AASLD Talk - Hepatitis C

Report
Hepatitis C Choices in Care
HCV State of the Art Management for a
Curable Disease
Robert G. Gish MD
Robert G Gish Consultants LLC
Member VHAC
Founding member of CEVHAP
Executive Committee (VP): NVHR
Senior Medical Director: St Josephs
Medical Center Phoenix
Professor of Clinical Medicine
University of Nevada Las Vegas
Complexity of Hepatitis C Patient
Management
Futur
e
After HEPTIC
EMR program
Why Treat Chronic Hepatitis C?

The disease


Common, chronic, and potentially progressive
Complications are becoming more common








Liver failure
Hepatocellular carcinoma (HCC)
Decrease transmission
Improve quality of life
Systemic disease
Improve survival due to the linkage of HCV to (non liver) all cause mortality
Decrease immediate and long-term health care costs
The treatment



Viral cure, or sustained virologic response (SVR), is achievable
SVR associated with histologic improvement and gradual regression of fibrosis 1
SVR leads to lower risk for liver failure and HCC, and
improved survival2,3
1. Poynard T, et al. Gastroenterology. 2002;122:1303-1313.
2. Craxi A, et al. Clin Liver Dis. 2005;9:329-346.
3. Shiratori Y, et al. Ann Intern Med. 2005;142:105-114.
Treatment starts NOW with behavior
modification




Alcohol abstinence
Weight loss of OW/Obese
No THC use
Stop IVDU
HCV as a Systemic Disease

Association between chronic HCV infection and:






Diabetes/insulin resistance
Cardiovascular disease
HCV and Brain: decreased cognitive function and QOL
Cancer
Renal impairment
Effects of antiviral therapy and SVR on prognosis:





Clear mixed cryoglobulinemia
Decrease liver-related mortality
Abrogate non-liver-related mortality
Stop graft loss in renal and liver transplant patients
Change outcomes in immune suppressed patients with HIV
and other treatments or disease states
SVR Reduces Risk of Development
of Diabetes in Patients with HCV



Veterans Affairs Clinical Case Registry: 27,636 patients with HCV
Followed for median 5 years
Antiviral treatment initiated 1998-2007
HR = 0.77: 95% CI 0.71-0.84
Hyder S. and et al Digestive Disease week, 2013
Hyder S et al. DDW 2013; poster 608.
HCV+ individuals die 15 years sooner
Pinchoff J et al. IDWeek 2013; poster 1777.
CHeCS: Annual Rate of Length of Stay
(days/year) by FIB4 score*, 2006-2010
10
LOS rate (day/person-year)
9
8
FIB4<=1.21
7
1.21<FIB4<=5.88
6
FIB4>5.88
5
4
3
2
1
0
2006
2007
Year
2008
2009
2010
*FIB4, calculated from ALT, AST, platelet count and patient age,
increases with worsening fibrosis; values > 5.88 indicate cirrhosis
and end-stage liver disease
HCV-infected persons in CHeCS:
Mortality rates also increasing*
Year
Mortality rate
(per 100 py)
2006
1.4
2007
2.1
2008
2.8
2009
3.2
2010
4.4
From: R Mahajan et al, Abstract submitted to IDWeek 2013
The real impact of HCV mortality in the
United States*




Despite high death rates, only 19% of the 1600 confirmed chronic
HCV patients in CHeCS had HCV infection noted on their death
certificate; only 30% even of those dying with liver-related conditions
70% had pre-mortem ICD9 codes, liver biopsies, and FIB4 scores
indicative of substantial liver damage
This suggests that even if all HCV-infected patients are identified
before death– clearly, not the case-- actual mortality in them
exceeds 80 000/yr, most of it contributed to by underlying HCVrelated liver disease
Whatever the listed cause of disease, HCV-infected persons died 15
years younger than everyone else
*Reena Mahajan et al, ‘Rates and Causes of Mortality…”, Manuscript submitted; IDWeek 2013 abstr 1774
Current Treatment
The Evolution of HCV Therapy
100
1998
1986
2001
2002
SVR (%)
80
2011-13
2014+
70-75
54-56
60
42
90+%
+/INF
RIBA
39
34
40
16
20
6
0
IFN
6 mo
IFN
12 mo
Strader DB, et al. Hepatology 2004;39:1147-71.
IFN/RBV
6 mo
IFN/RBV
12 mo
PEG-IFN
12 mo
PEG-IFN
/RBV
12 mo
PEG-IFN
/RBV + PI
6-12 mo
Side Effects
PEG IFN/RBV + new therapies results in increased SVR rates,
this may be accompanied by a higher incidence of











