HCV protease inhibitors in the treatment of naive and … · SVR, considered virologic cure, was...

HCV protease inhibitors in the treatmentof naive and experienced patients

Pr Dominique SalmonCochin Hospital, Paris Descartes University, Paris, France

2nd Congress of Federation of Arab Societies of ClinicalMicrobiology and Infectious Diseases

22nd Tunisian Congress of Infectious Diseases

http://www.infectiologie.org.tn

World prevalence of HCV

< 1%1 - 2,4%2,5 - 4,9%5 - 10%> 10%Data non available

WHO (97)http://www.infectiologie.org.tn

Distribution of HCV genotypes

North America

South America

South Africa

Central Africa

North EuropeRussia

ChinaJapan

AustraliaNew Zeland

Sout East Asia

1a 51b 2 3 4 6

Genotypes/sub-types

South Europa

Forns et Bukh (98)http://www.infectiologie.org.tn

Chronic hepatitis C progression

HCC3%/yr Decompensation

5%- 10%/anLiver mortality

2%- 5%/yr

5- 10 years 15- 30 years >30 years

Rapid Intermediate Slow

Progression speed

Cirrhosis

Fibrosis stage 0

1

2

3

4


Therapeutic objectives for HIV, HBV and HCV

H

HBV

Host cell

cccDNAHost DNA

Integrated DNA

Nucleus

H

HIVHost cell

Host DNA

Proviral DNA

Nucleus

H

HCVHost cell

Host DNA

Nucleus

HCV RNA

Life long suppression of viral replication

Definitive viral clearanceand SVR

Long term suppression of viral replication

Kieffer et al. J Antimicrob Chemother 2010; Sorriano et al. J Antimicrob Chemother 2009; Clavel et al. New Engl J Med 2004; Zoulim &Locarnini Gastroenterology 2009; Sarrazin & Zeuzem Gastroenterology 2010


Combinaison of peg interferon and ribavirin: first step towards cure …

PatientsachievingSVR (%)

100

80

60

40

20

024 48 78 Peg-IFN IFN +

ribavirinPeg-IFN +ribavirinWeeks

IFN monotherapy

All genotypesGenotype 1Genotypes 2 or 3

6-19 11-19 10-22

18-3935-43

61-79

33-36

76-82

42-46

*Range of values reported; lower bar represents lower value;


0%

20%

40%

60%

80%

100%

IFN 24 wk IFN 48 wk

IFN 48 wk& Ribavirin

PEG-IFN 48 wk& Ribavirin

1990 1998 2000 2002 2012- 2015

Sustained VirologicalResponses Rates

Direct antivirals

2007

Future of anti HCV therapy

Optimization and individualization


Better knowledge of HCV enzymes targeted by specific inhibitors

Di Bisceglie et al., Hepatology 2002http://www.infectiologie.org.tn






Efficacy of with HCV protease inhibitors with peg interferon and ribavirin in NAIVE

patients infected with genotype 1


Peg-IFNα-2a + RBV

Peg-IFNα-2a + RBV

eRVR*

YES

NO

Telaprevir1,2

Short duration (24W): 59–65%SVR: 89–92%

SVR: 54–64%

* HCV RNA <25 IU/mL at wks 4 and 12

1. Jacobson IM, et al. Hepatology 2010; 52 (S1) [abstract 211]2. Sherman KE, et al. Hepatology 2010; 52 (S1) [abstract LB-2]

Telaprevir in GT1 treatment-naive patients

0 Weeks 484 8 12 24 28

TPV + Peg-IFNα-2a + RBV


SVR rate with telaprevir and peginterferon/RBV versus PR

ADVANCE and ILLUMINATE trials

46

0

20

40

60

80

100

SVR

(%)

T12/PR

683/903

PR48

166/361n/N =

74–79*

INCIVO (telaprevir) EU SmPC

*p<0.0001 T12/PR vs PR48 (79% versus 46%) in ADVANCESVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was usedhttp://www.infectiologie.org.tn

1. Jacobson IM, et al. Hepatology 2010; 52 (S1) [abstract 211]; 2. Sherman KE, et al. Hepatology 2010; 52 (S1) [abstract LB-2];

