10iria y alvaro - agidei.orgagidei.org/wp-content/uploads/2014/12/cbm-2015-10iria-y-alvaro.pdf · Mathias A 14 th Int Workshop on Clin Pharm of HIV Ther; April 2013; Sofosbuvir USPI

HCV controversyIria Rodríguez Osorio & Álvaro Mena De CeaClinical Virology Group, INIBIC-CHUACInternal Medicine Service, [email protected]@sergas.es

CLINICAL CASE54 yo male. No comorbidities. No chronic treatment.

HCV chronic infection, known since 2004.

Genotype 1 a. HCV RNA: 5.2 log UI/mL. Treatment naive.

Blood test: Hb 14,8 gr/dL, Platelets 140000, AST 102 UI/L, ALT 124 UI/L. VHB, HIV negative. Autoinmune test negative.

Abdominal US: normal.

Fibroscan: 9,6 kPa (IQR 1,4 kPa). F3.

Never had a decompesation episode.

This patient has an HCV chronic infection, G1a, naive, anF3 stage, which would be our treatment options?

Treatment options in Spain TODAY

• IFN based regimen:– Simeprevir + Peg-IFN + RBV– Sofosbuvir + Peg-IFN + RBV

• IFN free regimen:– Sofosbuvir + RBV– Sofosbuvir + Simeprevir ± RBV– Coming soon:

• Daclatasvir + Sofosbuvir ± RBV• Daclatasvir + Simeprevir ± RBV• Sofosbuvir + Ledipasvir ± RBV• 3D ± RBV

o Efficacy on clinical trials (QUEST 1-2).

o Efficacy in real life cohorts.

o Week 4.

o Costs.

IFN regimen based on a PI

SIMEPREVIRP

hase

IIaP

hase

IIb

Pha

se

III

Prior relapser

PROMISE(NCT01281839)

Treatment experienced

Treatment naïve

Treatment-naïve & -experienced

RESTORE: HPC3011 (NCT01567735)

Long term follow up(NCT01349465)

Prior partial & null responder

ATTAIN (NCT01485991)

IFN freeGenotype 4 Other populations


C212 HCV/ HIV coinfected

(NCT01479868)

Treatment-naïve & null responder

LEAGUE-1 SMV + DCV

(NCT01628692)

Post-OLT, treatment-naïve & null responder

SMV + DCV ± RBV (NCT01938625)

Treatment-naïve, HCV GT 1b/4/6 and treatment-naïve/experienced

HCV GT1a/b

SMV + IDX719 ± RBV (NCT01852604)

GT 1 or 4 treatment-naïve & experienced

Shorter duration - 12 week study (NCT01846832)

Pbo-experienced prior relapsers, partial responder & null responder

C213 Rollover Study(NCT01323244)

Treatment-naïve & prior relapsers & non responders

OPERA 1 (NCT00561353)


COSMOS SMV + SOF (NCT01466790)

Treatment-naïve & null responder Non-cirrhotic

OPTIMIST-1HPC3017

(NCT02114177)Treatment-naïve & null responder

Cirrhotic

OPTIMIST-2HPC3018

(NCT02114151)

GT1, treatment-experienced

ASPIRE(NCT00980330)

GT1 treatment-naive

PILLAR(NCT0882908)

Treatment-naïve GT2-6

TMC435-C202 (NCT00812331)

GT1, treatment-naive

QUEST-1/2(NCT01289782 + NCT01290679)

EVIDENCE: QUEST 1-2

EVIDENCE: QUEST 1-2

EFFICACY ON CLINICAL TRIALS

0 12 24

SMV 150 mg/d +

PRPR

48 72 Weeks

N= 521

N= 264 PR + placebo PR

PR

Follow-upFollow-up

Follow-up

• Phase 3, randomised, double-blind, placebo-controlled trials: N= 785.

• Randomised by: Subtype and IL28B.

• Primary objetive: SVR12.

• Quest 1 and 2 were similar (design, population included, basal characteristics).

