Practical management of PI therapy - PowerPoint Presentation

Slide1

Practical management of PI therapy

in Hepatitis C Paris Februari 2012

Ola Weiland Karolinska InstitutetStockholm, Sweden

Slide2

New major adverse events with PIs

Exanthema for TVR

Prolonged anemia with BOC

Slide3

Telaprevir

Illuminate studySherman et al2011

Slide4

REALIZE:

AEs in ≥25% of TVR-treated patients during any treatment phase*

AE

, n (%)

Cirrhotics (F4)

N=139

Non-cirrhotics (F0–3) N=391

Rash SSC

93 (67)

206 (53)

Pruritus SSC

82 (59)

205 (52)

Fatigue62 (45)214 (55)Headache54 (39)167 (43)Anemia SSC†59 (42)134 (34)Nausea52 (37)129 (33)Influenza-like illness55 (40)124 (32)Insomnia39 (28)113 (29)Anorectal symptoms‡33 (24)101 (26)Diarrhea33 (24)102 (26)Pyrexia34 (25)97 (25)

*Grouped special search category (SSC); †Anemia reported by the investigator as an adverse event; ‡Grouped term including several different AEs in the anorectal area; AE=adverse event

Pol S, et al.

Hepatology

2011;54(Suppl. S1): Abstract 31

Slide5

Boceprevir

Respond studyBacon NEJM 2011

Slide6

Sulkowsky

et al 2011

Slide7

Case number 1

Slide8

HCV

case male born 1947

Chronic HCV

gt

1b

IFN + RBV

later part of 1990is

relapse

after Rx

Liver biopsy

2004

stage 1-2 Peg IFN alfa 2a + RBV in REPEAT study 72 ws Rx 2005 slow response-relapse 2005 Retinal emboli 2006 closure of atrial atrial septal defect

Slide9

Male born 1947

gt 1

relapser on SOC

Slide10

HCV

case male born 1947

Retreat with PI + peg-IFN + RBV

Wait for better DAAs

Slide11

HCV

case male born 1947

Retreatment with

Telaprevir

+ peg-IFN alpha 2a + RBV

In the realize study started

Randomized to placebo – outcome response-relapse

Later

switched

to

Telaprevir

+ peg-IFN alpha 2a + RBV

Slide12

Male born 1947

gt 1

relapser on SOC

Slide13

RVR achieved

but

Exanthema developed

Slide14

Slide15

Slide16

How to manage exanthema?

Stop Rx ?

Continue Rx ?

Treat the exanthema and continue Rx ?

Switch PI ?

Slide17

How to manage exanthema?

Initially Rx was continued

Topical-steroids were given

Desloratadine for pruritus

Slide18

Outcome of exanthema?

Continued to progress

Week 8

Slide19

Slide20

What to do?

Continue Rx with topical steroids ?

Stop TVR week 8 ?

Other measures ?

Slide21

Treatment was stopped week 8

Due to exanthema and pruritus?

Slide22

Grading of Rash (Skin Eruption) Severity

Grade 1

(Mild)

:

localized skin eruption and/or a skin eruption with limited distribution, with or without associated pruritus

Grade 2 (Moderate):

diffuse skin eruption involving up to 50% of body surface area, with or without superficial skin peeling, pruritus, or mucous membrane involvement with no ulcerationGrade 3 (Severe): generalized skin eruption involving either >50% of body surface area

OR

rash presenting with any of the following characteristics

Rash with vesicles or bullae, superficial ulceration of mucous membranes, epidermal detachment, atypical or typical target lesions, palpable purpura/non-blanching erythema, drug reaction with eosinophilia and systemic symptoms, erythema multiforme, acute generalized exanthematous pustulosis, severe alteration of general state. A skin eruption with appearance of new significant systemic signs and symptoms related to onset and/or progression of skin eruption must be considered as grade 3

Grade 4

(life-threatening)

:Toxic epidermal necrolysis, Stevens-Johnson syndrome, skin eruption with generalized bullous eruptionTelaprevir French cohort ATU ProtocolAvailable at http://www.afssaps.fr

Slide23

Summary of Rash Data from ADVANCE Telaprevir/placebo Treatment Phase

~90% of the rash was mild or moderate

6% of patients had a severe rash in the T12PR arm

Features

Typically pruritic and eczematous, involving <30% body surface area

Discontinuation (pooled telaprevir arms)