3. Poordad F, et al. Hepatology 2010; 52 (S1) [abstract LB-4]

TPV and BOC in GT1 treatment-naive patients

Peg-IFNα-2a + RBV

Peg-IFNα-2a + RBV

eRVR*

YES

NO

Telaprevir1,2

SVR: 54–64%

* HCV RNA <25 IU/mL at wks 4 and 12

0 Weeks 484 8 12 24 28

BOC + Peg-IFNα-2b + RBV

W8–W24 RVR **

BOC + Peg-IFNα-2b + RBV

** HCV RNA <9.3 IU/mL

0 Weeks 484 8 12 24 28

YES

NO

TPV + Peg-IFNα-2a + RBV

P/Rlead-in

BOC +P/R

Boceprevir3


38

63 66

0

20

40

60

80

100

SVR

(%)

BOC RGT

233/368

BOC44/PR48

242/366

PR48

137/363n/N =

VICTRELIS (boceprevir) EU SmPC

* *

*p<0.001 for both boceprevir arms versus PR48SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week value was carried forward

SVR rate with boceprevir and peginterferon/RBV versus PR

SPRINT 1 and SPRINT 2 trials


Impact of rapid virologic response on SVR : leading to different durations of treatment

Exemple of telaprevir

Sherman KE, et al. N Engl J Med 2011;365:1014–24

*Patients who achieved eRVR (undetectable HCV RNA at Weeks 4 and 12) and completed the Week 20 visit were randomized to receive an additional 4 or 28 weeks of PR alone65% of patients achieved an eRVR (352/540); 322/352 were randomized and 30/352 patients discontinued before randomization at Week 20

Treatment duration according to eRVR status

60%*n=32222%

n=118

92 88

64

23

0

20

40

60

80

100

SVR

(%)

<20 weeks

23/100

SVR rate

18%n=100

Eligible for 24 weeks and randomized to 24 or 48 weeks*

48 weeks

<20 weeks (due to premature treatment discontinuation)

eRVR+*

eRVR–

<20 weeks

eRVR–T12PR48

76/118

eRVR+ T12PR48140/160

eRVR+ T12PR24149/162

∆ 4% (2-sided 95% CI = –2% to +11%)


Efficacy of with HCV protease inhibitors with peg interferon and ribavirin in

patients infected with genotype 1, non responders to peg IFN/RBV


Definitions of non responses to Peg-IFN/RBV

Detection limit

Relapse

Null response

BreakthroughPartial response

Treatment

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72

HC

V R

NA

leve

l

Weeks

2 log10 drop

Non-response

Adapted from Shiffman M. Curr Gastroenterol Rep 2006;8:46–52Neumann A, et al. Science 1998;282:103–7; De Bruijne J, et al. Neth J Med 2008;66:311–22http://www.infectiologie.org.tn

SVR to telaprevir with PR in relapsers, partial responders and null responders to PR

22

88 84

15

5661

5

33 31

0

20

40

60

80

100

PR48

4/27

T12/PR48

30/49

SVR

(%)

Prior relapsers Prior partialresponders

LI T12/PR48

27/48n/N=

PR48

2/37

T12/PR48

22/72

LI T12/PR48

25/75

PR48

15/68

T12/PR48

122/145

LI T12/PR48

124/141

Prior null responders

**

**

* *

INCIVO (telaprevir) EU SmPC

*p<0.001 vs PR48SVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was usedhttp://www.infectiologie.org.tn

29

6975

7

40

52

0

20

40

60

80

100

PR48

2/29

BOC44/PR48

30/58

SVR

(%)

Prior relapsers Prior partialresponders

BOCRGT

23/57n/N=

PR48

15/51

BOC44/PR48

77/103

BOC RGT

72/105

Prior null responders were excluded from RESPOND-2

SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week 12 value was carried forward VICTRELIS (boceprevir) EU SmPC

SVR to boceprevir with PR in relapsers and partial responders to PR


Three main baseline predictors of SVR under tritherapy with PI

HCV viral load

HCV G1 subtype: 1b > 1a

Fibrosis stage


HCV G1 subtype as a Predictor of SVR (BOC Arms Combined)

