Practical management of PI therapyin Hepatitis C Paris Februari 2012

Ola Weiland Karolinska InstitutetStockholm, Sweden

New major adverse events with PIs• Exanthema for TVR

• Prolonged anemia with BOC

TelaprevirIlluminate studySherman et al2011

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)

Fatigue 62 (45) 214 (55)

Headache 54 (39) 167 (43)

Anemia SSC† 59 (42) 134 (34)

Nausea 52 (37) 129 (33)

Influenza-like illness 55 (40) 124 (32)

Insomnia 39 (28) 113 (29)

Anorectal symptoms‡ 33 (24) 101 (26)

Diarrhea 33 (24) 102 (26)

Pyrexia 34 (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

BoceprevirRespond studyBacon NEJM 2011

Sulkowsky et al 2011

Case number 1

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

Male born 1947 gt 1 relapser on SOC

HCV case male born 1947

• Retreat with PI + peg-IFN + RBV

• Wait for better DAAs

HCV case male born 1947

• Retreatment with Telaprevir + peg-IFN alpha 2a + RBVIn the realize study startedRandomized to placebo – outcome response-relapse

• Later switched to Telaprevir + peg-IFN alpha 2a + RBV

Male born 1947 gt 1 relapser on SOC

RVR achievedbutExanthema developed

How to manage exanthema?• Stop Rx ? • Continue Rx ?

• Treat the exanthema and continue Rx ?

• Switch PI ?

How to manage exanthema?

• Initially Rx was continued • Topical-steroids were given

• Desloratadine for pruritus

Outcome of exanthema?

• Continued to progress • Week 8

What to do?

• Continue Rx with topical steroids ? • Stop TVR week 8 ?

•Other measures ?

Treatment was stopped week 8Due to exanthema and pruritus?

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 ulceration

Grade 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 eruption

Telaprevir French cohort ATU ProtocolAvailable at http://www.afssaps.fr

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 armFeatures Typically pruritic and eczematous, involving <30% body surface areaDiscontinuation (pooled telaprevir arms) Telaprevir alone: 6% All treatment: 0.9%

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

Patie

nts

(%)

Patie

nts

(%)

566% severe

90% were mild or moderate

Incidence of rash Severity of rash

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

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 necessaryIf interruption is necessary, e.g. for progressive rash, recommend discontinue telaprevir firstIf no rash improvement within 7 days of stopping telaprevir (or earlier if worsening rash), consider interrupting ribavirin

Telaprevir French cohort ATU ProtocolAvailable at http://www.afssaps.fr

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

What SVR rate does the shortening of Telaprevir from 12 to 8 weeks Rx offer ?

1. 50%

2. 55%

3. 60%

4. 69%

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

Jacobson IM, et al. Hepatology 2010;52(Suppl.):427AT8PR: 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

PR48

158/361n/N =

ADVANCE: Overall On-treatment Virologic Failure

Telaprevir dosed for 12 weeks versus 8 weeks reduces subsequent failure during PR phase

T12PRVirologic failure 8%

0

4

8

12

16

20

4 12 24 28 36 40 48Weeks on treatment

Patie

nts

(%)

4 12 24 28 36 40 48Weeks on treatment

T8PRVirologic failure 13%

3%

5%

3%

10%

0

4

8

12

16

20

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

The outcome of our case?

• The exanthema vanished rapidly • Pruritus vanished rapidly

• SOC treatment was continued

• SVR was reached

Case number 2

Case no 2 57 year old lady1• 2005 advanced HCV • HCV gt 1b• Biopsy 2003 Fibrosis stage F3, A2• Treatment with peg-IFN ribavirin

prolonged to 72 weeks - response-relapse

57 yr old lady2

• 2010 advanced cirrhosis• Fibroscan mean kPa 50• No focal lesion on ultrasound• No major varices• Earlier Multiforme exanthem on peg-IFN

alfa 2b but not on alfa-2a• Desired treatment

57 year old lady3

• At baseline• ALT /AST 1,63/1,52 µkat/L• Platelets 51 x 109/L• Neutrophils 2 x 109/L

57 year old lady

• Should treatment be offered ?

