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Telaprevir-based triple therapy adverse events: case studies
Prof. I.G. Bakulin
6th conference «White nights of hepatology»
St. Petersburg, 6 June 2014
AE Management in triple therapy with first generation protease inhibitors (PI)
Monitoring of signs and symptoms, laboratory
analysis
AE assessment
AE correction
AE prognosis
Monitoring in patients during HCV therapy
Blood tests Time-points
During HCV-therapy
• Hematology
• Chemistry Every 4 wks /on demand
HСV РНК Week 4, 12, 24, 36, 48
ECG Every 4 wks
TSH Every 12 wks
After HCV-therapy
• Hematology
• Chemistry
• TSH
• HСV РНК
Week 12, 24, 48, 96
AE assessment in triple therapy
AE in standard (double) therapy
AE due to drug-to-drug interaction (DDI)
AE specific for PI (boceprevir and telaprevir)
Safety and tolerability with DAAs
Common AEs with PR include:1–3
• Fatigue, headache, nausea, pyrexia and myalgia
• Anemia and neutropenia
• Depression, irritability and insomnia
• Rash
Additional management considerations with DAAs
• Telaprevir:4–7 rash, pruritus, anemia, anorectal symptoms, nausea and diarrhea
• Boceprevir:8–10 anemia, dry skin, dysgeusia, rash and neutropenia
1. Pegintron EU SmPC; 2. Pegasys EU SmPC; 3. Rebetol EU SmPC; 4. Jacobson IM, et al. N Engl J
Med 2011;364:2405–16
5. Sherman KE, et al. N Engl J Med 2011;365:1014–24; 6. Zeuzem S, et al. N Engl J Med
2011;364:2417–28
7. INCIVO (telaprevir) EU SmPC; 8. Poordad F, et al. N Engl J Med 2011;364:1195–206
9. Bacon BR, et al. N Engl J Med 2011;364:1207–17; 10. Boceprevir EU SmPC
Telaprevir placebo-controlled Phase II/III studies: summary of AEs during telaprevir/placebo phase
Patients (%)
T12/PR
(750 mg q8h)
N=1346
Placebo/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 3 <0.5
Anorectal discomfort 8 2 <0.5
Anal pruritus 6 1 <0.5
Blood and lymphatic system disorders
Anemia (SSC) 32 15 0.9
http://www.fda.gov/downloads/AdvisoryCommittees/Committees/Meeting
Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf
*Discontinuation of all study drugs in the T12/PR arms (analyzed within SSC for
rash and anemia)
Telaprevir placebo-controlled Phase II/III studies: summary of AEs during telaprevir/placebo phase
Patients (%)
T12/PR
(750 mg q8h)
N=1346
Placebo/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 3 <0.5
Anorectal discomfort 8 2 <0.5
Anal pruritus 6 1 <0.5
Blood and lymphatic system disorders
Anemia (SSC) 32 15 0.9
http://www.fda.gov/downloads/AdvisoryCommittees/Committees/Meeting
Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf
*Discontinuation of all study drugs in the T12/PR arms (analyzed within SSC for
rash and anemia)
Clinical case
• 63 y. o. male
• 75 kg, 172 cm (BMI – 25.7 kg/m2)
Anamnesis
• Relapse (after treatment with PEG/RBV)
• HCV genotype – 1b
• HCV RNA: 6 log10 ME/ml
• Fibrosis stage: F4
• No varices
Anamnesis morbi
• Hb - 14 g/dl
• Albumin – 40 g/l
• Platelet level - 135 000
Additional info
HCV RNA levels
week 4: neutrophils - 1050/mm3; platelets - 87000/mm3
Hb
week 2:
4 log10
decrease
4,1 g/dl
decrease
4 week anti-viral therapy: Telaprevir (750 mg t.i.d.) +
PEG-IFN2а (180 mkg/week) + RBV (1200 mg/day)
HCV RNA
ADVANCE, ILLUMINATE & OPTIMIZE (telaprevir): incidence of Grade 2–4 anemia* by baseline fibrosis stage
P=0.009, comparing F0–2 vs F3–4
P=0.01, chi-squared for trend
*special search criteria – grouping of search terms to ensure all
relevant adverse events are captured
Zeuzem S, et al. AASLD 2013. Abstract 1908
n=630 n=580 n=247 n=185
Pro
po
rtio
n o
f p
ati
en
ts (
%)
TVR EAP: the incidence of adverse events by age
Moreno C, et al. AASLD 2013. Abstract 1911
Type of AE (%)
Age <45
(n=326)
Age 45–65
(n=1133)
Age >65
(n=128)
Grade 1–4 anemia SSC,
all cause 139 (42.6) 690 (60.9) 98 (79.7)
Grade 3–4 anemia SSC,
all cause 54 (16.6) 376 (33.2) 58 (45.3)
Grade 1–4 rash SSC, all
cause 70 (21.5) 383 (33) 52 (40.6)
Grade 3–4 rash SSC, all
cause 8 (2.5) 53 (4.7) 3 (2.3)
Any SAE 8 (2.5) 81 (7.1) 15 (11.7)
Clinical significance of anemia
Weakness increase
Onset/increase of respiratory insufficiency
Increased risk of cardio-vascular events
Increased risk of depression
Lowering of life quality
What to choose?
