Transcript Interferon Free HCV Treatment Regimens

Future HCV Treatment Paradigms
Mark Sulkowski, MD
Professor of Medicine
Medical Director, Viral Hepatitis Center
Divisions of Infectious Diseases and Gastroenterology/ Hepatology
Johns Hopkins Medical Institutions
Baltimore Maryland USA
2
Investigational Agents for HCV
Interferons
Antiviral
agents
Therapeutic
vaccines
Host
target
miRNA-122
Entry
Replication, polyprotein processing
and/or assembly
NS5B
polymerase
Inhibitors
NS3
protease
inhibitors
NS5A
replication
complex
inhibitors
Cyclophilin
CYP
inhibitors
Direct Acting Antivirals in Development
DAA combinations
Preclinical
Abbott
Gilead
Phase II
Others
Cyclophilin. I
ACH-2928
(Achillion)
Vitamine D
Nitazoxamide
(Romark)
Celgosivir
Bavituximab
BI
Vertex
BMS
BI
Phase I
ROCHE
Phase III
Filed
Japan Tobacco
R0622 (Roche)
Medivir (Tibotec)
IDX 184
(Idenix)
Nucleoside
NS5B
Polymerase
Inhibitors
GLS9393 (GSK)
R7128
(Roche)
GS- 7977
Gilead)
Debio 025/
Silibinine
IFN λ
NIM811
SCY-835
(Novartis)
BMS 790052
(BMS)
AZD-7295 ABT267
(ABT)
(AZN)
PPI-461
MSD
GS-5885
Idenix719
NS5A inhibitors
Nucleotide NS5B
Polymerase
Inhibitors
INX 189
(Inhibitrex)
Biocryst
BMS791325
Filibuvir (BMS)
(PFE)
GS9190
IDX 375
(Gilead)
Boceprevir
Telaprevir
(Idenix)
Vx222
ANA598
(MSD)
(Vertex/JJ)
(Vertex)
RG7348
BI201127 (Anadys)
BI201335
(Roche)
TMC-435
(BI)
ABT333
(BI)
TMC
647055
(Tibotec/JJ)
ABT072
Vertex
ITMN191/R7227
(Tibotec)
BMS 824393
MK7009(Roche/Intermune)
(ABT)
PPI-1301
(MSD)
(BMS)
A837093
BMS650032
GSK
(BMS)
(Abbott)
ABT450
EDP-239
(ABT)
VX-916
VBY-376
GS9256 GS9451
(Enanta)
VX-759
IDX 077
ACH2684
MK5172 (Gilead) (Gilead)
Non Nuc NS5B
(Idenix)
VX-985 (MSD)
(Achillion)
(Vertex)
IDX 079
Polymerase inhibitors
VX-813
AVL-192
(Idenix) (Vertex)
AVL-181
(Avila)
(Avila)
NS3/4A Protease inhibitors
Adapted from Bourliere M, et al. Clin Res Hepatol
Gastroenterol. 2011;35(suppl 2):S84-S95.
Investigational HCV Regimens in Phase
3
Regimens with
one DAA + pegIFN alfa/RBV
BI 201335 (PI)
 Daclatasvir (NS5A)
 Asunaprevir (PI)
 GS-7977 (NI)
 Simeprevir (TMC-435) (PI)
 Alisporivir (CYP)
 Vaniprevir (MK-7009, PI)

Regimens with two DAAs
(± pegIFN alfa and/or RBV)

Daclatasvir + asunaprevir
IFN-free Regimens
Sofosbuvir (GS-7977) + RBV
 Daclatasvir + asunaprevir
 Alisporivir ± RBV

New Interferons

NNI = non-nucleoside NS5B inhibitor, NI = nucleoside NS5B inhibitor,
PI = protease inhibitor, RBV = ribavirin, NS5A = replication complex inhibitor
Cyp= cyclophilin inhibitor
Peginterferon-lambda-1a
Multiple Combinations Will Emerge
A
+
Profound suppression of broad range of viral
variants, including pre-existing variants
B
+
Prevention of emergent resistance
(pre-existing or de novo)
C
• Different drugs can contribute variably to each goal. Not all
components must be direct-acting antivirals (DAAs).
