Trial: Conclusions
Conclusion: “In conclusion, treatment with a 24-week regimen of
sofosbuvir and ribavirin resulted in an SVR rate of 68% in the weight-
based ribavirin regimen and 48% in the low-dose ribavirin regimen
among patients with chronic HCV and unfavorable traditional predictors
of treatment response who are representative of the demographics of the
US HCV epidemic.”
Characteristics of New Generation DAA Regimens
• Antiviral activity seen in all genotypes
• High Barrier to Resistance
• Higher SVR rates and shorter treatment duration
• Oral, IFN-free, combination regimens have less side effects and higher SVR rates
• Patients with cirrhosis and decompensated cirrhosis will benefit from less toxic regimens
Sofosbuvir
Drug-Drug Interactions
Sofosbuvir not recommended for coadministration with*:
• Anticonvulsants- Carbamazepine- Oxcarbazepine- Phenobarbital- Phenytoin
• Antimycobacterials- Rifabutin- Rifampin- Rifapentine
• Herbal Supplements- St. John’s wort
• HIV Protease Inhibitors- Tipranavir/ritonavir
Source: Sofosbuvir (Sovaldi) Prescribing Information. Gilead Sciences.
*Not recommended because of potential marked decrease in sofosbuvir levels
EASL HCV Guidelines 2014: Genotype 1
Genotype Options for Therapy
Genotype 1*
PegIFN/ribavirin + sofosbuvir: 12 wks (A1)
PegIFN/ribavirin + simeprevir†: 12 wks, followed by 12 wks of pegIFN/ribavirin in
previously untreated pts and prior relapsers (A1), or 36 wks of pegIFN/ribavirin in
previous partial responders and null responders (B1)
PegIFN/ribavirin + daclatasvir (genotype 1b only; B1): 12 wks followed by 12 wks of
pegIFN/ribavirin alone or a further 12 wks of pegIFN/ribavirin + daclatasvir
(response-guided therapy) (B2)
Sofosbuvir + ribavirin: 24 wks for interferon-intolerant pts only, where no other
interferon-free option available (B2)
Sofosbuvir + simeprevir: 12 wks (ribavirin may be added for previous nonresponders
& cirrhotics) (B1)
Sofosbuvir + daclatasvir: 12 wks in previously untreated pts; 24 wks in treatment-
experienced patients (including TVR/BOC-experienced patients) (ribavirin may be
added in previous nonresponders and cirrhotics) (B1)
EASL. J Hepatology. 2014;60:392-420.
*In settings where recommended options are not available, treatment with pegIFN/ribavirin + TVR or BOC remains acceptable. †Not recommended in pts with genotype 1a and detectable Q80K polymorphism.
EASL HCV Guidelines 2014: Genotype 2-6
Genotype Options for Therapy
Genotype 2*Sofosbuvir + ribavirin: 12 wks (16-20 weeks in cirrhotic patients, especially treatment experienced) (A1)
PegIFN/ribavirin + sofosbuvir: 12 wks for cirrhotic and/or treatment-experienced patients (B1)
Genotype 3*
Sofosbuvir + ribavirin: 24 wks (unsuitable for treatment-experienced cirrhotics, no specific alternative proposed) (A2)
PegIFN/ribavirin + sofosbuvir: 12 wks (A2)
Sofosbuvir + daclatasvir: 12 wks (24 wks for treatment-experienced patients) (B1)
Genotype 4*
PegIFN/ribavirin + sofosbuvir 12 weeks (B1)
PegIFN/ribavirin + simeprevir: 12 wks, followed by 12 wks of pegIFN/ribavirin in previously untreated patients & prior relapsers (B1), or 36 wks of pegIFN/ribavirin in previous partial responders & null responders (B1)
PegIFN/ribavirin + daclatasvir: 12 wks followed by 12 wks of pegIFN/ribavirin alone or a further 12 wks of pegIFN/ribavirin + daclatasvir (response-guided therapy) (B1)
Sofosbuvir + ribavirin: 24 wks for interferon-intolerant patients (C2)
Sofosbuvir + simeprevir: 12 wks (ribavirin may be added in previous nonresponders and cirrhotics) (B2)
Sofosbuvir + daclatasvir: 12 wks in previously untreated patients; 24 wks in treatment-experienced patients (ribavirin may be added in previous nonresponders and cirrhotics) (B2)
Genotype 5/6*
PegIFN/ribavirin + sofosbuvir 12 wks (B1)
Sofosbuvir + ribavirin: 24 wks for interferon-intolerant patients (C2)
EASL. J Hepatology. 2014;60:392-420.
*In settings where recommended options are not available, treatment with pegIFN/ribavirin remains acceptable.
Summary of collated trials data
The emergence of all-oral regimens for HCV treatment with increasingly
sophisticated agents such as sofosbuvir will dramatically alter the management of
HCV patients.
Preliminary Results of New Interferon Free Regimens in Phase 2 Trials
Regimen SVR
Rate
Duration
in Weeks
Sufosbuvir + Ledipasvir + RBV >95% 8-12
ABT450/r + ABT267 + ABT333 + RBV 12 ~90%
Faldaprevir + 207127 + RBV (GT1B) 90% 12-24
DCV + ASV +BMS-791325 88-
94%
12-24
Presentations at European Association of Study of Liver Disease
and Press releases