Evidence: QUEST studies

Efficacy by subtype (European population)

EVIDENCE: QUEST 1-2

Jacobson IM, et al. Hepatol 2013;58(Suppl 1):756A-757A (Abstract 1122)

Q80K POLIMORPHISM

Subtype: 1a & 1b Subtype G1 and Q80K polimorphism

• Efficacy by fibrosis stage (European patients)

8681

71

58

44

25

0

20

40

60

80

100

F0–F2 F3 F4

SV

R1

2(%

)

191/217 64/110 29/36 7/16 10/14 4/16

Adj diff 38.695% CI: 27.2 - 50.0

Adj diff 46.695% CI: 32.5 - 60.8

Adj diff 50.095% CI: 38.2 - 61.8

Foster G et al. EASL 2014. Poster P1127

EVIDENCE: QUEST 1-2



o Week 4.

o Costs.


REAL LIFE COHORTS

No data at the Liver Congress of the AASDL 2014.

Coming data at the:

– EASLD 2015, Liver Congress.

– Spanish National Congress of Liver Disease.



o Week 4.

o Costs.


WEEK 4

78

12

0

20

40

60

80

100

SMV + PR Pbo + PR

RV

R (

%)

90

0

20

40

60

80

100

RVR patients

SV

R1

2 (

%)

Jacobson IM, et al. Hepatol 2013;58(Suppl 1):756A-757A (Abstract 1122).

WEEK 4

• Predicted value of week 4.

Subtype G1 Polimorfismo Q80K en VHV G1a

Jacobson IM, et al. Hepatol 2013;58(Suppl 1):756A-757A (Abstract 1122)



o Week 4.

o Costs.


COSTS

1.000 patients 25 Mil. € 25.000 €

2.000 patients 50 Mil. € 25.000 €

3.000 patients 70 Mil. € 23.300 €

4.000 patients 70 Mil. € 17.500 €

5.000 patients 70 Mil. € 14.000 €

6.000 patients 70 Mil. € 11.600 €

7.000 patients 70 Mil. € 10.000 €

Patients Total cost Cost by patient

100 patients 2,3 Mill. € 23.000 €*

150 patients 3,4 Mill. € 23.000 €*

170 patients 3,9 Mill. € 23.000 €*

200 patients 3,9 Mill. € 19.500 €*

400 patients 3,9 Mill. € 9.750 €*

600 patients 3,9 Mill. € 6.500 €*

1000 patients 3,9 Mill. € 3.900 €*

Patients Total cost Cost by patient

Aproximate cost in Galicia

COSTS

SUMMARY

• IFN based regimen (G1a, Naive, F3): Simeprevir + Peg-IFN + RBV:

– SVR 12w ≅ 80%.

– G1a without Q80K similar SVR rates as G1b ( 82% vs 90%).

– Predicted value of week 4. RVR: 90% achived SVR.

– Costs?





o Efficacy on clinical trials (NEUTRINO).

o Efficacy in real life cohorts (AASLD 2014).

o Interactions.

o Costs.

o Clinical guidelines.

IFN regimen based on SOF

0 12 16 24 36Week

Treatment-Naïve: NEUTRINO

SOF + PEG-IFN + RBV, n=292 SVR12

IFN-CONTAINING

THERAPY

IFN-FREEALL-ORAL THERAPY

No response guided therapy

Historical Control: TVR or BOC + PEG-IFN + RBV

Treatment-Naïve: Study 1910


Treatment-Naïve: QUANTUM/NIAID SPARE

SOF + RBV, n=159 SVR12

Treatment-Naïve HIV/HCV Co-infection: PHOTON-2


Treatment-Experienced: Retreatment of PI Failures


⸗

SOFOSBUVIR GT 1

EVIDENCE: NEUTRINO

N Engl J Med 2013;368:1878-87

NEUTRINO study

12 24

SVR12HCV GT 1Treatment-naïve

n=292

0Study week

SOF 400 mg/day +

PEG-IFN 180 µg/week +

RBV 1000‒1200 mg/day


Overall (GT 1, 4, 5, 6)SOF + PEG-IFN + RBV

N=327

Mean age, y (range) 52 (19‒70)

Male, n (%) 209 (64)

Black, n (%) 54 (17)

