Best Practices in the Management of HCV. 2015

Andrew J. Muir, MDChief, Division of GastroenterologyAssociate Professor of MedicineDepartment of MedicineDirector, Gastroenterology/Hepatology ResearchDuke Clinical Research InstituteDuke University School of MedicineDurham, North Carolina

Best Practices in the Management of HCV in 2015

Supported by educational grants from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, Merck, and ViiV.

clinicaloptions.com25th Annual CCO HIV and Hepatitis C Symposium

Disclosures

Andrew J. Muir, MD, has disclosed that he has received funds for research support from AbbVie, Achillion, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hologic, Intercept, Janssen, Merck, NGM Biopharm, and Roche and consulting fees from AbbVie, Achillion, Bristol-Myers Squibb, Gilead Sciences, Intercept, Janssen, Lumena, Merck, Regulus Therapeutics, Salix, and Theravance.


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Aims The rationale for HCV treatment

Treatment of genotypes 1-4

Future directions


AASLD/IDSA: When and in Whom to Initiate HCV Therapy ALL pts are candidates for HCV therapy, regardless of disease stage In regions where limited resources preclude treatment of all pts, the following

groups should be prioritized for therapy: – Highest Priority (based on highest risk for disease complications)

– Advanced fibrosis (F3) or compensated cirrhosis (F4)

– Organ transplant

– Type 2 or 3 essential mixed cryoglobulinemia with end-organ manifestations

– Proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritis

– High Priority (based on high risk for disease complications) – HIV-1 coinfection

– Fibrosis (Metavir F2)

– HBV coinfection

– Debilitating fatigue

AASLD/IDSA. HCV Management. http://www.hcvguidelines.org.

– Other coexistent liver disease (eg, NASH)

– Type 2 DM (insulin resistant)

– Porphyria cutanea tarda


1. van der Meer AJ, et al. JAMA. 2012;308:2584-2593. 2. van der Meer AJ. Expert Rev Gastroenterol Hepatol. 2015;9:559-566. 3. Younossi Z, et al. Clin Gastroenterol Hepatol. 2014;12:1349-1359.

HCV Treatment Improves Health Advanced fibrosis

– Multicenter study[1]

– 5 hospitals (Europe, Canada)

– 530 pts with HCV

– IFN regimens 1990-2003

– Advanced fibrosis or cirrhosis

– Median follow-up: 8.4 yrs

Early-stage disease

– Extra-hepatic manifestations[2]

– Health-related quality of life[3]

30

20

10

All cause mortality

Liver-related mortality or transplant

HCC

10-Yr Cumulative Incidence[1]

0

26

8.9

1.9

27.4

5.1

21.8

SVR No SVR

Perc

ent


Health Outcomes With DAA Treatment in Genotype 1 HCV Infection TURQUOISE-II: OBV/PTV/RTV + DSV + RBV for 12 or 24 wks in pts with

GT1 HCV and cirrhosis

– Post hoc analysis, SVR12 associated with improved noninvasive fibrosis estimates, AFP levels, and surrogate markers of liver function 48 wks after treatment [1]

Modeling outcomes with DAA regimens

– OBV/PTV/RTV + DSV ± RBV (vs no treatment) associated with reduced liver morbidity over lifetime horizon regardless of baseline fibrosis score (Markov model)[2]

– LDV/SOF associated with lowest incidence of disease progression (including decompensation, HCC, liver transplantation, death) vs comparator regimens* (decision-analytic Markov model)[3]

1. Wedemeyer H, et al. EASL 2015. Abstract P0808. 2. Johnson SJ, et al. EASL 2015. Abstract P0850. 3. Younossi ZM, et al. AASLD 2014. Abstract 1754.