Telaprevir alone: 6%

All treatment: 0.9%

Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A

Patients (%)

Patients (%)

56

6% severe

90% were mild or moderateIncidence of rash

Severity of rash

T12PR: 12 weeks of telaprevir plus 24–48 weeks of PR

Slide24

Study Drug Considerations: Grade 1 and 2 Rash

Treating patients with mild or moderate rash

Use topical corticosteroids

Permitted systemic antihistaminic drugs may be tried

Regular follow up is important

Limit exposure to sun/heat

Suggest baking soda or oatmeal baths, and loose-fitting clothes

Rash

Grade 1

Grade 2

Telaprevir interruption generally not necessary

Telaprevir interruption generally not necessary

If interruption is necessary, e.g. for progressive rash, recommend discontinue telaprevir first

If no rash improvement within 7 days of stopping telaprevir (or earlier if worsening rash), consider interrupting ribavirinTelaprevir French cohort ATU ProtocolAvailable at http://www.afssaps.fr

Slide25

How should exanthema be treated

Lubricants

Topical steroiders : betamethasone 10 days

b.i.d.10 days q.d

.

10 every other day

Desloratadine (Aerius®)

once daily for pruritus

Slide26

What SVR rate does the shortening of

Telaprevir from 12 to 8 weeks Rx offer ?

50%

55%

60%

69%

Slide27

ADVANCE: SVR Rates in Telaprevir-treated Patients compared with PR Alone

Jacobson IM, et al.

Hepatology

2010;52(Suppl.):427A

T8PR: 8 weeks of telaprevir plus 24–48 weeks of PR; *p<0.0001 vs PR48

*

*

6% difference

(95% CI: –12.5% to +0.6%)

T12PR

271/363

T8PR

250/364

PR48158/361n/N =

Slide28

ADVANCE: Overall On-treatment Virologic Failure

Telaprevir dosed for 12 weeks versus 8 weeks

reduces subsequent failure during PR phase

T12PR

Virologic failure 8%

0

4

8

12

16

20

4

12

24

28

36

40

48

Weeks on treatment

Patients (%)

4

12

24

28

36

40

48

Weeks on treatment

T8PR

Virologic failure 13%

3%

5%

3%

10%

0

4

8

12

16

20

Jacobson IM, et al.

Hepatology

2010;52(Suppl.):427A

Slide29

The outcome of our case?

The exanthema vanished rapidly

Pruritus

vanished rapidly

SOC treatment was continued SVR

was reached

Slide30

Slide31

Case number 2

Slide32

Case no 2 57 year old lady 1

2005 advanced HCV

HCV gt 1b

Biopsy 2003 Fibrosis stage F3, A2

Treatment with peg-IFN ribavirin prolonged to 72 weeks - response-relapse

Slide33

57

yr old lady 2

2010 advanced cirrhosis

Fibroscan

mean

kPa

50No focal lesion on ultrasound

No major varicesEarlier Multiforme exanthem on peg-IFN alfa 2b but not on alfa-2aDesired treatment

Slide34

57 year old lady 3

At baseline

ALT /AST 1,63/1,52 µkat/L

Platelets 51 x 10

9

/L

Neutrophils 2 x 109/L

Slide35

57 year old lady

Should treatment be offered ?

Are low platelets a contraindication ?

Slide36

Rx or not

PI + SOC ?

Slide37

57 year old lady 3

Treatment was given

Telaprevir

+ peg-IFN alfa2a + ribavirin

Slide38

Slide39

Exanthema already day 2

Slide40

Slide41

Slide42

57 year old lady

Stop Rx ?

Continue Rx and use exanthema plan ?

Switch PI?

Other option ?

Slide43

Treatment was con-d and for the exanthema the following was given

Lubricants

Topical steroiders : betamethasone

10 days b.i.d.

10 days q.d.

10 every other day

Desloratadine (Aerius®) once daily for pruritus

Slide44

What happened with the patient?

The exanthema vanished rapidly

Pruritus vanished rapidly

Tripel

therapy was continued

RVR was achieved

Slide45

Anemia during PI treatment

Management

Slide46

Hemoglobin

Shifts on Telaprevir Treatment

in the ADVANCE Trial

Jacobson IM, et al.