• Are low platelets a contraindication ?

Rx or not

PI + SOC ?

57 year old lady3

• Treatment was given• Telaprevir + peg-IFN alfa2a + ribavirin

Exanthema already day 2

57 year old lady

• Stop Rx ?• Continue Rx and use exanthema plan ?• Switch PI?• Other option ?

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

What happened with the patient?

• The exanthema vanished rapidly

• Pruritus vanished rapidly

• Tripel therapy was continued

• RVR was achieved

Anemia during PI treatment

• Management

Hemoglobin Shifts on Telaprevir Treatment in the ADVANCE Trial

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

0

Med

ian

hem

oglo

bin

(g/d

L)

Weeks

0

11

12

13

14

15

4 8 12 16 20 24

Telaprevir

T12PR (n=363)T8PR (n=364) PR (control; n=361)

Telaprevir End of telaprevir treatment

Peg-IFN/RBV

Sulkowsky et al 2011

57 year old lady

• At week 6 during treatment• ALT 0,82 µkat/L• Hemoglobin 93 g/L• Platelets 32 x 109/L• Neutrophils 0,6 x 109/L

Exanthema Anemia

Hemoglobin G/L

Hemoglobin G/L

Ribavirin dose was reduced and Rx continued

Exanthema AnemiaNeutropenia

Nuetrophils and platelets x 109/L

Nuetrophils and paltelets x 109/L

Managed by peg-IFN dose reductions but no TVR dose change

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

108/262n/N=

SVR

(%)

Pooled analysis: ADVANCE and ILLUMINATE Phase III studies

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

Sulkowsky et al 2011

Management of anemia Boceprevir studies

Sulkowsky et al 2011

Sulkowsky et al 2011

Sulkowsky et al 2011

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 EPO 51 (314) 62 (182)

Management of Anemia observed with Telaprevir and Boceprevir in Placebo-controlled Clinical Trials

Telaprevir Phase III trials1,2

Boceprevir Phase III trials3,4

Ribavirin dose reductions 25% (telaprevir arms)* 19–22% (boceprevir arms) vs

8–13% (control)

EPO use Not permitted 41–46% (boceprevir arms) vs 21–24% (control)

Transfusions Reported rarely (1.6%)‡ 2–9%3,4

DiscontinuationTelaprevir 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.):S33. Poordad F, et al. NEJM 2011;364:1195–12064. 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

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 3/4

35 (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 3/4

16 (12)

2 (1)

18 (13)

12 (3)

1 (<1)

13 (3)

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

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 AERash*Anemia*Pruritus*

10 (7)3 (2)

1 (<1)1 (<1)

17 (4)1 (<1)3 (<1)

0

Discontinuation 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

REALIZE: hemoglobin levels in TVR-treated patients

0 4 8 12 16 20 24 28 32 36 40 44 480

25

50

75

100

125

150

175

Week

Me

dia

n h

em

og

lob

in (

g/L

, ±IQ

R)

0 4 8 12 16 20 24 28 32 36 40 44 48-50

-40

-30

-20

-10

0

Week

Me

an

ch

an

ge

fro

m b

as

elin

e in

h

em

og

lob

in (

g/L

, ±S

E)

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 93Non-cirrhotics, n 341 367 360 344 339 333 306 297 340 366 359 343 338 332 306 297Total, 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)

REALIZE: platelet levels in TVR-treated patients

0 4 8 12 16 20 24 28 32 36 40 44 480

50

100

150

200

250

Week

Me

dia

n p

late

lets

(1

09

/L, ±

IQR

)

0 4 8 12 16 20 24 28 32 36 40 44 48-100

-80

-60

-40

-20

0

Week

Me

an

ch

an

ge

fro

m b

as

elin

e in

p

late

lets

(1

09

/L, ±

SE

)

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 90Non-cirrhotics, n 339 364 357 342 336 331 302 292 337 362 355 340 334 328 301 291Total, 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)