*Comparator regimens: SOF + PR; SMV + PR; SMV + SOF; SMV + SOF + RBV; SOF + RBV; BOC + PR; No treatment


Benefits of Early vs Delayed Treatment Retrospective analysis of pts with HCV infection in VA Clinical Case

Registry[1]

– Early vs delayed treatment associated with reduced risk of liver-related events and death

– Risk of delaying treatment increases as disease severity increases, due to diminished likelihood of achieving SVR

Markov disease utility state-transition modeling of OBV/PTV/RTV + DSV ± RBV therapy in genotype 1 HCV infection[2]

– Treatment prolongs survival and quality of life vs watchful waiting

– Treatment-related survival benefits of previously treated pts 1% to 6% lower than treatment-naive pts

1. McCombs J, et al. EASL 2015. Abstract O003. 2. Johnson S, et al. EASL 2015. Abstract P0806.


Sofosbuvir + ribavirin ± pegIFN

Ledipasvir/ sofosbuvir

Simeprevir + sofosbuvir

Ombitasvir/paritaprevir/ritonavir + dasabuvir

2015 Agents

Sofosbuvir + daclatasvir


Genotype 1 HCV Agents

Protease Inhibitors

Polymerase InhibitorsNS5A

Inhibitors OtherNucleotide Nonnucleoside

Simeprevir Sofosbuvir Ledipasvir RibavirinParitaprevir/

ritonavir Dasabuvir Ombitasvir

Daclatasvir

www.hcvguidelines.org


Key Data for HCV decisions HCV treatment history

– Interferon and ribavirin regimen?

– Protease inhibitor? Sofosbuvir?

Fibrosis stage?

– Options for fibrosis assessment

– If cirrhosis, is it decompensated?

Child Pugh B or C?

Transplant evaluation?

http://www.hcvguidelines.org


Genotype 1 HCV: FDA-Approved RegimensRegimen Approval for Genotype 1Simeprevir + peginterferon + ribavirin* 24-48 wks

Sofosbuvir + peginterferon + ribavirin 12 wks

Sofosbuvir + ribavirin Interferon ineligible, 24 wks; HCC awaiting transplant, up to 48 wks

Ledipasvir/sofosbuvir 8-24 wks

Ombitasvir/paritaprevir/ritonavir, dasabuvir, ± ribavirin 12-24 wks

Simeprevir + sofosbuvir 12-24 wks

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/

*Screening pts with genotype 1a HCV infection for NS3 Q80K polymorphism strongly recommended and alternative therapy should be considered if Q80K detected.


Genotype 1 HCV: AASLD/IDSA-Recommended RegimensRegimen Genotype 1 Regimen FeaturesSimeprevir + peginterferon + ribavirin

Not recommended QD-QWK; multiple tablets + injection

Sofosbuvir + peginterferon + ribavirin Not recommended QD-QWK; multiple tablets +

injection

Sofosbuvir + ribavirin Not recommended QD; multiple tablets

Ledipasvir/sofosbuvir Recommended QD; single-tablet regimen

Ombitasvir/paritaprevir/ritonavir, dasabuvir, ± ribavirin Recommended QD-BID; multiple tablets

Simeprevir + sofosbuvir ± ribavirin Recommended QD; multiple tablets



Genotype 1 HCV Treatment Naive AASLD-IDSA guidelines

– 3 regimens recommended

Ledipasvir/ Sofosbuvir*

Ombitasvir/ Paritaprevir/ Ritonavir +

Dasabuvir

Simeprevir + Sofosbuvir

Genotype 1a, no cirrhosis 12 wks 12 wks + RBV 12 wks ± RBV

Genotype 1a, cirrhosis 12 wks 24 wks + RBV 24 wks ± RBV

Genotype 1b, no cirrhosis 12 wks 12 wks 12 wks

Genotype 1b, cirrhosis 12 wks 12 wks + RBV 24 wks


*Ledipasvir/sofosbuvir for 8 wks can be considered in naive, noncirrhotic pts with baseline HCV RNA < 6 million IU/mL.