Hispanic, n (%) 46 (14)

Mean BMI, kg/m2 (range) 29 (18‒56)

IL28B CC, n (%) 95 (29)

GT 1, n (%) 292 (89)

GT 4/5/6, n (%) 35 (11)

Mean baseline HCV RNA, log10 IU/mL (SD) 6.4 (± 0.7)

Cirrhosis, n (%) 54 (17)

GT 1,4,5,6 Treatment-Naïve SOF + PR x 12 Wks

9199 99

0

20

40

60

80

100

On treatment

Pat

ient

s w

ith H

CV

RN

A <

LLO

Q (

%)

90

Post-treatment

Week 12

295/327299/327 321/325 326/327

N Engl J Med 2013;368:1878-87

EVIDENCE: NEUTRINO GT 1

N Engl J Med 2013;368:1878-87

SOF + PEG-IFN + RBV N=327

Overall safety

AEs, n (%) 310 (95)

Grade 3‒4 AEs, n (%) 48 (15)

Serious AEs, n (%) 4 (1)

Treatment D/C due to AEs, n (%) 5 (<2)

Hematologic abnormalities

Grade 3–4 laboratory abnormality, n (%) 159 (49)

Hemoglobin <10 g/dL, n (%) 74 (23)

Hemoglobin <8.5 g/dL, n (%) 8 (2)

Absolute neutrophil count <750/mm3, n (%) 66 (20)

Platelets <50,000/mm3, n (%) 1 (<1)

• SOF was well tolerated without any additive effects to the expected safety profile of PR

• Most common AEs were fatigue (59%), headache (36%), nausea (34%) and insomnia (25%)

• A total of 5/327 (1.5%) of patients D/C due to an AE

NEUTRINO: Safety summary

N Engl J Med 2013;368:1878-87



o Interactions.

o Costs.



REAL LIFE COHORTS

Patients in HCV- TARGET 2.0:N= 2330

ITT withSOF+PRN= 402

ITT withSOF+RBV

N= 699

ITT withSOF+SMV

N= 883

ITT withSOF+SMV+RBV

N= 234

TreatedSOF+PRN= 384

TreatedSOF+RBV

N= 667

TreatedSOF+SMV

N= 784

TreatedSOF+SMV+RBV

N= 228

Patients included: Flowchart

GT 1

SVR4 for 164/200 patients

90

70

85

0

20

40

60

80

100

No cirrosis Cirrosis Global

Jensen DM et al; Safety and Efficacy of Sofosbuvir- Containing Regimens for Hepatitis C: Real-World Experience in a Diverse, Longitudinal Ob servational Cohort

Boston Nov 2014

SVR4 in GT1 treated with PR+SOF

Patients included: Flowchart

Baseline characteristics

GT 1(n= 669)

SOF + PR x 12s

(44%)

SMV + SOF x 12s

(42%)

SOF + RBV x 24s

(12%)

GT 2(n=197)

SOF + RBV x 12s

(95%)

SOF + PR x 12s

(5%)

SOF + RBV x 24s

(93%)

SOF + PR x 12s

(6%)

GT 3(n=110)

85

91 9289

78

84

65

78

90 93

99

85 8794

80

8790 91 93

79

8992

83

0%

20%

40%

60%

80%

100%

Overall Naive Naive Non-

Cirrhosis

Naive

Cirrhosis

Experienced Exp Non-

Cirrhosis

Exp Cirrhosis PI Failure

SV

R 1

2 (

%)

G1 SOF/PR G1 SOF/SMV±RBV G2

Dieterich et al, Abstract 46Bacon et al., Abstract 975Flamm et al., Abstract 983

REAL LIFE: TRIO network

81

91

81

93

8287

0

20

40

60

80

100

SOF/PR (ITT) SOF/PR (PP)

g1 g1a g1b

169 125 33 150 109 31

SV

R1

2 (

%)

NAÏVE

72

78

71

79

7074

0

20

40

60

80

100

SOF/PR (ITT) SOF/PR (PP)

g1 g1a g1b

125 73 37 115 66 35S

VR

12

(%

)

Dieterich et al; Evaluation of sofosbuvir and simeprevir-based regimens in the TRIO network, AASLD Boston 2014

REAL LIFE: TRIO network GT1TREATMENT EXPERIENCED

NAÏVE


REAL LIFE: TRIO network GT1TREATMENT EXPERIENCED



o Interactions.

o Costs.



