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Side effects of Peg-Interferon & Ribavirin in treatment of chronic hepatitis C
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Side effects of Peg-Interferon & Ribavirin in treatment of chronic hepatitis C

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  • 1. Side effects of treatment of chronic hepatitis C Samir Haffar M.D. Assistant Professor of Gastroenterology
  • 2. Natural History of Hepatitis C Di Bisceglie AM. Hepatology 2000 ; 31 : 1014 – 1018.
  • 3. Major types of adverse events • Fatigue & influenza-like symptoms • Gastrointestinal disturbances • Hematologic abnormalities Anemia – Neutropenia – Thrombocytopenia Most frequent indication for dose reduction (25%) Most frequent indication for discontinuation (5%) • Neuropsychiatric symptoms
  • 4. Uncommon serious adverse events < 1% • Retinopathy, retinal hemorrhage, visual loss • Tinnitus • Hearing loss • Cardiac arrhythmias, congestive heart failure • Acute renal failure • Bacterial infections (particularly in cirrhosis) • Induction or exacerbation of autoimmune diseases • Hyperthyroidism, hypothyroidism • Acute psychosis, panic attacks, severe depression/suicide
  • 5. Because most of the AE associated with treatment are dose related, dose reduction or discontinuation has been proven to be safe & effective way to decrease them & minimize serious, life-threatening sequelae
  • 6. Effect of dose reduction or discontinuation on SVR • SVR rates higher in patients who receive > 80% of their full IFN & RBV doses > 80% of the intended duration of therapy • SVR rates higher in patients who received > 10.6 mg/kg/d of RBV • Delivering optimal dose of therapy is more crucial during the first 12 weeks of antiviral therapy
  • 7. SVR & RBV dose Manns MP et al. Lancet 2001; 358 : 958 – 65. Definitive cutoff at a critical dose of 10.6 mg/kg
  • 8. General Strategies for Management of AE Begin before first dose of medication administered • Patients exclusion: Psychiatric illnesses – substanc abuse – co-morbid conditions • Patients education of experiencing one or more AE • Remain fit: BMI < 30 & ideally < 25 • Adequate sleep • Maintaining adequate hydration • Dose schedules coincide with weekends • Mild to moderate exercise schedules • Regular follow-up visits
  • 9. Management of major types of adverse events
  • 10. Flu-like symptoms
  • 11. Treatment of flu-like symptoms • General Principles Injections given the evening before a weekend • Acetaminophen Limit the dosage to 2g / 24 h Altered pharmacokinetics in chronic liver disease • NSAIDs Avoided in established cirrhosis Precipitating renal impairment
  • 12. Anemia
  • 13. ∆ PEG alfa-2a alone PEG alfa-2a & RBV X Standard IFN alfa-2b & RBV Change in hemoglobin during 48 week of therapy within first 2- 4 w Mean decrease 3 g / dL PEG-IFN = IFN Plateauing thereafter Return to normal after stop
  • 14. Mechanisms of anemia Multifactorial in most cases • IFN Bone marrow suppression • RBV Extravascular hemolysis Bone marrow suppression
  • 15. Mechanism of RBV-induced Anemia RBV Erythrocytes Active form: RBV triphosphate (> 60-fold than plasma concentration) Reduces antioxidant defense Induces RBC membrane oxidative damage Depletion of RBC cell ATP Extravascular hemolysis via RES De Franceschi L. Hepatology 2000 ; 31 : 997 – 1004.
  • 16. Management of anemia • Dose reduction or discontinuation of RBV ½ dose Hb < 10 g / dL Stop Hb < 8.5 / dL • Epoetin alpha 40 000 units weekly Well tolerated Additional studies are needed before recommendation • Darbepoetin alfa 3 mcg / kg every other week Well tolerated Additional studies are needed before recommendation
  • 17. Indications of Epoetin alfa • Anemia associated with chronic renal failure • Zidovudine therapy for HIV infection • Anemia associated with cancer chemotherapy • Reduce need for blood transfusions in anemic pts undergoing elective surgery • Ribaverin-induced anemia?
  • 18. Neutopenia
  • 19. Change in neutrophils during 48-week of therapy ∆ PEG alfa-2a alone PEG alfa-2a & RBV X Standard IFN alfa-2b & RBV within first 2 weeks PEG-IFN > IFN Plateauing thereafter Return to nl after stop
  • 20. Management of neutropenia • Dose reduction or discontinuation ½ dose WBC < 1 500 / mm3 Neutrophils < 750 / mm3 Stop WBC < 1 000 / mm3 Neutrophils < 500 / mm3 • G-CSF (Filgrastim) 300 mcg twice a week Insufficient data to support its routine use now
  • 21. When do you order a neutrophil count in the follow-up?
  • 22. Timing of measuring neutrophils • After single injection of PEG-IFN, neutrophils decreased by a median of 21% within first 24 hours but generally stabilized over ensuing 4 weeks. • Measurement of neutrophils counts just before rather than just after injection may provide more complete picture & minimize dose reductions. Peck-Radosavljevic M et al. Gastroenterology 2002 ; 123 : 141 – 151.
  • 23. Why this neutrophil count threshold (1000 or 500/mm3) was chosen?
  • 24. Neutrophil count threshold used for dose modification • Empiric evidence extrapolated from cancer patients undergoing chemotherapy • 119 patients receiving IFN & RB: 22 infections none observed in neutropenic patients 1 bacterial infection required admission was in a patient with cirrhosis & neutrophils > 1 000/mm3 • Neutropenia may be better tolerated in HCV patients receiving combination therapy than in cancer patients
  • 25. Indications of G-CSF • Chemotherapy-associated neutropenia • Interferon-induced neutropenia?
