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Transcript of HCV – Treatment of Genotype 1: Now and in the...
Mark W. Russo, MD, MPH, FACG
HCV – Treatment of Genotype 1: Now and in the Future
Mark W. Russo, MD, MPH, FACG
Professor of Medicine
Chief, Division of Hepatology
Medical Director, Liver Transplantation
Carolinas HealthCare System, Charlotte
Evolution of Therapy in HCV GT1Sofosbuvir/Ledipasvir
Paritaprevir/Ombitasvir/Dasabuvir/RBVSofosbuvir/Simeprevir
Elbasvir/grazoprevir/RBV
1990 2001 2011 20161999
2%
10%15%
25%
40%
60%
75%
100%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
IFN 6m IFN 12m IFN/RBV6m
IFN/RBV12m
PEG/RBV12m
PEG/R/PI 6-12m
PEG/R/PI 6-12m
All oral DAA12-24weeks
SV
R (
cure
)
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 1 of 26
Mark W. Russo, MD, MPH, FACG
NS3 /4A Inhibitors (Protease inhibitor PI)
-previr
High potency
Limited genotypic coverage
Low barrier to resistance
Paritaprevir, Simeprevir are approved
NS5A Inhibitors--asvir
High potency
Multi-genotypic coverage
Low barrier to resistance
Ledipasvir, ombitasvir, daclatasvir, velpatasvir
NS5B Nucleos(t)ide Inhibitors (NI)-buvir
Intermediate potency
Pan genotypic coverage
High barrier to resistance
Sofosbuvir is approved
NS5B Non Nucleoside Inhibitors (NNI)
Intermediate potency
Limited genotypic coverage
Low barrier to resistance
Dasabuvir is approved
Therapies are directed against non-structural genes of hepatitis C virus
Ribavirin is a non-specific nucleoside analog used in combination with other DAAs hepatitis C therapies
AASLD-IDSA Guidance Recommended RegimensRegimen- Genotype 1
Elbasvir/grazoprevir +/-ribavirin Recommended
Ledipasvir+sofosbuvir Recommended
Paritaprevir/r + dasabuvir+ombitasivr +/- ribavirin (PrOD) Recommended
Simeprevir + sofosbuvir +/- ribavirin Recommended
Velpatasvir+sofosbuvir Recommended
Daclatasvir+sofosbuvir Recommended
Simeprevir + peginterferon + ribavirin Not Recommended
Sofosbuvir + peginterferon + ribavirin Not Recommended
Sofosbuvir + ribavirin Not Recommended
Recommended Optimal treatment favored for most patients
Alternative Optimal in a particular subset of patients in a specific category
Not Recommended Treatment is clearly inferior or is deemed harmful. Unless otherwise indicated, such regimens should not be administered
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org.Accessed Nov 6, 2016.
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 2 of 26
Mark W. Russo, MD, MPH, FACG
Five Variables Determine HCV Treatment Choice
• HCV genotype
• Cirrhosis status
• Previous HCV treatment
• Resistance
• Renal function
Outline Recommendations
Genotype 1Genotype 1a and 1b Treatment naïveo Noncirrhotico Cirrhotic
Treatment experiencedo PegIFN+RBVo PegIFN+RBV+TVR or BOCo Sof+RBV+/-PegIFNo Sof+Ledipasvir
Special populations
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 3 of 26
Mark W. Russo, MD, MPH, FACG
Grazoprevir/Elbasvir
1. Summa V, et al. Antimicrobial Agent Chemother. 2012:56; 4161-67. Coburn CA, et al. ChemMedChem. 2013:8; 1930–40. Harper S, et al. ACS Med Chem Lett. 2012:Mar 2; 3(4):332-6.