Genotype 1 HCV Treatment Naive NoncirrhoticRegimen Wks Study SVRLedipasvir/sofosbuvir (HCV RNA < 6 M IU/mL) 8 ION-3[1,2] 119/123 (97%)

Ledipasvir/sofosbuvir 12 ION-3[1] 206/216 (95%)

Simeprevir + sofosbuvir* 8-12 OPTIMIST-1[3] 8 wks: 128/155 (83%)12 wks: 150/155 (97%)

Ombitasvir/paritaprevir/ritonavir, dasabuvir (GT1b) 12 PEARL III[4] 207/209 (99%)

Ombitasvir/paritaprevir/ritonavir, dasabuvir, ribavirin (GT1a) 12 PEARL IV[4] 97/100 (97%)

Sofosbuvir + daclatasvir 12 AI444040[5] 41/41 (100%)

1. Kowdley K, et al. N Engl J Med. 2014;370:1879-1888. 2. Ledipasvir/sofosbuvir [package insert]. 3. Kwo PY, et al. EASL 2015. Abstract LP14. 4. Ferenci P, et al. N Engl J Med. 2014;370:1983-1992. 5. Sulkowski M, et al. N Engl J Med. 2014;370:211-221.

*GT1a + Q80K-8 wks: 36/49 (73%); GT1a + Q80K-12 wks: 44/46 (96%).


Genotype 1 HCV PegIFN/RBV Treatment Experienced AASLD-IDSA guidelines

– 3 regimens recommended

Ledipasvir/ Sofosbuvir

Ombitasvir/ Paritaprevir/ Ritonavir + Dasabuvir

Simeprevir + Sofosbuvir

Genotype 1a, no cirrhosis 12 wks 12 wks + RBV 12 wks ± RBV

Genotype 1a, cirrhosis 24 wks12 wks + RBV

24 wks + RBV 24 wks ± RBV

Genotype 1b, no cirrhosis 12 wks 12 wks 12 wks ± RBV

Genotype 1b, cirrhosis 24 wks12 wks + RBV

12 wks + RBV 24 wks ± RBV



Genotype 1 HCV Previous PI Failure AASLD-IDSA guidelines

– 1 regimen recommended

Ledipasvir/ Sofosbuvir

Ombitasvir/ Paritaprevir/ Ritonavir + Dasabuvir

Simeprevir + Sofosbuvir ±

Ribavirin

Genotype 1a, no cirrhosis 12 wks None None

Genotype 1a, cirrhosis 24 wks12 wks + RBV

None None

Genotype 1b, no cirrhosis 12 wks None None

Genotype 1b, cirrhosis 24 wks12 wks + RBV

None None



Genotype 1 HCV Previous PI Failure

Regimen Cirrhosis Wks Study SVR

Ledipasvir/sofosbuvir No 12 ION-2[1] 50/52 (96%)

Ledipasvir/sofosbuvir Yes 24 ION-2[1] 14/14 (100%)Ledipasvir/sofosbuvir Yes 24 SIRIUS[2] 75/77 (97%)Ledipasvir/sofosbuvir, ribavirin Yes 12 SIRIUS[2] 74/77 (96%)Sofosbuvir + daclatasvir Mix 24 AI444040[3] 21/21 (100%)

Sofosbuvir, daclatasvir, ribavirin Mix 24 AI444040[3] 19/20 (95%)

1. Afdhal N, et al. N Engl J Med. 2014;370:1483-1493. 2. Bourlière M, et al. Lancet Infect Dis. 2015;15:397-404. 3. Sulkowski M, et al. N Engl J Med. 2014;370:211-221.


