Transcript HCV treatment options, considerations, management

Terapia dell’epatite virale C tra
passato e futuro
L’attesa dei nuovi farmaci antivirali
Edoardo G. Giannini, MD, PhD
Cattedra di Gastroenterologia
Dipartimento di Medicina Interna
Università di Genova
Genova
XI Congresso Trisocietario Ligure di Gastroenterologia. Genova, 26 novembre 2011
Agenda
HCV management in 2012
1. Where we were in 2011
2. New drugs: for many but not for everyone
3. Therapeutic gain with DAAs
4. How to use DAAs
5. Conclusions
Where we were in 2011
Beckett S. En Attendant Godot. 1952 Editions de Minuit, Paris, France.
The Evolution of Initial HCV Treatment
1991
1998
2001
2002
2012
Smith RET. Nature Rev Drug Disc. 2006; 5: 715-716.
The Evolution of HCV Therapy
2002
2012
PegIFN/RBV
Protease inhibitor
Nucleos(t)ide polymerase inhibitor
Nonnucleoside polymerase inhibitor
NS5A inhibitor
Host targeting agent
Beyond
New Drugs:
For Many But Not For
Everyone
Bad Bugs Need More Drugs
HCV Standard of Care in 2011
Genotype 1:
 Least responsive to PegIFN/RBV
 Comonly associated with older age and advanced disease
100
PegIFN alfa-2b 1.5 µg/kg/wk +
RBV for 48 Wks
82
SVR (%)
80
60
100
76
80
60
54
PegIFN alfa-2a 180 µg/wk +
Weight-Based RBV for 48 Wks
56
46
42
40
40
20
20
0
n = 511
Overall
348
147
GT1
GT2/3
Manns MP, et al. Lancet. 2001;358:958-965.
0
n = 453
Overall
298
140
GT1
GT2/3
Fried MW, et al. N Engl J Med. 2002;347:975-982.
HCV Life Cycle and DAA Targets
Receptor binding
and endocytosis
Transport
and release
Fusion
and
uncoating
ER lumen
(+) RNA
LD
LD
NS3/4
protease
inhibitors
Translation
and
polyprotein
processing
LD
Membranous
web
ER lumen
Virion
assembly
NS5B polymerase
RNAinhibitors
replication
Nucleoside/nucleotide
Nonnucleoside
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
HCV NS3/4A Serine Protease:
The “Master Switch” for Replication
PKR
capsid
envelope
5'
A
core E1
E2 p7 NS2
NS3
B
NS4
Protease domain
RdRp
regulator
A
B
un 3'
NS5
Helicase domain
NS3: 70 kDa
NS4A: 54aa
Lindenbach BD, et al. Nature. 2005;436:933-938.
Kim JL, et al. Cell. 1996;87:343-355.
Love RA, et al. Cell. 1996;87:331-342.
Yao N, et al. Structure. 1999;7:1353-1363.
Kim JL, et al. Structure. 1998;6:89-100.
HCV NS5B RNA Polymerase:
Nucleoside and Nonnucleoside Inhibition
Allosteric GTP-Binding Sites
Flap
Thumb
Fingers
Non-nucleoside
Inhibitors
Thumb
Inhibitors
Catalytic Site
Nucleoside Analogues
Non-nucleoside Inhibitors
(potentially active across all genotypes)
(gradient activity across HCV 1 subtypes)
Palm
Butcher SJ, et al. Nature. 2001;410:235-240.