5
INTERFERONS +/- DAA
EMERGE: PegIFN lambda-1a vs PegIFN
alfa-2a in GT 2/3 HCV Treatment-Naive
Pts
•
Interim analysis of randomized, blinded, active-controlled phase IIb trial
Genotyping
at baseline
Wk 24
PegIFN lambda-1a 120 µg/wk + RBV†
(n = 29)
Treatment-naive
patients infected with
genotype 2/3 HCV
PegIFN lambda-1a 180 µg/wk + RBV†
(n = 29)
PegIFN lambda-1a 240 µg/wk + RBV†
(n = 30)
(N = 118)
PegIFN alfa-2a 180 µg/wk + RBV†
(n = 30)
†RBV
dosed at 800 mg/day for genotype 2/3 patients.
Zeuzem S, et al. EASL 2012. Abstract 10.
EMERGE: Efficacy and Safety
Outcomes
SVR24 (%)
6.9
44.8
RBV dose reduction
(Hemoglobin associated)
0
23.3
Neutrophils low
< 750/mm3
0
27.6
Platelets low
< 100,000/mm3
0
24.1
PegIFN dose reduction
(hematologic abnormality)
0
23.3
Hemoglobin low
<10g/dL or ∆ > 3.4 g/dL
75.9
65.5
60.0
60
53.3
40
20
•
Alfa
180 µg
(n = 30)
Adverse Event, %
100
80
Lambda
180 µg
(n = 29)
N = 29
0
Lambda
120 µg
29
Lambda
180 µg
30
Lambda
240 µg
30
Alfa
180 µg
PegIFN lambda-1a 180 μg dosage
chosen for phase III trials
Zeuzem S, et al. EASL 2012. Abstract 10.
ATOMIC: Sofosbuvir (GS-7977 (NI) +
PegIFN/RBV
Treatment naïve, mainly Gen1 (few G4/6), non-cirrhotic
GS-7977 + PR
n=125
n=155
GS-7977 + PR
n=52
GS-7977 + PR
0
GS-7977 ± RBV
12
weeks
Viral Response Rates (%)
RVR
EOT
SVR4
SVR12
98
99
92
NA
97
99
92
NA
94
98
94
90
24
No S282T mutation seen in 4 relapse pts
Kowdley KV, et al. EASL 2012. Abstract 1
ASPIRE: Simeprevir (PI) + PegIFN/RBV
in Treatment Experienced Patients
Treatment experienced, G1, includes cirrhotics
PegIFN + RBV
n=66
100
n=68
SVR24 (%)
Simeprevir +
PegIFN + RBV
PegIFN/RBV
75*
80
Simeprevir + PegIFN + RBV
n=65
85*
60
40
51*
37
19
20
Simeprevir
n=66
+ P/R
0
12
PegIFN + RBV
24
weeks
Zeuzem S, et al. EASL 2012. Abstract 2
0
9
Relapsers
Partial
Responders
Null
Responders
48
* Represents pooled simeprevir duration at 150mg dose
Quad Therapy: SVR12 with 16 Weeks of Tegobuvir and
GS-9256 plus Peginterferon-alfa 2a and Ribavirin in
Treatment-Naïve Genotype 1 HCV Patients
Day 1
Wk 16
Wk 24
Wk 48
SVR12
Group 1
N = 163
GS-9256 150 mg BID +
TGV 20 mg BID + PEG + RBV
100%
98%
PEG + RBV
Response-Guided
Therapy
Patients with vRVR →
16 or 24 wks
95%
80%
Per protocol/
completer analysis
60%
40%
20%
0%
SVR 4
SVR 12
Very rapid virologic response (vRVR) = HCV RNA <LLOQ at Week 2
RVR = HCV RNA <LLOQ at Week 4
Nelson DR. EASL 2010. Abstract 12
CYCLOPHILIN INHIBITOR + RBV
VITAL-1: Alisporivir-Based Therapy for
Trt-Naive GT2/3 Pts
Stratified by HCV RNA
and HCV genotype
Wk 4: RVR
assessed
Alisporivir 1000 mg QD