• HCV NS3/4A inhibitor• 100 mg once daily, oral
Grazoprevir(MK-5172)
Elbasvir(MK-8742)
• HCV NS5A inhibitor• 50 mg once daily, oral
• Retains in vitro activity against many clinically relevant RAVs1-3
• All-oral, once-daily regimen
C-EDGE Treatment-Naive study of 12-weeks grazoprevir/elbasvir in patients with chronic HCV genotype 1, 4, or 6
Pat
ien
ts, %
All Patients
144/157 129/131299/316
92% 99%95%
GT1a GT1b GT4
100%
18/18
0%
25%
50%
75%
100%
GT6
80%
8/10
Non-virologicfailure
4 3 1 0 0
Breakthrough 1 1 0 0 0
Relapse 12 9 1 0 2
Zeuzem et al Annals of Internal Medicine 2015
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 4 of 26
Mark W. Russo, MD, MPH, FACG
C-EDGE: Final SVR24 Data With Elbasvir/Grazoprevir in Treatment-Naïve, HCV Genotypes 1, 4, or 6
• Overall SVR24 rate: 94%– Genotype 1a/1b: 93%/99%
• Lower SVR24 rates in genotype 1a with RAVs at positions 28, 30, 31, or 93
Zeuzem S, et al. J Hepatol. 2016;64(suppl 2):S821. Abstract SAT-266.
SVR24: Genotype 1a
0
20
40
60
80
100
Next Generation Sequencing*
PopulationSequencing
Prevalenceof RAVs (%): 25 12
SV
R24
(%
)
97%99%
75%
65%
No RAVs With RAVs
(n=149)(n=51) (n=178) (n=126)
Study DesignGT 1 Treatment-Naïve (ION-1)
with and without cirrhosis
• GT 1 HCV treatment-naïve patients in Europe and USA
• Broad inclusion criteria– Targeted 20% enrollment of patients with cirrhosis
– No upper age or BMI limit
– Platelet count ≥50,000/mm3, no neutrophil minimum
• 865 patients randomized 1:1:1:1 across four arms
• Stratified by HCV subtype (1a or 1b) and cirrhosis
Wk 0 Wk 12 Wk 36Wk 24
LDV/SOF SVR12
LDV/SOF + RBV
LDV/SOF
LDV/SOF + RBV
Afdhal et al. NEJM 2014;370:1889-98
Patient population
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 5 of 26
Mark W. Russo, MD, MPH, FACG
Error bars represent 95% confidence intervals.
Absence of Cirrhosis Cirrhosis
179/180 32/34 178/184 33/33 181/184 31/33 179/181 36/36
12 Weeks 24 Weeks
LDV/SOF + RBV LDV/SOF + RBVLDV/SOF LDV/SOF
SVR12: Absence of Cirrhosis vs CirrhosisGT 1 Treatment-Naïve (ION-1)
SV
R
GT 1 Treatment-Naïve (ION-3) : 8 weeks of therapy with SOD/LDV leads to high SVR rates in non-cirrhotic naïve viral
load<6 million patients
• GT 1 treatment-naïve patients without cirrhosis
• Broad inclusion criteria
– No upper age or BMI limit
– Opiate substitution therapy allowed
• 647 patients randomized 1:1:1 across three arms
• Stratified by HCV subtype (1a or 1b) 12
LDV/SOF
LDV/SOF
LDV/SOF + RBV
Wk 0 Wk 8 Wk 12 Wk 24Wk 20
SVR12
SVR12
SVR12
Kowdley KV et al. NEJM 2014; 370:1879-88
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 6 of 26
Mark W. Russo, MD, MPH, FACG
8 Wks 12 Wks
SOF/LDVSOF/LDV SOF/LDV + RBV
201/216202/215 206/216
P = .52
SV
R12
(%
)ION 3: SVR12 With 8 or 12 Wks SOF/LDV ± RBV in Tx-Naive Non-cirrhotic Patients
• SVR12 rates did not differ by GT1a vs GT1b in any treatment arm
• Virologic failure: 23 relapses (11 in 8-wk SOF/LDV, 9 in 8-wk SOF/LDV/RBV, 3 in 12-wk SOF/LDV)
100
80
60
40
20
0
94 93 95
P = .70 P = .30
Treatment DurationSOF/LDV
SVR (%) with Baseline HCV RNA <6 million IU/mL
8 wks 97 (119/123)
12 wks 96 (126/131)
Post hoc analysisnotes high SVR rates
in those with HCV RNA <6 x 106 IU/mL
Sofosbuvir+simeprevir+/- ribavirin for 12 or 8 weeks in treatment naive patients non cirrhotic: OPTIMIST-1
Kwo, et al. Hepatology 2016;64:370-380.
