WHAT’S NEW IN HCV TREATMENT · WHAT’S NEW IN HCV TREATMENT HIV Clinical Grand Rounds AMC Peter...

1

WHAT’S NEW IN HCV TREATMENT

HIV Clinical Grand Rounds

AMC

Peter F Ells MD

clinicaloptions.com/hepatitis

Evolving HCV Management in Harder-to-Treat Populations

Sofosbuvir +

ribavirin ±

pegIFN

Ledipasvir/

sofosbuvir

Simeprevir +

sofosbuvir

Ombitasvir/

paritaprevir/

ritonavir +

dasabuvir

2015

Agents

Sofosbuvir +

daclatasvir

2



Genotype 1 HCV Agents

Protease

Inhibitors

Polymerase Inhibitors NS5A

Inhibitors Other

Nucleotide Nonnucleoside

Simeprevir Sofosbuvir Ledipasvir Ribavirin

Paritaprevir/

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

3



Genotype 1 HCV: FDA-Approved

Regimens

Regimen Approval for Genotype 1

Simeprevir + 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 Regimens

Regimen Genotype 1 Regimen Features

Simeprevir + 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


org

4



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


org

*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

Noncirrhotic

Regimen Wks Study SVR

Ledipasvir/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%)


dasabuvir (GT1b) 12 PEARL III[4] 207/209 (99%)


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%).

5



Genotype 1 HCV PegIFN/RBV Treatment

Experienced


– 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 wks

12 wks + RBV

24 wks + RBV 24 wks ± RBV

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

Genotype 1b, cirrhosis 24 wks

12 wks + RBV

12 wks + RBV 24 wks ± RBV


org



Genotypes 2 and 3


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)

http://www.hcvguidelines.org

Genotype 3 Sofosbuvir + Ribavirin Peginterferon-α, Ribavirin

+ Sofosbuvir

Treatment naive 24 wks 12 wks (alternative)

PegIFN/RBV nonresponders 24 wks 12 wks (alternative)

6

Management of HCV in

Patients With Genotype 3



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

83 90

96

57

82 91

76 82

94

47

77 86 100

80

60

40

20

0

SV

R12

(%

)

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

wks

n/N =

7



ALLY-3: SOF + DCV for 12 Wks in Pts With

GT3 HCV Infection

Of 16 pts with relapse, 11 had cirrhosis

1 of 16 relapses occurred between posttreatment Wks 4 and 12

Nelson DR, et al. Hepatology. 2015;61:1127-1135.

Treatment-Naive Pts

Treatment-Experienced Pts

Overall

No cirrhosis Cirrhosis

SV

R12 (

%)

96

63

97

58

94 69

105/ 109

20/ 32

73/ 75

11/ 19

32/ 34

9/ 13

100

80

60

40

20

0 n/N =



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.

73

75 32

34

No Cirrhosis Cirrhosis

SV

R12 (

%)

Naive Experienced

97

58

94

69

0

100

80

60

40

20

8



AASLD/IDSA Guidance for Treatment-

Naive or Treatment-Experienced GT3 Pts

Population Recommended Alternative

DCV + SOF SOF + RBV SOF + RBV

Naive, no cirrhosis 12 wks 12 wks + pegIFN 24 wks†

Naive, cirrhosis 24 wks ± RBV 12 wks + pegIFN 24 wks†

P/R failure, no cirrhosis 12 wks 12 wks + pegIFN Not recommended

P/R failure with cirrhosis,

or SOF/RBV failure 24 wks + RBV

† 12 wks + pegIFN

Not recommended

Decompensated cirrhosis‡ 12 wks +

low-dose RBV Up to 48 wks*

Not recommended

*RBV dosed 1000-1200 mg/day based on weight, with consideration for pt’s CrCl and hemoglobin. †For IFN-ineligible pts. ‡Pts with GT3 HCV decompensated cirrhosis should be referred to a medical

practitioner with expertise in that condition

AASLD/IDSA. HCV guidelines.

