12 weeks - American Gastroenterological Association

Report
HCV 2014 and beyond the
interferon era
Patrick M. Horne, MSN, ARNP, FNP-BC
Assistant Director of Hepatology Clinical Research
Division of Gastroenterology, Hepatology and
Nutrition
University of Florida Health
Disclosures and Off-label Discussion
• Financial relationships to disclose within
the past 12 months:
• Scientific consultant for Gilead Sciences
• Off-label discussion:
• Combination sofosbuvir + simeprevir
Objectives
• Discuss the history and worldwide
prevalence of hepatitis C
• Review the current approved therapeutic
options for HCV therapy based on genotype
• Discuss some future treatment options in
development
Direct Acting Antivirals
Nucleoside
inhibitor
Protease
2013
inhibitor
Developments in Treatment and Cure Rates
Peginterferon
2011
2001
>70%
Ribavirin
55%
1998
SVR (%)
SVR
%
Standard
Interferon
42%
34%
1991
16%
6%
TIME
>90%
Seroprevalence of Hepatitis C:
170 to 200 Million Worldwide
Eastern Europe
10 M
United States
5M
Americas
12-15 M
Western Pacific
60 M
Western Europe
5M
Highest Prevalence:
Egypt-4M
(45% adults >40y)
Africa
30-40M
Southeast Asia
30-35 M
Australia
.2 M
1. World Health Organization. Wkly Epidemiol Rec. 2000;75:17-28.
2. Edlin B et al. AASLD; November 11-15; 2005 San Francisco, California. Oral Presentation #44.
P-DS-D-159
SVR is Associated with Reduced Mortality Among
HCV-infected Persons
30
P<0.001
Liver-related mortality
or liver
transplantation, %
All-cause mortality,
%
• 530 adults in Europe prospectively followed for median 8.4 years
after HCV treatment
All-cause mortality
Liver-related mortality or liver
30
• 192 (36%)
achieved SVR
transplantation
20
10
Without SVR
0
0
1
2
3
4
5
With SVR
6
7
8
9
P<0.001
20
Without SVR
10
0
10
0
Time, y
No. at risk
Without SVR
With SVR
405 393 382 363 344 317 295 250207 164 135
192 181 168 162 156 144 125 88 56 40 28
Van der Meer, et al. JAMA 2012:308:2584-2593.
With SVR
1
2
3
4
5
6
7
8
9
10
Time, y
No. at risk
Without SVR
With SVR
405 392 380 358 334 305 277 229 187 146 119
192 181 168 162 156 144 125 88 56 40 28
75% of Infected Individuals Are Not
Aware of Their HCV Status
1. Institute of Medicine. Hepatitis and Liver Cancer, A National Strategy for Prevention
and Control of Hepatitis B and C. Washington, DC. The National Academies Press,
2010; 2.United States Department of Health and Human Services. Combating the
Silent Epidemic of Viral Hepatitis, Action Plan for the Prevention, Care & Treatment of
Viral Hepatitis. 2011
CDC Releases Birth Cohort Screening
Guidelines
• Adults born during 1945–1965 should receive one-time testing for HCV without
prior ascertainment of HCV risk
• All persons identified with HCV infection should receive a brief alcohol
screening and intervention as clinically indicated, followed by referral to
appropriate care and treatment services
Smith BD, et al. MMWR Recomm Rep. 2012;61(RR-4):1-32.
Case 1
• 60 year old Caucasian male presents
recently found to be HCV Ab positive.
– Confirmatory testing confirms genotype 1a with
a viral load of 1,245,300 IU/mL.
• Hx of illicit drug use in the 1960s
• Medical hx includes
– Hypertension-well controlled
– GERD-well controlled with PPI
Case 1
• Naïve to treatment
• Baseline labs:
– AST 66, ALT 70
– Total bilirubin 0.5
– Hemoglobin 14.0
– Platelet count 175,000
– Fibrotest=F2 disease
Case 1
• What do you do?