Anemia, often requiring erythropoietin and/or transfusion
Rash
Taste abnormalities (dysgeusia)
Fatigue
Flu-like symptoms
Nausea
Pruritus/dry skin
Neutropenia/thrombocytopenia
Fever
Depression
+++
Poordad F, et al. N Engl J Med. 2011;364:1196-1206.
Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.
Sherman KE, et al. 61st AASLD; October 29-November 2, 2010; Boston, Mass. Abstract LB-2.
Telaprevir NDA 201-917. April 28, 2011. Available at: www.fda.gov.
INF + Riba +Telaprevir:
SVR12 safety findings
Patients, n (% patients with at least one event)
Serious adverse events (SAEs)*
Premature discontinuation / due to SAEs
Telaprevir n = 295
535 in 160 patients (54.2%)
139 (47.1%) / 63 (21.3%)
Death
7 (2.4 %)
Infection (Grade 3/4)†
27 (9.1 %)
Hepatic decompensation (Grade 3/4)
15 (5.1 %)
Rash (grade 3/SCAR)
16 (5.4 %) / 2 (0.6 %)
Anemia (Grade 3/4 : Hb < 8 g/dL)
EPO use / blood transfusion
38 (12.9 %)
168 (57 %) / 53 (18 %)
GCSF use
TPO use
*SAEs in patients; SCAR: severe cutaneous adverse reaction
†3 septicemia, 1 variceal hemmoragia, 1 enkephalopthy, 1 pulmonary neoplasia, 1 pulmonary infection
8 (2.7 %)
6 (2 %)
INF + Riba + Boceprevir:
SVR12 safety findings
Patients, n (% patients with at least one event)
Serious adverse events (SAEs)*
Premature discontinuation / due to SAEs
Boceprevir n = 190
321 in 97 patients (51.0%)
80 (42.1%) / 27 (14.2%)
Death†
3 (1.6 %)
Infection (Grade 3/4)
8 (4.2 %)
Hepatic decompensation (Grade 3/4)
9 (4.7 %)
Rash (grade 3/SCAR)
2 (1.0 %)
Anemia (Grade 3/4: Hb < 8 g/dL)
EPO use / blood transfusion
19 (10.0 %)
119 (62.6 %) / 26 (13.7 %)
GCSF use
13 (6.8 %)
TPO use
3 (1.6 %)
*SAEs in patients; SCAR: severe cutaneous adverse reaction
†1 pulmonary infection, 1 anevrysmal beeding, 1 septicemia
HCV — The Revolution Has Begun
Antiviral activity
in all HCV genotypes
All-oral combination regimen
QD (or BID) dosing
No/less selection of resistance
Short treatment
duration 6-12 weeks
Excellent safety and tolerability
Less or no DDI
Applicable in difficult-to-treat populations:
 Transplant
 Coinfection
 End-stage renal disease, etc.
HCV Therapy—Past, Present, and Future
Interferon
1990
Proof
of concept for
DAA (PI)
2000
Frequent
curability of
diverse
populations
without IFN
Suppression of
HCV with DAA
combination
(PI + NI)
Ribavirin
2005
Pegylated
interferons
Thank you to Dr Ira Jacobson
Telaprevir
and
boceprevir
2010
IFN-free DAA
combinations (G1)
SVR 90-100%
2011
2012
Curability of
HCV without
Interferon
Target >90% SVR
reached in Phase
II and III trials
Potential
approval of
other DAAs
with IFN
(eg faldaprevir)
2013
2014
2015
Approval of
simeprevir and
sofosbuvir with
IFN:G1, others?
First approved
IFN-free therapy:
SOF+RBV: G2, 3
Two New Protease Inhibitors are
coming in combination with PEG
IFN/RBV

Simeprevir






NS3 protease Inhibitor
Q daily dosing
Improved side effect profile
No anemia
Fewer DDIs
Faldaprevir




NS Protease inhibitor
Q daily dosing
Improved side effect
profile
No anemia
18
Simeprevir (TMC 435)

