Practical management of PI therapy
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
Sherman et al
2011
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
Boceprevir
Respond study
Bacon 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 + RBV
In the realize study started
Randomized to placebo – outcome response-relapse
• Later switched to Telaprevir + peg-IFN alpha 2a + RBV
Male born 1947 gt 1 relapser on SOC
RVR achieved
but
Exanthema 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 8
Due 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 Protocol
Available at http://www.afssaps.fr
Summary of Rash Data from ADVANCE
Telaprevir/placebo Treatment Phase
Severity of rash
Patients (%)
Patients (%)
Incidence of rash
56
6% severe
90% were mild or
moderate
 ~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%
T12PR: 12 weeks of telaprevir plus 24–48 weeks of PR
Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A
Study Drug Considerations: Grade 1
and 2 Rash
Rash
Grade 1
Telaprevir interruption generally not necessary
Grade 2
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 ribavirin
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
Telaprevir French cohort ATU Protocol
Available 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
6% difference
(95% CI: –12.5% to +0.6%)
*
*
n/N =
PR48
T12PR
T8PR
158/361
271/363
250/364
T8PR: 8 weeks of telaprevir plus 24–48 weeks of PR; *p<0.0001 vs PR48
Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A
ADVANCE: Overall On-treatment Virologic Failure
Telaprevir dosed for 12 weeks versus 8 weeks
reduces subsequent failure during PR phase
T12PR
Virologic failure 8%
Patients (%)
20
16
16
12
12
8
0
3%
4
10%
8
5%
4
T8PR
Virologic failure 13%
20
3%
4
12
24
28
36
Weeks on treatment
40
48
0
4
12
24
28
36
Weeks on treatment
40
48
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 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
57 yr old lady
•
•
•
•
•
2
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 lady
•
•
•
•
At baseline
ALT /AST
Platelets
Neutrophils
1,63/1,52 µkat/L
51 x 109/L
2 x 109/L
3
57 year old lady
• Should treatment be offered ?
• Are low platelets a contraindication ?
Rx or
not
PI +
SOC ?
57 year old lady
• Treatment was given
• Telaprevir + peg-IFN alfa2a + ribavirin
3
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
Telaprevir
End of telaprevir treatment
Telaprevir
Peg-IFN/RBV
Median hemoglobin (g/dL)
15
T12PR (n=363)
14
T8PR (n=364)
PR (control; n=361)
13
12
11
0
0
4
8
12
16
20
24
Weeks
Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A
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
Ribavirin dose was reduced and Rx continued
Hemoglobin G/L
Exanthema
Anemia
Neutropenia
Nuetrophils and platelets x 109/L
Managed by peg-IFN dose reductions but no TVR dose change
Nuetrophils and paltelets x 109/L
Effect of Anemia on Efficacy in Treatment-naïve
Patients who Received Telaprevir
Pooled analysis: ADVANCE and ILLUMINATE Phase III studies
Patients without anemia
SVR (%)
Patients with anemia
n/N=
T12PR24
T12PR48
T12PR
PR
T12PR24
T12PR48
T12PR
PR
149/196
118/165
267/361
46/92
206/269
178/255
384/524
108/262
Sulkowski MS, et al. J Hepatol 2011;54(Suppl.):S195
Management of anemia Boceprevir studies
Sulkowsky et al 2011
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
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)
*Multiple stepwise regression analysis
Sulkowski MS, et al. Hepatology 2011;54(Suppl. S1): Abstract 934
