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

2. Medical 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

3. Treatment by Peg-riba : relapse S0S4S12S24S36S48S72 - - S0S4S12S24S36S48S60S72S96 - - - -- 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 Viral load

4. 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

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. Relapsers Partial respondersNul responders 2/15 n/N= 53/62 144/16712/380/510/1834/473/170/915/3811/321/5 F0-2F4 Stade 2 bras T12/PR48 Pbo/PR48 2/1548/5724/59 1/187/50 1/10 F3F0-2F4F3F0-2 F4 F3 n/N RVS (%) 0 2020 4040 6060 8080 10 0 REALIZE study Decision to start triple therapy with telaprevir

8. Start 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

9. Seen in emergency at week 1 Severe diffuse myalgias Elevetad CPK : 640 IU/l Creatinin = 80  mol / l What could be the reasons for that ?

10. Seen 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

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

12. Outcome W0 – W4 W0W2W4 Asthenia++++++ Myalgias-++- Pruritus / dry skin-++ Hemoglobin (g/dl)12.610.69.3 Neutrophils (G/l)1.81.10.7 Platelets (G/l)1349874 Viral load (Log IU/ml)6.42.41.8 How to manage blood count toxixity ?

13.  REALIZE 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, 76 83 16 22 11 28 170 203 41 75 36 119 113 126 28 46 16 47 133 160 29 51 31 99 RelapsePartial responseRéponse nulle Impact of anemia and riba dose reduction

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

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

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. -W8 : grade 3 -How to manage ? -Continue triple combination ? -Stop TPV continue PR ? -Stop TPV + PR ? Evolution of rash : worsening 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