(n = 83)
Alisporivir 600 mg QD
+ RBV
(n = 84)
Treatmentnaive patients
with chronic
GT 2/3 HCV
infection
Alisporivir 800 mg QD
+ RBV
(N = 340)
Alisporivir 600 mg QD
+ PegIFN
(n = 94)
(n = 39)
Wk 6
RVR:
Wk 24
Alisporivir 1000 mg QD
No RVR:
Alisporivir 600 mg QD + PegIFN/RBV
RVR:
Alisporivir 600 mg QD + RBV
No RVR:
Alisporivir 600 mg QD + PegIFN/RBV
RVR:
No RVR:
RVR:
No RVR:
Alisporivir 800 mg QD + RBV 800 mg/day
Alisporivir 600 mg QD + PegIFN/RBV
24-wk
F/U
Alisporivir 600 mg QD + PegIFN
Alisporivir 600 mg QD + PegIFN/RBV
PegIFN alfa-2a/RBV (n = 40)
Pawlotsky JM, et al. EASL 2012. Abstract 1405.
All pts received alisporivir loading dose of 600 mg BID during first wk.
PegIFN alfa-2a dosed 180 µg/wk. RBV dosed 800 mg/day.
VITAL-1: SVR12 by Per-Protocol
Analysis
•
High SVR rates with alisporivir-based therapy, including IFN-free regimens
– However, development of alisporivir currently on hold due to 3 cases of pancreatitis
(with 1 death) in > 1800 patients treated to date
Overall SVR12
SVR12 in Pts Receiving IFN-free Therapy
100
100
81
SVR12 (%)
80
83
81
58
20
20
82
84
93
39
40
ALV1000
ALV600
RBV
ALV800
RBV
ALV600
Peg
P/R
Pawlotsky JM, et al. EASL 2012. Abstract 1405..
29
32
ALV1000
ALV600
RBV
ALV800
RBV
60
40
n=
17
80
40
0
91
82
77
60
93
0
n=
PI +/- NON-NUCLEOSIDE POLYMERASE
INHIBITOR +/- NS5A INHIBITOR +/- RBV
Co-Pilot (M12-746) Study:
ABT-450/r + ABT-333 Treatment
12 Weeks (On Treatment)
Arm 1
Treatment-naïve
(N=19)
Arm 2
Treatment-naïve
(N=14)
Arm 3
Prior P/R nonresponders (N=17)
ABT-450/r 250/100 mg QD +
ABT-333 400 mg BID + RBV
ABT-450/r 150/100 mg QD +
ABT-333 400 mg BID + RBV
ABT-450/r 150/100 mg QD +
ABT-333 400 mg BID + RBV
Poordad F, et al. 47th EASL; Barcelona, Spain; April 18-22, 2012. Abst. 1399.
Follow Up
Period
Co-Pilot Study: Demographics
and Baseline Characteristics
Arm 1
N=19
Arm 2
N=14
Arm 3
N=17
10 (52.6)
15 (78.9)
3 (15.8)
53.6 ± 9.78
27.3 ± 3.84
14 (100)
12 (85.7)
0
50.9 ± 10.45
24.6 ± 3.08
11 (64.7)
13 (76.5)
4 (23.5)
52.3 ± 9.03
27.6 ± 4.65
IL28 genotype , n (%)
CC
CT
TT
10 (52.6)
7 (36.8)
2 (10.5)
5 (35.7)
7 (50.0)
2 (14.3)
0
12 (70.6)
5 (26.3)
HCV genotype, n (%)
1a
1b
17 (89.5)
2 (10.5)
11 (78.6)
3 (21.4)
16 (94.1)
1 (5.9)
6.25 ± 0.80
14 (73.7)
6.44 ± 1.15
11 (78.6)
6.93 ± 0.47
17 (100)
-
-
11 (64.7)
6 (35.3)
Male, n (%)
White, n (%)
Hispanic/Latino, n (%)
Mean Age ± SD (years)
Mean BMI ± SD (kg/m2)
HCV RNA
Mean ± SD (log10 IU/mL)
>800,000 IU/mL, n (%)
Non-responder status
Partial responder
Null responder
Poordad F, et al. 47th EASL; Barcelona, Spain; April 18-22, 2012. Abst. 1399.