RBV dose reduction
EPO
Blood transfusion TVR stop
In clinically significant anemia (Hb <10 g/dl) ribavirin dose should be reduced by 200 mg
Ribavirin should be stopped if Hb < 8.5 g/dl
Ribavirin should be restarted with Hb >10 г/дл
Ribavirin-induced anemia : Dose modification and stopping rules
EASL Clinical Practice Guidelines:
Management of hepatitis C virus infection (2014)
SVR by minimal dose of RBV/day in telaprevir/placebo phase
SV
R (
%)
n/N=
No dose
reduction
800–1000mg
346/
439
291/
395
≤ 600mg
38/
51
Naïve patients
133/
292
13/
24
16/
38
No dose
reduction
800–1000mg
73/
89
27/
29
≤ 600 mg
20/
24
Relapse
11/
55
2/
7
2/
6
PR T12/PR or T12/PR48
Sulkowski MS, et al. J Hepatol 2012;56 (Suppl 2):S459–S460
ADVANCE и ILLUMINATE (telaprevir): SVR by the time of the 1st RBV dose reduction
SV
R (
%)
n/N=
0-4 >4 - 12
160/ 221 85/99
>12-24
171/237
Time to the first dose reduction (weeks)*
>24-48
36/43
*Время от первой лечебной дозы до первого снижения дозы
Sulkowski MS, et al. J Hepatol 2012;56 (Suppl 2):S459–S460
Boceprevir: EPO vs RBV dose reduction in anemia management
• 37% of patients that received EPO RBV dose was reduced to treat secondary anemia
• 18% of patients that reduced RBV dose needed treatment with EPO
• Poordad F, et al. EASL 2012. Abstract 1419
18% 37%
100
80
60
40
20
0 No EPO EPO No dose reduction RBV dose reduction
RBV dose reduction EPO
SV
R (
%)
Management of anemia
69
82
68
76
141/204 37/45 107/158 71/93
What to chose?
RBV dose reduction
EPO
Blood transfusion TVR stop
CUPIC: the incidence and management of anemia according to age
Hézode C, et al. AASLD 2013. Abstract 1845
22/221 16/
78
26/
221 27/
78
106/
221
63/
78
Telaprevir
P=0.028
P<0.001
P<0.001
12 week treatment
Week 4
↓RBV: 1000 mg/day
PEG-IFN а2а
Week 5-6
↓RBV: 800 и 600
mg/day
Telaprevir stopped
after 12 weeks
HCV RNA Hb telaprevir + PR Telaprevir + PR
5
week 8: plateletes: 79 000/mm3
week 12: platelets: 67 000/mm3
11th week of treatment: moderate grade rash, itching
Summary of rash data from placebo-controlled Phase II and III trials: telaprevir treatment phase
>90% of all rash =
mild/moderate
Incid
en
ce o
f ra
sh
(%
)
Features:
Typically pruritic and eczematous, and involving <30% BSA
Progression was infrequent (<10% of cases)
Time to onset:
Approximately 50% of rashes started during the first 4 weeks
But rash can occur at any time during telaprevir treatment
Incid
en
ce o
f ra
sh
(%
)
Telaprevir EU SmPC
http://www.fda.gov/downloads/AdvisoryCommittees/Committees/Meeting
Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf
N=1346 N=764
T12/PR arm
TVR EAP: the incidence of adverse events by age
Moreno C, et al. AASLD 2013. Abstract 1911
Type of AE (%)
Age <45
(n=326)
Age 45–65
(n=1133)
Age >65
(n=128)
Grade 1–4 anemia SSC,
all cause 139 (42.6) 690 (60.9) 98 (79.7)
Grade 3–4 anemia SSC,
all cause 54 (16.6) 376 (33.2) 58 (45.3)
Grade 1–4 rash SSC, all
cause 70 (21.5) 383 (33) 52 (40.6)
Grade 3–4 rash SSC, all
cause 8 (2.5) 53 (4.7) 3 (2.3)
Any SAE 8 (2.5) 81 (7.1) 15 (11.7)
Treating patients with mild or moderate rash
Use topical corticosteroids* or systemic antihistamines
Permitted topical antihistaminic drugs may be tried for the treatment of
associated pruritus
Limit exposure to sun/heat and wear loose-fitting clothes
Drug considerations: mild and moderate rash
Rash
Mild
Moderate
Monitor for progression or systemic symptoms until the
rash is resolved
For moderate rash, consider consultation with a specialist
in dermatology. For moderate rash that progresses,
permanent discontinuation of telaprevir should be
considered
If the rash does not improve within 7 days following
telaprevir discontinuation, ribavirin should be interrupted.