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
Discontinuation
Telaprevir alone:
4%** vs 0 % (control)¥
All treatment at the same time:
1%** vs 1% (control)
0–3% (boceprevir arms) vs
0–1% (control)
*In the REALIZE trial; ‡pooled placebo-controlled Phase II/III trials
**T12PR in ADVANCE; ¥discontinuation of placebo
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
REALIZE: laboratory abnormalities
Cirrhotics (F4)
N=139
Non-cirrhotics (F0–3)
N=391
≤10g/dL
63 (46)
156 (40)
≤8.5g/dL
19 (14)
49 (13)
Grade 3 (500 to <750/mm3)
35 (25)
68 (17)
Grade 4 (<500/mm3)
10 (7)
9 (2)
Grade 3/4
45 (32)
77 (19)
16 (12)
12 (3)
2 (1)
1 (<1)
18 (13)
13 (3)
n (%)
Hemoglobin
Neutrophils
Platelets
Grade 3 (25,000 to <50,000/mm3)
Grade 4 (<25,000/mm3)
Grade 3/4
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 (%)
10 (7)
17 (4)
Rash*
3 (2)
1 (<1)
Anemia*
1 (<1)
3 (<1)
Pruritus*
1 (<1)
0
Any AE
Discontinuation of TVR during TVR treatment phase, n (%)
Any AE
*Grouped SSC
21 (15)
46 (12)
Rash*
8 (6)
14 (4)
Anemia*
4 (3)
11 (3)
Pruritus*
2 (1)
2 (<1)
Pol S, et al. Hepatology 2011;54(Suppl. S1): Abstract 31
REALIZE: hemoglobin levels in TVR-treated
patients
Cirrhotics (N=139)
0
Median hemoglobin levels
over time
Mean change from baseline in
hemoglobin (g/L, ±SE)
Median hemoglobin (g/L, ±IQR)
175
Non-cirrhotics (N=391)
150
125
100
75
50
25
0
Mean change from baseline in
hemoglobin
-10
-20
-30
-40
-50
0
4
8 12 16 20 24 28 32 36 40 44 48
Week
Number of patients with data at each stated time point
Cirrhotics, n
124 135 131 128 120 114
Non-cirrhotics, n
341 367 360 344 339 333
Total, n
465 502 491 472 459 447
95
306
401
93
297
390
0 4 8 12 16 20 24 28 32 36
36 40 44 48
Week
124 135 131 128 120 114
340 366 359 343 338 332
464 501 490 471 458 446
95
306
401
93
297
390
Pol S, et al. Hepatology 2011;54(Suppl. S1): Abstract 31
REALIZE: platelet levels in TVR-treated patients
Cirrhotics (N=139)
0
Median platelet levels over
time
Mean change from baseline in
platelets (109/L, ±SE)
Median platelets (109/L, ±IQR)
250
Non-cirrhotics (N=391)
200
150
100
50
0
Mean change from baseline in
platelets
-20
-40
-60
-80
-100
0
4
8 12 16 20 24 28 32 36 40 44 48
Week
Number of patients with data at each stated time point
Cirrhotics, n
121 131 128 125 116 112
Non-cirrhotics, n
339 364 357 342 336 331
Total, n
460 495 485 467 452 443
93
302
395
90
292
382
0 4 8 12 16 20 24 28 32 36
36 40 44 48
Week
121 131 128 125 116 112
337 362 355 340 334 328
458 493 483 465 450 440
93
301
394
90
291
381
Pol S, et al. Hepatology 2011;54(Suppl. S1): Abstract 31
Case no 3
Stopping rules during boceprevir
dosing period
Stop all drugs
If ≥100 IU/mL
at Week 12
Weeks 0
4
8
12
If detectable at
Week 24
24
28
36
48
Boceprevir EU SmPC
Response-guided therapy criteria for
TVR and BOC
RT-PCR assay used in Phase III studies
Limit of quantification (LOQ)
Limit of detection (LOD)
25 IU/mL
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)
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: real-time PCR; RGT: response-guided therapy
Telaprevir EU SmPC; Boceprevir EU SmPC
New on-treatment response-guided
criteria with TVR and BOC
HCV RNA undetectable at:
TVR + PR
Weeks 0
4
PR
8
PR
12
PR
24
BOC + PR
28
36
BOC + PR
48
PR +/- BOC
Extension depending on on-treatment response, fibrosis stage and/or treatment experience
Telaprevir EU SmPC; Boceprevir EU SmPC
Telaprevir (ILLUMINATE): no RGT in treatment-naïve
patients with cirrhosis
