Treatment of HCV : 100 % cure ? - APHC – International … · · 2018-02-12German P, et al....

Treatment of HCV : 100 % cure ?

PHC 2018

PARIS

January 15th, 2018

Tarik Asselah (MD, PhD)

Professor of MedicineHepatology, Chief INSERM UMR 1149,

Hôpital Beaujon, Clichy, France.

PHC 2018 - www.aphc.info

Disclosures

• Employee of Paris Public University Hospitals (AP-HP, Beaujon’s Hospital) and University of Paris

• Principal investigator for research grants : Funds paid to Hospital (AP-HP)

• Consultant, expert and speaker for: Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp Dohme, Roche.

• Grants from : ANR, CNRS , INSERM , University of Paris, ANRS

2

1 Introduction

2 Sofosbuvir/Velpatasvir (Epclusa®)

3 Glecaprevir/Pibrentasvir (Maviret®)

4 Grazoprevir/Elbasvir (Zepatier®)

5 Challenges to achieve HCV elimination


Estimated 70 Million Persons Living With HCV

0% to < 0.6%0.6% to < 0.8%0.8% to < 1.3%1.3% to < 2.9%2.9% to < 6.7%

Prevalence(Viremic)

Polaris Observatory HCV Collaborators. Lancet Gastroenterol Hepatol. 2017;2:161-176.

Direct-acting antivirals : a Revolution

Capsid

MetalloproteaseSerine protease

RNA helicaseEnvelope

glycoproteins

E1C E2

Non-structural proteinsStructural proteins5’NTR 3’NTR

NS1 NS2 NS3 NS4A NS4B

Cofactors

NS5A

Protease inhibitors« …previr »

Polymerase inhibitors« …..buvir »

NS5A inhibitors« ….asvir »

RNApolymerase

NS5B

ParitaprevirGlecaprevirGrazoprevirVoxilaprevir

LedipasvirVelpatasvirPibrentasvirOmbitasvirElbasvirDaclatasvir

Nucs Sofosbuvir

Non-Nucs

Dasabuvir

Asselah et al. Liver Int 2018, in press.

SOF + RBV12–24 weeks

SOF + SMV± RBV12–24 weeks

SOF/LDV± RBV8†–24 weeks

SOF + DCV± RBV12–24 weeks

OMV/PTV/RTV

± DSV ± RBV 12–24 weeks

SOF/VEL± RBV

12 weeks

GRZ/EBV ± RBV 12–16 weeks

GLE/PIB8–12 weeks

SOF/VEL/VOX12 weeks

Jan 2014 May 2014 Sept 2014 Nov 2014 Jan 2015 July 2016 July 2017

SOFVELLDV

SMV DCV

VOX

PIB

GRZ

EBV

GLE

PIB

PTV

DSVOMV

O

O

N

NF

F

O

O

OO

O O OS

NH

FF

HN

N

NH


SVR > 95%

Safety

Tolerability

Pangenotypic:

High barrier to resistance

Short duration; Low pill burden

Minimal drug–drug interactions

Access/cost

Priorities for Direct-acting antivirals

Top Priorities

SVR > 95%

Safety

Tolerability

High barrier to resistance

Short duration; Low pill burden

Minimal drug–drug interactions

Pan-genotypic

Access/cost

Priorities for Direct-acting antivirals

Top Priorities

Secondary Priorities

1 Introduction






SOF Nucleotide NS5B polymerase inhibitor

♦ Sofosbuvir (SOF)1,2‒ Potent antiviral activity against

HCV GT 1‒6

‒ Once-daily, oral, 400-mg tablet

SOF VEL

VELNS5A inhibitor

♦ Velpatasvir (VEL; GS-5816)3-5● Picomolar potency against GT 1‒6● 2nd-generation inhibitor with

improved resistance profile

♦ SOF/VEL Single Tablet Regimen (STR)● Once daily, oral, STR (400/100 mg)

1. Jacobson IM, et al. N Engl J Med 2013;368:1867-77; 2. Lawitz E, et al. N Engl J Med 2013;368:1878-87; 3. Cheng G, et al. EASL 2013, poster 1191; 4. German P, et al. EASL 2013, poster 1195; 5. Lawitz E, et al. EASL 2013, poster 1082.

