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Hepatitis C Choices in Care
HCV State of the Art Management for a Curable Disease
Robert G. Gish MDRobert G Gish Consultants LLCMember VHACFounding member of CEVHAPExecutive Committee (VP): NVHRSenior Medical Director: St Josephs Medical Center PhoenixProfessor of Clinical Medicine University of Nevada Las Vegas
Future
After HEPTIC EMR
program
Complexity of Hepatitis C Patient Management
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
fibrosis1
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
Hyder S et al. DDW 2013; poster 608.
Hyder S. and et al Digestive Disease week, 2013
HR = 0.77: 95% CI 0.71-0.84
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
2006 2007 2008 2009 20100
1
2
3
4
5
6
7
8
9
10
FIB4<=1.21
1.21<FIB4<=5.88
FIB4>5.88
Year
LOS
rate
(day
/per
son-
year
)
*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 HCV-related 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
Strader DB, et al. Hepatology 2004;39:1147-71.
Series10
20
40
60
80
100
SV
R (
%)
IFN6 mo
IFN/RBV6 mo
PEG-IFN /RBV
12 mo
IFN12 mo
IFN/RBV12 mo
PEG-IFN12 mo
1986 1998 2001 2002
6
16
34
42 39
54-56
70-75
PEG-IFN /RBV + PI6-12 mo
2011-13 2014+
90+%+/-INF
RIBA
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.
Patients, n (% patients with at least one event)
Telaprevir n = 295
Serious adverse events (SAEs)* 535 in 160 patients (54.2%)
Premature discontinuation / due to SAEs 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) 38 (12.9 %)
EPO use / blood transfusion 168 (57 %) / 53 (18 %)
GCSF use 8 (2.7 %)
TPO use 6 (2 %)*SAEs in patients; SCAR: severe cutaneous adverse reaction†3 septicemia, 1 variceal hemmoragia, 1 enkephalopthy, 1 pulmonary neoplasia, 1 pulmonary infection
INF + Riba +Telaprevir: SVR12 safety findings
Patients, n (% patients with at least one event)
Boceprevir n = 190
Serious adverse events (SAEs)* 321 in 97 patients (51.0%)
Premature discontinuation / due to SAEs 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) 19 (10.0 %)
EPO use / blood transfusion 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
INF + Riba + Boceprevir: SVR12 safety findings
Antiviral activity in all HCV genotypes
No/less selection of resistance
All-oral combination regimenShort treatment
duration 6-12 weeks
QD (or BID) dosingExcellent safety and tolerability
Less or no DDI
Applicable in difficult-to-treat populations: Transplant Coinfection End-stage renal disease, etc.
HCV — The Revolution Has Begun
1990 2000 2005 2010 2011 2012 2013 2014 2015
Interferon
Ribavirin
Pegylatedinterferons
Proof of concept for
DAA (PI)
Suppression of HCV with DAA combination
(PI + NI)
Telaprevir and
boceprevir
Curability of HCV without
InterferonTarget >90% SVR reached in Phase
II and III trials
Frequent curability of
diverse populations without IFN
Approval of simeprevir and sofosbuvir with IFN:G1, others?First approved
IFN-free therapy: SOF+RBV: G2, 3
IFN-free DAAcombinations (G1) SVR 90-100%
Potential approval of other DAAs
with IFN(eg faldaprevir)
HCV Therapy—Past, Present, and Future
Thank you to Dr Ira Jacobson
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.
QUEST-1 QUEST-2 PROMISE0
20
40
60
80
100
Simeprevir/PEG/RBV PEG/RBV
SV
R1
2 (
%)
Simeprevir + PEG/RBV Achieved SVR in ~80% of Treatment-Naïve and Prior Relapsers
210/264
65/130
206/260
209/257
67/134
49/133
80*
50
81*
50
79*
37
*P<0.001Jacobson 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
Jacobson I, et al. EASL 2013;Abstract 1425.
Fibrosis Genotype IL28B genotype
Q80K polymorphism affected SVR
F0-F2 F3-F4 1a 1b/other CC CT TT0
20
40
60
80
100
SIM+PR PR
SV
R1
2 (
%)
8390
60
70
28
71
49 52
94
78 76
42
65
24
152/183
54/90 54/77 11/40 105/147
36/74 105/117
29/56 72/77 29/37 114/150
32/76 24/37 4/17
QUEST-2—SVR by Stage of Fibrosis
Jacobson I, et al. EASL 2013;Abstract 1425. Manns M, et al. EASL 2013;Abstract 1413. Lawitz E, et al. DDW 2013; Abstract 869b.
F0-F2 F3 F4 (Cirrhosis)0
20
40
60
80
100
Simeprevir/PEG/RBV + PR PEG/RBV
SV
R1
2 (
%)
85
67
53
65
51
40
165/195 52/102 24/36 9/17 11/17 6/15
ASPIRE—Virologic Response to Simeprevir + PEG/RBV in Prior Partial and Null Responders
SMV 100 mg* + PEG/RBV SMV 150 mg* + PEG/RBVPlacebo + PEG/RBV
*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.