Co-Pilot Study: Virologic Results
Poordad F, et al. 47th EASL; Barcelona, Spain; April 18-22, 2012. Abst. 1399.
ABT-267 + PegIFN/RBV in treatment-naïve
subjects Results
Patients achieving Week 12 cEVR (%)
Week 12 cEVR rates
100%
100
12,5
90
70
<LLOQ, >LLOD
86%
75%
80
66%
60
50
33
40
87,5
86
75
30
20
33
10
0
Placebo
•
<LLOQ, <LLOD
ABT-267 5 mg
QD
ABT-267 50 mg ABT-267 200 mg
QD
QD
Safety:
− ABT-267 had an adverse event profile similar to placebo
− No serious adverse events
cEVR, complete early virological response; LLOD, lower limit of detection (15 IU/mL);
LLOQ, lower limit of quantitation (25 IU/mL); P/R, PegIFN/RBV;
SE, standard error; QD, once daily
EASL, Barcelona, Spain, 18–22 April 2012; Abstract 1210
A Randomized, Open Label, Multi-center Study to Evaluate the
Antiviral Activity, Safety, and Pharmacokinetics, of ABT-450
With Ritonavir (ABT-450/r) in Combination With ABT-267
and/or ABT-333 With and Without Ribavirin (RBV) in
Treatment-Naïve and Null Responder Subjects With Genotype 1
Chronic Hepatitis C Virus Infection
• N = 560
• 14 active treatment arms testing combinations of DAAs and
RBV
– No interferon
• This study is ongoing, but not recruiting participants
ClinicalTrials.gov Identifier: NCT01464827
SOUND-C2: BI 201335 + BI 207127 ± RBV in
Trt-Naive GT1 Pts
Wk 16
Stratified by HCV subtype and IL28B
genotype
Wk 28
Wk 40
BI 201335 120 mg QD +
BI 207127 600 mg TID + RBV
(n = 81)
BI 201335 120 mg QD +
BI 207127 600 mg TID + RBV
(n = 80)
Treatment-naive
pts with GT1 HCV
BI 201335 120 mg QD +
BI 207127 600 mg TID + RBV
(n = 77)
[7% to 17% in
each group had
cirrhosis]
12-wk followup
for SVR12
BI 201335 120 mg QD +
BI 207127 600 mg BID + RBV
(n = 78)
(N = 362)
BI 201335 120 mg QD +
BI 207127 600 mg TID, no RBV
(n = 46)*
Weight-based RBV dosing (1000-1200 mg/day).
Zeuzem S, et al. EASL 2012. Abstract 101.
*Randomization to this arm stopped early due to
US FDA concerns regarding lack of RBV.
SOUND-C2: Higher SVR12 in Pts With
GT 1b HCV, IL28B CC, BID Dosing
SVR according to IL28B and HCV subtype:
BID28wk + RBV (ITT)
SVR according to IL28B and HCV subtype
(ITT)
100
84
75
82
80
60
20
n/N =
0
All 1b and 1a-CC
82
SVR12 (%)
SVR12 (%)
80
40
1a non-CC
100
32
71
71
62
60
40
53
32
38
42
32
20
7/22
6/8
31/37
9/11
1b
1a
1a
1b
CC
non-CC
CC
non-CC
HCV Subtype and IL28B Genotype
Zeuzem S, et al. EASL 2012. Abstract 101.