Velpatasvir/Sofosbuvir: A Single Tablet Regimen (STR)

O

O

N

NF

F

O

O

OO

O O OS

NH

FF

HN

N

NH

Sofosbuvir (SOF)/Velpatasvir (VEL)SOF: Nucleotide polymerase inhibitor with

activity against HCV GT 1–6

VEL: Potent pangenotypic NS5A inhibitor

Voxilaprevir (VOX)HCV NS3/4A PI with potent antiviral activity against GT 1–6, including most RASs

SOF/VEL/VOXOnce daily, oral, fixed-dose combination (400/100/100 mg) for GT 1–6

VOXNS3/4A Proteaseinhibitor

VOXNS3/4A proteaseinhibitor

VELNS5A inhibitor

SOF Nucleotide polymerase

inhibitor

VOXNS3/4A proteaseinhibitor

VELNS5A inhibitor

SOF Nucleotide polymerase

inhibitor

Voxilaprevir/Velpatasvir/Sofosbuvir: STR

Velpatasvir/Sofosbuvir (Epclusa®) for 12 weeks across all genotypes (ASTRAL-1, ASTRAL-2 and ASTRAL-3)

AE: adverse event; D/C: discontinuation; LTFU: lost to follow-up; SAE: serious adverse eventAgarwal K, et al. EASL 2016; Poster #SAT-195; Jacobson I, et al. EASL 2016; Poster #SAT-168

SV

R12

(%

)

1015/1035

323/328

237/238

264/277

116/116

34/35

41/41

2 relapses

2 LTFU

1 D/C

1 D/C11

relapses

2 D/C1 death

• 2% of patients experienced one or more SAE; no SAEs were considered study drug related

• 2 patients discontinued treatment due to AEs

SOF/VEL (Epclusa®) is effective in patients with advanced fibrosis and cirrhosis (ASTRAL 1, 2 & 3)

Asselah T, et al. Liver Int 2018, in press

Overall

98

CirrhosisAdvanced fibrosis

490/501

212/220

278/281

9699P

atie

nts

wit

h S

VR

(%

)

0

20

40

60

80

10097

1 2

97

2 3

97

2 4

99

1 6

100

0

10

96

3 5

95

412

100

0

98100

0

46

100

0

98

SVR12, %

GT 4

11

431445

150155

3636

126132

3941

222228

Total GT 1 Total GT 1a GT 1b GT 2 GT 3 GT 5 GT 6 Other

11

66

6869

SOF/VEL/VOX for 12 Weeks in DAA-Experienced Patients

Breakthrough 1* 1 1 0 0 0 0 0 0 0

Relapse 7 2 2 0 0 4 1 0 0 0

Other 6 3 2 1 0 2 1 0 0 0

*Patient had drug levels consistent with nonadherence.Roberts, EASL 2017, SAT-280

Integrated Efficacy Analysis of POLARIS-1 and -4

The SVR12 rate was 97% (431/445) in DAA-experienced patients treated with SOF/VEL/VOX for 12 weeks; Rates were similar regardless of genotype

1 Introduction






In vitro:1,2

● High barrier to resistance● Potent against common NS3 polymorphisms (eg.,

positions 80, 155, and 168) and NS5A polymorphisms (eg., positions 28, 30, 31 and 93)

● Additive/synergistic antiviral activity

Clinical PK & metabolism:

● Once-daily oral dosing● Minimal metabolism and primary biliary excretion● Negligible renal excretion (<1%)

G/P is co-formulated and dosed once daily as three 100 mg/40 mg pills for a total dose of 300 mg/120 mg.Glecaprevir was identified by AbbVie and Enanta.