  • 26. Thrombopenia
  • 27. Change in platelet count during 48 week of therapy ∆ PEG alfa-2a alone PEG alfa-2a & RBV X Standard IFN alfa-2b & RBV gradually over 8 weeks PEG-IFN > IFN Plateauing thereafter Return to normal within 4 w
  • 28. Mechanisms of thrombopenia • Reversible bone marrow suppression • Autoimmune related thrombocytopenia may occur N.B. Concurrent use of RBV may blunt thrombocytopenic effect of IFN as a result of reactive thrombocytosis
  • 29. Management of thrombocytopenia • Dose reduction or discontinuation ½ dose Platelets < 50 000 / mm3 Stop Platelets < 25 000 / mm3 • IL-11 (Oprelvekin) 50 mg / kg sc three times per week SE: fluid retention & lower extremity edema Its use is currently not recommended
  • 30. Depression
  • 31. Proportion of Patients with Depression Approximately 20 – 30 % of patients Fried MW et al. N Engl J Med 2002; 347: 975 – 82.
  • 32. IFN-induced depression one third of patients • More frequently during first 24 weeks of therapy • Early identification of depression is crucial Numerous scales available: Beck Depression Inventory • Most episodes remain mild to moderate in severity & managed by specific antidepressants particularly SSRIs • At extreme end: Suicidal ideation or suicidal behavior Treatment should be terminated Immediate referral to a mental health professional
  • 33. Etiology of IFN-induced depression Remains largely speculative • IFN increases levels of IL-6 & IL-8 • Reductions in serotonin & tryptophan levels in brain Rationale for use of SSRIs • Depletion of tryptophan stores Primary precursor of serotonin • Effects on hypothalamic-pituitary-adrenal (HPA) axis
  • 34. What is the therapeutic strategy in IFN-induced depression? To prevent or to treat?
  • 35. Prevention or treatment of depression • Prevention High frequency of depression Significant decrease with paroxetine (SSRI) Inappropriate for 70% to 80% of patients Potential risks: Retinal & GI hemorrhage Stimulation of secondary mania • Treatment Frequent monitoring of patients Begin antidepressants once symptoms arise
  • 36. Use of antidepressants in the setting of therapy for Chronic Hepatitis C should be tailored to the history & symptomatology of the individual patient
  • 37. Treatment of IFN-induced depression Selective Serotonin Reuptake Inhibitors (SSRIs) • Ease of use & overall tolerability • Overall success rate close to 90% in recorded trials • Efficacy against anxiety (10 – 20 % of patients) • Side effects: Sexual dysfunction Insomnia Retinal bleeding (cotton-wool spots) Gastrointestinal bleeding Affect platelet function
  • 38. SSRIs Drug Daily dosage Comments Citalopram (Celexa) 10 - 60 mg Fluoxetine (Prozac) 5 - 80 mg Paroxetine (Paxil) 10 - 60 mg Discontinuation Paroxetine CR (Paxil CR) 12.5 - 62.5 mg Sertraline (Zoloft) 25 - 200 mg
  • 39. Injection-site reactions
  • 40. Injection-site reactions • Usually red & slightly raised • May expand to a circumference of 5 cm or more • Rotating injection sites: lesions may take wks to resolve • If continues to enlarge or becomes warm & tender Patient examined for development of abscess • If abscess: Drain site & treat with oral antibiotics No interruption of PEG-IFN • Large abscess considered as potentially severe AE Therapy discontinued until healed or even indefinitely
  • 41. Other side effects of Ribaverin
  • 42. RBV-induced cough Management is difficult • Dry non-productive cough • Typically will not clear until RBV is stopped • Most patients are able to tolerate the cough • In some cases cessation of RBV is necessary • If productive cough or fever: chest X-ray (pneumonitis) • If bacterial pneumonia: Withheld antiviral therapy until antibiotics given & Clear evidence of clinical improvement
  • 43. RBV-induced skin eruption & pruritis Management is difficult • Rash seen usually on trunk & back • Macular-papular & pruritic • No response to steroid creams or soothing baths • Disappears within weeks of stopping RBV • Occasionally, spreads to face with severe periorbital edema RBV should be discontinued in such cases
  • 44. Case report
  • 45. Case report • 28 year old man ALT: 75 (N 40) Anti HCV + HCV RNA PCR 65 000 copies/ml Genotype: 3 • PEG/IFN 180 g/w & RBV 800 mg/day • Asthenia & fatigue What are the cause of asthenia?
  • 46. Causes of fatigues • Adverse events of IFN/PEG-IFN • RBV-induced anemia • Hypothyroidism • Depression
  • 47. Case report (Ctd) • Hg: 12 g/dL – Ht: 37 % – RBC: 5 millions/mm3 • Na: 141 mEq/L – • K: 4.5 mEq/L • TSH: 15 (Normal: 0.3 - 6 U/ml ) • Free T4 0.1 (Normal: 0.9 - 2 ng/dL) • Absence of mood disturbance, anhedonia, insomnia, anorexia, or sexual dysfunction What is the diagnosis & the management?
  • 48. Case report (Ctd) • Diagnosis Primary Hypothyroidism • Management - Replacement therapy Thyroxine 75 - 100 g/day once-a-day - Continue antiviral treatment
  • 49. Indications of TSH testing during therapy • Before initiation of treatment • At least once during treatment: usually at week 12 • At any time the patient reports symptoms suggestive of hypo- or hyperthyroidism
  • 50. Regular follow-up during treatment of chronic viral hepatitis C is crucial The main Message