TURQUOISE II: OBV/PTV/RTV + DSV + RBV in Cirrhotic Pts With GT1 HCV Pts (N = 380):

– Treatment-naive and experienced pts

– All compensated cirrhosis

Design

– Open-label phase III

Regimen

– Paritaprevir/ritonavir, dasabuvir, ombitasvir, ribavirin

– Duration: 12 vs 24 wks

Safety Outcome

12 Wks(n = 208)

24 Wks(n = 172)

SAE, n (%) 13 (6.2) 8 (4.7)AE leading to d/c, n (%)

4 (1.9) 4 (2.3)

Fatigue, % 32.7 46.5Headache, % 27.9 30.8

Poordad F, et al. N Engl J Med. 2014;370:1973-1982.


SIRIUS: LDV/SOF in Pts With GT1 HCV and Previous PegIFN/RBV ± PI Failure Pts:

– Treatment-experienced, failure of both pegIFN/RBV and PI + pegIFN/RBV regimens

– Compensated cirrhosis

Design

– Randomized, double-blinded

Regimens

– Placebo 12 weeks followed by LDV/SOF + RBV for 12 wks

– LDV/SOF + Placebo for 24 wks

2 AEs higher with LDV/SOF vs placebo during first 12 wks

– Headache: 35% vs 21%

– Fatigue: 17% vs 4%

7577

Safety Outcome, %

Placebo 12 wks Then LDV/SOF +

RBV 12 wks(n = 78)

LDV/SOF 24 wks(n = 77)

SAE 5 10

AE leading to d/c

1 0

Headache 27 40

Fatigue 9 19

Bourlière M, et al. Lancet Infect Dis. 2015;15:397-404.


http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205834s001lbl.pdf. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205123s008lbl.pdf.

Update to sofosbuvir and ledipasvir/sofosbuvir US package inserts

Update to simeprevir US package insert

LDV/SOF.

simeprevir.


LDV/SOF + RBV in Pts With Genotype 1 HCV and Previous Sofosbuvir Failure Pts

– GT1 treatment-experienced pts who experienced failure of prior SOF regimens (n = 51)

– SOF + pegIFN/RBV: 49%

– SOF + RBV: 39%

– SOF placebo + pegIFN/RBV: 10%

– GS-0938 monotherapy: 2%

– 16% black

– 59% GT1a

– 27% cirrhosis

Design– Open-label cohort

Regimen– Ledipasivr/sofosbuvir + RBV for 12 wks

1 pt relapsed: genotype 3a

Wyles D, et al. Hepatology. 2015;[Epub ahead of print]. Wyles DL, et al. AASLD 2014. Abstract 235.

Prior Regimen SVR12, n/N (%)PegIFN/RBV/SOF 25/25 (100)

SOF/RBV 19/20 (95)


Genotypes 2 and 3 AASLD-IDSA guidelines

Genotype 2 Sofosbuvir + Ribavirin Peginterferon-α, Ribavirin + Sofosbuvir

Treatment naive 12 wks(16 wks for cirrhosis)

None

PegIFN/RBV nonresponders 12-16 wks 12 wks (alternative)


Genotype 3 Sofosbuvir + Ribavirin Peginterferon-α, Ribavirin + Sofosbuvir

Treatment naive 24 wks 12 wks (alternative)

PegIFN/RBV nonresponders 24 wks 12 wks (alternative)


Treatment Naive Treatment Experienced

BOSON: SVR12 With SOF-Based Regimens in GT3 by Tx History and Cirrhosis Status

Foster GR, et al. EASL 2015. Abstract LO5.

58/70

65/72

68/71

12/21

18/22

21/23

26/34

17/36

30/35

44/54

49/52

41/54

No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis

8390 96

57

82 91

7682

94

47

7786100

80

60

40

20

0

SVR

12 (%

)

SOF + RBV 16 wks SOF + RBV 24 wks SOF + PegIFN/RBV 12 wks

n/N =


Sofosbuvir + PegIFN/RBV or RBV in Pts With GT3 HCV and Previous SOF Failure Pts

– SOF + RBV treatment failures from FISSION, POSITRON, FUSION

– Cirrhosis included

Design

– Open-label cohorts

– Pt/investigator selected regimen

Regimen

– Sofosbuvir + ribavirin for 24 wks

– PegIFN/RBV + sofosbuvir for 12 wks

Esteban R, et al. EASL 2014. Abstract O8.

n/N =

100

80

60

40

20

0

91

63

20/22

24/38

SVR

12 (%

)

SOF + PegIFN/ RBV

SOF + RBV


0

LDV/SOF + RBV in Treatment-Experienced Pts With Genotype 3 HCV Ledipasvir/sofosbuvir?