0
0
TID
16wk
RBV
TID
28wk
RBV
TID
40wk
RBV
BID
28wk
RBV
TID
28wk
4-Drug Therapy With GS-5885, GS-9451,
Tegobuvir, and RBV in Tx-Naive GT1 HCV
•
Interim analysis of randomized phase II study
Randomized 1:2;
stratified by HCV RNA
(≤ vs > 800,000 IU/mL) and
HCV 1 subtype (1a vs 1b)
Tx-naive patients
with chronic GT1
HCV infection
(N = 140)
Wk 2*
Wk 12
Wk 24
GS-5885 30 mg QD +
GS-9451 200 mg QD +
Tegobuvir 30 mg BID +
Ribavirin
(n = 46)
GS-5885 90 mg QD +
GS-9451 200 mg QD +
Tegobuvir 30 mg BID +
Ribavirin
(n = 94)
*Patients with HCV RNA ≥ 25 IU/mL at Wk 2 offered
rescue therapy including pegIFN or study discontinuation.
†Patients rerandomized if HCV RNA < 25 IU/mL at Wks 2-10.
Sulkowski M, et al. EASL 2012. Abstract 1421.
Follow-up
Rerandomized†
GS-5885 90 mg QD +
GS-9451 200 mg QD +
Tegobuvir 30 mg BID +
Ribavirin
Follow-up
for SVR24
SVR-4 rates among patients with HCV
RNA < 25 IU/mL at week 2
Effect of IL28B genotype, subtype and NS5A
dose on week 2 response and breakthrough
Viral breakthrough was associated
with resistance to PI, NS5A and NNI
Daclatasvir (NS5A) + Asunaprevir (PI)
Gen1b, non-cirrhotic
Null
responder
100
IFN
intolerant
91
80
Daclatasvir + Asunaprevir
Daclatasvir + Asunaprevir
0
24
SVR24 (%)
Null
responder
IFN ineligible
and intolerant
64
60
40
20
0
9/10
n=21
n=22
Weeks
Suzuki F, et al. EASL 2012. Abstract 14
Among pts with breakthrough (7%) or relapse (9%),
low plasma concentrations of DAC and ASU
NUCLEOS(T)IDE ANALOGUE
POLYMERASE INHIBITOR +/- PI +/- NS5A
INHIBITOR +/- RBV
INFORM-SVR: Mericitabine + danoprevir/ritonavir ± RBV
in treatment-naïve GT-1: Study design
•
Randomised Phase 2b study of response-guided mericitabine + ritonavir-boosted danoprevir ± RBV in treatment-naive
GT-1 HCV patients
–
n=169: 67% HCV GT-1a; 69% IL28B non-CC
A
B
Mericitabine 1000 mg BD +
danoprevir/ritonavir
100/100 mg BD
+ RBV 1000/1200 mg QD
Mericitabine 1000 mg BD +
danoprevir/ritonavir
100/100 mg BD
+ placebo
Week 4
No
eRVR
Mericitabine + danoprevir/ritonavir + RBV
Mericitabine + danoprevir/ritonavir + RBV
eRVRa
No treatment
No eRVR
Mericitabine + danoprevir/ritonavir + placebob
Mericitabine + danoprevir/ritonavir + placebob
eRVRa
No treatmenta
Week 12
Week 24
apatients
with eRVR were re-randomised at Week 12 to maintain or stop treatment
to unacceptable relapse rates, re-randomisation was halted and patients in
Arm B on active treatment were offered PegIFN/RBV
BID, twice daily; eRVR, early rapid virological response;
GT, genotype; PegIFN, pegylated interferon; RBV, ribavirin
bDue
EASL, Barcelona, Spain, 18–22 April 2012; Abstract 1412
INFORM-SVR: Mericitabine + danoprevir/ritonavir ± RBV
