HCV – Treatment of Genotype 1: Now and in the Futures3.gi.org/meetings/na2016/16ACG_Hep_School_Southern_0005.pdfHCV – Treatment of Genotype 1: Now and in the Future Mark W. Russo,

Mark W. Russo, MD, MPH, FACG

HCV – Treatment of Genotype 1: Now and in the Future


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


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


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


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.


Page 2 of 26


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


Page 3 of 26


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


Page 4 of 26


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


Page 5 of 26


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


– 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


Page 6 of 26


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(%)


Page 7 of 26


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


96% 95% 98%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Overall GT1a GT1b

SV

R12


Page 8 of 26


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.


Page 9 of 26


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.


Page 10 of 26


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


Page 11 of 26


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


Treatment Experienced


Page 12 of 26


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.


Page 13 of 26


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


Page 14 of 26



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


– 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


Page 15 of 26


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


Page 16 of 26


• 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.


Page 17 of 26


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.


Page 18 of 26


HCV: Genotype 1A/1BTreatment Experienced (PEG-RBV), Non-cirrhotic


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.


HCV: Genotype 1A/1BTreatment Experienced (PI+PEG-RBV), Non-

cirrhotic


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.



Page 19 of 26


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



HCV: Genotype 1BTreatment Experienced (PEG/RBV), Compensated

Cirrhotic


Page 20 of 26


HCV: Genotype 1A/1BTreatment Experienced (PI+PEG-RBV) Compensated-cirrhosis


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



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


Page 21 of 26


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%


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,



Page 22 of 26


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.


Page 23 of 26


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


Page 24 of 26


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


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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


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Documents

HCV – Treatment of Genotype 1: Now and in the Futures3.gi.org/meetings/na2016/16ACG_Hep_School_Southern_0005.pdfHCV – Treatment of Genotype 1: Now and in the Future Mark W. Russo,