Treatment of chronic hepatitis C can cause several side effects including fatigue, gastrointestinal issues, and hematologic abnormalities like anemia and neutropenia. Management of side effects may involve dose reduction or discontinuation of treatment. Regular monitoring of blood counts and symptoms is important. Depression is also common and can usually be managed with antidepressants like SSRIs. Rare but serious side effects include cardiac or renal issues.

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
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