9783
95
77
0
20
40
60
80
100
12 8
TN TE
SVR12(%)
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 7 of 26
Mark W. Russo, MD, MPH, FACG
SAPPHIRE-I: PTV/OMB/DSB + RBV in HCV GT1
Treatment naive noncirrhotic
Paritaprevir/r (150/100 mg) co-formulated with ombitasvir (25 mg) and administered once daily. Dasabuvir (250 mg) + RBV (weight-based dosing) administered twice daily.*After week 12, placebo patients received open-label paritaprevir/r/ombitasvir + dasabuvir + RBV for 12 weeks.Primary outcome: SVR12.
Inclusion Criteria• HCV GT1• Treatment-naïve• No cirrhosis • No HIV or HBV
0 12 24
Paritaprevir/ritonavir/ombitasvir qd+Dasabuvir bid + RBV bid (n=473)
Week
Placebo*(n=158)
Paritaprevir/ritonavir/ombitasvir qd +Dasabuvir bid + RBV bid (n=158)
Double-Blind
Open-Label
Feld JJ, et al. N Engl J Med. 2014;370:1594-1603.
SAPPHIRE-I Results:ITT SVR12 Rates
Feld JJ, et al. N Engl J Med. 2014;370:1594-1603.
96% 95% 98%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Overall GT1a GT1b
SV
R12
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 8 of 26
Mark W. Russo, MD, MPH, FACG
Paritaprevir/ RTV Ombitasvir + Dasabuvir ± RBVin GT1 Patients Without Cirrhosis:
Is RBV Necessary? (PEARL III and PEARL IV)Wk 12 SVR12, %
PTV/RTV/OMB + DBV + placebo (n = 205)
PTV/RTV/OMB + DBV + RBV (n =100)
PEARL IIIDAA-naive pts with
GT1a HCV(N = 305)
Wk 24
PTV/RTV/OMB + DBV + placebo (n = 209
PTV/RTV/OMB + DBV + RBV (n = 210)PEARL IV
DAA-naive pts with
GT1b HCV(N =419)
9790
99.599
Ferenci P et al. N Engl J Med 2014;370:1983-1992.
ALLY-2: Overall Efficacy (SVR12)-Treatment naïve and experiencedDCV+SOF for 8-12 weeks HIV/HCV
N Engl J Med 2015;373:714-25.
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 9 of 26
Mark W. Russo, MD, MPH, FACG
0
20
40
60
80
100
97
76
98
Pat
ien
ts a
chie
vin
g S
VR
12, %
Naive 12 weeks Experienced 12 weeks Naive 8 weeks
98101
3850
5152
Naive 12 weeks
Experienced 12 weeks
Naive 8 weeks
ALLY-2: Overall Efficacy (SVR12)DCV+SOF for 8-12 weeks HIV/HCV
Results: SVR12 by GenotypeASTRAL-1, SOF/VEL
Previously treated, untreated, , cirrhotic, noncirrhotic
99 98 99 100 100 97 100
0
20
40
60
80
100
SV
R12
(%
)
618624
206210
117118
104104
116116
3435
4141
Error bars represent 95% confidence intervals. 20
Total 1a 1b 2 4 5 6
Genotype
1 relapse2 lost to follow-up1 withdrew consent
1 relapse 1 death
N Engl J Med 2015;373:2618-28.
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 10 of 26
Mark W. Russo, MD, MPH, FACG
HCV: Genotype 1A and 1B Treatment Naïve, Non-cirrhotic
Regimen Weeks Study SVR12
Sofosbuvir + ledipasvir(HCV RNA <6 M IU/mL)(HCV RNA >6 M IU/mL)
812
ION-3119/123 (97%)206/216 (95%)
Elbasivr/grazoprevir (1b)(-) -NS5A RAVs (1a)
12 C-EDGE 133/135 (99%) 129/131 (99%)
PrOD (1b) 12 PEARL III 207/209 (99.5%)
PrOD +/- ribavirin (1a) 12 PEARL IVSAPPHIRE-I
97/100 (97%)307/322 (95%)
Simeprevir + Sofosbuvir 12 COSMOSOPTIMIST-1
20/21 (95%)112/115 (97%)
Daclatasvir + Sofosbuvir 12 ALLY-2 (HIV Co-infected)
70/72 (97%)
Sofosbuvir+velpatasvir 12 ASTRAL 323/328 98%-99%
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 11/ 6/2016.NOT HEAD TO HEAD TRIALS
HCV: Genotype 1ATreatment Naïve, Compensated Cirrhotic
Regimen (recommended) Weeks Study SVR12
Sofosbuvir + ledipasvir 12 ION-1 32/33 (97%)
Elbasvir/grazoprevir1a (-) NS5A RAV (no RAVS)
12 C-EDGE 135/138 (98%)total
Sofosbuvir/Velpatasvir 12 ASTRAL 1 98%
AlternativePROD+ rbvSimeprevir+sofosbuvir+/-rbv(no Q80K)Elbasvir+grazoprevir+rbv if RAVS(treatment experienced*)
2424
16
TURQUOISE IIOPTIMIST-2
C-EDGE-TE
95%>84%?