SOF is activated in hepatocyte

� Hydrolases (CES1, Cat A; HNT1)

� Phosphorylated to active GS-4612003

� Predominant circulating form GS-331007

SOF not metabolised by or inhibits CYP

SOF interacts with P-gp (and BCRP) - Victim

Interaction Potential - WEAK

Mathias A 14th Int Workshop on Clin Pharm of HIV Ther; April 2013; Sofosbuvir USPI.

SOF: Interactions

Drug Interaction Potential of 22 Highly Utilized medications in US Patients

Medication BOC TVR SOF SIM

Zolpidem

Alprazolam

Amlodopine

Prednisone

Tramadol

Codeine

Fluticasone

Methylprednisolone

Escitalopram

Trazodone

Clindamycin

Medication BOC TVR SOF SIM

Diazepam

Sertraline *

Lansoprazole

Clonazepam

Sildenafil

Fluconazole **

Simvastatin

Venlafaxine

Salmeterol

Clarithromycin **

Tacrolimus

Modified from Lauffenburger JC et al. Eur J Gastro & Hepatology 2014)

* No PK interaction but sertraline should not be used in patients with severe hepatic impairment;

** Not recommended – increased SIM expected.



o Interactions.

o Adverse events & Costs.



REAL LIFE: ADVERSE EVENTS


Boston Nov 2014

Costs: Spanish National Health System

o SOF 12w: 24,531 €

o PR+SOF 12w: 25,571 €

o PR+SIM 24w: 27,700 €

o SIM+SOF 12w: 50,191 €



o Interactions.

o Adverse events & Costs.



GUIDELINES

GUIDELINES

• IFN based regimen: SOF + Peg-IFN + RBV:

– SVR 12w: 82% (ITT), 92% (PP) in real life.

– Costs.

– Less IFN exposure.

SUMMARY





o Efficacy on clinical trials (QUANTUM/NIAID SPARE).


o Adverse effects

IFN free regimen: SOF+RBV

0 12 16 24 36Week

Treatment-Naïve: NEUTRINO


IFN-CONTAINING

THERAPY

IFN-FREEALL-ORAL THERAPY


Historical Control: TVR or BOC + PEG-IFN + RBV

Treatment-Naïve: Study 1910


Treatment-Naïve: QUANTUM/NIAID SPARE


Treatment-Naïve HIV/HCV Co-infection: PHOTON-2


Treatment-Experienced: Retreatment of PI Failures


⸗

SOFOSBUVIR GT 1

QUANTUM: Trial design

Lalezari JP, et al. EASL. 2013; Abstract 845

QUANTUM: Patients with GT 1(SVR12)


5347

66

0

20

40

60

80

100

SOF + RBV x 12 Wks SOF + RBV x 24 Wks SOF + RBVRetreatment x 24 Wks

Pat

ient

s (%

) w

ith S

VR

12

10/19 9/19 69/105

QUANTUM: Patients with GT 1(SVR12)


5347

71

50 50 48

0

20

40

60

80

100

SOF + RBV x 12 Wks SOF + RBV x 24 Wks SOF + RBVRetreatment x 24 Wks

Pat

ient

s (%

) w

ith S

VR

12

Genotype 1a Genotype 1b

8/15 2/4 7/15 2/4 57/80 12/25

NIAID SPARE: Difficult-to-Cure HCV GT 1 naïve Patients

Osinusi A, et al. JAMA 2013;310:804–11

• In this difficult-to-cure treatment-naïve, HCV GT 1 population (n=60),

an IFN-free regimen of SOF + RBV was well-tolerated and effective in achieving SVR

– Full dose RBV: SVR12 of 68% (ITT), 71% (mITT)

– Low dose RBV: SVR12 of 48% (ITT), 55% (mITT)

– There were no safety signals or drug-related discontinuations in this study

Part 1 Part 2

QUANTUM/NIAID SPARE: Patients with GT

8/15 2/4 7/15 2/4 57/80 12/25

• SOF + RBV resulted in rapid suppression of HCV RNA with ≥98% RVR rate

• In the SOF+RBV x12w 56% (QUANTUM) and x24w 52% (QUANTUM) and 68% (NIAID SPARE) achieved SVR12.

