in Hepatitis C Paris Februari 2012 Ola Weiland Karolinska Institutet Stockholm Sweden New major adverse events with PIs Exanthema for TVR Prolonged anemia with BOC Telaprevir Illuminate study ID: 931460
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Slide1
Practical management of PI therapy
in Hepatitis C Paris Februari 2012
Ola Weiland Karolinska InstitutetStockholm, Sweden
Slide2New major adverse events with PIs
Exanthema for TVR
Prolonged anemia with BOC
Slide3Telaprevir
Illuminate studySherman et al2011
Slide4REALIZE:
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
Slide5Boceprevir
Respond studyBacon NEJM 2011
Slide6Sulkowsky
et al 2011
Slide7Case number 1
Slide8HCV
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
Slide9Male born 1947
gt 1
relapser on SOC
Slide10HCV
case male born 1947
Retreat with PI + peg-IFN + RBV
Wait for better DAAs
Slide11HCV
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
Slide12Male born 1947
gt 1
relapser on SOC
Slide13RVR achieved
but
Exanthema developed
Slide14Slide15Slide16How to manage exanthema?
Stop Rx ?
Continue Rx ?
Treat the exanthema and continue Rx ?
Switch PI ?
Slide17How to manage exanthema?
Initially Rx was continued
Topical-steroids were given
Desloratadine for pruritus
Slide18Outcome of exanthema?
Continued to progress
Week 8
Slide19Slide20What to do?
Continue Rx with topical steroids ?
Stop TVR week 8 ?
Other measures ?
Slide21Treatment was stopped week 8
Due to exanthema and pruritus?
Slide22Grading 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
Slide23Summary 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
Slide24Study 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
Slide25How 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
Slide26What SVR rate does the shortening of
Telaprevir from 12 to 8 weeks Rx offer ?
50%
55%
60%
69%
Slide27ADVANCE: 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 =
Slide28ADVANCE: 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
Slide29The outcome of our case?
The exanthema vanished rapidly
Pruritus
vanished rapidly
SOC treatment was continued SVR
was reached
Slide30Slide31Case number 2
Slide32Case 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
Slide3357
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
Slide3457 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
Slide3557 year old lady
Should treatment be offered ?
Are low platelets a contraindication ?
Slide36Rx or not
PI + SOC ?
Slide3757 year old lady 3
Treatment was given
Telaprevir
+ peg-IFN alfa2a + ribavirin
Slide38Slide39Exanthema already day 2
Slide40Slide41Slide4257 year old lady
Stop Rx ?
Continue Rx and use exanthema plan ?
Switch PI?
Other option ?
Slide43Treatment 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
Slide44What happened with the patient?
The exanthema vanished rapidly
Pruritus vanished rapidly
Tripel
therapy was continued
RVR was achieved
Slide45Anemia during PI treatment
Management
Slide46Hemoglobin
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
Slide47Sulkowsky
et al 2011
Slide4857 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
Slide49Exanthema Anemia
Slide50Hemoglobin G/L
Slide51Hemoglobin G/L
Ribavirin dose was reduced and Rx continued
Slide52Exanthema Anemia Neutropenia
Slide53Nuetrophils
and platelets x 10
9/L
Slide54Nuetrophils
and
paltelets x 109/LManaged by peg-IFN dose reductions but no TVR dose change
Slide55Slide56Effect 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
Slide57Sulkowsky
et al 2011Management of anemia Boceprevir
studies
Slide58Sulkowsky
et al 2011
Slide59Sulkowsky
et al 2011
Slide60Sulkowsky
et al 2011
Slide61Fewer 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)
Slide62Management 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
Slide63Slide64Slide65REALIZE:
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
Slide66REALIZE:
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
Slide67REALIZE
: 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)
Slide68REALIZE: 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)
Slide69Case no 3
Slide70Slide71Stopping 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
Slide72Response-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
Slide73New 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:
Slide74Telaprevir (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
Slide75ADVANCE 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
Slide76Telaprevir
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
Slide77Boceprevir
(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
Slide78Boceprevir
(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
Slide79Boceprevir
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
Slide80SPRINT-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
Slide8148
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
Slide82HCV 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
Slide83This 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
Slide84Slide85Thanks
Slide86Good Luck with the treatment
of your HCV patients 2012