How to optimize triple therapy with 1st generation

of protease inhibitors in genotype-1 patients

Assoc. Prof. Adrian Goldis
University of Medicine Timisoara,
Clinic of Gastroenterology and Hepatology

Deuffic-Burban.S et al. Gastroenterology 2012; 143:974-85

The launch of Boceprevir (BOC)and Telaprevir(TVR)

dramatically improved SVR rates in genotype-1
patients
In phase III studies ,SVR rates improved by nearly
30%, reaching 63% with BOC+PEG-IFN+RBV and
75% with TLV+PEG-IFN+RBV in treatment nave
genotype-1 patients
Benefit higher:treatment-experienced patients-SVR
increased by 60% in relapsers, 45% in partial
responders and 25% in null responders

The side effects profiles(of BOC and TVR) + the costs

per SVR patients with advanced hepatic fibrosis =>
they should ideally no longer be used in patients
infected with HCV genotype 1
New HCV DAAs in the firts half of 2014 in the EU:
1. Sofosbuvir,
2. Simeprevir,
3. Daclatasavir

EASL:The panel recognises the heterogenity

of per capita incomes and health insurance
systems across Europe and in the other
regions, and therefore the possible necessity
to continue to utilise current standards of
care with pegylated IFN-alfa and ribavirin,
with or without the first-generation protease
inhibitors telaprevir and boceprevir

S
V
R
%

99/180

6/32

58/107

6/22

1081/
1638

122/
436

Vierling JM, et al. EASL 2013

S
V
R
%

96/180

48/100

65/73

28/96

Vierling JM, et al. EASL 2013

The good candidates:

Naives
Effect

OR(95% CI)

P Value

HCV RNA
level
400000 vs
>400000

11.6
(1.5-87.8)

0,02

IL28B CC vs
TT

2.6 (1.3-5.1)

0.006

IL28B CC vs
CT

2.1(1.2-3.7)

0.01

Cirrhosis No
vs Yes

4.3(1.611.9)

0.04

Genotype 1b
vs 1a

2(1.2-1.4)

0.005

Non Black vs
Balck

2(1.1-3.7)

0.03

Gordon SC et al. J Clin Gastroenterol 2013.

Treatment-experienced
Effect

OR(95% CI)

P Value

Relapser vs
nonresponder

2.6(1.3-5)

0.06

HCV RNA at
baseline

SVR(%)

1000000 UI/ml

78-83%

>1000000 UI/ml

57-68%

Poordad F et al. Gastroenterology

2012;143:608-618

CUPIC (n=212): 2 baseline factors associated with the

occurrence of death at cirrhotic patients:
1.
Platelet count<100000/mmc
2.
Seric albumin<35 g/dl;
At these subgroup:

Risk of SAE=51,4% vs 6,2% (platelet count

>100000/mmc+seric albumin>3,5 g/dl
subgroup)

SVR12 =27% vs 54.9% (platelet count

>100000/mmc+seric albumin>3,5 g/dl
subgroup)

Marc Bourliere, et al.:How to optimize current

therapy of HCV genotype 1 infection with
Boceprevir, Paris 2014

Risk factors for decompensation among cirrhotic patients during PI

therapy
Baseline
Characteristics

Odds ratio Minimally

Adjusted Estimates

P value

CrCl(ml/min)

0.99

0.03

Albumin (g/dl)

0.3

<0.1

HCV RNA
(log UI/ml)

0.76

<0.1

Bilirubin
(log mg/dl)

2.93

0.2

Afdhal N, et al. AASLD 2013.Abstract 1865

The patient who do not be treated:Null responder

cirrhotic
BOCEPREVIR -CUPIC
P=0.0013
P=0.032
P=0.014

55/ 102

36/ 94

0/10

Fontaine H, France, AFEF 2013

Jacobson I et al. Hepatology

2012;56:567-575

BOC:New TW8 stopping rules in patients with cirrhosis

Early viral kinetics allows to stop or continue

treatment
Vierling JM et al. EASL 2013, Abs. 1430

Boceprevir:New TW8 stopping rules in patients with

cirrhosis-CUPIC
P<0.001

Fontaine H, France, AFEF 2013,

Marc Bourlier, Paris Hepatite

Conference 2014

Treatment-nave G1 patients (n=687) received BOC-based

therapy.Overall, 500 patients developed anemia(Hb 10g/dl or were
expected to reach that nadir before next visit) and were randomized to
have anemia managed with either EPO(40000 units/week SC), or RBV
dose reduction(by 200-400 mg/day).Transfussion in patients with Hb 8,5
g/dl was allowed to prevent study discontinuation
Poordad F, et al. EASL
2012.Abstract 1419

Hezode C, et al. AASLD 2013

N=167 treatment-experienced patients (85,6 % relapsers)