– No data in sofosbuvir failure

Pts:

– Treatment naive and experienced

– With and without cirrhosis

Design

– Open-label cohorts

Regimen

– Ledipasvir/sofosbuvir + RBV for 12 wks

Gane E, et al. EASL 2014. Abstract O6. Gane E, et al. AASLD 2014. Abstract LB-11.

n/N =

100

80

60

40

20

Naive No Cirrhosis

Cirrhosis

10089

73

26/26

25/28

16/22

SVR

12 (%

)


Daclastavir + Sofosbuvir in Tx-Naive and Tx-Exp’d Pts With Genotype 3 HCV

ALLY-3[1]

Pts:

– Treatment naive and experienced

– Prior sofosbuvir and alisporivir included

– Prior NS5A inhibitors excluded

– Cirrhosis: 21%

Design

– 2 open-label cohorts

– Phase III

Regimen

– Daclatasvir + sofosbuvir once daily for 12 wks

EASL recommendations for DCV + SOF in GT3[2]

– No cirrhosis: DCV + SOF for 12 wks

– Compensated cirrhosis: DCV + SOF + RBV for 24 wks

1. Nelson DR, et al. Hepatology. 2015;61:1127-1135. 2. EASL HCV Guidelines. April 2015.

7375

3234

No Cirrhosis Cirrhosis

SVR

12 (%

)

Naive Experienced

97

58

94

69

0

100

80

60

40

20


Genotype 4 HCV Treatment Experienced

Regimen Wks FDA Approved AASLD/IDSA Study SVR12

Sofosbuvir + pegIFN/RBV 12 Yes Recommended NEUTRINO[1] 27/28*

(96%)

Sofosbuvir + ribavirin 24 No Recommended Ruane et al2] 13/15 (87%)

Ledipasvir/sofosbuvir 12 No Recommended Multiple[3,4]19/20†[3]; 20/22[4]

(91-95%)

Ombitasvir/paritaprevir/ritonavir, ribavirin

12 No Recommended PEARL-I[5] 49/49(100%)

1. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. 2. Ruane PJ, et al. J Hepatol. 2015;62:1040-1046. 3. Kapoor R, et al. AASLD 2014. Abstract 240. 4. Abergel A, et al. EASL 2015. Abstract O056. 5. Hézode C, et al. Lancet. 2015;[Epub ahead of print].

*Study included treatment-naive pts only.†Treatment-naive and treatment-experienced pts.


Genotype 5/6 HCV Treatment Naive AASLD-IDSA guidelines

Recommended Regimen Duration

Genotype 5 Sofosbuvir + ribavirin + peginterferon 12 wks

Genotype 6 Ledipasvir/sofosbuvir 12 wks

Alternative Regimen DurationGenotype 5 Peginterferon + ribavirin 48 wks

Genotype 6 Sofosbuvir + ribavirin + peginterferon 12 wks



Sofosbuvir + ribavirin

Sofosbuvir + ledipasvir

Simeprevir + sofosbuvir

Paritaprevir/ritonavir +

dasabuvir + ombitasvir

Sofosbuvir + GS-5816


Grazoprevir +elbasvir

Daclatasvir + asunaprevir +

beclabuvir


Future HCV Treatment: Shorter Duration With Triple-Drug Regimens Pts

– Treatment naive, genotype 1 (N = 60)

Design

– Single-center, open-label, phase IIA trial

Regimens

– 12 wks of SOF + LDV

– 6 wks of SOF, LDV, GS-9669

– 6 wks of SOF, LDV, GS-9451

Kohli A, et al. Lancet. 2015;385:1107-1113.