HCV-specific NS3/4A protease inhibitor

Antiviral activity in patients infected with GT
1, 2, 4, 5, and 6

Oral, once-daily tablet

Limited drug-drug interactions as CYP 3A4
inhibitor only at level of intestine

Safe and well tolerated, n ~3800 patients
Simeprevir—Completed Phase III Studies


QUEST-1 and QUEST-2

Same study design, but conducted independently
of each other

Treatment-naïve GT 1 patients
PROMISE

Same study design as QUEST-1 and QUEST-2

GT 1 prior relapsers
Jacobson I, et al. EASL 2013, Abstract 1425. Manns M, et al. EASL 2013, Abstract 1413. Lawitz E, et al. DDW 2013,
Abstract 869b.
Simeprevir + PEG/RBV Achieved SVR in
~80% of Treatment-Naïve and Prior
Relapsers Simeprevir/PEG/RBV PEG/RBV
100
SVR12 (%)
80
81*
80*
60
79*
50
50
37
40
20
210/
264
65/
130
209/
257
67/
134
206/
260
49/
133
0
QUEST-1
QUEST-2
PROMISE
*P<0.001
Jacobson I, et al. EASL 2013;Abstract 1425. Manns M, et al. EASL 2013;Abstract 1413. Lawitz E, et al. DDW 2013;
Abstract 869b.
QUEST-1—SVR by Subgroup
SIM+PR
100
PR
94
90
83
78
SVR12 (%)
80
60
71
70
76
65
60
52
49
42
40
28
24
20
152/ 54/90
183
54/77
11/40
105/
147
36/74
105/
117
29/56
72/77 29/37
114/
150
32/76
24/37 4/17
0
F0-F2
F3-F4
Fibrosis
1a
1b/other
Genotype
CC
IL28B genotype
Q80K polymorphism affected SVR
Jacobson I, et al. EASL 2013;Abstract 1425.
CT
TT
QUEST-2—SVR by Stage of Fibrosis
Simeprevir/PEG/RBV + PR
PEG/RBV
100
85
80
SVR12 (%)
67
60
65
53
51
40
40
20
165/195
52/102
24/36
9/17
11/17
6/15
0
F0-F2
F3
F4 (Cirrhosis)
Jacobson I, et al. EASL 2013;Abstract 1425. Manns M, et al. EASL 2013;Abstract 1413. Lawitz E, et al. DDW 2013;
Abstract 869b.
ASPIRE—Virologic Response to
Simeprevir + PEG/RBV in Prior Partial
and Null Responders
Placebo + PEG/RBV
SMV 100 mg* + PEG/RBV
SMV 150 mg* + PEG/RBV
100
85
85
80
75
60
57
SVR24 (%)
46
37
40
19
20
0
51
9
n=
27
79
Relapsers
79
23
68
69
Partial Responders
16
50
Null Responders
*For each dose, SVR for different treatment durations were similar so results were pooled.
Abbreviation: SMV, simeprevir.
Zeuzem S, et al. EASL 2012;Abstract 2.
51
QUEST-2—Safety Profile
Patient %
Adverse Events
SMV/PR
(n = 257)
Placebo/PR
(n = 134)
Grade 1 or 2 AE
70.0
Grade 3 or 4 AE
25.7
Serious AE
2.3
AE leading to discontinuation of SMV*
1.6
Most common AEs (≥25% in SMV arm)
Headache
37.0
Pyrexia
30.4
Fatigue
34.6
Influenza-like illness
25.7
Other AEs of interest
Rash (any type)
23.7
Anemia
13.6
Pruritus
18.7
 Photosensitivity
Data for the first conditions
12 weeks of treatment are shown3.9
 The majority of rash AEs in the SMV/PR group (97.0%) were grade 1 or 2
*Without regard to PEG IFN and RBV.
Abbreviations: AE, adverse event; PR, PEG IFN + ribavirin; SMV, simeprevir.
Manns M, et al. EASL 2013;Abstract 1413.
73.1
23.9
1.5
0.7
33.6
35.8
38.8
25.4
11.2
15.7
14.9
0.7
Simeprevir—Benefits