Current options
• Approved options
– Pegylated interferon (Peg-INF) and ribavirin
(RBV), weight based times 48 weeks
– Peg-INF, RBV plus either telaprevir (TVR) or
bocepravir (BOC) for 24-48 weeks
– Peg-INF, RBV plus simeprevir (SIM) for 24-48
weeks
– Peg-INF, RBV plus sofosbuvir (SOF) times 12
weeks or SOF and RBV for 24 weeks
Current options
• Not approved option but with good data
– SOF + SIM with or without ribavirin for 12
weeks- COSMOS study
• Wait for something else
100
90%
90
75%
80
80%
76%
70
60
50%
50
40
30
20
10
0
Peg-INF/RBV
Package inserts
PEG-INF/RBV/TVR
or BOC
Peg-INF/RBV/SIM
Peg-INF/RBV/SOF
SOF/RBV
Recommendations for HCV Genotype 1
Treatment-Naïve
Population
Recommended Regimen
Duration
Treatment-naïve genotype 1
Sofosbuvir (400 mg) + PEG-INF
+ RBV (1000-1200 mg/d)
12 weeks
• Alternative regimens:
• Simeprevir + PEG-INF+ RBV x 12 wks
• SIM + SOF+/- RBV x 12 wks
• SOF + RBV x24 wks
• Regimens specifically not recommended:
• Peg-INF/RBV x 48 wks with or without TVR or
BOC
• Monotherapy with PEG, RBV, or DAA
Peg-INF = pegylated interferon;
RBV=ribavirin; DAA = direct acting antiviral
AASLD/IDSA Treatment Recommendations.
www.hcvguidelines.org. Accessed January 31, 2014.
Neutrino Study
Overall
1 (1a, 1b, 1a/b)
HCV GT
1a
1b
4, 5, 6
SOF + PEG-IFN + RBV
Cirrhosis
SVR by Subgroups
Race
HCV RNA level
IL28B
No
Yes
Black
Non-black
<6 log10 IU/mL
≥6 log10 IU/mL
CC
Non-CC
SVR
Lawitz E, et al. EASL 2013, Abstract 1411;
Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
SVR %
60
70
80
90
100
Genotype 1 Treatment Options
Phase 3 Landscape
SVR (est)
2014 (now)
90%
PEG/RBV + SOF
> 90%
SOF + SMV (off-label)
60-70%
SOF + RBV (select populations)
12
1212
weeks
0
00
24-48
2014-2015
SOF + LPV + RBV
> 94%
ABT-450+ 333 + 267 + RBV
>94%
DCV + ASU (1b)
90%
SOF + DCV
> 94%
Courtesy of David Nelson, M.D.
Case 2
• 55 year old African-American female with
HCV genotype 2b who was a prior relapser
to Peg-INF + RBV times 24 weeks.
• Liver biopsy in 2013-F3 fibrosis
• Other medical hx:
– Diabetes
– Hyperlipidemia
– Anxiety
Case 2
• Labs:
– HCV RNA 550,000 IU/mL
– AST 100, ALT 98
– Total bilirubin 1.0
– Hemoglobin 12.5
– Platelet count 110,000
Case 2
• What do you do?
Options
• Re-treat with Peg-INF + RBV for 48 weeks
– Prior treatment she required multiple dose
reductions of Peg-INF due to side effects
• SOF + RBV for 12 weeks
• Wait
Recommendations for HCV Genotype 2
Treatment-Experienced
Population
Recommended Regimen
Duration
Previous treatment with
PEG/RBV
Sofosbuvir (400 mg) +
RBV (1000-1200 mg/d)
12 weeks*
*Patients with cirrhosis may benefit by extension of therapy to 16 weeks
Population
Alternative Regimen
Previous treatment with Sofosbuvir (400 mg) + PEG-IFN +
PEG/RBV
RBV (1000-1200 mg/d)
Duration
12 weeks
AASLD/IDSA Treatment Recommendations.
www.hcvguidelines.org. Accessed January 31, 2014.
Sofosbuvir + RBV in HCV GT 2/3
Genotype 2 = 3
FISSION
GT-2
GT-3
12 week
GT-2
97%
12 Week
5656%%
93%
12 week
POSITRON
12 week
61%
12 week
FUSION
FUSION
12 week
86%
30%
GT-3
94%
16 week
FUSION
16 week
62%
12 week
VALENCE
93%
62%
24 week
SVR12 rate (%)
0
10
Lawitz E, et al. N Engl J Med 2013;368:1878-87.
20
30
40
50
84%
60
70
80
90
100
Jacobson IM, et al. N Engl J Med 2013;368:1867-77.
23
Case 3
• 54 year old Hispanic male with HCV
genotype 3.
– Diagnosed 5 years ago
– Relapser to Peg-INF and RBV
– Liver biopsy 2013-F1 fibrosis
• Other medical history:
– Bipolar disorder
– GERD
– Arthritis
Case 3
• Labs:
– HCV RNA 1,200,000 IU/mL
– AST 55, ALT 80
– Total bilirubin 0.6
– Hemoglobin 13.4
– Platelet count 200,000
Treatment options
• Peg-INF + RBV for 24 weeks
• SOF + RBV for 24 weeks
• Peg-INF + RBV + SOF for 12 weeks
Recommendations for HCV
Genotype 3, Treatment – Naïve/Experienced
Population
Recommended Regimen
Duration
Regardless of IFN eligibility
Sofosbuvir (400 mg) +
RBV (1000-1200 mg/d)
24 weeks
Population
Alternative Regimen
Duration
Consider only if eligible for
IFN
Sofosbuvir (400 mg) +
Peginterferon +
RBV (1000-1200 mg/d)
12 weeks
Not recommended:
• PEG/RBV
• Telaprevir, boceprevir, simeprevir
AASLD/IDSA Treatment Recommendations.
www.hcvguidelines.org. Accessed January 31, 2014.