No fibrosis,
minimal fibrosis,
or portal fibrosis
Bridging fibrosis
Cirrhosis
22%
n=118
T12PR24
T12PR48
T12PR24
T12PR48
T12PR24
T12PR48
119/124
115/127
19/20
18/21
11/18
11/12
SVR: 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
Telaprevir EU SmPC
Patients with undetectable
HCV RNA (%)
ADVANCE and ILLUMINATE
(telaprevir): eligibility for shorter
Weeks 4 and 12 (eRVR)
Week 4 (RVR)
treatment
duration
100
80
Patients eligible to
receive 24 weeks
of treatment in total
70
63
60
40
20
9
8
0
n/N=
PR48
T12PR
PR48
T12PR
34/361
635/903
29/361
565/903
Adapted from Sherman KE, et al. CROI 2011. Abstract 957
Telaprevir regimen in G1 HCV-infected
patients: treatment-NAÏVE without
cirrhosis
Stop at Week 24 if undetectable at Week 4
and 12
Peg-IFN alfa +
ribavirin
Telaprevir + PR
Peg-IFN alfa + ribavirin
if detectable at Week 4 or 12*
Weeks
HCV RNA:
0
4
12
If >1000 IU/mL at Week 4 or 12:
discontinue all drugs
36
24
48
If detectable at Week 24 or 36:
discontinue PR
*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
Boceprevir (SPRINT-2): RGT in treatment
naïve patients
Undetectable HCV RNA
Detectable HCV RNA ≥1
between Weeks 8–24*
time between Weeks 8–24*
BOC 24
PR 28
BOC 44
PR 48
BOC 24W
PR 48W
BOC 44
PR 48
55/73
SVR (%)
Overall SVR
137/363
233/368
242/366
156/162
155/161
45/68
PR48
BOC
RGT
BOC44/
PR48
BOC
RGT
BOC44/
PR48
BOC
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
BOC44/
PR48
Boceprevir EU SmPC
Boceprevir (SPRINT-2): no RGT for
patientsNo,with
cirrhosis
minimal
Bridging fibrosis (F3)
Cirrhosis (F4)
SVR (%)
or portal fibrosis (F0–F2)
n/N=
PR48
BOC RGT
BOC44/
PR48
PR48
BOC RGT
BOC44/
PR48
PR48
BOC RGT
BOC44/
PR48
123/328
213/319
211/313
3/11
9/18
12/18
6/13
5/16
10/24
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
Poordad F, et al. N Engl J Med 2011;364:1195–206
Boceprevir regimen in G1 HCV-infected
patients: treatment-NAÏVE without
cirrhosis
Stop treatment at Week 28
if undetectable at Week 8 and 24
PR
lead-in
BOC + PR
If detectable at Week 8 but undetectable at Week 24:
BOC + PR
Weeks
HCV RNA
0
4
8
12
Assess for
If ≥100 IU/mL
RGT criterion discontinue all
drugs
24
28
PR*
36
48
If detectable
discontinue all
drugs
*This regimen has only been tested in patients who have failed previous therapy who were late responders
Boceprevir EU SmPC
SPRINT-2 (boceprevir): eligibility for shorter
treatment duration
Week 81
Weeks 8 to 242
Patients with undetectable
HCV RNA (%)
Patients eligible to
receive 28 weeks
of total treatment
PR48
n/N= 60/363
BOC RGT
BOC44/PR48
PR48
BOC RGT
BOC44/PR48
208/368
204/366
43/363
162/368
161/366
1. Boceprevir EU SmPC
2. Poordad F, et al. N Engl J Med 2011;364:1195–206
Dosing duration in all patients with compensated
cirrhosis
TVR
+ Peg-IFN + RBV
>1000 IU/mL:
Stop 3 drugs
Peg-IFN + RBV
>1000 IU/mL:
Stop 3 drugs
Peg-IFN +
RBV
0
4
Detectable:
Stop PR
Detectable:
Stop PR
BOC+ Peg-IFN + RBV
≥100 IU/mL:
Stop 3 drugs
Detectable:
Stop 3 drugs
12
24
36
48
Telaprevir EU SmPC; Boceprevir EU SmPC
HCV RNA levels in patients who met the >1000 IU/mL HCV RNA
Week 4 futility rule
Treatment-experienced patients
(n=11)
108
108
107
107
106
106
HCV RNA (IU/mL)
HCV RNA (IU/mL)
Treatment-naïve
patients (n=15)
105
104
105
104
103
103
102
102
10
10
0
2
4
6
8
Weeks on treatment
10
12
0
2
4
6
8
Weeks on treatment
10
12
Adda N, et al. HepDART 2011; Abstract 45
This year has brought a paradigm
shift to gt 1 treatment
Addition 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