80
SV
R24
(%
)
0
40
60
20
Relapsers Partial Responders Null Responders
37
85 85
9
57
75
19
4651
27 79 79 23 68 69 16 50 51n =
100
QUEST-2—Safety Profile
Adverse Events SMV/PR
(n = 257)Placebo/PR (n = 134)
Grade 1 or 2 AE 70.0 73.1Grade 3 or 4 AE 25.7 23.9Serious AE 2.3 1.5AE leading to discontinuation of SMV* 1.6 0.7Most common AEs (≥25% in SMV arm)
Headache 37.0 33.6Pyrexia 30.4 35.8Fatigue 34.6 38.8Influenza-like illness 25.7 25.4
Other AEs of interestRash (any type) 23.7 11.2Anemia 13.6 15.7Pruritus 18.7 14.9Photosensitivity conditions 3.9 0.7· Data for the first 12 weeks of treatment are shown
· 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.
Patient %
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 RibavirinGenotype 2 and 3*
81
97 100
50
87
98 100
73
0
20
40
60
80
100
2 4 EOT SVR
% H
CV
RN
A (
-)
Treatment Week
12
16
Jacobson IM, et al. . N Engl J Med 2013;368:1867-77.
Weeks ofTreatment:
(N=100)
(N=95)
*Patients with previous non-response to IFN-based treatment
All Oral: Sofosbuvir plus RibavirinCirrhosis vs No Cirrhosis
No Cx Cx No Cx Cx0
20
40
60
80
100 96
60
37
19
100
78
63 61
12
16
SV
R (
%)
Jacobson IM, et al. . N Engl J Med 2013;368:1867-77.
Weeks ofTreatment:
Genotype 3Genotype 2
(N=100)
(N=95)
25/26
23/23
6/10
7/9
14/38
25/40
5/26
14/23
Sofosbuvir + RBVVALENCE: Genotype 2,3 IFN naïve, ineligible or treatment failures
SOF+RBV (n=73)
SOF+RBV (n=250)
SVR12 =93% G2
G3
Series10
102030405060708090
100Genotype 3
93 9285
60
Naïve Treatment-experienced
Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic
SVR 12 (%)
86/92 12/13 85/100 27/45
FDA Advisory Committee Meeting, Oct 25, 2013; Zeuzem S et al, AASLD 2013, #1085
Wk 0 Wk 24
Sofosbuvir/PegIFN/RibavirinGenotype 1 (N=327)
9199 99
90
0
20
40
60
80
100
2 4 EOT SVR
% H
CV
RN
A (
-)
Treatment Week
Lawitz E, et al. N Engl J Med 2013;368:1878-87.
SMV/ SOF12 Wks
SMV/ SOF/RBV12 Wks
0102030405060708090
100
92 96
7.83.7
24 week treatment
13/14 26/27
SMV/SOF12 wks
SMV/SOF/RBV12 wks
SVR12 (SMV/SOF)
SVR12 (SMV/SOF/RBV)
1/271/14
0102030405060708090
100
100 79
16.7
4.2
14/14 19/24
SMV/SOF24 wks
SMV/SOF/RBV 24 wks
Pat
ien
ts (
%)
1/24
4/24
Non-virologic failure
Relapse
Cohort 1: Null responders (F0-2)
12 week treatment
Total Naives Nulls0
102030405060708090
100100 100 10096.3 100
93.3
Pat
ien
ts (
%)
1/27
SVR4 (SMV/SOF)
SVR4 (SMV/SOF/RBV)
12 week treatment
7/7 12/12 7/7 14/15
1/15
Relapse
26/2714/14
Cohort 2: Naïve and prior null responders (F3-4): Interim analysis, SVR4
9 naïve and 9 null responders METAVIR F4 patientsOnly 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 SummaryCross-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 SummaryPhase 2 Study Results
Weeks SVR
ABT450/r + ABT267 + ABT333 + RBV (N=571)
12 ~90%
Sofosbuvir + ledipasvir + RBV (N=34) 8-12 95-100%
Faldaprevir + deleobuvir + RBV (GT1b, N=20)
16 ~95%
DCV + ASV + BMS-791325 (N=66) 12-24 88-94%
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.
2013 2014 2015 2016
Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
2013 2014 2015 2016
Projected Timing for New Regimen Launches
Sofosbuvir + RBV
GT2/3, Naïve/Tx-EXP/
IFN Ineligible TX-Exp
BMS DCV/ASV/RBV*
-----GT1b Naïve/Tx-
Exp/IFN IntolerantDaclatasvir
Triple-----
Gt1. Naïve onlySofosbuvir +
lepedisvir-----
GT1/2/3, Naïve/TX-EXP/
IFN Ineligible
ABT-450/267/333/RBV
----GT1, Naïve/Tx-EXP
Faldaprevir(BI201335) Triple
----GT1 Naïve, Tx-EXP
Sofosbuvir Triple----
GT1, 4, 5, 6, Naive
Simeprevir Triple----
GT1, Naïve, Tx-Exp
TripleIFN-Free
* Precise timing TBD
COSMOS StudyOff Label use
SOF + SIM G-1
To Treat or not to Treat:
A Constellation of Considerations
Duration ofinfection
Personal plans(marriage,
pregnancy)Age
COST
HIV coinfectionExtrahepatic
Features(Fatigue, EMC, PCT)
Patient"mindset"
Genotype virusGenotype Patient (IL28)
Q80K mutation or others
Contraindications& comorbidities
Insulin Resistance
Histologic stage20%+ life time risk
Of cirrhosis
Family and othersupport
Occupation
To Treat or not to Treat:A Constellation of Considerations