Sofosbuvir + RBV in HCV GT 2/3
Genotype 2 = 3
FISSION
GT-2
GT-3
12 week
GT-2
97%
12 Week
5656%%
93%
12 week
POSITRON
12 week
61%
12 week
FUSION
FUSION
12 week
86%
30%
GT-3
94%
16 week
FUSION
16 week
62%
12 week
VALENCE
93%
62%
24 week
SVR12 rate (%)
0
10
Lawitz E, et al. N Engl J Med 2013;368:1878-87.
20
30
40
50
84%
60
70
80
90
100
Jacobson IM, et al. N Engl J Med 2013;368:1867-77.
28
VALENCE: Sofosbuvir + RBV
Genotype 3 IFN naïve, ineligible or treatment failures
0
weeks
12
24
G3 SOF+RBV (n=250)
100
80
93
92
85
60
SVR 12 (%)
60
40
20
86/92
12/13
85/100
27/45
0
Noncirrhotic
Naïve
Zeuzem S et al, AASLD 2013, #1085
Cirrhotic
Noncirrhotic
Cirrhotic
Treatment-experienced
Impact of Duration on Efficacy
of SOF in Tx-experienced GT 3
FUSION: 12 Weeks SOF/RBV
FUSION: 16 Weeks SOF/RBV
VALENCE: 24 Weeks SOF/RBV
100
85
80
63
SVR12 (%)
60
40
60
14/
23
27/
45
37
19
20
n/N =
0
61
14/
38
25/
40
85/
100
5/
26
No Cirrhosis
Cirrhosis
Genotype 3
SOF = sofosbuvir; RBV=ribavirin
Lawitz E, et al. AASLD 2013.
Zeuzem, et al. AASLD 2013.
Lonestar-2
Peg-INF + RBV +
SOF times 12
weeks
Lawitz E AASLD 2013
What about waiting?
• What may be coming?
Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 2-3
Treatment-Naïve 24 Week Rx
Week
Rx Naïve
GT 2 or 3
n = 44
0
12
24
36
n = 16
SOF × 7 days, then DCV + SOF
SVR12 = 88%
n = 14
DCV + SOF
SVR12 = 93%
n = 14
DCV + SOF + RBV
SVR12 = 86%
Drug Dosing
Daclatasvir (DCV): 60 mg once daily
Sofosbuvir (SOF): 400 mg once daily
Genotype 3
(n= 150)
- naïve
- experienced
•
Phase 3 Trial (NCT02032901): ongoing, but closed to enrollment
DCV + SOF
Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.; Clinical Trials.gov
Core E1
Protease
HCV PIs
Viral enzyme
Active site
Telaprevir
Boceprevir
Simeprevir
Faldaprevir
Asunaprevir
ABT-450
MK-5172
Sovaprevir
ACH-2684
E2
NS2
NS3
NS5A
Inhibitors
Non-enzyme
Replication complex
Daclatasvir
Ledipasvir
ABT-267
GS-5816
ACH-3102
PPI-668
GSK2336805
Samatasvir
MK-8742
Courtsey of David Nelson, M.D.
4A
5’UTR
p7
The New Era of HCV Therapy
Multiple Direct Acting Antivirals
NS4B
NS5A
3’UTR
NS5B
Polymerase
NS5B
Nucs
NS5B
Non-nucs
Viral enzyme
Active site
Viral enzyme
Allosteric site
Sofosbuvir
VX-135
IDX20963
ACH-3422
ABT-333
Deleobuvir
BMS-791325
PPI-383
GS-9669
TMC647055
HCV Future Treatment Paradigm
Many Options to Choose From
Direct Acting Antivirals
IL28B CC
SOF + RBV
SOF + PI
SOF + NS5A
NS5A + PI
PEG-IFN + RBV
+ RBV
+ RBV
+ NNI + RBV
+ DAA
NI: nucleotide polymerase inhibitor (SOF), NNI: non-nucleotide polymerase inhibitor
PI: protease inhibitor, NS5A: NS5A replication complex inhibitor
Summary
• Large cohort of patients that have yet to be
diagnosed.
• Treatment options are becoming better and
short and more individualized.
• More patients will have access to
medications options as we will no longer be
limited by contraindications to treatment
due to medical co-morbidities or side effects
Thank you!

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