Alpha Interferon

Publication Details



Alpha interferon is a cytokine produced by the innate immune system in response to environmental exposures including viral infections. Alpha interferon in various formulations has been developed as therapy of several forms of cancer and viral infections, but its major use has been as therapy of chronic hepatitis C. Alpha interferon therapy can be associated with transient, mild-to-moderate serum aminotransferase elevations and it has been linked to induction of autoimmune conditions, including autoimmune hepatitis in susceptible persons.


Alpha interferon (in"' ter feer' on) is a naturally occurring cytokine which is produced by cells of the innate immune system in reaction to viral infection or other environmental stresses. Alpha and beta interferon are considered type I interferons which share antiviral, immunomodulatory as well as antiproliferative effects. The pathways of induction and actions of alpha interferon are quite complex and the antiviral effects are due to induction of multiple intracellular genes. Overall, type I interferons produce an antiviral state inside of cells that decreases viral replication and protects against infection. There are at least 20 copies of the alpha interferon gene in the human genome and multiple formulations of standard recombinant interferon have been produced (alfa-2a, alfa-2b and alfa-con1 or “consensus” interferon). Furthermore, the interferon molecule can be pegylated which causes a prolongation of its half-life, allowing for once weekly as opposed to daily or every other day administration. Because interferon is a protein, it must be given parenterally (usually subcutaneously). Recombinant human interferons were approved for use in cancer in the 1980s, for hepatitis B in 1991 and for hepatitis C in 1992. Peginterferon became available in 2000 and has largely replaced the standard preparations. The typical dose of peginterferon alfa-2a is 180 µg once weekly for 24 or 48 weeks, and for peginterferon alfa-2b 1.5 µg/kg once weekly for 24 to 48 weeks. In chronic hepatitis C, peginterferon is usually given with ribavirin and, more recently, as triple therapy with a protease inhibitor, such as boceprevir, telaprevir, simiprevir or sofosbuvir. Ultimately, oral antiviral regimens are likely to replace peginterferon therapy in chronic hepatitis C. Standard interferon alfa is also approved for use in hairy cell leukemia, malignant melanoma, follicular lymphoma and AIDS-related Kaposi's sarcoma. Local injections of interferon are used to treat condylomata acuminata. Interferon has many side effects which often limit the dose and duration of therapy. The most common side effects include fatigue, muscle aches, headaches, depression, anxiety, bone marrow suppression and rash.


Therapy with interferon or peginterferon can be associated with transient and asymptomatic mild-to-moderate serum aminotransferase elevations in up to half of patients. Because the major use of peginterferon is for hepatitis C or in patients with cancer on multiple other medications, serum ALT elevations are often difficult to attribute to the therapy as opposed to the underlying disease. Importantly, however, 1% to 2% of persons receiving alpha interferon for 24 to 48 weeks develop an autoimmune condition, which can be autoimmune hepatitis characterized by development of marked serum aminotransferase activities and jaundice. This side effect usually arises within 1 to 2 months of starting therapy, but can arise later or even after therapy is completed (Case 1). The typical pattern of serum elevations is hepatocellular, and most but not all patients develop or have preexisting autoantibodies such as antinuclear antibody (ANA) or antibody to liver kidney microsomes (anti-LKM) in serum. Instances of primary biliary cirrhosis, sarcoidosis and hepatic granulomas have also been reported after interferon therapy. Finally, interferon therapy of hepatitis B can trigger an acute exacerbation of the hepatitis that is often associated with clearance of HBV DNA and HBeAg and may actually be a favorable prognostic sign suggesting a sustained response (Case 2).

Likelihood score: A (well known cause of clinically apparent liver injury).

Mechanism of Injury

Interferon has diverse effects on multiple cell types. The autoimmune hepatitis-like syndrome that has been attributed to interferon therapy appears to occur in patients who are predisposed to autoimmune diseases, and is probably due to the immunomodulatory effects of alpha interferon in increasing cell surface display of HLA antigens and in affecting CD4 and CD8+ T cell activity. Alpha interferon therapy can cause an acute exacerbation of autoimmune disease and some instances of an acute hepatitis-like syndrome developing on interferon therapy may represent an exacerbation of autoimmune hepatitis that coexisted with or was mistaken for chronic hepatitis B or C.

Outcome and Management

The serum aminotransferase abnormalities that arise during interferon therapy are usually asymptomatic and self-limited and rarely require dose modification. In contrast, the autoimmune hepatitis-like syndrome induced by interferon calls for prompt discontinuation of therapy. In most instances, the condition improves or resolves with stopping therapy, but instances of self-perpetuating autoimmune hepatic diseases (sarcoidosis, autoimmune hepatitis, primary biliary cirrhosis) have been reported. Patients with autoimmune hepatitis due to interferon may require corticosteroid or immunosuppressive therapy, which appears to ameliorate the course of injury and may be required long term. Several cases of acute liver failure and cases of chronic autoimmune hepatitis triggered by interferon therapy have been reported, but treatment has not been associated with chronic vanishing bile duct syndrome.

Related biological agents include beta interferon, gamma interferon, interleukin 2.

Agents active against hepatitis C include alpha interferon, peginterferon, boceprevir, ribavirin, simeprevir, sofosbuvir, telaprevir.

Drug Class: Antiviral Agents, Hepatitis C Agents


Case 1. Induction of autoimmune hepatitis by a course of peginterferon and ribavirin for chronic hepatitis C.