100%*
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 11/ 6/2016
NOT HEAD TO HEAD TRIALS
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 11 of 26
Mark W. Russo, MD, MPH, FACG
HCV: Genotype 1BTreatment Naïve, Compensated Cirrhotic
Regimen Weeks Study SVR12Sofosbuvir + ledipasvir 12 ION-1 32/33 (97%)
PrOD (1b) 12 TURQUOISE III 27/27 (100%)
Elbasvir/grazoprevir 12 C-EDGE 100%
Sofosbuvir+velpatasvir 12 ASTRAL I 99%
AlternativeDaclatasvir+sofosbuvirSimeprevir+sofosbuvir+/-RBV
2424
ALLY-2 OPTIMIST-2
12/12 (100%)92%
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 11/ 6/2016
NOT HEAD TO HEAD TRIALS
Treatment Experienced
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 12 of 26
Mark W. Russo, MD, MPH, FACG
SAPPHIRE-II: GT1 Treatment-experienced noncirrhotic patients
PTV/OMB/DSB: co-formulated Paritaprevir/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir, 250 mg BID
RBV: 1000-1200 mg daily according to body weight (<75 kg and ≥75 kg, respectively)
Zeuzem S, et al. N Engl J Med. 2014;370:1604-1614.
Week 0 Week 12 Week 24 Week 60 Week 72
PTV/OMB/DSB + RBV
(n=297)
Placebo(n=97)
Double-BlindTreatment
PeriodOpen-LabelTreatment
Period
48-weekFollow-up
48-weekFollow-up
PTV/OMB/DSB + RBV
Primary Analysis: SVR12
SAPPHIRE-II Results: ITT SVR12 Rates in Treatment-experienced Patients
96% 96% 97% 95%100%
95%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Overall GT1a GT1b Prior relapse* Prior partialresponse*
Prior nullresponse*
SV
R12
* ITT SVR12 rates >95% in all prior peginterferon/ribavirin response groups
Zeuzem S, et al. N Engl J Med. 2014;370:1604-1614.
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 13 of 26
Mark W. Russo, MD, MPH, FACG
Paritaprevir/ RTV Ombitasvir + Dasabuvir + RBV in HCV
Genotype 1 Cirrhosis (TURQUOISE-II):
0 12 24
PTV/RTV/OMB + DBV BID +RBV BID (n=208)
Phase 3 Study
Paritaprevir/ RTV (150/100 mg) co-formulated with Ombitasvir (25 mg) and administered once-daily. Dasabuvir (250 mg) + RBV (weight-based dosing)
administered twice-daily.Primary outcome: SVR12.
• HCV genotype 1• Treatment-naïve and
treatment-experienced• Compensated cirrhosis
(Child-Pugh score <6)• HCV RNA >10K IU/mL• No HIV or HBV
Key eligibility criteria
Week
PTV/RTV/OMB + DBV BID +RBV BID (172)
Poordad F, et al al. N Engl J Med. 2014;370:1973-1982
124/140
Naive Relapse PartialResponse
NullResponse
Overall OverallPartialResponse
NullResponse
TURQUOISE II: 12 vs 24 WksOMV/PTV/RTV + DSV + RBV in
Cirrhotics
Poordad F, et al. EASL 2014. Abstract O163. Poordad F, et al al. N Engl J Med. 2014;370:1973-1982.
12 wks 24 wks100 100
Naive Relapse
100100
86
100 100100
Genotype 1b
SV
R12
(%
)
Genotype 1a
59/64
14/15
52/56
13/13
11/11
40/50
10/10
39/42
100
80
60
40
20
0
92 93 93100 100 100
80
93
22/22
14/14
18/18
10/10
6/7
25/25
3/3
20/20
115/121
8995 99 100
67/68
51/51
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 14 of 26
Mark W. Russo, MD, MPH, FACG
Feld JJ, et al. N Engl J Med. 2014;370:1594-1603.