Hepatology

2010;52(Suppl.):427A

0

Median hemoglobin (g/dL)

Weeks

0

11

12

13

14154812162024

Telaprevir

T12PR (n=363)

T8PR (n=364)

PR (control; n=361)

Telaprevir

End of telaprevir treatment

Peg-IFN/RBV

Slide47

Sulkowsky

et al 2011

Slide48

57 year old lady

At week 6 during treatment

ALT 0,82 µkat/L

Hemoglobin 93 g/L

Platelets 32 x 10

9

/LNeutrophils 0,6 x 10

9/L

Slide49

Exanthema Anemia

Slide50

Hemoglobin G/L

Slide51

Hemoglobin G/L

Ribavirin dose was reduced and Rx continued

Slide52

Exanthema Anemia Neutropenia

Slide53

Nuetrophils

and platelets x 10

9/L

Slide54

Nuetrophils

and

paltelets x 109/LManaged by peg-IFN dose reductions but no TVR dose change

Slide55

Slide56

Effect of Anemia on Efficacy in Treatment-naïve Patients who Received Telaprevir

Patients with anemia

Patients without anemia

T12PR24

149/196

T12PR

267/361

T12PR48

118/165

PR

46/92

T12PR24

206/269

T12PR

384/524

T12PR48

178/255

PR

108/262

n/N=

SVR (%)

Pooled analysis: ADVANCE and ILLUMINATE Phase III studies

Sulkowski MS, et al. J Hepatol 2011;54(Suppl.):S195

Slide57

Sulkowsky

et al 2011Management of anemia Boceprevir

studies

Slide58

Sulkowsky

et al 2011

Slide59

Sulkowsky

et al 2011

Slide60

Sulkowsky

et al 2011

Slide61

Fewer patients on BOC with low ITPA activity have RBV dose reduction and/or EPO use

Sulkowski MS, et al. Hepatology 2011;54(Suppl. S1): Abstract 934

*Multiple stepwise regression analysis

ITPA activity

% (n)

Normal

(n=616)

Low

(n=292)

RBV dose reduction (regardless of EPO)

RBV dose reduced (alone)

RBV dose reduced plus EPO used

29 (177)

7 (44)22 (133)21 (63)8 (22)14 (41)EPO used (alone)20 (125)16 (47)No RBV dose reduction and no EPO51 (314)62 (182)

Slide62

Management of Anemia observed with Telaprevir and Boceprevir in P

lacebo-controlled Clinical Trials

Telaprevir

Phase III trials

1,2

Boceprevir

Phase III trials

3,4

Ribavirin dose reductions

25% (telaprevir arms)*

19–22% (boceprevir arms) vs

8–13% (control)

EPO use

Not permitted41–46% (boceprevir arms) vs 21–24% (control)TransfusionsReported rarely (1.6%)‡2–9%3,4DiscontinuationTelaprevir alone: 4%** vs 0 % (control)¥All treatment at the same time: 1%** vs 1% (control)0–3% (boceprevir arms) vs 0–1% (control)

1.Jacobson IM, et al.

Hepatology

2010;52(Suppl.):427A

2. Zeuzem S, et al. J Hepatol 2011;54(Suppl.):S3

3. Poordad F, et al. NEJM 2011;364:1195–1206

4. Bacon B, et al. NEJM 2011;364:1207–1217

*In the REALIZE trial;

‡

pooled placebo-controlled Phase II/III trials

**

T12PR in ADVANCE;

¥

discontinuation of placebo

Slide63

Slide64

Slide65

REALIZE:

laboratory abnormalities

n (%)

Cirrhotics (F4)

N=139

Non-cirrhotics (F0–3) N=391

Hemoglobin

≤10g/dL

≤8.5g/dL

63 (46)

19 (14)

156 (40)

49 (13)Neutrophils Grade 3 (500 to <750/mm3) Grade 4 (<500/mm3) Grade 3/435 (25)10 (7)45 (32)68 (17)9 (2)77 (19)Platelets Grade 3 (25,000 to <50,000/mm3) Grade 4 (<25,000/mm3) Grade 3/416 (12)

2 (1)18 (13)

12 (3)

1 (<1)

13 (3)

Pol S, et al. Hepatology 2011;54(Suppl. S1): Abstract 31

Slide66

REALIZE:

AEs leading to study drug discontinuation in pooled TVR arms

Cirrhotics (F4)

N=139

Non-cirrhotics (F0–3) N=391

Discontinuation of

all study drugs

during TVR treatment phase, n (%)