A week 8 model predicting lack of EVR was created:
Association between clinical/biological parameters and presence of
a viral load >100 IU/ml at week 12

Variable

OR

95% CI for OR

P value

Baseline ALT (IU/L)

1.0116

1.0053 to 1.0180

0.0003

F4 METAVIR

2.4103

1.0515 to 5.5251

0.03

Hb level at 8
week(g/dl)

1.6357

1.2772 to 2.0948

0.0001

ALT at 8 week(IU/L)

1.0211

1.0089 to 1.0334

0.0007

>1 log HCV RNA

decrease at week 4

0.1276

0.0407 to 0.3995

0.0004

>2log HCV RNA

decrease at week 8

0.0985

0.0383 to 0.2531

<0.0001

L Gheorghe et al. JGLD, March 2014 Vol 23 No 1:45-50

Patients with mild disease often achieve a

rapid virological response
These patients only need 24 weeks therapy
Side effects are manageable

F0-F1

F2

F3

F4

Marcellin P, et al. J Hepatol 2011;54:S183

 4%
(2-sided 95% CI:2,11)

Sherman KE, et al. N Engl J Med

2011;365:1014-24

Prior relapsers

Prior partial responders

Prior null responders

Pol S. et al Hepatology 2011;54(Suppl.S1):37 4A

<1 log10 HCV RNA reduction after

4-week Peg-IFN/RBV lead-in phase

1 log 10 HCV-RNA reduction after 4-week

Peg-IFN/RBV lead-in phase

Proportion of patients in each category with

<1 log10 HCV RNA reduction

10%

n/N =

8/13

40%

10/18

59%

6/41

106/113

16/27

15/28

Foster GR, et al. J Hepatol 2011;54(Suppl.1)S3

Patients (%)

T12/PR
(750 mg q8h)
N=1346

Pbo/PR48
N=764

Leading to
discontinuation of
all study drugs(%)

Skin and subcutaneous tissue disorders

Pruritus(SSC)

52

26

0.6

Rash (SSC)

55

33

2.6

Gastrointestinal disorders
Nausea

39

29

<0.5

Diarrhea

26

19

<0.5

Hemorrhoids

12

<0.5

Anorectal discomfort

<0.5

Anal pruritus

<0.5

15

0.9

Blood and lymphatic system disorders

Anemia(SSC)

32

http://fda.gov/downloads/AdvisoryCommittees/Drugs/AntiviralDr
ugsAdvisoryCommittee/UCM252563.pdf

Telaprevir

Boceprevir

Rash(55%) vs 33%
Severe 5%

Anemia x2 (50% vs 25%)

Anemia x 2 (32% vs 15%)

Dysgeusia(37-45% vs 11-18%)

Anorectal symptoms (26% vs 6%)

Neutropenia<750/mmc 20-24% vs 914%

McHutchinson J et al., N Eng J Med 2009;360:1827-1838;

Hezode C et al.,N Eng J Med 2009;360:1839-1850
Jacobson IM et al., N Eng J Med 2011;364:2405-16

Kwo P et al.,Lancet 2010;376:705-716;

Bacon BR., et al. N Eng J Med 2011;364:1207-1217

Real-world(cirrhotics only)

Treatmentnave

Treatmentexperienced

Patients with serious AEs(%)

Patients with serious AEs(%)

Treatment experienced

n=299

N=212

TVR CUPIC
N=299

Serious adverse event

53.8

BOC CUPIC
N=212

Premature
discontinuations due to
serious adverse events

23.8

17.5

Death, n(%)

8(2.7)

3(1.4)

Infections (grade 3/4)

9.7

2.4

Hepatic decompensation

4.7

4.2

EPO use

56.5

56.1

Transfusion

17.7

11.8

RBV dose reduction

27.8

23.6

Outcomes,%

44.3

Hezode C, et al. Unpublished data

Updated 26 September

IL28 B CC

non F4:
Naives
Relapsers

Follow up

T(1125
mgBID)+PR

PR

12

24 weeks

Randomization 2:1 in patients

with RVR who continued all study
drugs through Week 12
Nelson DR et al. EASL 2013; Abstract 881

Buti M, et al. AASLD 2012:LB-8

o
o

Optimal patients selection is crucial to

achieve high SVR rate with reasonable safety
profile
Optimizing BOC treatment includes:
Optimizing treatment design according to
baseline characteristics
Following optimal stopping rules
Preventing and managing SAE

Marc Bourliere, et al.:How to optimize

current therapy of HCV genotype 1
infection with Boceprevir, Paris 2014

Early futility rules and short duration therapy

allow personalised, cost-effective therapy
For patients with more advanced disease
drugs with fewer side effects may be
preferable
For patients with mild disease-telaprevir is a
highly cost effective choise
For patients with advanced disease-telaprevir
is not ideal

Graham R Foster:Personalised
treatment with Telaprevir in
2014,Paris 2014