GT 1 Treatment-Experienced (ION-2):Study Design
• GT 1 HCV patients who had failed prior IFN-based therapy, including regimens containing a NS3/4A protease inhibitor
• Broad inclusion criteria– Targeted 20% enrollment of patients with cirrhosis
– No upper age or BMI limit
– Platelet count ≥50,000/mm3, no neutrophil minimum
• 440 patients randomized 1:1:1:1 across four arms• Stratified by HCV subtype (1a or 1b), cirrhosis, prior treatment response
Wk 0 Wk 12 Wk 36Wk 24
LDV/SOF SVR12
LDV/SOF + RBV
LDV/SOF
LDV/SOF + RBV
SVR12
SVR12
SVR12
Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.
ION 2: SVR12 With 12 or 24 Wks of SOF/LDV ± RBV by Cirrhosis Status24 weeks duration for cirrhosis patients
• SVR12 rates were significantly lower in cirrhotic vs noncirrhotic patients in the pooled 12-wk arms
• Previous treatment with protease inhibitor or did not matter
Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.
No cirrhosis
Cirrhosis
83/87
19/22
89/89
18/22
86/87
22/22
88/89
22/22
12 Wks 24 Wks
LDV/SOF + RBV LDV/SOF + RBVLDV/SOF LDV/SOF
SV
R12
(%
)
100
80
60
40
20
0
95 86 10082
1009910099
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 15 of 26
Mark W. Russo, MD, MPH, FACG
92 94 92 97
0
20
40
60
80
100
1 2 3 4
SVR1
2 (%
, 95%
CI)
EFFICACY AND SAFETY OF GRAZOPREVIR / ELBASVIR +/-RBV FOR 12 or 16 WEEKS IN PATIENTS WITH HCV G1, G4 or G6
INFECTION WHO PREVIOUSLY FAILED PEGINTERFERON / RBV (C-EDGE treatment-experienced trial)
97105
103106
97105
98104
Breakthrough 0 0 1 0Rebound 0 0 2 0Relapse 6 6 4 0LTFU/Early DC* 2 0 1 3
No RBV +RBV
12 Weeks 16 Weeks
No RBV +RBV
* LTFU/Early DC = Lost to follow up / Early discontinuation due to reasons other than virologic failure Kwo, Gastro 2016
Sofosbuvir+simeprevir for 12 weeks in treatment naïve and experienced cirrhotic patients:OPTIMIST-2
Hepatology 2016;64:360-369
SVR12(%)
8879
74
0102030405060708090
100
Naïve experienced Q80K
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 16 of 26
Mark W. Russo, MD, MPH, FACG
• GT 1-6 treatment-naïve or treatment-experienced patientsa without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12weeks
Sofosbuvir-Velpatasivr for 12 weeks in genotype 1-6 previously treated and untreated, non cirrhotic and cirrhotic ASTRAL 1
• The dosing information listed here does not include patients with decompensated cirrhosis (Child-Pugh B or C)1
• EPCLUSA offers simple dosing as the first and only single-tablet regimen for HCV GT 2 and GT 3 patients1
SOF/VELDAILY
Results: SVR12 by GenotypeASTRAL-1, SOF/VEL
99 98 99 100 100 97 100
0
20
40
60
80
100
SV
R12
(%
)
618624
206210
117118
104104
116116
3435
4141
Error bars represent 95% confidence intervals. 34
Total 1a 1b 2 4 5 6
Genotype
1 relapse2 lost to follow-up1 withdrew consent
1 relapse 1 death
N Engl J Med 2015;373:2599-607.
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 17 of 26
Mark W. Russo, MD, MPH, FACG
SIRIUS: Ledipasvir + Sofosbuvir in Compensated Cirrhosis after Failure of PEG+RBV+PI
12 Weeks Alone Versus 24 Weeks With RBV
LDV + SOF + RBV
Genotype 1Treatment-experienced: Did not achieve SVR after sequential PR and PR + protease inhibitor therapy
LDV + SOF
SVR12
SVR12
Weeks
Placebo
96 97
0
20
40
60
80
100
LDP + SOF +RBV12 Weeks
LDP + SOF24 Weeks
SV
R12
, % P
atie
nts
7477
7577
3 relapses 2 relapses
0 12 24 48
Lancet Infect Dis. 2015 Apr;15(4):397-404
Sofosbuvir+Ledipasvir+RBV in decompensated genotype 1 cirrhosis
(SOLAR-1)
0
20
40
60
80
100
Child B Child C
12 wk 24 wk
SVR 12 (%)
Gastroenterol 2015;149:649-659.
