Post on 11-Jan-2016
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)
6
4
2
6
4
2
Vira
l loa
dV
iral l
oad
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