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|
|Resp tract congestion||11||10||14|
|Thyroid test abnormal||3||9||4|
table 2. Laboratory Variables
|Value||Phase||Observation||3ug CIFN||9 ug CIFN||15 ug IFN
|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.
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)
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)
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.
- Fattovich G, Giustina G, Favarato S, Ruol A, Macarri G, Orlandi F, Iaquinto G, Ambrosone L, Francavilla A, Pastore G, Santantonio MT, Romagno D, Bolondi L, Sofia S, Marchesini A, Pisi E, Mazzella G, Roda E, Attaro L, Chiodo F, Mori F, Verucchi G, Lanzini A, Salmi A. A survey of adverse events in 11241 patients with chronic viral hepatitis treated with alfa interferon. J Hepatol 1996;24:38-47.
- Russello M, Vasquez E, Fraggetta F, Zammataro M. Recombinant interferon alpha therapy in elderly patients with chronic hepatitis C without cirrhosis. Arch Gerontol Geriatr 1996;321-5.
- Bresci G, Del Corso L, Romanelli AM, Giuliano G, Pentimone F. The use of recombinant interferon alfa-2b in elderly patients with anti-HCV-positive chronic active hepatitis. J Am Geriatr Soc 1993;41:857-62.
- Bortolotti F, Giacchino R, Vajro P, Barbera C, Crivellaro C, Alberti A, Nebbia G, Zancan L, De Moliner L, Bertolini A, Balli F, Callea F. Recombinant interferon-alfa therapy in children with chronic hepatitis C. Hepatology 1995;22:1623-7.
- Bonkovsky HL, Clifford BD, Smith LJ, Allan C, Banner B. High-dose interferon-a2b for re-treatment of nonresponders or relapsing patients with chronic hepatitis C-a controlled randomized trial. Dig Dis Sci 1996;41:149-154.
- Iino S. High dose interferon treatment in chronic hepatitis C. Gut 1993;34 (Suppl):SI 14-8.
- Okanoue T, Sakamoto S, Itoh Y, Minami M, Yasui K, Sakamoto M, Nishioji K, Katagishi T, Nakagawa Y, Tada H, Sawa Y, Mizuno M, Kagawa K, Kashima K. Side effects of high-dose interferon therapy for chronic hepatitis C. J Hepatol 1996;25:283-91.
- 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.
- Shakil AO, Di Bisceglie AM, Hoofnagle JH. Seizures during alpha interferon therapy. J Hepatol 1 996;24:48-5 1 .
- Mayet WJ, Hess G, Gerken G, Rossol S, Voth R, Manns M, Meyer-zum-Buschenfelde KH. Treatment of chronic type B hepatitis with recombinant alpha-interferon induces autoantibodies not specific for autoimmune chronic hepatitis. Hepatology 1989;10:24-8.
- Preziati D, La Rosa L, Covini G, Marcelli R, Rescalli S, Persani L, Del Ninno E, Meroni PL, Colombo M, Beck-Peccoz P. Autoimmunity and thyroid function in patients with chronic active hepatitis treated with recombinant interferon alpha-2a. Eur J Endocrinol 1995;132:587-93.
- Carella C, Amato G, Biondi B, Rotondi M, Morisco F, Tuccillo C, Chiuchiolo N, Signoriello G, Caporaso N, Lombardi G. Longitudinal study of antibodies against thyroid in patients undergoing interferon-a therapy for HCV chronic hepatitis. Horm Res 1995;44:110-4.
- Marcellin P, Pouteau M, Renard P, Grynblat J-M, Colas Linhart N, Bardet P, Bok B, Benhamou J-P. Sustained hypothyroidism induced by recombinant a interferon in patients with chronic hepatitis C. Gut 1992;33:855-6.
- Noda K, Enomoto N, Arai K, Masuda E, Yamada Y, Suzuki K, Tanaka M, Yoshihara H. Induction of antinuclear antibody after interferon therapy in patients with type-C chronic hepatitis: its relation to the efficacy oftherapy. Scand J Gastroenterol 1996;31:716-22.