Any AE

Rash*

Anemia*

Pruritus*

10 (7)

3 (2)1 (<1)1 (<1)17 (4)1 (<1)3 (<1)0Discontinuation of TVR during TVR treatment phase, n (%)Any AERash*Anemia*Pruritus*21 (15)8 (6)4 (3)2 (1)46 (12)14 (4)11 (3)2 (<1)Pol S, et al. Hepatology 2011;54(Suppl. S1): Abstract 31*Grouped SSC

Slide67

REALIZE

: hemoglobin levels in TVR-treated patients

Median hemoglobin levels over time

Mean change from baseline in hemoglobin

Cirrhotics, n 124 135 131 128 120 114 95 93 124 135 131 128 120 114 95 93

Non-cirrhotics, n 341 367 360 344 339 333 306 297 340 366 359 343 338 332 306 297

Total, n 465 502 491 472 459 447 401 390 464 501 490 471 458 446 401 390

36

36

Number of patients with data at each stated time point

Pol S, et al. Hepatology 2011;54(Suppl. S1): Abstract 31

Cirrhotics (N=139)

Non-cirrhotics (N=391)

Slide68

REALIZE: p

latelet levels in TVR-treated patients

Median platelet levels over time

Mean change from baseline in platelets

Cirrhotics, n 121 131 128 125 116 112 93 90 121 131 128 125 116 112 93 90

Non-cirrhotics, n 339 364 357 342 336 331 302 292 337 362 355 340 334 328 301 291

Total, n 460 495 485 467 452 443 395 382 458 493 483 465 450 440 394 381

36

36

Number of patients with data at each stated time point

Pol S, et al. Hepatology 2011;54(Suppl. S1): Abstract 31

Cirrhotics (N=139)

Non-cirrhotics (N=391)

Slide69

Case no 3

Slide70

Slide71

Stopping rules during boceprevir dosing period

0

48

Weeks

28

4

8

24

36

12

If ≥100 IU/

mL

at Week 12If detectable at Week 24Stop all drugsBoceprevir EU SmPC

Slide72

Response-guided therapy criteria for TVR and BOC

TVR SmPC:

Detectable HCV RNA below the lower LOQ should not be used as a substitute for ‘undetectable’ for making decisions on treatment duration, as this may lead to an insufficient duration of therapy and higher relapse rates

RT-PCR assay

used

in Phase III

studies

Limit of quantification (LOQ)

25

IU

/

mL

Limit

of detection (LOD)9.3–15 IU/mLRGT criteria used in Phase III studiesTVR: Undetectable HCV RNA at Week 4 and 12 (<LOD)BOC (naives): Undetectable HCV RNA at Week 8 and 24 (<LOD)RT-PCR: real-time PCR; RGT: response-guided therapyTelaprevir EU SmPC; Boceprevir EU SmPC

Slide73

New on-treatment response-guided criteria with TVR and BOC

Telaprevir EU SmPC; Boceprevir EU SmPC

TVR + PR

0

48

Weeks

28

4

8

24

36

12

BOC + PR

BOC + PRPR +/- BOCPRPRPRExtension depending on on-treatment response, fibrosis stage and/or treatment experienceHCV RNA undetectable at:

Slide74

Telaprevir (ILLUMINATE): no RGT in treatment-naïve patients with cirrhosis

22%

n=118

T12PR48

115/127

T12PR24

119/124

No fibrosis,

minimal fibrosis,

or portal fibrosis

Bridging fibrosis

Cirrhosis

T12PR24

19/20T12PR4818/21T12PR2411/18T12PR4811/12Telaprevir EU SmPCSVR: 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 used

Slide75

ADVANCE and ILLUMINATE (telaprevir): eligibility for shorter treatment duration

Patients with undetectable

HCV RNA (%)

Week 4 (RVR)

Weeks 4 and 12 (eRVR)

Patients eligible to

receive 24 weeks

of treatment in total

PR48

34/361

T12PR

635/903

T12PR

565/903PR4829/361n/N=Adapted from Sherman KE, et al. CROI 2011. Abstract 957

Slide76

Telaprevir

regimen in G1 HCV-infected patients: treatment-NAÏVE without cirrhosis

*In Phase III studies, a sensitive real-time PCR assay with a limit of quantification of 25 IU/mL and a limit of detection of