20

54

27

43

25

47

0

20

40

60

80

100

% S

VR

1154

1935

33124

44178

2661

4596

1a 1b 1a 1b 1a 1b

RESPOND-2 SPRINT-2 CombinedStudies

p = 0.001 p = 0.028 p < 0.001

Bacon, AASLD, 2011http://www.infectiologie.org.tn

Fibrosis Score as a Predictor of SVR (BOC Arms Combined)

41

21

37

15

38

17

0

20

40

60

80

100

% S

VR

2663

419

58157

842204

278

46

F0/1/2 F3/4RESPOND-2 SPRINT-2 Combined

Studies

p = 0.11 p = 0.025 p = 0.007

F0/1/2 F3/4 F0/1/2 F3/4


HCV Viral Load as a Predictor of SVR (BOC Arms Combined)

59

27

52

26

54

26

0

20

40

60

80

100

% S

VR

1017 20

73

2752

376936

14056

213

RESPOND-2 SPRINT-2 CombinedStudies

p = 0.014 p <0.001 P<0.001

< 2.106 > 2.106 UI/ml < 2.106 > 2.106 UI/ml < 2.106 > 2.106 UI/ml


SAFETY OF TELAPREVIR OR BOCEPREVIR IN COMBINATION WITH PEGINTERFERON

ALFA/RIBAVIRIN, IN CIRRHOTIC NON RESPONDERS FIRST RESULTS OF THE FRENCH EARLY ACCESS

PROGRAM (ANRS CO20-CUPIC)

C Hézode1, C Dorival2, F Zoulim3, T Poynard4, P Mathurin5, S Pol6, D Larrey7, P Cacoub4, V de Ledinghen8, M Bourlière9, PH Bernard10, G Riachi11, Y Barthe2, H Fontaine6, F Carrat2, JP Bronowicki12

for the CUPIC study group (ANRS CO 20)

Hôpital Henri Mondor, Créteil1, UMR-S 707, Paris2, INSERM U871, Lyon3, Hôpital de la Pitié-Salpêtrière, Paris4, Hôpital Claude Huriez, Lille5, Hôpital Cochin, Paris6, Hôpital Saint-

Eloi, Montpellier7, Hôpital Haut-Lévèque, Pessac8, Fondation Hôpital Saint Joseph, Marseille9, Hôpital Saint André, Bordeaux10, Hôpital Charles Nicolle, Rouen11, Hôpital de Brabois, Nancy12, France


CUPIC Patients HCV genotype 1 patients

Compensated cirrhosis (Child Pugh A)

Non-responders

– Relapsers

– Partial responders

(↓ >2 log10 HCV RNA decline at Week 12)

– Null responders theoretically excluded

Treated in the French early access program


Treatment regimen

Peg-IFN α-2a + RBVTVR + Peg-IFN α-2a + RBV Follow-up

484 160 128Weeks

72

SVR assessment

BOC + Peg-IFN α-2b + RBV Follow-upPeg-IFN + RBV

36

http://www.afssaps.fr/var/afssaps_site/storage/original/application/4b8c53711bab9d8f7d4c3f947caa90f6.pdfhttp://www.afssaps.fr/var/afssaps_site/storage/original/application/fa78af08e029caf9d82bcd9d3e77eb09.pdf

BOC: 800 mg/8h; Peg-IFNα-2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/day

TVR: 750 mg/8h; Peg-IFNα-2a: 180 µg/week; RBV: 1000 to 1200 mg/day

Interim analysis


Patients, (% patients with >1 event) Telaprevirn=296

BoceprevirN=159

Serious adverse events (SAEs)* 48.6% 38.4%

Premature discontinuation 26.0% 23.9%

Death 2.0% 1.3%

Infection (Grade 3/4) 8.8% 2.5%

Anemia (Grade 3/4) 19.6% 22.6%

EPO use 56.8% 66.0%

Transfusion 15,2% 10.7%

Rash Grade 3Grade 4

6.8%0.7%

0%0%

Pruritus (Grade 3/4) 3.7%*407 SAEs in 144 patients; SCAR: severe cutaneous adverse reaction