Virtually all patients qualify for short-duration
(24 weeks) therapy

Limited drug-drug interactions

Daily dosing
Simeprevir—Data Gaps

GT 2 and 4 subtypes

Phase III data in prior PEG/RBV partial
and null responders

Renal disease

Pre and post transplant
All Oral: Sofosbuvir plus Ribavirin
Genotype 2 and 3*
97 98
100
100 100
87
81
% HCV RNA (-)
80
73
60
50
40
Weeks of
Treatment:
12 (N=100)
16 (N=95)
20
0
2
4
EOT
SVR
Treatment Week
*Patients with previous non-response to IFN-based treatment
Jacobson IM, et al. . N Engl J Med 2013;368:1867-77.
All Oral: Sofosbuvir plus Ribavirin
Cirrhosis vs No Cirrhosis
100
96
100
78
SVR (%)
80
63
60
60
61
Weeks of
Treatment:
12
37
40
16 (N=95)
19
20
25/
26
23/
23
6/
10
7/
9
14/
38
25/
40
5/
26
14/
23
0
No Cx
Genotype 2
Jacobson IM, et al. . N Engl J Med 2013;368:1867-77.
Cx
No Cx
Cx
Genotype 3
(N=100)
Sofosbuvir + RBV
VALENCE: Genotype 2,3 IFN naïve, ineligible or treatment failures
SVR12 =93%
G2 SOF+RBV (n=73)
G3 SOF+RBV (n=250)
Wk 24
Wk 0
Genotype 3
100
93
92
85
80
SVR 12 (%)
60
60
40
20
0
86/92
12/13
85/100
Noncirrhotic
Cirrhotic
Noncirrhotic
Naïve
27/45
Cirrhotic
Treatment-experienced
FDA Advisory Committee Meeting, Oct 25, 2013; Zeuzem S et al, AASLD 2013, #1085
Sofosbuvir/PegIFN/Ribavirin
Genotype 1 (N=327)
% HCV RNA (-)
100
99
99
91
90
80
60
40
20
0
2
4
Treatment Week
Lawitz E, et al. N Engl J Med 2013;368:1878-87.
EOT
SVR
Patients (%)
Cohort 1: Null responders (F0-2)
100
90
80
70
60
50
40
30
20
10
0
24 week treatment
4.2
1/24
100
90
4/24
16.7
80
70
60
79
100
50
40
30
20
10
14/14
19/24
0
SMV/SOF
SMV/SOF/RBV
24 wks
24 wks
SVR12 (SMV/SOF)
Non-virologic failure
SVR12 (SMV/SOF/RBV)
Relapse
12 week treatment
7.8
1/14
3.7
92
96
13/14
26/27
SMV/SOF
SMV/
SOF…
12 wks
1/27
SMV/SOF/RBV
SMV/
SOF/RBV…
12 wks
Cohort 2: Naïve and prior null responders
(F3-4): Interim analysis, SVR4
Patients (%)
12 week treatment
100
90
80
70
60
50
40
30
20
10
0
1/27
100
96.3
1/15
100
100
100
93.3
SVR4 (SMV/SOF)
SVR4 (SMV/SOF/RBV)
Relapse
14/14
26/27
Total
7/7
12/12
Naives
7/7
14/15
Nulls
9 naïve and 9 null responders METAVIR F4 patients
Only relapser was a F4 prior null responder
Conclusion

Treatment with SMV + SOF ± RBV results in:





High SVR12 rates in HCV GT 1 null responder patients
High SVR4 rates in naïve and null-responder patients with
METAVIR F3-F4
These findings suggest that addition of RBV to SMV +
SOF may not be necessary to achieve good virologic
response in this patient population
12 weeks’ treatment may confer similar clinical benefit to
24 weeks’ treatment
SMV + SOF ± RBV was generally well tolerated
IFN-free Summary
Cross-company Studies
Weeks
SVR
Daclatasvir + Sofosbuvir (N=41, GT-1)
12
100%
Simeprevir + Sofosbuvir COSMOS (N=80)
12
100%
Sulkowski MS, et al. EASL 2013; abstract 1417.
Lawitz EM, et al. CROI 2013; abstract 155LB.
IFN-free Summary
Phase 2 Study Results
ABT450/r + ABT267 + ABT333 + RBV
(N=571)
Sofosbuvir + ledipasvir + RBV (N=34)
Faldaprevir + deleobuvir + RBV (GT1b,
N=20)
DCV + ASV + BMS-791325 (N=66)
Kowdley K, et al. EASL 2013; abstract 3.
Gane E, et al. CROI 2013; abstract 41LB.
Zeuzem S, et al., APASL 2013.
Everson GT, et al. IDSA 2013; abstract 1828.
Weeks
SVR
12
~90%
8-12
95-100%
16
~95%
12-24
88-94%
Projected Timing for
New Regimen Launches
2013
2014
2015
2016
BMS DCV/ASV/RBV*
----GT1b Naïve/Tx-Exp/
IFN Intolerant
COSMOS Study
Off Label use
SOF + SIM G-1
Daclatasvir Triple
----Gt1. Naïve only
Sofosbuvir + RBV
Sofosbuvir + lepedisvir
----GT1/2/3, Naïve/TXEXP/
IFN Ineligible
GT2/3, Naïve/TxEXP/
IFN Ineligible TX-Exp
Sofosbuvir Triple
---GT1, 4, 5, 6,
Naive
ABT450/267/333/RBV
---GT1, Naïve/Tx-EXP
Simeprevir Triple
---GT1, Naïve, TxExp
Q1
Q2
Q3
Q4
2013
* Precise timing TBD
Q1
Triple
IFN-Free
Faldaprevir
(BI201335) Triple
---GT1 Naïve, Tx-EXP
Q2
Q3
Q4
2014
Q1
Q2
Q3
Q4
2015
Q1
Q2
Q3
Q4
2016
To Treat or not to Treat:
A Constellation of Considerations
Genotype virus
Genotype Patient (IL28)
Q80K mutation or others
Histologic stage
20%+ life time risk
Of cirrhosis
Duration of
infection
Personal plans
(marriage,
pregnancy)
Age
Family and other
support
Patient
"mindset"
COST
Occupation
HIV coinfection
Contraindications
& comorbidities
Insulin Resistance
To Treat or not to Treat:
A Constellation of Considerations
Extrahepatic
Features
(Fatigue, EMC, PCT)

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