LDV/SOF or OMV/PTV/RTV + DSV not recommended for GT3



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.

9

Management of HCV in Pts With

Compensated Cirrhosis



AASLD/IDSA Guidance for GT1 HCV:

Treatment-Naive Pts

Population SMV + SOF LDV/SOF OMV/PTV/RTV

+ DSV

DCV + SOF

GT1a,

no cirrhosis 12 wks ± RBV 12 wks 12 wks + RBV 12 wks

GT1a,

compensated

cirrhosis

24 wks ± RBV

(without Q80K) 12 wks 24 wks + RBV 24 wks ± RBV

GT1b,

no cirrhosis 12 wks 12 wks 12 wks 12 wks

GT1b,

compensated

cirrhosis

24 wks ± RBV 12 wks 12 wks 24 wks ± RBV


10



Reddy KR, et al. Hepatology. 2015;62:79-86.

Pooled Data: Impact of Tx Duration and

RBV in Cirrhotic GT1 Pts (LDV/SOF) Pooled data (ONESTAR, ELECTRON, ELECTRON-2, 337-0113, ION-1, ION-2, SIRIUS)

No difference in SVR rate by HCV subtype

100

80

60

40

20

0 Total Treatment Naive

92 96 98 100

SV

R12 (

%)

118 204 133 58

96 98 97

47 45 33 36

100

Treatment

Experienced

90 96 98

71 159 100 22

100

12 wks of LDV/SOF

12 wks of LDV/SOF + RBV

24 wks of LDV/SOF

24 wks of LDV/SOF + RBV

n =



SIRIUS: Impact of Tx Duration and RBV in

Cirrhotic, PI-Exp’d, GT1 Pts (LDV/SOF) 12 wks of LDV/SOF + RBV

100

80

60

40

20

0

N =

24 wks of LDV/SOF

SV

R12

(%

)

77

97 96

77

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

Pts with previous boceprevir, telaprevir, simeprevir, or faldaprevir

11



Partial Null

OMV/PTV/RTV + DSV + RBV x 12 wks

SV

R12 (

%)

OMV/PTV/RTV + DSV + RBV x 24 wks

Tx Experienced

n/N = 22/

22

18/

18

25/

25

20/

20

6/

7

3/

3

14/

14

10/

10

59/

64

52/

56

14/

15

13/

13

11/

11

10/

10

40/

50

39/

42

TURQUOISE II: Impact of Tx Duration in

Cirrhotic GT1 Pts (OMV/PTV/RTV + DSV)

Poordad F, et al. N Engl J Med. 2014;370:1973-1982. Poordad F, et al. EASL 2014. Abstract O163.

GT1b GT1a

Tx Experienced

100 100 100 100 100 100 100 100 100

86

100

92 93 93

80

93

Naive Relapser Partial Null Naive Relapser

100

80

60

40

20

0



Daclatasvir and Sofosbuvir ± RBV in Pts

With GT 1 HCV

Phase Regimen GT1 SVR, % GT1 Baseline Cirrhosis, %

III 12 wks DCV + SOF +

RBV (ALLY-1)[1]

82 (advanced cirrhosis)

95 (posttransplantation)

100

III 8-12 wks DCV + SOF

(ALLY-2)[2]

76 (8 wks; naive)

96 (12 wks; naive)

98 (12 wks; tx exp’d)

< 18

IIb 12-24 wks DCV +

SOF ± RBV[3]

98 (12 wks; naive)

100 (24 wks; naive)

98 (24 wks; tx exp’d)

16

1. Poordad F, et al. EASL 2015. Abstract LO8. 2. Wyles DL, et al. CROI 2015. Abstract 151LB.

3. Sulkowski M, et al. N Engl J Med. 2014;370:211-221.

12




Treatment-Experienced Pts Previous Treatment,

Cirrhosis Status

SMV + SOF LDV/SOF OMV/PTV/RTV +

DSV

DCV + SOF

PegIFN/RBV, no cirrhosis 12 wks 12 wks 12 wks + RBV (1a)