Preliminary safety findings


Telaprevir: preliminary efficacy data

0

20

40

60

80

100

Week 4 Week 8 Week 12 Week 16

53

85 86 86

% o

f pat

ient

s w

ith u

ndet

ecta

ble

HC

V R

NA

145/276 224/265 219/254 177/205


Boceprevir: preliminary efficacy data

0

20

40

60

80

Week 4 Week 8 Week 12 Week 16

% o

f pat

ient

s w

ith u

ndet

ecta

ble

HC

V R

NA

1

37

61

71

2/155 55/149 88/144 89/126


Practical use of boceprevir and telaprevir in France

• Indications : treatment of hepatitis C, genotype 1, in association with PR, in patients with compensated liver disease, naive or non responders to previous anti HCV treatment.

BOCEPREVIR ( VICTRELIS°) 4 capsules 200 mg x 4/d Lead-in : PegIFN+RBV

for 1 month BOC+PegIFN+RBV until

W44, or W28 (if eRVR+)

TELAPREVIR (INCIVO°) 2 capsules 750 mg, TID,

with meal Duration : 12 weeks Followed by PR until

W48 or 24 (if eRVR+)


The future?

Combinations of direct active drugs (DADs)– High barrier of resistance– With and without interferon

Short duration of treatment : 24, 12, 8 weeks

Pangenotypic or genotype specific

Questions unresolved– Interactions – Place of ribavirin


Novel anti HCV drugs

Pawlotsky JM. Hepatology 2011 [epub ahead of print]Zeuzem S. CCO slide set

NS3 ProteaseNS5B Polymerase

NS5A CyclophilinNucleos(t)ide(NPOL)

Non-nucleoside(NNI)

TelaprevirBoceprevirDanoprevirTMC435 BI 201335asunaprevirBMS-650032ABT-450GS-9451GS-9256MK-5172ACH-1625VX-985CTS-1027

MericitabineGS7977IDX 184

TegobuvirFilibuvirANA598BI 207127ABT-333VX-222ABT-072BMS-791325

daclatasvirBMS 824393CF102

AlisporivirSCY-465




43/7748/81 49/80 53/78 18/46

x 3/j16+

x 3/j28+

x 3/j40+

x 2/j28+

x 3/j28-

Doses de BI-7127Durée (sem.)

RBV +/-

RVS12%

Zeuzem S, EASL 2012, Abs. 101*RVS4

Traitement without interferon in genotype 1b naive patients

60

• BI-201335 (prot inhib) + BI-207127 ( NS5B pol inhib) +/- RBV


Gane EJ, EASL 2012, Abs. 1113

Genotypes2/3

Naive8 weeks

n (%)

Genotype 1Null

responders12 weeks

n (%)

Genotype 1Naive

12 weeksn (%)

Genotypes2/3

Non responders12 weeks

n (%)

W2 10/10 (100) 7/10 (70) 17/24 (71) 21/25 (84)

SVR4 10/10 (100) 1/9 (11) 22/25 (88) 12/15 (80)

SVR12 10/10 (100) - - -

Virologic response

ELECTRON : bitherapy GS-7977/ribavirin 49

8 weeks for GT 2/3 naive but 12 weeks not suffisant for GT1 nullresponders


Efficacy of daclatasvir and GS-7977 +/-ribavirine in genotype 1 naive patients

Mal

ades

(%)