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 18 of 26
Mark W. Russo, MD, MPH, FACG
HCV: Genotype 1A/1BTreatment Experienced (PEG-RBV), Non-cirrhotic
Regimen Weeks Study SVR12
Sofosbuvir + ledipasvir 12ION-2 98%
PrOD (1b)12 PEARL II
SAPPHIRE-II (+RBV)
91/91(100%)119/123 (97%)
PrOD + ribavirin (1a) 12 SAPPHIRE-II 166/173 (96%)
Simeprevir + Sofosbuvir 12 COSMOSOPTIMIST-1
20/21 (95%)38/40 (95%)
Daclatasvir + Sofosbuvir 12 ALLY-2 28/28 (100%)
Elbasvir + grazoprevir1B and 1A (RAV-)
12 C-EDGE94-97%
Sofosbuvir+velpatasvir 12 ASTRAL-196-100%
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 11/ 6/2016.
NOT HEAD TO HEAD TRIALS
HCV: Genotype 1A/1BTreatment Experienced (PI+PEG-RBV), Non-
cirrhotic
Regimen Weeks Study SVR12
Sofosbuvir + ledipasvir 12ION-2 83/87 (95%)
Daclatasvir+Sofosbuvir 12 ALLY-2 98%
Elbasvir+grazoprevir1B and 1A (RAV-)
12 C-EDGE96%
Sofosbuvir+velpatasvir 12 ASTRAL-1100%
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 11/6/2016.
NOT HEAD TO HEAD TRIALS
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 19 of 26
Mark W. Russo, MD, MPH, FACG
HCV: Genotype 1ATreatment Experienced (PEG/RBV)
Compensated CirrhoticRegimen Weeks Study SVR12
Sofosbuvir + ledipasvir+RBV 12 ION-2SOLAR-I 96-100%
Elbasvir+grazoprevir1A (and No NS5A RAV-)M28, Q30, L31, H58, Y93
12 C-EDGE95%
Sofosbuvir+velpatasvir 12 ASTRAL 198%
Alternative regimensPROD+RBV 24 weeksSofosbuvi+ledipasvir for 24 weeksElbasvir+grazoprevir+rbv for 16 weeks with NS5A RAVSDaclatasvir+sofosbuvir +/- RBV fro 24 weeksSimeprevir+sofosbuvir +/-RBV for 24 weeks (no Q80K)
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 11/6/2016.NOT HEAD TO HEAD TRIALS
Regimen Weeks Study SVR12Sofosbuvir + ledipasvir+RBV
12ION-2
SOLAR-I 22/22 (100%)74/77 (96%)
PrOD 12 TURQUOISE-III 33/33 (100%)
Elbasvir+grazoprevir 12 C-EDGE 89% (33/37) Total
Sofosbuvir + Velpatasvir 12 ASTRAL 1 98%
AlternativeDaclatasvir + sofosbuvir +/- RBV for 24 weeksSimeprevir+sofosbuvir+/-RBV for 24 weeksSofosbuvir+Ledipasvir for 24 weeks
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 11/6/2016.
NOT HEAD TO HEAD TRIALS
HCV: Genotype 1BTreatment Experienced (PEG/RBV), Compensated
Cirrhotic
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
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Mark W. Russo, MD, MPH, FACG
HCV: Genotype 1A/1BTreatment Experienced (PI+PEG-RBV) Compensated-cirrhosis
Regimen Weeks Study SVR12
Sofosbuvir + ledipasvir + RBV 12SIRUS 96%
Sofosbuvir + ledipasvir 24 ION-2 94-98%
Daclatasvir + Sofosbuvir+/-RBV
24 ALLY-298%
Elbasvir + grazoprevir + RBV1B and 1A (RAV-)
12 C-EDGE94%
Elbasvir + grazoprevir + RBV1A + RAV
16 C-EDGE
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 11/6/2016.