12 wks (1b) 12 wks

PegIFN/RBV, cirrhosis

24 wks ± RBV

(GT1a w/out Q80K

or GT1b)*

24 wks or

12 wks + RBV

24 wks + RBV (1a)

12 wks (1b) 24 wks ± RBV

SOF + RBV, no cirrhosis Not recommended 12 wks + RBV Not recommended Not recommended

SOF + RBV, cirrhosis Not recommended 24 wks + RBV Not recommended Not recommended

HCV PI, + PegIFN/RBV,

no cirrhosis Not recommended 12 wks Not recommended 12 wks

HCV PI + PegIFN/RBV,

cirrhosis Not recommended

24 wks or

12 wks + RBV Not recommended 24 wks ± RBV

SMV + SOF, no cirrhosis Not recommended 12 wks + RBV Not recommended 12 wks

SMV + SOF, cirrhosis Not recommended 24 wks + RBV Not recommended 24 wks ± RBV

*Not recommended if both GT1a and positive for Q80K.


Management of HCV in GT1 Pts

With Decompensated Cirrhosis

13



AASLD/IDSA Guidance for Pts With

Decompensated Cirrhosis

Refer to experienced HCV practitioner (ideally liver transplant center)

Avoid IFN, TVR, BOC, SMV, OMV/PTV/RTV + DSV, or monotherapy with RBV or DAA


*Initial dose of 600 mg/day, increased as tolerated.

Population RBV Eligible RBV Ineligible

DCV + SOF LDV/SOF DCV + SOF

GT1/4 12 wks +

low-dose RBV*

12 wks +

low-dose RBV* 24 wks

GT1/4, SOF failure Not

recommended

24 wks +

low-dose RBV* Not

recommended



100

80

60

40

20

0

SV

R12 (

%)

CTP B CTP C CTP B CTP C

SOLAR-1 SOLAR-2

87 89 86 90 87 96

85 72

SOLAR-1 and -2: Impact of Tx Duration in

Decompensated Cirrhosis (LDV/SOF + RBV)

Error bars represent 90% CIs.

26/

30

3 relapses

1 death

24/

27

1 relapse

2 deaths

19/

22

1 relapse

1 death

1 LTFU

18/

20

1 relapse

1 death

26/

30

3 relapses

22/

23

1 relapse

17/

20

1 relapse

2 deaths

13/

18

1 relapse

3 deaths

1 w/d consent

Flamm SL, et al. AASLD 2014. Abstract 239. Manns M, et al. EASL 2015. Abstract P0774

LDV/SOF + RBV 12 wks LDV/SOF + RBV 24 wks

n/N =

14



ALLY-1: SOF + DCV + RBV for 12 Wks in

Pts With HCV and Cirrhosis

Treatment naive or treatment experienced

Poordad F, et al. EASL 2015. Abstract LO8.

SV

R12

(%

)

All Genotypes

100

60

80

40

20

0

37/45 39/41

82 95

Advanced Cirrhosis

Post-transplant

GT1

100

80

60

40

20

0 A B C

Child-Pugh Class

92 94

56

11/ 12

30/ 32

9/ 16

n/N = n/N =



SOF + NS5A Inhibitors ± RBV for 12 Wks

in GT1 Pts With Decompensated Cirrhosis

Foster GR, et al. EASL 2015. Abstract O002.