• Well tolerated, with no safety signals noted• 2% D/C due to AE.• For those who relapsed, no resistance mutations seen.



o Adverse effects.


REAL LIFE: SOF+RBV

REAL LIFE: SOF+RBV

77

50

85

78

0

20

40

60

80

100

SOF/PR SOF/R SOF/PR SOF/R

SV

R1

2 (

%)

295 14

ITT PP

266 9

Dieterich et al; Evaluation of sofosbuvir and simeprevir-based regimens

in the TRIO network, AASLD Boston 2014



o Adverse effects.


REAL LIFE: SOF+RBV


Boston Nov 2014

• IFN free regimen: SOF + RBV:

– SVR 12w: 50-60%.

– Adverse events common, but none severe or moderate.

– For those who relapsed, no resistance mutations seen.

SUMMARY





o Efficacy on clinical trials (COSMOS).


o Adverse effects

o Cost

IFN free regimen: Simeprevir + Sofosbuvir

SIMEPREVIRP

hase

IIaP

hase

IIb

Pha

se

III

Prior relapser

PROMISE(NCT01281839)

Treatment experienced

Treatment naïve


RESTORE: HPC3011 (NCT01567735)

Long term follow up(NCT01349465)

Prior partial & null responder

ATTAIN (NCT01485991)

IFN freeGenotype 4 Other populations


C212 HCV/ HIV coinfected

(NCT01479868)


LEAGUE-1 SMV + DCV

(NCT01628692)

Post-OLT, treatment-naïve & null responder

SMV + DCV ± RBV (NCT01938625)

Treatment-naïve, HCV GT 1b/4/6 and treatment-naïve/experienced

HCV GT1a/b

SMV + IDX719 ± RBV (NCT01852604)

GT 1 or 4 treatment-naïve & experienced

Shorter duration - 12 week study (NCT01846832)

Pbo-experienced prior relapsers, partial responder & null responder

C213 Rollover Study(NCT01323244)

Treatment-naïve & prior relapsers & non responders

OPERA 1 (NCT00561353)


COSMOS SMV + SOF (NCT01466790)

Treatment-naïve & null responder Non-cirrhotic

OPTIMIST-1HPC3017

(NCT02114177)Treatment-naïve & null responder

Cirrhotic

OPTIMIST-2HPC3018

(NCT02114151)

GT1, treatment-experienced

ASPIRE(NCT00980330)

GT1 treatment-naive

PILLAR(NCT0882908)

Treatment-naïve GT2-6

TMC435-C202 (NCT00812331)

GT1, treatment-naive

QUEST-1/2(NCT01289782 + NCT01290679)

EVIDENCE: COSMOS

EVIDENCE: COSMOSSMV + SOF + RBV Follow up

0 4 1

2

2

4

3

6

4

8

Arm 1

Week

SMV + SOF

SMV + SOF

+ RBV

SMV + SOF

Follow up

Follow up

Follow up

Arm 2

Arm 3

Arm 4

• Phase 2a, multicentric, randomised and open trial: n= 107.

– Cohort 1 (n=80): Null responders and F0-F2.

– Cohort 2 (n=87): Treatment naive or previous null responders, F3-F4.

93 93

0

20

40

60

80

100

SMV + SOF +

RBV

SMV + SOF

SVR in treatment naive and null, F3-F4

High efficiency (92% SVR) of an IFN free regimen: Simeprevir+Sofosbuvir±ribavirin. 12 weeks regimen. Regardless subtype of G1, Q80K polimorphism, fibrosis stage, IL28B

or previous response to treatment.

EVIDENCE: COSMOS



o Adverse effects

o Cost


Longitudinal, observational study of the clinical practice. > 18 yo on HCV treatment.> 4700 patients included.