10–15 IU/mL was used to determine whether HCV RNA levels were undetectable.Detectable HCV RNA below the lower limit of assay quantification should not be used as a substitute for ‘undetectable’

for making decisions on treatment duration, as this may lead to an insufficient duration of therapy and higher relapse rates

Telaprevir EU SmPC

Peg-IFN

alfa + ribavirin if detectable at Week 4 or 12*

Peg-IFN

alfa

+ ribavirin

Stop at Week 24 if undetectable at Week 4 and 12

Telaprevir + PR

If >1000 IU/mL at Week 4 or 12:discontinue all drugsIf detectable at Week 24 or 36:discontinue PRHCV RNA:048Weeks4243612

Slide77

Boceprevir

(SPRINT-2): RGT in treatment naïve patientsSVR (%)

BOC44/

PR48Undetectable HCV RNA between Weeks 8–24*

Detectable HCV RNA ≥1

time between Weeks 8–24*

BOC44/

PR48BOC

RGT

*Not including 256/734 (35%) BOC-treated patients discontinuing prior to Week 28 due to a stopping rule, adverse events or non-medical reasons;

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

Boceprevir EU SmPC

BOC 24

PR 28Overall SVR156/162BOCRGT155/16145/6855/73BOC 24WPR 48WBOC 44PR 48BOC 44PR 48BOC44/PR48BOCRGTPR48137/363233/368242/366

Slide78

Boceprevir

(SPRINT-2): no RGT for patients with cirrhosis

SVR (%)

PR48

123/328

BOC44/

PR48

211/313

n/N=

No, minimal

or portal fibrosis (F0–F2)

BOC RGT

213/319Poordad F, et al. N Engl J Med 2011;364:1195–206Cirrhosis (F4)Bridging fibrosis (F3)PR483/11BOC44/PR48 12/18BOC RGT 9/18PR486/13BOC44/PR48 10/24BOC RGT 5/16SVR 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

Slide79

Boceprevir

regimen in G1 HCV-infected patients: treatment-NAÏVE without cirrhosis

PR

lead-inBOC +

PR

0

48

Weeks

28

4

8

24

BOC + PR

36PR*If detectable at Week 8 but undetectable at Week 24:12HCV RNA*This regimen has only been tested in patients who have failed previous therapy who were late respondersBoceprevir EU SmPCAssess for RGT criterionIf ≥100 IU/mLdiscontinue all drugsIf detectablediscontinue all drugsStop treatment at Week 28 if undetectable at Week 8 and 24

Slide80

SPRINT-2 (boceprevir):

eligibility for shorter treatment duration

Patients with undetectable

HCV RNA (%)

PR48

60/363

BOC44/PR48

204/366

n/N=

Week 8

1

Weeks 8 to 24

2

BOC RGT 208/368BOC44/PR48 161/366BOC RGT162/368Patients eligible to receive 28 weeks of total treatment1. Boceprevir EU SmPC2. Poordad F, et al. N Engl J Med 2011;364:1195–206PR48 43/363

Slide81

48

4

0

12

36

24

Dosing duration in all patients with compensated cirrhosis

BOC+ Peg-IFN + RBV

Peg-IFN + RBV

≥100 IU/mL:

Stop 3 drugs

Detectable:

Stop 3 drugs

TVR + Peg-IFN + RBV Peg-IFN + RBV >1000 IU/mL:Stop 3 drugs>1000 IU/mL:Stop 3 drugsDetectable:Stop PRDetectable:Stop PRTelaprevir EU SmPC; Boceprevir EU SmPC

Slide82

HCV RNA levels in patients who met the >1000 IU/mL HCV RNA Week 4 futility rule

Treatment-naïve

patients (n=15)

Treatment-experienced patients (n=11)

10

8

10

7

10

6

10

5

10

410310210046812102Weeks on treatmentHCV RNA (IU/mL)

10

8

10

7

10

6

10

5

10

4

10

3

10

2

10

0

4

6

8

12

10

2

Weeks on treatment

HCV RNA (

IU/mL

)

Adda

N, et al.

HepDART

2011; Abstract 45

Slide83

This year has brought a

paradigm

shift to

gt

1 treatment

Addition of a 1

st

gen

protease inhibitor to SOC

Achieves 30 % higher SVR in naïve

HCV

genotype 1 patientsOffers shorter treatment for a majority

Slide84

Slide85

Thanks

Slide86

Good Luck with the treatment

of your HCV patients 2012