in treatment-naïve GT-1 (Abstract 1412): Results
HCV RNA ≤15 IU/mL at Week
4 (%)
Mericitabine +
danoprevir/ritonavir
+ RBV
Mericitabine +
danoprevir/ritonavir
+ placebo
91
93
Mericitabine 1000 mg + danoprevir/ritonavir
+ RBV scheduled for 24 weeks
(n=63)
SVR8: Overall, % (n)
•
41 (26/63)
GT-1a
26 (11/42)
GT-1b
71 (15/21)
Four serious AEs and two discontinuations due to AEs in overall population
AEs, adverse events;
SVR8: sustained virological response at Week 8
EASL, Barcelona, Spain, 18–22 April 2012; Abstract 1412
Electron Study:
Treatment of GS-7977
Wk 0
Wk 4
n= 10
GS-7977 + PEG + RBV
GS-7977 + RBV
GS-7977 + PEG + RBV
n= 11
GS-7977 + PEG + RBV
n= 10
GS-7977
n= 10
Wk1 2
GS-7977 + RBV
n= 10
n= 9
Wk 8
GT 2/3 Treatment-Naïve (GS-7977 + RBV +PEG)
n= 10
GS-7977 + RBV (GT 1 Null Responders)
n= 25
GS-7977 + RBV (GT 1 Treatment-Naive)
n= 25
GS-7977 + RBV (GT 2/3 Treatment-Experienced)
Gane E, et al. 47th EASL; Barcelona, Spain; April 18-22, 2012. Abst. 1113.
GT 2/3
Tx-naive
Electron Study:
Virologic Response
Patients with HCV RNA <LOD Over Time, n/N (%)
GT 2/3
Treatment-naïve
8 wks
(N=10)
GT 1
Null Responders
12 wks
(N=10)
GT 1
Treatment-naïve
12 wks
(N=25)
GT 2/3 Treatmentexperienced
12 wks
(N=25)
Week 1
6/10 (60)
1/10 (10)
7/25 (29)
8/25 (32)
Week 2
10/10 (100)
7/10 (70)
17/24 (71)
21/25 (84)
Week 4
10/10 (100)
10/10 (100)
25/25 (100)
25/25 (100)
EOT
10/10 (100)
9/9 (100)
25/25 (100)
21/21 (100)
SVR 4
10/10 (100)
1/9 (11)
22/25 (88)
12/15 (80)
SVR 8
10/10 (100)
1/9 (11)
-
SVR 12
10/10 (100)
-
-
Gane E, et al. 47th EASL; Barcelona, Spain; April 18-22, 2012. Abst. 1113.
-
Study AI444-040: Treatment with
GS-7977 + BMS-790052
Week 1
Chronic HCV
GT1a/1b or GT2/3
infection,
treatment-naive
Week 4
Week 12
Week 24 SVR4
SVR12
N = 15
Group A: (GT1a/1b) GS-7977 400 mg QD x 7d,
then add DCV 60 mg QD
Follow-up
N = 16
Group B: (GT2/3) GS-7977 400 mg QD x 7d,
then add DCV 60 mg QD
Follow-up
N = 14
Group C: (GT1a/1b) DCV 60 mg QD
+ GS-7977 400 mg QD
Follow-up
N = 14
Group D: (GT2/3) DCV 60 mg QD +
GS-7977 400 mg QD
Follow-up
N = 15
Group E: (GT1a/1b) DCV 60 mg QD +
GS-7977 400 mg QD + RBV
Follow-up
N = 14
Group F: (GT2/3) DCV 60 mg QD +
GS-7977 400 mg QD + RBV
Follow-up
RBV: 1000-1200 mg daily according to body weight for GT1 patients ; 800 mg daily for GT2/3 patients
Sulkowski M, et al. 47th EASL; Barcelona, Spain; April 18-22, 2012. Abst. 1422.
SVR48
Study AI444-040: Key Results
N=
67
79
67
100
100
100
100
93
100
87
86
93
100
SVR4
100
100
% < LLOQ
% < LOD
Week 2
Week 4
Week 12
mITT analysis, bars not reaching 100% after Week 4 reflect missing values.
PT, post treatment
Sulkowski M, et al. 47th EASL; Barcelona, Spain; April 18-22, 2012. Abst. 1422.