Glecaprevir(ABT-493)

pangenotypic NS3/4A protease inhibitor

Pibrentasvir(ABT-530)

pangenotypic NS5A inhibitor

Collectively: G/P2nd generation3 2nd generation3

1. Ng TI, et al. Abstract 636. CROI, 2014. 2. Ng TI, et al. Abstract 639. CROI, 2014. 3. Pawlotsky, Gastroenterology 2016

Glecaprevir/Pibrentasvir (Maviret®)

Glecaprevir/Pibrentasvir (Maviret) in Patients with HCV GT1, 2, 4-6 Infection with or without Compensated Cirrhosis

383387

193197

177186

9899

98

93

100 10099 99

100 100 100 100

SVR1

2 (%

)

348351

596606

nN

MAVIRET for 12 Weeks inTN/TE CC Patients:

EXPEDITION-1

MAVIRET for 12 Weeks inTN/TE CC Patients:

EXPEDITION-1

MAVIRET for 8 Weeks inTN/TE NC Patients:

ENDURANCE-1 and SURVEYOR-2

MAVIRET for 8 Weeks inTN/TE NC Patients:

ENDURANCE-1 and SURVEYOR-2

193197

3131

145146

8990

1010

BT 1 1

Relapse 2 2 1 1

Non-VF* 7 2 2 3

1616

22

77

All analyses are using the ITT population.TN, treatment-naïve; TE, treatment-experienced with IFN or pegIFN ± RBV, or SOF + RBV ± pegIFN; NC, non-cirrhotic; CC, compensated cirrhotic; ITT, intent-to-treat; BT, breakthrough; VF, virologic failure.*Includes patients who discontinued due to adverse events, lost to follow-up, or withdrew.

4346

22

MAVIRET Summary of Product Characteristics; Accessed August 2017.. Asselah T, et al. Clin Gastroenterol Hepatol. 2017

Integrated Efficacy Analysis: High SVR Rates with 8 and 12 Weeks of Glecaprevir/Pibrentasvir in GT1–6 Patients without Cirrhosis

Puoti M, et al. J Hepatol 2017; 66(Suppl):S721 (poster presentation SAT-233).

BT, breakthrough; mITT, modified intent-to-treat, (excludes non-virologic failures); *TE, treatment-experienced (includes patients with prior SOF use); TN, treatment-naive Includes patients with prior SOF use (8-week Maviret [n = 7] and 12-week Maviret [n = 9]);† All GT3 patients were treatment-naïve.

Integrated efficacy analysis of 8- or 12-weeks Maviret treatment in non-cirrhotic patients with GT1–6 infection across seven phase 2 or 3 clinical trials

Integrated efficacy analysis of 8- or 12-weeks Maviret treatment in non-cirrhotic patients with GT1–6 infection across seven phase 2 or 3 clinical trials

Overall GT1 GT2 GT3 GT4 GT5 GT60

20

40

60

80

10099 99,7 99 97 100 100 10099,6 100 100 98 100 100 100

8 week G/P 12 week G/P

SVR12 (%)

383384

400400

193195

232232

177183

258262

4343

111111

22

2828

99

3131

807816

10601064

nN

TN/TE* (mITT)

†

2 BT

7 relapse

1 BT

3 relapse

Failure rate was similar between 8 and 12 week

Maviret®

Failure rate was similar between 8 and 12 week

Maviret®

GP—VHC—RMR—093—sept17—R—A—DLU sept18 v2

Glecaprevir/Pibrentasvir (Maviret) in Patients with HCV GT3 Infection with or without Compensated Cirrhosis

SVR1

2 (%

)

BT 1 1

Relapse 5 3 1

Non-VF* 2 7 3

nN

All analyses are using the ITT population.TN, treatment-naïve; TE, treatment-experienced with IFN or pegIFN ± RBV, or SOF + RBV ± pegIFN; BT, breakthrough; CC, compensated cirrhosis; NC, noncirrhotic; DCV, daclatasvir; ESRD, end-stage renal disease; SOF, sofosbuvir; TE, treatment experienced; TN, treatment naive; VF, virologic failure.*Includes patients who discontinued due to adverse events, lost to follow-up, or withdrew.