N = 0

20

40

60

80

100

15 15

67

14

79 67

87

100

93

100

73

100

100

100

93

93

100

100

87

87

86

86

93

93

100

100

100

100

100

100

15 1514 15 1514 15 1514 15 1514S2 S12 S24

(Fin traitement)S4 RVS4

Sulkowski M, EASL 2012, Abs. 1422

100 % (44/44) of G1 patients had an RVS W4 with the combinationDCV + GS7977

GS-7977 LI + DCV

DCV + GS-7977+ RBV

DCV + GS-7977

% < LDQ

% < LDD

69


First generation protease inhibitors associated with pegylated interferon and ribavirin– 30% increase of SVR rate, in naive and non responders

patients

– GT1 only

– Low efficacy if cirrhosis and null responders

– Severe side effects

Future– Several new molecules with high genetic barrier

– dual or triple triple therapy with ou without RBV

– End of life for interferon in HCV disease

Conclusions


Course of acute infection towards chronicity

Symptoms +/-

Time after Exposure

Tite

ranti-HCV

ALT

Normal

0 1 2 3 4 5 6 1 2 3 4YearsMonths

HCV RNA


Patients, n (% patients with at least one event)

Telaprevir n=296

Serious adverse events (SAEs)* 144 (48.6%)

Premature discontinuationDue to SAEs

77 (26.0%)43 (14.5%)

DeathSepticemia, Septic shock, Pneumopathy, Oesophageal varices Bleeding, Encephalopathy, Lung carcinoma

6 (2.0%)

Infection (Grade 3/4) 26 (8.8%)

Asthenia (Grade 3/4) 14 (4.7%)

RashGrade 3Grade 4 (SCAR)

20 (6.8%)2 (0.7%)

Pruritus (Grade 3/4) 11 (3.7%)

Hepatic decompensation (Grade 3/4) 13 (4.4%)*407 SAEs in 144 patients; SCAR: severe cutaneous adverse reaction

Telaprevir: preliminary safety findings


Patients, n (% patients with at least one event) Telaprevir (n=296)

AnemiaGrade 2 (8.0 – <10.0 g/dL)Grade 3/4 (<8,0 g/dL)EPO useBlood transfusion

58 (19.6%)30 (10.1%)

168 (56.8%)45 (15.2%)

NeutropeniaGrade 3 (500 – <1000/mm3)Grade 4 (<500/mm3)G-CSF use

12 (4.0%)2 (0.7%)7 (2.4%)

Thrombopenia Grade 3 (25 000 – <50 000)Grade 4 (<25 000)Thrombopoïetin Use

35 (11.8%)4 (1.3%)5 (1.7%)EPO: érythropoïétine; G-CSF: granulocyte-colony stimulating factor

Telaprevir: preliminary safety findings


Patients, n (% patients with at least one event) Boceprevir (n=159)

Serious adverse events (SAEs)* 61 (38.4%)

Premature discontinuationDue to SAE

38 (23.9%)12 (7.4%)

DeathBronchopulmonary infection, Sepsis 2 (1.3%)Infection (Grade 3/4) 4 (2.5%)

Asthenia (Grade 3/4) 9 (5.7%)

RashGrade 3Grade 4 (SCAR)

00

Pruritus (Grade 3/4) 1 (0.6%)

Hepatic decompensation (Grade 3/4) 7 (4.4%)

*158 SAEs in 61 patients; SCAR: severe cutaneous adverse reaction

Boceprevir: preliminary safety findings


Patients, n (% patients with at least one event) Boceprevir (n=159)

AnemiaGrade 2 (8.0 – <10.0 g/dL)Grade 3/4 (<8,0 g/dL)EPO useBlood transfusion

36 (22.6%)16 (10.1%)

105 (66.0%)17 (10.7%)

NeutropeniaGrade 3 (500 – <1000/mm3)Grade 4 (<500/mm3)G-CSF use

7 (4.4%)1 (0.6%)6 (3.8%)

Thrombopenia Grade 3 (25 000 – <50 000)Grade 4 (<25 000)Thrombopoïetin Use

10 (6.3%)1 (0.6%)3 (1.9%)

EPO: érythropoïétine; G-CSF: granulocyte-colony stimulating factor

Boceprevir: preliminary safety findings


Main classes of anti HCV inhibitors

Protease inhibitors

– 1st generation and approved: telaprevir, boceprevir

– 2nd generation

Polymerase inhibitors– Nucleosidic inhibitors

– Non nucleosidic inhibitors

NS5A inhibitors

Entry inhibitors

Immunomodulators


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HCV protease inhibitors in the treatment of naive and … · SVR, considered virologic cure, was...

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