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Side Effects of Interferon Alpha in Viral Hepatitis

Geoffrey Dusheiko, M.D., F.R.C.P.

Interferon alphas have been widely used to treat chronic hepatitis C virus infection. These include recombinant interferons, or purified natural leucocyte or Lymphoblastoid interferon. Interferon alpha is usually administered by subcutaneous or intramuscular injection. The terminal half-life of interferon alpha is 4-5 hours. Renal excretion is the predominant route of elimination.

A wide array of side effects have been encountered in several large trials of treatment of hepatitis C. Side effects are common; they are usually minor but are problematic for a significant proportion of patients. Major adverse events can occur, but life-threatening adverse events have been rare in large surveys. (1) Tolerance in elderly patients and children is usually similar. (2-4)

Early flu-like side effects are predictable and are encountered in the majority of patients. These tend to occur within 6-8 hours after starting treatment and are worst with the first injections. These side effects include fever, malaise, tachycardia, chills, headache, arthralgias, and myalgias. However, they are usually acceptable at doses of 3-6 million units (MU) of interferon alpha, and tachyphylaxis generally develops after the first few injections. These side effects are ameliorated by paracetamol (acetaminophen).

Later side effects develop after some days. These include fatigue, malaise, apathy, and cognitive changes. Between 10 and 15 percent of patients find the chronic side effects intolerable and discontinue treatment. Higher doses (above 5-6 MU three times weekly) tend to give higher rates of adverse events. (5-7)

Neuropsychiatric Side Effects

Neuropsychiatric side effects can be the most troublesome and unpredictable , but their mechanisms are poorly understood. Interferon is not thought to readily cross the blood-brain barrier. These effects include fatigue, asthenia, drowsiness, lack of initiative, irritability, confusion, and apathy; behavioral, mood, and cognitive changes are a relatively frequent dose-limiting toxicity. Severe depression may occur and suicidal ideation is well described. This can be more marked in patients with a history of depression, but suicide has been reported in patients without a previous psychiatric history. (8)

Administration at night may reduce the frequency of these side effects. They usually regress after discontinuing therapy, albeit after some weeks. Severe depression is a medical emergency. The overall incidence of neurotoxicity is 25-33 percent. Seizures have been recorded in 1.3 percent of patients. (9) There are isolated reports of extrapyramidal syndromes with ataxia and akathisia. Paraesthesias have been recorded. table 1 lists common adverse events associated with interferon alpha in a recent trial, and table 2 lists a range of laboratory variables.

table 1. Most Common Adverse Events in a Recent Large Trial of Patients Treated With Consensus Interferon (CIFN) or Interferon Alfa 2b (3 MU=15 ug) (percentage)

Preferred Term CIFN 3ug CIFN 9ug IFN a-2b 15ug
Headache 75 82 82
Fatigue 58 69 67
Fever 30 60 45
Rigors 22 57 44
Myalgia 46 57 55
Pain 39
Arthralgia 43 44
Back pain 33 41 36
Abdominal pain 37 40 39
Nausea 41 40 35
Insomnia 26 38 30
Pharyngitis 28 33 31
Nervousness 26 31 28
Infection upper 32 31 33
Diarrhea 25 28 24
Pain limb 20 26 25
Depression 21 26 25
Anorexia 17 23 17
Granulocytopenia 9 23 25
Erythema 22.2 22.5 15.3
Dizziness 25 22 24
Cough 14 22 17
Dyspepsia 22 20 18
Anxiety 15 19 18
Thrombocytopenia 11 18 16
Sinusitis 15 17 22
Influenza like 22.6 15 11
Leukopenia 7 14 12
Pain neck 10 14 12
Pain skeletal 13 14 14
Alopecia 6 14 25
Paraesthesia 10 13 9
Pruritus (itching) 13 13 13
Rash 12 13 14
Chest pain 15 12 14
Hot flushes 6 12 7.2
Emotional lability 8 12 11
Rhinitis 12 12 15
Increased sweating 5 12 11
Vomiting 12 11 10
Resp tract congestion 11 10 14
Dysmenorrhea 7.8 9.4 9.4
Thyroid test abnormal 3 9 4
Conjunctivitis 6.1 8.2 8.1
Constipation 10 8 5
Thinking abnormal 10 7.8 12
Hypertriglyceridemia 6 6 6
Tinnitus 3 5 4
Pain eye 2.6 4.8 5.5
Earache 10 4 6

table 2. Laboratory Variables

Value Phase Observation 3ug CIFN 9 ug CIFN 15 ug IFN
alpha-2b
Hemoglobin End Rx Median change (%) -2.6 -4.8 -4.5
White blood cells End Rx Median change (%) -9.7 -18.5 -22.8
Treatment period Incid low WBC (%) 19.20% 35.20% 35.20%
Neutrophil count End Rx Median change (%) -13.7 -22.9 -33.4
Treatment period Incid low neutrophils (%) 20.10% 42.60% 40.10%
Segmented neutrophil count End Rx Median change (%) -13.6 -22.8 -33.2
Basophil count End Rx Median change (%) -7.7 -13 -29
Eosinophil count End Rx Median change (%) 14 -3.2 -19
Lymphocyte count End Rx Median change (%) -0.3 -9.4 -42
Monocyte counts End Rx Median change (%) 9.7 10.1 13.4
Platelet counts End Rx Median change (%) -7.5 -15.6 -18.9
Treatment period Incid low platelets (%) 38 46.1 45.3
Serum calcium End observation Median change (%) -1.03 -0.3 0.07
Treatment period Incid low calcium (%) 7.4 8.7 9.5
Serum triglyceride End Rx Median change (%) 11.6 40.8 27.4


Source: Amgen Inc. Phase 3: (9210). With acknowledgment.