95 95

97

SVR1

2 (%

)

111115

222233

149157

nN

BT 1

Relapse 2

Non-VF* 1

MAVIRET for 8 or 12 Weeks inTN NC Patients:ENDURANCE-3

MAVIRET for 8 or 12 Weeks inTN NC Patients:ENDURANCE-3

MAVIRET8 weeks

MAVIRET12 weeks

DCV + SOF12 weeks

MAVIRET for 12 Weeks in TN CC Patients, or 16 Weeks in TE NC/CC

Patients: SURVEYOR-2 Part 3

MAVIRET for 12 Weeks in TN CC Patients, or 16 Weeks in TE NC/CC

Patients: SURVEYOR-2 Part 3

98

96

TN CC12 weeks

TE NC/CC16 weeks

MAVIRET Summary of Product Characteristics; Accessed August 2017.

3940

6669

1 Introduction






HCV NS5A inhibitor, 50 mg

Elbasvir(MK-8742)

Grazoprevir(MK-5172)

HCV NS3/4A inhibitor, 100 mg

Elbasvir/Grazoprevir (Zepatier®)

• High activity in vitro1–3 • Efficacious in GT1 & GT4 treatment-naive and treatment-

experienced cirrhotic and noncirrhotic patients with HCV, and in HIV/HCV coinfected patients4–6

• All-oral, once-daily regimen

HCV = hepatitis C virus; HIV = human immunodeficiency virus.1. Summa V et al. Antimicrob Agents Chemother. 2012:56;4161–4167. 2. Coburn CA et al. ChemMedChem. 2013;8:1930–1940. 3. Harper S et al. ACS Med Chem Lett. 2012;3:332–336. 4. Zeuzem S et al. Ann Intern Med. 2015;163:1–13. 5. Lawitz E et al. Lancet. 2015;385:1075–1086. 6. Rockstroh JK et al. Lancet HIV. 2015;2:e319–e327.

EBR/GZR in Treatment-Naive Patients With Cirrhosis

LTFU/early discontinuation 1b 1b 0 0

Breakthrough 1 1 0 0

Relapse 1 1 0 0a mFAS excludes patients who discontinued treatment for reasons unrelated to study medication.bDeath (coronary artery disease).EBR/GZR = elbasvir/grazoprevir; RBV = ribavirin; FAS = full analysis set; SVR12 = sustained virologic response 12 weeks after the cessation of treatment; GT = genotype; LTFU = lost to follow up; mFAS = modified full analysis set.

1. Jacobson I et al. AASLD 2015, Abstract 42.

Patie

nts

Achi

evin

g SV

R12,

%66

98 96 100 100

0

25

50

75

100

5656

7376

135138

• Integrated analysis of patients with cirrhosis from 6 clinical trials in the Phase 2/3 clinical program

• Patient population● Treatment-naive● With or without HIV-1

coinfection

Efficacy of 12 Weeks of EBR/GZR Without RBV in Patients With Compensated Cirrhosis99 97 100 100