Interruption of ribavirin may be required sooner if the rash
worsens despite discontinuation of telaprevir
Peginterferon alfa may be continued unless interruption is
medically indicated
For moderate rash that progresses to severe (≥50% body
surface area), permanently discontinue telaprevir
*Concomitant use of systemic dexamethasone with telaprevir may result in loss of therapeutic effect of
telaprevir. This combination should be used with caution or alternatives should be considered Telaprevir EU SmPC
Symptomatic therapy: topical corticosteroids (ointments) +
desloratadine (Erius 5 mg/day) – week 16
Week 48: Treatment results
Hb PR T/PR PR T/PR
HCV RNAК
week 8: platelets -79 000/mm3
week 12: platelets- 67 000/mm3 week 24: platelets 65 000/mm3
weeks 36-48: platelets 72-76 000/mm3
AE Management in triple therapy with first generation protease inhibitors (PI)
Monitoring of signs and symptoms, laboratory
analysis
AE assessment
AE correction
AE prognosis
AE PROGNOSIS IN TRIPLE THERAPY
*Missing data for 63 patients
Severe complications include death, hospitalisation and hepatic decompensation Hézode C, et al. J Hepatol 2013;
Factors
Platelets ≤100,000/mm3
Platelets >100,000/mm3
Albumin <35 g/L
n Complications, n (%) SVR12, n (%)
37 19 (51.4%) 10 (27.0%)
31 5 (16.1%) 9 (29.0%)
Albumin ≥35 g/L
n Complications, n (%) SVR12, n (%)
74 9 (12.2%) 27 (36.5%)
306 19 (6.2%)
168 (54.9%)
ADVANCE, ILLUMINATE & OPTIMIZE (telaprevir): proportion of patients who experienced a SAE by baseline
fibrosis stage
• Patients with F0–2 stage fibrosis were significantly less likely to experience a SAE than patients with F3–4 fibrosis (P=0.017)
• The probability of experiencing a SAE increased with more advanced levels of fibrosis (P=0.007)
P=0.017, comparing F0–2 vs F3–4
P=0.007, chi-square for trend
Zeuzem S, et al. AASLD 2013. Abstract 1908
n=630 n=580 n=247 n=185 n=630 n=580 n=247 n=185
F0–1 F2 F3 F4
TARGET cohort: impact of age on safety and efficacy of TVR and BOC-based triple therapy
Aronsohn A, et al. AASLD 2013. Abstract 22
<65 years ≥65 years
Treatment discontinuation 36% 44%
Among which
discontinuation due to AE 42% 53%
Hb <8.5 g/dL (TVR/PR) 15% 27%
Hb <8.5g/dL (BOC/PR) 12% 35%
SVR rates were similar in patients <65 or
≥65 years old:
– TVR/PR: 60–75% in treatment naïve,
53–59% in treatment experienced
– BOC/PR: 57–67% in treatment naïve,
36–37% in treatment experienced
SAE were more frequent in patients ≥65
vs <65 years old:
– TVR/PR: 20% vs 10%
– BOC/PR: 41% vs 13%
Summary
• Patients with a more advanced stage of disease at baseline were more likely to experience AEs than patients with less advanced disease1
• With experience and close monitoring, patients with cirrhosis can be successfully treated with DAA-based triple therapy2
• The frequency of complications increases with severity of liver disease
• However, even when only F3–F4 patients were treated (in TVR EAP), the incidence of SAEs and discontinuations was similar to Phase 3 trials1,3,4
1. Colombo, et al. EASL 2013. Abstract 806; 2. Fontaine H, et al. AFEF 2013
3. Zeuzem S, et al. N Engl J Med 2011; 364:2417–28; 4. Jacobson I, et al. N Engl J
Med 2011;364:2405–16. 5. Moreno C, et al. AASLD 1911
6. Hezode C, et al. AASLD 2013. Abstract 1845;
Treatment of patients with
advanced fibrosis
Older patients can still be effectively treated with TVR and BOC but
are at greater risk of anemia, rash and SAEs 5,6
Outcomes and management in
elderly patients
Thank you!