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Management of side effects Cirrhotic on telaprevir

Management of side effects Cirrhotic on telaprevir. Vincent LEROY Clinique Universitaire d’Hépato-Gastroentérologie INSERM U823 CHU de Grenoble. Medical history. 55 year-old male patient Arterial hypertension (amlodipine) Smoker, alcohol < 10 g/d

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Management of side effects Cirrhotic on telaprevir

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  1. Management of sideeffectsCirrhotic on telaprevir Vincent LEROY Clinique Universitaire d’Hépato-Gastroentérologie INSERM U823 CHU de Grenoble

  2. Medicalhistory • 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

  3. Treatment by Peg-riba : relapse Trt 1 (2005) 48 weeks 6 4 Viral load 2 - - - - S0 S4 S12 S24 S36 S48 S72 Trt 2 (2007) 72 weeks + optimized ribavirin (1400 mg according to dosage) Tolerance : asthenia, anemia (EPO) 6 4 Viral load 2 - - - - - S0 S4 S12 S24 S36 S48 S60 S72 S96

  4. Medicalhistory • 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

  5. Laboratory 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)

  6. Diagnosis of cirrhosis Grade 2 varices : propranolol

  7. Decision to start triple therapywithtelaprevir Relapsers Partial responders Nul responders 2 bras T12/PR48 100 Pbo/PR48 80 60 RVS (%) 40 20 0 n/N 1/18 7/50 n/N= 144/167 12/38 2/15 48/57 2/15 34/47 3/17 10/18 0/5 11/32 1/5 24/59 15/38 0/9 1/10 53/62 Stade F4 F0-2 F3 F4 F0-2 F3 F4 F0-2 F3 REALIZE study

  8. Start of treatment • Therapeuticeducation • Pegylated-IFN a2a : 180 mg SC / week • Ribavirin 1200 mg / d • Telaprevir 750 mg every 8 hours (with snack) • Triple combination 12 weeks • + PR 36 weeks

  9. Seen in emergency atweek 1 • Severe diffuse myalgias • Elevetad CPK : 640 IU/l • Creatinin = 80 mmol / l • Whatcouldbe the reasons for that ?

  10. Seen in emergency at week 1 • Severe diffuse myalgias • Elevetad CPK : 640 IU/l • Creatinin = 80 mmol / 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

  11. Drug interactions Inhibitoreffect + Cyt P3A - Drugs Metabolites + Increase of therapeutic effect Toxixity Concentration increase

  12. Outcome 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 ?

  13. Impact of anemia and riba dose reduction • REALIZE study : impact on SVR 76 83 16 22 11 28 170 203 41 75 36 119 113 126 28 46 16 47 133 160 29 51 31 99 Relapse Partial response Réponse nulle • 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,

  14. 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 ?

  15. Back to week 6 : rash + itching +++ • Grade 1 : localized • Grade 2 : < 50% : continue TPV • Grade 3 : > 50% : stop TPV Grade 3

  16. How to quantify the skin surface ? Rule of Walace Patient : 35% (grade II) How to manage ? 18%

  17. Management 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

  18. Evolution of rash : worsening • W8 : grade 3 • How to manage ? • Continue triple combination ? • Stop TPV continue PR ? • Stop TPV + PR ? HCV RNA < LOQ but detectable

  19. Management 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

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