66

5656

7375

135137

mFASa

FAS

Comorbidity - Stage 4-5 CKD

OAT/PWID ± HIV IBLD ± HIV HIV ± HIV ± HIV

Genotypes 1,4,6 1 1,4,6 1,4 1,4,6 1,4,6 1,4,6

Treatment Experience TN TN/PR-PTF TN TN/PR-PTF TN PR-PTF PR-PTF

12 Weeks EBR/GZR Without RBV 16 Weeks EBR/GZR +

RBV

Elbasvir/Grazoprevir (Zepatier): Efficacy in Different Patient Populations

210217

100106

299312

97103

104104

189198

115116

Phase 3 studies vs placebo

amFAS excludes patients who failed for reasons unrelated to study medication.EBR/GZR = elbasvir/grazoprevir; SVR12 = sustained virologic response 12 weeks after the cessation of treatment; CKD = chronic kidney disease;OAT = opioid agonist therapy; PWID = people who inject drugs; IBLD = inherited blood disorders; TN = treatment naive; HIV = human immunodeficiency virus;TE = treatment experienced; RBV = ribavirin; PR = peginterferon + ribavirin; PTF = prior-treatment failure; mFAS= modified full analysis set.1. Roth D et al. Lancet. 2015;386:1537–1545. 2. Dore GJ et al. EASL 2016, SAT-163. 3. Hezode C et al. EASL 2016, SAT-128. 4. Zeuzem S et al. Ann intern Med. 2015;163:1–13. 5. Rockstroh JK et al. Lancet HIV. 2015;2:e319–e327. 6. Kwo P et al. Gastroenterology. 2017;152:164–175.

Patie

nts

Achi

evin

g SV

R12,

%

99 96 9496 97 94100

Overall mFASa SVR12 rates from the Phase 3 clinical trial program

Treatment-experienced

1 Introduction






ASCEND: Nonrandomized Phase IV Trial of HCV Treatment Outcomes by DAA Prescriber Type

• Pts (N = 600) from 13 urban, FQHCs in DC, all treated with LDV/SOF per FDA prescribing info; all providers given 3-hr training in AASLD/IDSA HCV guidance

Kattakuzhy S, et al. Ann Intern Med. 2017;167:311-318.

SV

R12

(%

)

100

80

60

40

20

0NP/PA Primary MD Specialist MD Overall

89 87 84 86

134/150

139/160

243/290

516/600n/N =

IFN-Free DAA Therapy: Opioid Substitution Therapy vs No Opioid Substitution Therapy

1. Feld JJ, et al. N Engl J Med. 2014;370:1594-1603.; 2. Puoti M, et al. AASLD 2014. Abstract 1938.3. Grebely J, et al. EASL 2017. Abstract FRI-236.; 4. Grebely J, et al. Clin Infect Dis. 2016;63:1405-1411.5. Grebely J, et al. Clin Infect Dis. 2016;63:1479-1481.; 6. Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.7. Dore GJ, et al. Ann Intern Med. 2016;165:625-634.; 8. Grebely J, et al. EASL 2017. Abstract FRI-235. .

OBV/PTV/RTV + DSV + RBV[1,2]

OBV/PTV/RTV + DSV ± RBV[3]

LDV/SOF+ RBV[4]

n/N =0

60

80

40

20

100

49/51

966/984

98 96

455/473

54/56

269/296

299/316

66/70

1822/1882

96 97 95 91

SVR1

2 (%

)

9496 94

SOF/VEL[5] EBR/GZR[6,7]

No OST OST

140/ 149

4405/

4598

96 8897

7/8

424/437

SOF/VEL/VOX[8]

9895

40/ 41

543/570

12 Wks 8 Wks

The need to cure of all HCV infected Patients, No patient left behind

Asselah et al. Eliminating Hepatitis C within Low Income Countries – the need to cureGenotypes 4, 5, 6. Journalof Hepatology, 2018 in press

WHO region Map key Bestestimate

Africa 31,0

America 6,4

Middle East 62,5

Europa a 61,8

South Est Asia 14,8

West Pacific 6,0

Total 23,7

Incidence rate (per 100 000)

Hutin J-F, Suisse, WHO, EASL 2017

How to achieve HCV elimination

PREVENTION

• Harm reduction• Infection control• Blood safety


PREVENTION


AWARENESS

• Increase awareness

• Fights barriers & stigma

• Advocacy


PREVENTION


TEST AND TREAT

• HCV screening (universal)

• Linkage to care : Treat with optimal DAAs

AWARENESS



• Advocacy


PREVENTION


TEST AND TREAT

• HCV screening (universal)

• Linkage to care : Treat with optimal DAAs

AWARENESS



• Advocacy

HCV elimination


Treatment of HCV : 100 % cure ? - APHC – International … · · 2018-02-12German P, et al....

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