12-wk SOF + LDV + RBV 12-wk SOF + LDV 12-wk SOF + DCV + RBV 12-wk SOF + DCV

n =

100

80

60

40

20

0 All GT1

SV

R12

(%

; IT

T)

252 28 172 15 164 21 45 5

80

71 74 73

86 81 82

60

15


Patients With Renal Impairment



AASLD/IDSA Dosing Considerations for

Pts With Renal Impairment

eGFR/CrCl OMV/PTV/RTV +

DSV[1]

LDV/SOF[2] SMV + SOF,[3]

DCV + SOF[4]

RBV[5]

30-50 mL/min No adjustment

needed

No adjustment

needed

No adjustment needed Alternating

200 mg and

400 mg every

other day

15-30 mL/min No adjustment

needed

Safety and efficacy

not established

No adjustment needed

for SMV or DCV;

Safety and efficacy of

SOF not established

200 mg/day

< 15 mL/min or

hemodialysis

Safety and efficacy

not established

Safety and efficacy

not established

Safety and efficacy not

established

200 mg/day

1. OMV/PTV/RTV + DSV [package insert]. 2. LDV/SOF [package insert]. 3. AASLD/IDSA/IAS-USA.

Recommendations for testing, managing, and treating hepatitis C. 4. DCV [package insert]. 5. RBV

[package insert]. 6. AASLD/IDSA. HCV guidelines.

In noncirrhotic pts for whom tx is urgent and renal transplant not an immediate option:

Recommended Recommended if RBV intolerant/ineligible, in consultation with expert[3]

16



RUBY-1: OMV/PTV/RTV + DSV ± RBV in

Tx-Naive, Noncirrhotic GT1 Pts With CKD

SVR4: 10/10 pts reaching posttreatment Wk 4

– SVR12: 2/2 pts reaching posttreatment Wk 12

– No virologic failures observed as of time of reporting

Pockros PJ, et al. EASL 2015. Abstract L01.

Pt 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

GT 1a 1a 1a 1a 1b 1a 1a 1a 1a 1a 1b 1a 1a 1a 1b 1b 1b 1b 1b 1a

Renal Stage

4 4 5 5 5 5 5 4 5 5 5 5 4 4 5 4 5 5 5 5

BL (x 1000)

746 25300 17100 3520 2980 429 1730 43300 12600 6670 9820 292 6980 2570 3680 383 1230 6500 1850 4210

W1

W2

W4

W8

W12EOT

PTW4

PTW12

PTW24

HCV RNA: ≥ 25 IU/mL < 25 IU/mL Undetectable


HCV/HIV-Coinfected Patients

17



ION-4: LDV/SOF for 12 Wks in HCV/HIV-

Coinfected Pts GT1 or 4 HCV, 20% with compensated cirrhosis, 55% treatment

experienced

Naggie S, et al. CROI 2015. Abstract 152LB.

SV

R12

(%

)

96 95 97 96 94

Overall Naive Exp’d

321/

335

142/

150

100

179/

185

258/

268

63/

67

No

Cirrhosis

Cirrhosis

n/N =

80

60

40

20

0



ALLY-2: SOF + DCV in HCV/HIV-

Coinfected Pts

12 pts with relapse, 10 in 8-wk arm

Wyles DL, et al. CROI 2015. Abstract 151.

12-Wk

Naive

12-Wk

Exp’d

8-Wk

Naive

12-Wk

Naive

12-Wk

Exp’d

8-Wk

Naive

SV

R12 (

%)

96 98

76

97 98

80/83 43/44

0

20

40

60

80

100

31/41 98/101 51/52

76

38/50

GT1 GT1-4

n/N =

18



94

TURQUOISE-1: OMV/PTV/RTV + DSV + RBV

for 12 vs 24 Wks in GT1 HCV/HIV Coinfection

65% HCV treatment–naive pts in 12-wk arm, 69% in 24-wk arm

19% pts with METAVIR F4 fibrosis

Sulkowski M, et al. JAMA. 2015;313:1223-1231.