Immune Disorders

Interferon has important immunomodulatory properties. Non-organ-specific antibody titers may increase, and indeed may be associated with autoimmune thyroiditis, hypothyroidism, and hyperthyroidism. (10-15) Other autoimmune endocrine diseases have been induced, but thyroid disease is particularly important. (16) Thyroid disorders have been reported in 2.5-20 percent of patients. This may not be reversible after stopping therapy, unless therapy is stopped early, and long-term thyroid replacement may be required. (17-19) It is possible that underlying thyroid disease is more common in chronic hepatitis C infection.

An aggravation of the chronic hepatitis may occur. Patients may be genetically predisposed to this complication and can be recognized by prior autoantibody measurement and HLA haplotyping. An exacerbation of psoriasis may be part of this syndrome. Discontinuation may be required, particularly for hyperthyroidism, unless transient hyperthyroidism followed by hypothyroidism is recognizable. Autoimmune hepatitis usually necessitates discontinuation of therapy. Interferon may promote the development of systemic lupus erythematosus.

Cardiovascular Side Effects

Both benign and severe cardiac manifestations have been reported. Cardiac arrhythmias, including supraventricular tachycardia but also sudden death and ventricular arrhythmias, have been reported. There are single case reports of dilated cardiomyopathy. Hypotension has been reported in large trials.

Renal Side Effects

Proteinuria is relatively common, but is usually benign and not nephrotic. lnterstitial nephritis and acute renal failure have been reported. Interferon alpha is, however, reasonably tolerated in hemodialyzed patients. (20) Renal impairment occurs in kidney transplant patients. (21)

Hepatic Side Effects

Serum aminotransferases may increase during interferon alpha treatment. These are generally mild and resolve with continued treatment in responsive patients. Exacerbations occur in hepatitis B infection; these severe cytolytic episodes may presage a response, but are poorly tolerated in patients with cirrhosis. Hepatic decompensation may occur in patients with cirrhosis, and these patients are more susceptible to infections. (22,23) Autoimmune hepatitis should not be misdiagnosed as hepatitis C infection, as severe exacerbation of the disease with cholestasis and severe liver injury can occur. Patients with documented hepatitis C infection may deteriorate after interferon alpha treatment if an underlying autoimmune diasthesis is present. This has been observed in LKM antibody-positive individuals. These patients require careful monitoring if interferon is considered the first line of treatment. (24) Rejection may occur if interferon is used after liver transplantation. (25)

Gastrointestinal Side Effects

Nausea, vomiting, dyspepsia, diarrhea, and abdominal pain are relatively frequent.

Dermatologic Side Effects

A variety of rashes including erythema multiforme have been noted. Pruritus can be troublesome. Mild hair loss is relatively common but is reversible. Local erythema is common. Psoriasis can develop de novo, or be aggravated, and is usually difficult to treat. Vitiligo has been reported. (26)

Myelosuppression

Granulocytes, thrombocytes, and red blood cell counts are commonly decreased during treatment. These are usually mild if normal counts are present initially, but can be dose limiting in the presence of low counts, for example in patients with hypersplenism. Patients may be predisposed to infections. The mechanism of granulocytopenia is unknown, but inhibition of cell release from the bone marrow has been suggested.

Hormonal and Metabolic Side Effects

A sustained increase in serum triglyceride levels has been reported. Diabetes mellitus may worsen or develop.

Rare Adverse Events

Ocular: Retinopathy has been reported in Japanese patients. (27) Lung: interstitial fibrosis of the lung and hearing impairment have been found. (7) The cases of pneumonitis may also be due to the use of Sho-Saiko and interferon. (28)

Conclusion

This array of side effects indicates the importance of selecting patients for therapy and optimizing response. Careful assessment is required before treatment, and monitoring is required during treatment. Relatively little is known about the mechanisms of many of the side effects of interferon alpha. (29)

Combination antiviral therapy, particularly ribavirin and interferon, is likely to be given to many patients with chronic hepatitis C. Interactive pharmacokinetic studies examining the distribution and metabolism of these two drugs are in progress.

Table of Contents

References

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  8. Janssen HLA, Brouwer JT, Van der Mast RC, Schalm SW. Suicide associated with alfa-interferon therapy for chronic viral hepatitis. J Hepatol 1994;21:241-3.
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  29. Nakamuta M, Ohashi M, Fukutomi T, Tanabe Y, Hiroshige K, Nawata H. Rise of plasma myeloperoxidase during interferon therapy. J Gastroenterol Hepatol 1995;10:277-80.

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