Jensen DM et al; Safety and Efficacy of Sofosbuvir- Containing Regimens for Hepatitis C: Real-World Experience in a Diverse, Lo ngitudinal Observational Cohort

Boston Nov 2014

REAL LIFE: TARGET

REAL LIFE: TARGET

> 1000 Patients have been treated with SMV/SOF o SMV/SOF/RBV

HCV- TARGET 2.0:N= 2330

ITT conSOF+PRN= 402

ITT conSOF+RBV

N= 699

ITT conSOF+SMV

N= 883

ITT conSOF+SMV+RBV

N= 234

TreatedSOF+PRN= 384

TreatedSOF+RBV

N= 667

TreatedSOF+SMV

N= 784

TreatedSOF+SMV+RBV

N= 228

REAL LIFE: TARGET

8695

0

20

40

60

80

100

Genotipo 1a Genotipo 1b

SV

R4

(%

)

154/180 88/93

8087 88

94

8288 87

93

0

20

40

60

80

100

1a concirrosis

1a sincirrosis

1b concirrosis

1b sincirrosis

Sin RBV

Con RBV

SOF + SMV ± RBV by subtype


Genotipo 1(n= 669)

SOF + PR x 12s(44%)

SMV + SOF x 12s(42%)

SOF + RBV x 24s(12%)

Genotipo 2(n=197)


SOF + PR x 12s(5%)

Genotipo 3(n=110)


SOF + PR x 12s(6%)



82

90

0

20

40

60

80

100

SIM/SOF±RBV SIM/SOF±RBV

ITT PP

83

93

80

929297

0

20

40

60

80

100

SIM/SOF± RBV (ITT) SIM/SOF± RBV (ITT)

(PP)

g1 g1a g1b

75

8588

99

0

20

40

60

80

100

SIM/SOF± RBV (ITT) SIM/SOF± RBV (PP)

Cirrosis No cirrosis

ITT PPITT PP


PACIENTES NAÏVE



o Adverse effects

o Cost


ADVERSE EVENTS

Patients, %

12 weeks 24 weeks

SMV + SOF + RBV

(n=54)

SMV + SOF

(n=28)

SMV + SOF + RBV

(n=54)

SMV + SOF

(n=31)

Any AE 46 (85.2) 20 (71.4) 50 (92.6) 28 (90.3)

Grade 3-4 AEs 6 (11.1) 1 (3.6) 4 (7.4) 4 (12.9)

SAEs* 0 0 2 (3.7) 1 (3.2)

AEs leading to permanent

treatment discontinuation**

0 0 2 (3.7) 2 (6.5)

Deaths during treatment† 0 0 1 (1.9) 0

Jacobson IM, et al. AASLD 2013. Oral Presentation LB-3

*Serious AEs: anemia, injury, retinal tear; **AEs leading to discontinuation: injury, increased blood creatine phosphokinase , aggression and renal failure (1 incidence of each); †Death during treatment was due to injury;

Cohort 1 and Cohort 2 of COSMOS study

ADVERSE EVENTS

Real life: AASLD 2014.



o Adverse effects

o Cost


COSTS

• IFN free regimen (G1a, Naive, F3): Simeprevir + Sofosbuvir ± RBV:

– SVR 12w: >85%.

– SVR achived regardless subtype, Q80K polimorphism, ILB28, fibrosis stage and previous response to treatment.

– Adverse events comon, but none severe or moderate.

– A cost-effective regimen.

SUMMARY

TAKE HOME MESSAGES

PR+SIM PR+SOF SOF+RBV SIM+SOF±RBV

Effectiveness ≅80-85% ≅85-95% ≅50-60% ≅85-95%

Costs Basal = x2 x2

IFN exposure 24w 12w Free Free

G1a, Naive, F3.

Documents

10iria y alvaro - agidei.orgagidei.org/wp-content/uploads/2014/12/cbm-2015-10iria-y-alvaro.pdf · Mathias A 14 th Int Workshop on Clin Pharm of HIV Ther; April 2013; Sofosbuvir USPI