Management of side effectsManagement of side effects

Cirrhotic on telaprevirCirrhotic on telaprevir

Vincent LEROYVincent LEROY

Clinique Universitaire d’Hépato-Gastroentérologie Clinique Universitaire d’Hépato-Gastroentérologie

INSERM U823INSERM U823

CHU de GrenobleCHU de Grenoble

Medical historyMedical history

• 55 year-old male patient

• Arterial hypertension (amlodipine)

• Smoker, alcohol < 10 g/d

• Hepatitis C diagnosed in 1998 (asthenia)

• No risk factor of contamination

• Genotype 1b

• Liver biopsy : METAVIR A2F2

Treatment by Peg-riba : relapseTreatment by Peg-riba : relapse

S0 S4 S12 S24 S36 S48 S72

- - - -

S0 S4 S12 S24 S36 S48 S60 S72 S96

- - - - -

Trt 1 (2005) 48 weeks

Trt 2 (2007) 72 weeks + optimized ribavirin (1400 mg according to dosage)

Tolerance : asthenia, anemia (EPO)

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Medical history Medical history

• Seen again in 2010 (no follow-up for 3 years)

• Myocardial infarction in 2008 (stent placed)

• Treatment : atenolol + aspirin

• Moderate asthenia

• Willing to be treated

Laboratory tests and USLaboratory tests and US

• ALT = 120 IU/l, AST = 93 IU/l

• PT=79%

• Hb = 12.4 g/dl, Platelets = 124 G/l

• Viral load : 6.4 log IU/ml. IL28B : CT

• US scan : hepatomegaly

• Transient elastography : 22 kPa (IQR/S > 0.3)

Diagnosis of cirrhosisDiagnosis of cirrhosis

Grade 2 varices : propranolol

Relapsers Partial responders Nul responders

2/15n/N= 53/62144/167 12/38 0/510/1834/47 3/17 0/915/3811/32 1/5

F0-2 F4Stade

2 bras T12/PR48

Pbo/PR48

2/1548/57 24/59 1/18 7/50 1/10

F3 F0-2 F4F3 F0-2 F4F3

n/Nn/N

RV

S (

%)

0

20

40

60

80

100

REALIZE study REALIZE study

Decision to start triple therapy with telaprevirDecision to start triple therapy with telaprevir

Start of treatmentStart of treatment

• Therapeutic education

•Pegylated-IFN a2a : 180 g SC / week

• Ribavirin 1200 mg / d

• Telaprevir 750 mg every 8 hours (with snack)

• Triple combination 12 weeks

• + PR 36 weeks

Seen in emergency at week 1Seen in emergency at week 1

• Severe diffuse myalgias

• Elevetad CPK : 640 IU/l

• Creatinin = 80 mol / l

• What could be the reasons for that ?

Seen in emergency at week 1Seen in emergency at week 1

• Severe diffuse myalgias

• Elevetad CPK : 640 IU/l

• Creatinin = 80 mol / l

• What could be the reasons for that ?

• Comedication by simvastatin (coronary stent)

• Rhabdomyolysis

• Favourable outcome after stopping simvastatin

• Then replaced by pravastatin : no problem

Cyt P3ACyt P3ADrugsDrugs

Inhibitor effect Inhibitor effect

Concentration increase

MetabolitesMetabolites

Increase of therapeutic effect

Toxixity

-

+

+

Drug interactionsDrug interactions

Outcome W0 – W4Outcome W0 – W4

W0 W2 W4

Asthenia + ++ +++

Myalgias - ++ -

Pruritus / dry skin - + +

Hemoglobin (g/dl) 12.6 10.6 9.3

Neutrophils (G/l) 1.8 1.1 0.7

Platelets (G/l) 134 98 74

Viral load (Log IU/ml) 6.4 2.4 1.8

How to manage blood count toxixity ?

REALIZE study : impact on SVRREALIZE study : impact on SVR

➜No impact of ribavirin dose reduction on RVS➜ But similar according to HCV RNA status ?➜ In PR therapy, negative impact when HCV RNA still +

Roberts SK et al. AASLD 2011, Abstract 1368,

7683

1622

1128

170203

4175

36119

113126

2846

1647

133160

2951

3199

Relapse Partial response Réponse nulle

Impact of anemia and riba dose reductionImpact of anemia and riba dose reduction

Management of anemia (patient case)Management of anemia (patient case)

• Ferritin and vitamin B9 : normal dosage

• No ribavirin dose reduction

• Epoetin : 30 000 SC / week

• W6 : hemoglobin = 88 g/dl Reticulocytes 45 G/l

• Epoetin : 60 000 SC / week

• W8 : hemoglobin = 86 g/dl Reticulocytes 52 G/l

• HCV RNA < LOQ but detectable

• What to do with EPO : stop or continue ?

- Grade 1 : localized

- Grade 2 : < 50% : continue TPV

- Grade 3 : > 50% : stop TPV

Back to week 6 : rash + itching +++ Back to week 6 : rash + itching +++

Grade 3

How to quantify the skin surface ?How to quantify the skin surface ?

18%

Rule of Walace

Patient :

35% (grade II)

How to manage ?

Management of grade 2 rashManagement of grade 2 rash

• Symptomatic treatment of prurirus : anti-H1

• Dermo-corticoids

• Close surveillance by dermatologist (every week)

• Patient should be given explanations : consultation in

emergency if worsening

- W8 : grade 3

- How to manage ?- Continue triple combination ?- Stop TPV continue PR ?- Stop TPV + PR ?

Evolution of rash : worseningEvolution of rash : worsening

HCV RNA < LOQ but detectable

Management of grade 3 rashManagement of grade 3 rash

• Look for severity signs (mucosa, fever, adenopathy)

• If isolated grade 3 rash : stop TPV and continue PR

• But monitor very closely (dermatologist / 2 days)

• Stop PR if no improvement after one week

• Hospitalization if grade 4

• For this patient : rapid improvement : PR continued

• But relapse : HCV RNA = 3.4 log at W12