HEPATITIS C TREATMENT / INTERFERON

Since interferon was first introduced as a therapy for chronic non-A, non-B hepatitis in 1986, almost all patients using interferon and its combinations (i.e. ribavirin) have experienced side effects, some life threatening. Many have had to stop treatment altogether since these side effects were too overwhelming and too debilitating for them to continue treatment. Because of the low success rate in clearing the body of the hepatitis c virus in most people (especially in those with genotype 1A, and 1B commonly found in the United States and in Europe), it is now apparent that interferon cannot be considered a cure in most persons. Rather, for those who respond to this therapy (only 15-20%), interferon must be considered a method of viral suppression, not eradication or cure.

For those individuals who absolutely cannot live with the thought of a virus lurking inside them and, therefore, are considering the use of interferon and interferon + ribavirin, we would like to present the following information on the side effects of these drugs. We do not present this information as a technique to scare you, but rather to inform you. We believe that in today’s world, individuals should be armed with as much information about their health and bodies as possible. In that way, they can better make an informed decision regarding the treatments they wish to undergo for their ailments.

All “drugs” have side effects. Since the genetic make-up of each individual is different, people will react in different ways to the same administered drugs and their combinations. The literature on interferon therapy lists the following side-effects of interferon: flu-like symptoms (fever, chills, muscle and joint pain, headache), hair loss, tiredness, low blood count, trouble with concentration and thinking, moodiness and depression. For some people, the effects are even more life threatening. They include: blood infection, thyroid disease, suicidal thoughts, seizures, acute heart, kidney, eye and lung problems, and in some instances, deaths due to liver failure or blood infections.

A most important side effect of interferon therapy is the actual worsening of the liver disease it is designed to treat. In approximately 40 out of 100 persons treated with interferon, the dosage has had to be reduced because of the severity of side effects, and treatment stopped completely in about 15 out of 100 persons.

These side effects are experienced with only using monotherapy, or interferon by itself. Now, add to this the combination of interferon and ribavirin and the side effects multiply. In addition to the side effects due to interferon alone, ribavirin can cause: severe anemia (low red blood cell count) and can result in kidney failure. Anemia can be life threatening for people with certain types of heart or blood vessel disease. Ribavirin has also been known to cause serious birth defects in pregnant women. The following article: “Side Effects of Interferon Alpha in Viral Hepatitis” by Geoffrey Dusheiko, M.D. appeared as part of the National Institute of Health Conference on Hepatitis C, held from March 24-26, 1997 Volume 15, Number 3. The complete conference can be found at the following website address:

This article can be located on pages 82 thru 88 of the “Related Conference Material Program and Abstracts” section of the above web address.

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 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	5¡	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

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.

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.

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)

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)

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

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)

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.

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

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)

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.