Each Drug Class Has Unique Features
NS3/4A
Protease
Inhibitors
 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
NS5B Polymerase Inhibitors
NS5A
Inhibitors
Cyclophilin A
Inhibitors
 Supports HCVspecific RNA
replication,
protein
expression
Nucleos(t)ide
Analogue
Nonnucleos(t)ide
 Mimic natural
substrates of the
polymerase
 Bind to several
different
allosteric
enzyme sites;
results in
conformational
change
 NS5A has role
in assembly of
replication
complex
 Resistance
more frequent
than nucs
 Phase III:
Daclatasvir
 May regulate
(BMS-790052)
polypeptide
processing,
viral assembly
 Incorporated into
RNA chain
causing chain
termination
 Broad genotypic
coverage
 High genetic
barrier to
resistance
 Phase III:
PSI-7977
 Several agents
in phase II
 Mechanism of
inhibition
under study
 Interacts with
NS2, NS5A,
NS5B
 Phase III:
Alisporivir
Therapeutic Gain With DAAs
On-Treatment Viral Kinetics
PEG-Interferon
HCV RNA
First phase
Ribavirin
Second phase
HCV RNA negative in blood
0
4
12
24
Weeks
36
48
On-Treatment Viral Kinetics
Improve both first and second phase kinetics
1. Increase efficacy
HCV RNA
First phase
Boceprevir /
Telaprevir
HCV RNA negative in blood
0
4
12
24
Weeks
36
48
On-Treatment Viral Kinetics
Improve both first and second phase kinetics
1. Increase efficacy
2. Shorten treatment duration
HCV RNA
First phase
Boceprevir /
Telaprevir
HCV RNA negative in blood
Second
phase
0
4
12
24
Weeks
36
48
2 Protease Inhibitors Approved for
Genotype 1 HCV Infection
Protease Inhibitor
Additional Regimen
Components
Considerations
Boceprevir 800 mg TID
(q7-9hrs)
PegIFN alfa
+
weight-based RBV





Naive to previous therapy
Previous treatment failure
Compensated cirrhosis
RGT
Take with food
Telaprevir 750 mg TID
(q7-9hrs)
PegIFN alfa
+
weight-based RBV





Naive to previous therapy
Previous treatment failure
Compensated cirrhosis
RGT
Take with food (not low fat)
For patients with genotype 2/3 infection, HCV therapy with pegIFN/RBV
remains the standard of care
Ghany MG, et al. Hepatology. 2011;54:1433-1444.
SVR Rates With BOC and TPV in GT1
Treatment-Naive and -Experienced
Patients
100
Current Standard of Care
100
80
+ 30%
60
38-44
40
60
40
+ 40%
17-21
20
20
0
63-75
59-66
SVR (%)
SVR (%)
80
SOC + Protease Inhibitors
Treatment-Naive
Pts
TreatmentExperienced
0
Treatment-Naive
Pts
TreatmentExperienced
Asselah T, et al. Liver Int 2011; 31 Suppl 1: 69-77.
Telaprevir and Boceprevir SVR by
Patient Type
100
75-83
SVR (%)
80
68-75
53-62
60
29-38
40
20
0
52-59
14*
Relapser
Naive
White/
Nonblack
Naive
Black
Partial
Null
Cirrhotic
Responder Responder
Null
Responder
*Pooled TVR arms of REALIZE trial.
Asselah T, et al. Liver Int 2011; 31 Suppl 1: 69-77.
How to Use DAAs
(Treatment-Naïve Patients)
New Standard of Care for Genotype 1
Treatment-Naive Patients

Recommendation: Optimal treatment for all genotype 1 treatment-naive
patients is BOC or TVR + pegIFN/RBV
–
BOC and TVR should not be used without pegIFN/RBV
Boceprevir
PegIFN
+ RBV
0
4
Early response*; stop at Wk 28;
f/u 24 wks
BOC + PegIFN + RBV
PegIFN + RBV
BOC + PegIFN + RBV
8
12
24
28
36
F/u
24 wks
48
Telaprevir
eRVR†; stop at Wk 24, f/u 24 wks
TVR + PegIFN + RBV
0
4
PegIFN + RBV
12
No eRVR; PegIFN + RBV
24
F/u
24 wks
48
*Undetectable HCV RNA at Wk 8 of therapy (Wk 4 of triple therapy).
†Undetectable HCV RNA at Wks 4 and 12 of triple therapy.
Ghany MG, et al. Hepatology. 2011;54:1433-1444.