NOT HEAD TO HEAD TRIALS
LDV/SOF + RBV in Treatment-Experienced Sofosbuvir exposed GT 1
HCV
Wyles, AASLD, 2014, Oral #235
98 100 98
0
20
40
60
80
100
Wk 4 EOT SVR12
51/51
HC
V R
NA
<L
LO
Q,
%
50/51
Error bars represent 95% CIs.EOT, end of treatment.
50/51
*One patient who relapsed had GT 3a infection
*
LDV/SOF+RBV for 12 weeks achieved 100% SVR in GT 1 patients who failed prior SOF-based therapy
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 21 of 26
Mark W. Russo, MD, MPH, FACG
HCV: Genotype 1Treatment Experienced (SOF+RBV, +/-PEG)
Regimen Weeks SVR12
No-Cirrhosis
Sofosbuvir + ledipasvir+RBV 12 50/50 (100%)
Cirrhosis
Sofosbuvir + ledipasvir+RBV 24 95-98%
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 11/6/2016.
HCV: Genotype 1Treatment Experienced: SMV+SOF or NS5A
Experienced
No Cirrhosis
Deferral of treatment is recommended, pending availability of data for patients with HCV genotype 1, regardless of subtype
Cirrhosis
Testing for resistance-associated variants NS3 PI and NS5A inhibitors is recommended for patients with HCV genotype 1, regardless of subtype.The specific drugs used in the retreatment regimen should be tailored based on the results,
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 11/6/2016.
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 22 of 26
Mark W. Russo, MD, MPH, FACG
Drug InteractionsHCV regimen PPI recommendation for product insert
Dasabuvir+ombitasvir+paritaprevir-ritonavir
Avoid use of more than 40 mg/domeprazole
Elbasvir+grazoprevirdaclatasvir
No interaction
Ledipasvir+sofosbuvir 20 mg or lower, simultaneously, fasting
Velpatasivr+sofosbuvir Not recommended, if medically necessary with food, 4 hrs apart <20 mg omeprazole
Some other interactions: Antiepileptics, amiodarone, cyclosporine, tacrolimus, anti-retrovirals, tenofovir, statins
DAA’s and potential risks
Increase risk HCC, recurrence
Reactivation ofhepatitis B
Reactivation of herpes
J Hepatol 2016;65:727-33.GI&Hepatology News November 2016 p. 12, 33.
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
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Mark W. Russo, MD, MPH, FACG
SVR Decreases but Does Not Eliminate Risk for Liver Related Complications in those with hepatitis C
Van der Meer, et al. JAMA 2012:308:2584-2593.
2017 and beyond
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
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Mark W. Russo, MD, MPH, FACG
Regimens in development
AASLD 2016
Regimen Population SVR 12
Glecaprevir/PibrentasvirENDURANCE (8 vs 12 wk),MAGELLAN (DAA fail), EXPEDITION (renal fail)
Noncirrhotic,coinfected12 vs 16 weeksGFR<30, 12 weeks
99%-100%Pending99% SVR 4
Sof/Vel/VoxPOLARIS 1 NS5A exp.POLARIS 2, naïve 8 wks
NS5A experienced,12 wksNaïve, 8 vs 12 wks
96-97%92%-99%(1a 8wk 92%)
MK-3682/Grazoprevir/Ruzasvir+/-RbvC-Crest, 8 wks, 12 wks, 16 wks
Naïve, P/R experiencedWith/without cirrhosis
95-100% (1a 8wks-95%)
C-SURGE (DAA failure) 24 wks SOF/LDV, EBR/GZR 100% SVR8
NS5A DAA
failure
No NS5A RAVS
SOF/LDV + RBV
24 weeks
No Q80K(or other PI
RAVs)
SOF + SMV + RBV
24 weeks
+ NS5A RAVs(Q30, L31, H58, Y93)
SOF + SMV + RBV
24 weeks(even if Q80K)
+NS5A RAVs
+ NS3 RAVs(R155, A156, D168)
Desperation time
3D + SOF (SOF + SMV + DCV + RBV
SOF/LDV + RBV
Defer therapy if mild disease or Investigational
Regimens
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
Page 25 of 26
Mark W. Russo, MD, MPH, FACG
Summary
Several options with high efficacy and well tolerated No one left behind, few if any exclusions Aware of drug interactions Continue to screen cirrhotics with virologic cure for HCC For the DAA experienced patient or resistance- data are
emerging so wait, or sim/sof/rbv, sof/elbasvir/grazoprevir/rbv
ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology
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