Week 24
(EOT)
PT Week 4
Study AI444-040: SVR-4 according
to genotype 1A/B and IL28B
IL28B Genotype
(rs12979860)
•
•
•
•
Overall SVR4 – 95.5% across GT 1,2 & 3
GT1: 100% of patients (44/44) achieved SVR4
No difference in SVR4 by HCV GT1 subtype or IL28B genotype
Ribavirin did not increase the magnitude of HCV RNA decline or influence SVR
Sulkowski M, et al. 47th EASL; Barcelona, Spain; April 18-22, 2012. Abst. 1422.
Study AI444-040: GT2/3 Naïve
N=44
GT2/3
SVR4=40/44
GT2
Total n=26
SVR4=24/26
GT3
Total n=18
SVR4=16/18
Sulkowski M, et al. 47th EASL; Barcelona, Spain; April 18-22, 2012. Abst. 1422.
1 breakthrough (3a)
1 relapse (3a)
2 LTFU (2a, last RNA UND)
GT2/3 – No RBV
SVR4=28/30
2 viral failures
GT2/3 + RBV
SVR4=12/14
2 LTFU
2012 - 201X: Multiple DAA
Combinations in Developmen
• Clinical trials to determine “best”
combinations and minimum duration needed
to achieve cure
– Multiple regimens may lead to reduced cost per
cure
• Role of Interferon alfa (lambda?) will evolve
but not become extinct
TYPICAL DAY IN THE CLINIC, JUNE
201X
Patient 1
• 47 year old woman presents after being declined
for life insurance
– Infection likely due to blood shortly after birth
– PMH: None
– Social history: Married with 3 children; Recent
change to new job with more responsibility
– HCV genotype 1B; IL28B CC; Biopsy shows no fibrosis
• Treatment:
– Oral therapy --- combination of 2 DAAs with no IFN
and no RBV for 12 weeks ($$)
– PegIFN/RBV ($)
Patient 2
• 66 year old man infected at age 20 via IDU
– PMH: type 2 DM, hypertension, obesity, mild
renal insufficiency; anemia; heroin use off/on
(methadone); depression (incompletely
controlled)
– HCV genotype 1A; IL28B TT; Biopsy shows
cirrhosis
• Treatment:
– Multiple DAAs with nucleos(t)ide analogue ($$$)
– No IFN due to contraindications
Patient 3
• 59 year old man otherwise healthy
– HCV genotype 1A; IL28B TT; Biopsy shows
Ishak 3/6 fibrosis
• Prior therapy
– 1997: IFN alfa/RBV – stop at wk 24 with HCV RNA
5,500 copies/mL
– 2011: PegIFN/RBV/Telaprevir – stop at wk 5
• Week 0: 11,389,000 IU/mL (7.06 log10)
• Week 2:
17,710 IU/mL (4.25 log10)
• Week 4:
153, 060 IU/mL (5.18 log10)
• Treat: Multiple DAAs +/- IFN +/- RBV ($$$$)
Patient 4
• 59 year old man with decompensated liver
disease
– MELD = 25
– Ascites
– HCC less than 2 CM on MRI
• Treatment:
– :Multiple DAAs – pre or post-transplant ($$$$)
– 5 year survival for HCV expected to be similar to
similar to HBV
Patient 5
• 22 year old man tested positive for HCV EIA using
finger stick test while attending needle exchange
– Actively injecting heroin (~30 USD/day) uses new needles
when he can
– Staying with “friends”
– HIV seronegative
• Lost to follow-up
• Treatment:
– Contingent Incentive Care x oral DAAs for 12 weeks ($$)
– Cost-effective with individual and public health benefit?
Future Treatment Paradigms
• Personalized medicine
– Cost
– Virus – 1A or 1B or other genotype; Resistance to
DAAs
– Patient – cirrhosis, ESLD, HCC, willing and able to
take IFN alfa; substance abuse?
• Effectiveness may be limited by failure to
translate to the infected populations