telaprevir-based triple therapy adverse events: case...

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)

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)


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)


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)


all cause 139 (42.6) 690 (60.9) 98 (79.7)


all cause 54 (16.6) 376 (33.2) 58 (45.3)


cause 70 (21.5) 383 (33) 52 (40.6)


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!

telaprevir-based triple therapy adverse events: case...

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