20/20 19/20 19/20n/N =

SOF + LDV

20/20 19/20 19/20

10095 95100

80

60

40

20

0

SVR

12 (%

)

SOF + LDV + GS-9669

SOF + LDV + GS-9451

12 wks 6 wks 6 wks


Tx Naive, No Cirrhosis

Txt Naive, Cirrhosis

Txt Exp’d, +/- Cirrhosis

Tx Naive, No Cirrhosis

Short-Duration Sofosbuvir/GS-5816 + GS-9857: Efficacy Results

All pts who did not achieve SVR12 relapsed

SVR12 rates for treatment-experienced pts: no cirrhosis, 68% (17/25 pts); cirrhosis, 60% (3/5 pts)

Gane EJ, et al. EASL 2015. Abstract LP03.

6 Wks

100

80

60

40

20

0

SVR

12 (%

)

93 87

67

14/15 13/15 20/30n/N =

4 Wks

27

4/15


UNITY-1: Efficacy of 12-Wk DCV/ASV/BCV in Noncirrhotic GT1 by Treatment Experience

Treatment-Naive Pts Treatment-Experienced Pts

100

80

60

40

20

0

SVR

12 (%

)

All GT1a GT1b

92 9098

287/312

206/229

81/83

All GT1a GT1b

92/103

64/75

28/28

89 85100

Poordad F, et al. JAMA. 2015;313:1728-1735.

n/N =


C-SWIFT: Short-Duration GZR/EBV + SOF in GT1 or 3 HCV Infection Pts: treatment-naive, genotype 1 (n = 102) or genotype 3 (n = 41) Design: multicenter, open-label, phase II trial Regimen: grazoprevir/elbasvir FDC + sofosbuvir

– GT1 noncirrhotic: 4 vs 6 wks; cirrhotic: 6 vs 8 wks

– GT3 noncirrhotic: 8 vs 12 wks; cirrhotic: 12 wks

Poordad F, et al. EASL 2015. Abstract O006.

SVR

12 (%

)

100

80

60

40

20

04 Wks 6 Wks 6 Wks 8 Wks 8 Wks 12 Wks 12 Wks

Genotype 1 Genotype 3

33

26/30

16/20

17/18

14/15

14/14

10/11*

87 8094 93 100 91

10/30*

*Excluded pts who discontinued due to reasons other than virologic failure.

NoncirrhoticCirrhotic

n/N =


C-EDGE: Grazoprevir/Elbasvir for Tx-Naive and Tx-Experienced Pts

1. Zeuzem Z, et al. EASL 2015. Abstract G07. 2. Kwo P, et al. EASL 2015. Abstract P0886.

Tx-Naive: Grazoprevir/Elbasvir for 12 Wks in GT1, 4, or 6 HCV[1]

SVR

12 (%

)

All Pts GT1a GT1b GT4 GT6

95 92 99 10080

299/316

144/157

129/131

18/18

8/10n/N =

100

80

60

40

20

0

Tx-Exp’d: Grazoprevir/Elbasvir ± RBV for 12 or 16 Wks in GT1, 4, or 6 HCV[2]

0

100

80

60

40

20

GZR/ EBV

GZR/EBV + RBV

GZR/EBV + RBV

GZR/EBV

92

97/105

98/104

97/105

103/106

94 9792

12 Wks 16 Wks


Sofosbuvir + ribavirin

Sofosbuvir + ledipasvir Simeprevir +

sofosbuvir

Paritaprevir/ritonavir +

dasabuvir + ombitasvir

Sofosbuvir + GS-5816


Grazoprevir +elbasvir

Daclatasvir + asunaprevir +

beclabuvir

Many other DAA combinations currently under investigation

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Best Practices in the Management of HCV. 2015

Health & Medicine