SVR Rates With BOC + PegIFN/RBV in
Genotype 1 Treatment-Naive Patients
SPRINT-2
P < .001
P < .001
80
68
67
60
40
40
20
n/ 125/
0 N= 311
PR 48
P = .04
100
211/
316
BOC RGT
213/
311
BOC/PR48
Nonblack Patients
Patients (%)
Patients (%)
100
P = .004
80
60
53
42
40
23
20
0
n/
N=
12/
52
PR 48
22/
52
BOC RGT
29/
55
BOC/PR48
Black Patients
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
SVR Rates With TVR + PegIFN/RBV in
Genotype 1 Treatment-Naive Patients
ADVANCE
P < .001
100
Nonblack
Black
100
75
60
44
40
75
80
SVR (%)
80
SVR (%)
Pooled Analysis From
ADVANCE and ILLUMINATE
61
60
45
40
25
20
0
n/
N=
158/
361
271/
363
PR
T12PR
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
20
0
n/
N=
151/ 7/
333 28
PR
599/ 60/
804 99
T12PR
Dusheiko GM, et al. EASL 2011. Abstract 1788.
Futility Rules for BOC or TVR +
PegIFN/RBV in Tx-Naive Patients
 Recommendation:
All therapy should be discontinued in patients with the following:
Boceprevir
Time Point
Criteria
Action
Wk 12
HCV RNA ≥ 100 IU/mL
Discontinue all therapy
Wk 24
HCV RNA detectable
Discontinue all therapy
Telaprevir
Time Point
Criteria
Action
Wk 4 or 12
HCV RNA > 1000 IU/mL
Discontinue all therapy
HCV RNA detectable
Discontinue pegIFN/RBV
Wk 24
Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA
detection of approximately 10-15 IU/mL.
Ghany MG, et al. Hepatology. 2011;54:1433-1444.
How to Use DAAs
(Treatment-Experienced
Patients)
Suboptimal Virologic Responses
PegIFN/RBV
8
HCV RNA (log10 IU/mL)
7
6
Relapse
Null response
5
Breakthrough
2 log10 decline
4
3
2
1 Incomplete
treatment
0
0 4 8 12
Partial
response
18
24
Limit of detection
30
36
42
48
54
60
66
72
78
Wks
McHutchison JG, et al. N Engl J Med. 2009;361:580-593.
Retreatment of PegIFN/RBV
Nonresponders Yields Low SVR Rates
REPEAT
EPIC3
DIRECT
80
80
80
60
40
20
60
40
20
8.0
SVR (%)
100
SVR (%)
100
SVR (%)
100
PegIFN alfa-2a/RBV
for 48 Wks in
PegIFN alfa-2b/RBV
Nonresponders
40
20
6.3
0
0
60
PegIFN alfa-2b/RBV
for 48 Wks in
PegIFN/RBV
Nonresponders
10.7
0
cIFN for 48 Wks
in PegIFN/RBV
Nonresponders
Poynard T, et al. Gastroenterology. 2009;136:1618-1628.
Jensen D, et al. Ann Intern Med. 2009;150:528-540.
Bacon BR, et al. Hepatology. 2009;49:1838-1846.
Retreatment of PegIFN/RBV Relapsers
McHutchison et al.
EPIC3
80
80
SVR (%)
100
SVR (%)
100
60
40
20
20
60
40
33
20
0
0
PegIFN alfa-2a/RBV
for 48 Wks
in PegIFN/RBV
Relapsers
McHutchison JG, et al. N Engl J Med. 2010;362:1292-1303.
PegIFN alfa-2b/RBV
for 48 Wks
in PegIFN/RBV
Relapsers
Poynard T, et al. Gastroenterology. 2009;136:1618-1628.
Retreatment With BOC + PegIFN/RBV
in Treatment-Experienced Patients

Recommendation: BOC approved for previous relapsers, partial, and null responders.
–
AASLD guidelines say BOC “recommended” for previous relapsers and partial responders;
advise caution in null responders given lack of definitive information from phase III studies
PegIFN
+ RBV
44
BOC + PegIFN + RBV
1212
88
100
80
SVR (%)
00
Early response;
stop at Wk 36; f/u 24 wks
F/u
PegIFN + RBV
24 wks
BOC + PegIFN + RBV
2424
2828
36
Previous partial response
Previous relapse
69
75
60
52
40
40
20
0
48
48
29
7
n/N = 2/29
15/51
PR48
23/57 72/105
30/58 77/103
BOC RGT
BOC/PR48
Ghany MG, et al. Hepatology. 2011;54:1433-1444.
Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.
Retreatment With TVR + PegIFN/RBV
in Treatment-Experienced Patients

Recommendation: TVR approved for previous relapsers, partial, and null responders
–
AASLD guidelines say TVR “recommended” for previous relapsers and partial responders;
“may be considered” for previous null responders
Previous relapsers* (same as naives)
TVR + PegIFN + RBV
eRVR; stop at Wk 24, f/u 24 wks
PegIFN + RBV
No eRVR; PegIFN + RBV
0
4
12
24
F/u
24 wks
48
Previous partial responders† and null responders
TVR + PegIFN + RBV
0
4
PegIFN + RBV
12
24
F/u
24 wks
48
*Response-guided therapy not studied in relapsers in registration trials.
†AASLD guidelines say RGT “may be considered” for prior partial responders but package insert
recommends 48 weeks of therapy
Telaprevir [package insert]. 2011.
Ghany MG, et al. Hepatology. 2011;54:1433-1444.
SVR in Previous Relapsers,
Partial Responders, Null Responders
REALIZE: TVR + PegIFN/RBV in G1 Previous Relapsers and Partial/Null Responders
Lead-in examined but found not to influence response and not included in TVR label
PR48
Previous Relapsers
100
83*
88*
T12/PR48
LI T12/PR48
Previous Partial
Responders
Previous Null
Responders
SVR (%)
80
59*
60
54*
40
29*
24
15
20
n/N=
16/68
0
121/145
124/141
4/27
33*
5
29/49
26/48
21/72
25/75
2/37
*P < .001 vs PR48.
Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.
Futility Rules for BOC or TVR +
PegIFN/RBV in Tx-Exp Patients
 Recommendation: All therapy should be discontinued in
patients with the following:
Boceprevir
Time Point
Criteria
Action
Wk 12
HCV RNA ≥ 100 IU/mL
Discontinue all therapy
Wk 24
HCV RNA detectable
Discontinue all therapy
Telapevir
Time Point
Criteria
Action
Wk 4 or 12
HCV RNA > 1000 IU/mL
Discontinue all therapy
HCV RNA detectable
Discontinue pegIFN/RBV
Wk 24
Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA
detection of approximately 10-15 IU/mL.
Ghany MG, et al. Hepatology. 2011;54:1433-1444.
Challenges as HCV Therapy Evolves to
Incorporate DAAs
Baseline predictors of response
Resistance issues
 Who to treat
 Impact of baseline variants
 Tailored therapies
 Persistence of resistant variants
 Tailored duration
 Cross-resistance within classes
 Impact of dosing/adherence
New viral kinetic rules with new
therapies
 Positive predictive values
Markers of complete viral
eradication
 Negative predictive values
 Tailored duration
Toxicities
Success Does Not Come Alone
 Increased incidence of adverse events
 Increased use of growth factors
 Interaction with drugs metabolised by CYP-450
 Selection of drug-resistance
 Increased costs
The Reality of Current 48-Wk
Standard-of-Care HCV Therapy
SVR
(40-50%)
•TreatmentNaive G1
Patients
SOC Tx
Discontinue
(10-20%)
Relapse
(10-20%)
NR
(15-20%)
Initial Treatment
Present
Evolving Therapies: Where Will We Be
Soon?
SVR
SVR
(60-70%)
•TreatmentNaive G1
Patients
Standard
of Care Tx
Discontinue
Relapse
NR
Discontinue
(10-20%)
Relapse
(5-10%)
NR
(10-20%)
Initial Treatment
Near Future
Conclusions
 The advent of DAAs has drmatically modified our approach to
antiviral therapy in HCV genotype 1 patients.
 Boceprevir and Telaprevir provide a definite opportunity of cure
especially to treatment-experienced patients.
 Evaluation of viral kinetics is the key and should be used to
shorten duration of therapy in rapid responders, and terminate
early treatment in patients who are unlikely to respond
 Use of DAAs may be associated with difficult treatment
schedules and burdened with side effects.
 This “first wave” of drugs undoubtedly represents a useful
paradigm for HCV treatment, and will open new avenues for
new drugs.