30/31 31/32 29/31 n/N =

100

80

60

40

20

0

97 97

EOTR SVR12

Pts

(%

) OMV/PTV/RTV +

DSV + RBV 12 wks

OMV/PTV/RTV +

DSV + RBV 24 wks

91

29/32



AASLD/IDSA Guidance for HCV/HIV

Coinfection

Same recommendations as in HCV-monoinfected pts, but consider drug–drug interactions

– Avoid combination of LDV and tenofovir DF if CrCl < 60 mL/min or if receiving tenofovir with RTV-boosted PIs

– When LDV/SOF and tenofovir DF are coadministered with antiretrovirals, monitor for nephrotoxicity

– Adjust/withhold RTV if receiving a boosted PI with OMV/PTV/RTV + DSV

– Adjust DCV with atazanavir/RTV, efavirenz, or etravirine

DCV + SOF ± RBV is recommended when ART regimen changes cannot be made to accommodate other DAAs

Other interactions at aidsinfo.nih.gov/guidelines, hiv-druginteractions.org, hep-druginteractions.org


19



Sofosbuvir +

ribavirin

Sofosbuvir +

ledipasvir

Simeprevir +

sofosbuvir

Paritaprevir/

ritonavir +

dasabuvir +

ombitasvir

Sofosbuvir +

GS-5816

Sofosbuvir +

daclatasvir

Grazoprevir +

elbasvir

Daclatasvir +

asunaprevir +

beclabuvir



Investigational Agents

Population Regimen Trial Phase SVR12,

%

GT1 HCV + stage 4/5

CKD

12 wks of

grazoprevir/elbasvir C-SURFER[1] III 99

GT3 HCV (treatment-

naive, noncirrhotic or

cirrhotic)

8-12 wks

grazoprevir/elbasvir

+ SOF

C-SWIFT[2] II 91-100

GT1, 4, 6 HCV + HIV

coinfection

12 wks of

grazoprevir/elbasvir C-EDGE[3] III 96

GT3 HCV (treatment-

naive, noncirrhotic)

8 wks of

SOF + GS-5816

± RBV

ELECTRON-

2[4] II 88-100

1. Roth D, et al. EASL 2015. Abstract LP02. 2. Poordad F, et al. EASL 2015. Abstract O006.

3. Rockstroh JK, et al. EASL 2015. Abstract P0887. 4. Gane EJ, et al. AASLD 2014. Abstract 79.

20



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 19/20 n/N =

SOF + LDV

20/20 19/20 19/20

100 95 95 100

80

60

40

20

0

SV

R12 (

%)

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

SV

R12 (

%)

93 87

67

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

4 Wks

27

4/15

21



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

SV

R1

2 (

%)

All GT1a GT1b

92 90 98

287/ 312

206/ 229

81/ 83

All GT1a GT1b

92/ 103

64/ 75

28/ 28

89 85

100

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.

SV

R12 (

%)

100

80

60

40

20

0 4 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 80

94 93 100 91

10/ 30*

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

Noncirrhotic Cirrhotic

n/N =

22



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]

SV

R12 (

%)

All Pts GT1a GT1b GT4 GT6

95 92

99 100

80

299/ 316

144/ 157

129/ 131

18/ 18

8/ 10 n/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 97 92

12 Wks 16 Wks



Sofosbuvir +

ribavirin

Sofosbuvir +

ledipasvir Simeprevir +

sofosbuvir

Paritaprevir/

ritonavir +

dasabuvir +

ombitasvir

Sofosbuvir +

GS-5816

Sofosbuvir +

daclatasvir

Grazoprevir +

elbasvir

Daclatasvir +

asunaprevir +

beclabuvir

Many other DAA combinations

currently under investigation

23



Summary

All-oral HCV therapy has significantly improved tolerability and efficacy, but challenging populations remain

Cirrhotics may require addition of RBV or longer duration with current therapy to achieve SVR rates comparable to noncirrhotics

GT3 pts remain a challenging population although the recent availability of DCV introduces a new, IFN-free option in this population

HIV-coinfected individuals can now achieve SVR rates comparable to monoinfected, but drug–drug interactions must be carefully considered

Go Online for More CCO

Coverage of HCV in

Harder-to-Treat Populations!