- Nagayama Y, Ohta K, Tsuruta M, Takeshita A, Kimura H, Hamasaki K, Ashizawa K, Nakata K, Yokoyama N, Nagataki S. Exacerbation of thyroid autoimmunity by interferon alpha treatment in patients with chronic viral hepatitis: our studies and review ofthe literature. Endocr J 1994;41:565-72.
- Imagawa A, Itoh N, Hanafusa T, Oda Y, Waguri M, Miyagawa J-l, Kono N, Kuwajima M, Matsuzawa Y. Autoimmune endocrine disease induced by recombinant interferon-a therapy for chronic active type C hepatitis. J Clin Endocrinol Metab 1995;80:922 6.
- Lisker-Melman M, Di Bisceglie AM, Usala SJ, Weintraub B, Murray LM, Hoofnagle JH. Development of thyroid disease during therapy of chronic viral hepatitis with interferon alfa. Gastroenterology 1992;102:2155-60.
- Marazuela M, Garcia-Buey L, Gonzalez-Fernandez B, Garcia-Monzon C, Arranz A, Borque MJ, Moreno-Otero R. Thyroid autoimmune disorders in patients with chronic hepatitis C before and during interferon-a therapy. Clin Endocrinol (Oxf ) 1996;44:635-42.
- Baudin E, Marcellin P, Pouteau M, Colas-Linhart N, Le Floch J-P, Lemmonier C, Benhamou J-P, Bok B. Reversibility of thyroid dysfunction induced by recombinant alpha interferon in chronic hepatitis C. Clin Endocrinol(Oxf) 1993;39:657-61.
- Pol S, Thiers V, Carnot F, Zins B, Romeo R, Berthelot P, Brechot C. Efficacy and tolerance of a-2b interferon therapy on HCV infection of hemodialyzed patients. Kidney Int 1995;47:1412-8.
- Rostaing L, Izopet J, Baron E, Duffaut M, Puel J, Durand D. Treatment of chronic hepatitis C with recombinant interferon alpha in kidney transplantrecipients. Transplantation 1995;59:1426-31.
- Perrillo R, Tamburro C, Regenstein F, Balart L, Bodenheimer H, Silva M, Schiff E, Bodicky C, Miller B, Denham C, Brodeur C, Roach K, Albrecht J. Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus. Gastroenterology 1995;109:908-16.
- Hoofnagle JH, Di Bisceglie AM, Waggoner JG, Park Y. Interferon alfa for patients with clinically apparent cirrhosis due to chronic hepatitis B. Gastroenterology 1993;104:1116-21.
- Todros L, Saracco G, Durazzo M, Abate ML, Touscoz G, Scaglione L, Verme G, Rizzetto M. Efficacy and safety of interferon alfa therapy in chronic hepatitis C with autoantibodies to liver kidney microsomes. Hepatology 1995;22:1374-8.
- Feray C, Samuel D, Gigou M, Paradis V, David MF, Lemonnier C, Reynes M, Bismuth H. An open trial of interferon alfa recombinant for hepatitis C after liver transplantation: antiviral effects and risk of rejection. Hepatology 1995;22:1084-9.
- Simsek H, Savas C, Akkiz H, Telatar H. Interferon-induced vitiligo in a patient with chronic viral hepatitis C infection. Dermatology 1996;193:65-6.
- Kawano T, Shigehira M, Uto H, Nakama T, Kato J, Hayashi K, Maruyama T, Kuribayashi T, Chuman T, Futami T, Tsubouchi H. Retinal complications during interferon therapy for chronic hepatitis C. Am J Gastroenterol 1996;91:309-13.
- Nakagawa A, Yamaguchi T, Takao T, Amano H. [Five cases of drug-induced pneumonitis due to Sho-saiko-to or interferon-alpha or both]. Nippon Kyobu Shikkan Gakkai Zasshi 1995;33:1361 6.
- 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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