Case no 3

Stopping rules during boceprevir dosing period

0 48Weeks 284 8 24 3612

If ≥100 IU/mL at Week 12

If detectable at Week 24

Stop all drugs

Boceprevir EU SmPC

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/mL

RGT criteria used in Phase III studies

TVR: 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 therapy Telaprevir EU SmPC; Boceprevir EU SmPC

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

Telaprevir EU SmPC; Boceprevir EU SmPC

TVR + PR

0 48Weeks 284 8 24 3612

BOC + PR BOC + PR PR +/- BOCPR

PR PR

Extension depending on on-treatment response, fibrosis stage and/or treatment experience

HCV RNA undetectable at:

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

19/20

T12PR48

18/21

T12PR24

11/18

T12PR48

11/12

Telaprevir 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

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

Series10

20

40

60

80

100

9

70

8

63

Patie

nts

with

und

etec

tabl

e H

CV R

NA

(%)

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

565/903

PR48

29/361n/N=

Adapted from Sherman KE, et al. CROI 2011. Abstract 957

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 drugs

If detectable at Week 24 or 36:discontinue PR

HCV RNA:

0 48Weeks 4 24 3612

Boceprevir (SPRINT-2): RGT in treatment naïve patients

SVR

(%)

BOC44/PR48

Undetectable HCV RNA between Weeks 8–24*

Detectable HCV RNA ≥1 time between Weeks 8–24*

BOC44/PR48

BOCRGT

*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 24PR 28

Overall SVR

156/162

BOCRGT

155/161 45/68 55/73

BOC 24WPR 48W

BOC 44PR 48

BOC 44PR 48

BOC44/PR48

BOCRGT

PR48

137/363 233/368 242/366

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

SVR

(%)

PR48

123/328

BOC44/PR48

211/313n/N=

No, minimal or portal fibrosis (F0–F2)

BOC RGT

213/319

Poordad F, et al. N Engl J Med 2011;364:1195–206

Cirrhosis (F4)Bridging fibrosis (F3)

PR48

3/11

BOC44/PR48

12/18

BOC RGT

9/18

PR48

6/13

BOC44/PR48

10/24

BOC RGT

5/16

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

PRlead-in

BOC + PR

0 48Weeks 284 8 24

BOC + PR

36

PR*

If detectable at Week 8 but undetectable at Week 24:

12

HCV RNA

*This regimen has only been tested in patients who have failed previous therapy who were late responders Boceprevir EU SmPC

Assess for RGT criterion

If ≥100 IU/mLdiscontinue all

drugs

If detectablediscontinue all

drugs

Stop treatment at Week 28 if undetectable at Week 8 and 24

SPRINT-2 (boceprevir): eligibility for shorter treatment duration

Patie

nts

with

und

etec

tabl

e H

CV R

NA

(%)

PR48

60/363

BOC44/PR48

204/366n/N=

Week 81 Weeks 8 to 242

BOC RGT

208/368

BOC44/PR48

161/366

BOC RGT

162/368

Patients eligible to receive 28 weeks of total treatment

1. Boceprevir EU SmPC2. Poordad F, et al. N Engl J Med 2011;364:1195–206

PR48

43/363

4840 12 3624

Dosing duration in all patients with compensated cirrhosis

BOC+ Peg-IFN + RBVPeg-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 drugs

Detectable:Stop PR

Detectable:Stop PR

Telaprevir EU SmPC; Boceprevir EU SmPC

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)

108

107

106

105

104

103

102

100 4 6 8 12102

Weeks on treatment

HCV

RN

A (IU

/mL)

108

107

106

105

104

103

102

100 4 6 8 12102

Weeks on treatment

HCV

RN

A (IU

/mL)

Adda N, et al. HepDART 2011; Abstract 45

This year has brought a paradigm shift to gt 1 treatmentAddition of a 1st gen protease inhibitor to SOC

-Achieves 30 % higher SVR in naïve HCV genotype 1 patients-Offers shorter treatment for a majority

Thanks

Good Luck with the treatment of your HCV patients 2012