CME-certified Interactive Text Module with expert faculty commentary

clinicaloptions.com/flipped

http://www.clinicaloptions.com/Hepatitis/Treatment Updates/HCV Flipped Classroom/Module/Evolving_HCV_Management.aspx

24



Genotype 1 HCV Previous PI Failure


– 1 regimen recommended

Ledipasvir/

Sofosbuvir

Ombitasvir/

Paritaprevir/

Ritonavir +

Dasabuvir

Simeprevir +

Sofosbuvir ±

Ribavirin

Genotype 1a, no cirrhosis 12 wks None None

Genotype 1a, cirrhosis 24 wks

12 wks + RBV

None

None

Genotype 1b, no cirrhosis 12 wks None None

Genotype 1b, cirrhosis 24 wks

12 wks + RBV

None None


org



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.

25



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 46.5

Headache, % 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%

75

77

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.

26



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)



Treatment Naive Treatment Experienced

BOSON: Is SOF + PegIFN/RBV for 12 Wks

Superior to SOF + RBV for 24 Wks in GT3?

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

65/

72

68/

71

18/

22

21/

23

26/

34

30/

35

44/

54

49/

52

No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis

90 96

82 91

82

94

77 86 100

80

60

40

20

0

SV

R12

(%

)

SOF + RBV 24 wks SOF + pegIFN/RBV 12 wks

n/N =

27



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

SV

R12 (

%)

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

100

89

73

26/

26

25/

28

16/

22

SV

R12 (

%)

28




Previous Treatment With NS5A Inhibitor

If minimal liver disease, defer treatment, pending further data

If cirrhotic or treatment otherwise urgent, resistance testing for RAVs that confer decreased susceptibility to NS3 PIs, NS5As recommended

– If both NS5A and NS3 RAVs detected, treatment within clinical trial recommended


Previous

Treatment,

Cirrhosis Status

DCV + SOF LDV/SOF OMV/PTV/RTV

+ DSV

SMV + SOF

NS5A, cirrhosis or

urgent treatment

required

Not

recommended

If no NS5A RAVs:

24 wks + RBV

Not

recommended

If NS5A RAVs but no

NS3 RAVs:

24 wks + RBV



AASLD Guidance on HCV/HIV Drug–Drug

Interactions SMV SOF LDV DCV OMV/PTV/RTV + DSV

ATV/RTV No data No data LDV↑; ATV↑ DCV↑

PTV↑; ATV↑

DRV/RTV SMV↑; DRV↔

SOF↑; DRV↔

LDV↑; DRV↔

DCV↑; DRV↔

PTV ↓/↑; DRV↓

LPV/RTV No data No data No data DCV↑; LPV↔

PTV↑; LPV↔

Tipranavir/RTV No data No data No data No data No data

EFV SMV↓; EFV↔

SOF↔; EFV↔

LDV↓; EFV↓ DCV↓ No PK data

RPV SMV↔; RPV↔

SOF↔; RPV↔

LDV↔; RPV↔ No data

PTV↑; RPV↑

Etravirine No data No data No data DCV↓ No data

RAL SMV↔; RAL↔

SOF↔; RAL↔

LDV↔; RAL↔ No data

OMV/PTV/RTV + DSV↔; ↑RAL

EVG/COBI No data COBI↑; SOF↑

COBI↑;

LDV↑ No data No data

DTG No data No data LDV↔; DTG↔

DCV↔; DTG↑

PTV↓ DTG↑

Maraviroc No data No data No data No data No data

TDF SMV↔; TDF↔

SOF↔; TDF↔

LDV↔; TDF↑

DCV↔; TDF↔

OMV/PTV/RTV + DSV↔; TDF↔


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