[NIH Patient #P40]

A 52 year old woman with chronic hepatitis C developed sudden worsening of disease and jaundice 4 weeks after starting peginterferon therapy. She was known to have chronic hepatitis C for 12 years when she was found to have elevations in serum aminotransferase levels and antibody to hepatitis C in serum. She was largely asymptomatic and had no other medical problems. The source of hepatitis C was believed to be blood transfusions after Caesarian section 25 years previously. She had mild chronic hepatitis on liver biopsy and portal fibrosis (2+ fibrosis on a scale of 0 to 6+). HCV RNA levels ranged from 1 to 2 million IU/mL and HCV genotype was 1b. She was started on peginterferon alfa-2a in a dose of 180 µg weekly and ribavirin (1200 mg daily) was added 4 weeks later. With therapy, her serum levels of HCV RNA fell rapidly (Table). Serum aminotransferase levels, however, started to rise and were above 1000 U/L by week four. By week five she was jaundiced and both peginterferon and ribavirin were stopped. Serum ANA was negative, but SMA was weakly positive (1:40) and anti-LKM was present. IgM anti-HAV, HBsAg, anti-HBc and anti-HDV were negative. Ultrasound showed no evidence of biliary obstruction. Immunoglobin levels were elevated before therapy and had risen further (IgG 2130 to 2910 mg/dL). Jaundice worsened for a week and prednisone (20 mg daily) was started, whereupon both bilirubin and aminotransferase levels began to improve. Once ALT levels had returned to baseline, prednisone was gradually decreased and then stopped. However, serum ALT and immunoglobulin levels began to rise again and prednisone was reintroduced. After serum ALT levels had again fallen, the dose of prednisone was reduced and azathioprine was started (100 mg daily initially and later 50 mg daily), ultimately allowing for discontinuation of prednisone. Serum aminotransferase levels remained normal on azathioprine alone, but ANA became weakly positive. HLA typing showed A33, B42, B53 and DRB 3.

Key Points

Laboratory Values

Abbreviations: Peg, peginterferon; Rbv, ribavirin; Pred, prednisone; Az, azathioprine.


A patient with chronic hepatitis C and hyperglobulinemia developed worsening of serum aminotransferase levels and jaundice after 4-5 weeks of peginterferon therapy. Because of the autoimmune features and the lack of immediate improvement on stopping peginterferon, prednisone was started. Prednisone was gradually reduced in dose and discontinued 9 months later, but serum aminotransferases rose and hyperglobulinemia reappeared. Ultimately, the combination of prednisone and azathioprine led to control of the disease and normal serum aminotransferase levels. After a year of tapering doses of prednisone, it was stopped and she was maintained on azathioprine alone, with normal serum aminotransferase levels despite high levels of HCV RNA. One interpretation of the events is that she had autoimmune hepatitis even before interferon therapy, and the HCV infection was benign and not the cause of the serum aminotransferase elevations. Peginterferon is known to be immunomodulatory and capable of causing an exacerbation or flare of autoimmune conditions. The presence of a serious autoimmune disease is a relative contraindication to use of interferon.

Case 2. Acute flare of hepatitis B during alpha interferon therapy.

[NIH Case #T37]

A 47 year old man with chronic hepatitis B was enrolled in a clinical trial of alpha interferon therapy in early 1989. He was known to have had HBsAg and HBeAg in serum for the previous 8 years and had persistent elevations in serum aminotransferase levels. He was symptomatic with mild fatigue with occasional periods of nausea, but denied dark urine, jaundice, itching, weight loss or abdominal swelling. Physical examination was unrevealing. A liver biopsy showed chronic hepatitis with marked activity (histology activity score=11 of a possible 18) and bridging hepatic fibrosis (Ishak fibrosis score 4 of a possible 6). He was started on interferon alfa-2b in a dose of 10 million units (MU) three times weekly. When he returned after 4 weeks of therapy, he complained of fatigue, nausea and jaundice and serum bilirubin was 10.4 mg/dL. However, HBV DNA was no longer detectable (lower limit of detection was 160,000 copies/mL). The dose of interferon was decreased to 5 MU three times weekly. His symptoms resolved rapidly and, in follow up, serum bilirubin and aminotransferase levels fell into the normal range. He became HBeAg as well as HBsAg negative, but did not develop anti-HBs. During long term follow up, he remained HBsAg negative, with normal serum aminotransferase levels and no detectable HBV DNA.

Key Points

Laboratory Values


A patient with HBeAg positive chronic hepatitis B developed an acute flare of disease and jaundice within 4 weeks of starting interferon alfa therapy. The flare was accompanied by a dramatic decrease in HBV DNA levels, followed by clearance of both HBeAg and HBsAg and resolution of the chronic hepatitis. Thus, the liver injury reflected clearance of hepatitis B virus rather than direct hepatotoxicity of interferon. An acute flare of hepatitis is often considered a favorable prognostic sign during the therapy of chronic hepatitis B presaging loss of HBeAg and, sometimes, loss of HBsAg as well. The initial HBV DNA testing was based upon a relatively insensitive method which had a lower limit of detection of 160,000 copies/mL. In follow up, polymerase chain reaction based assays for HBV DNA were used that had a lower limit of detection of 500 copies/mL.



Alpha Interferon – Avonex®

Peginterferon – Pegintron®


Antiviral Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 04 May 2018

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    (Among 44 patients with liver transplant for hepatitis C treated with peginterferon for more than 6 months, 9 had abnormal liver tests despite virological response, some of whom appeared to have autoimmune hepatitis, ANA positive in 5, SMA in 2, AMA in 1; 5 subsequently appeared to improve with prednisone therapy).
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    (Analysis of liver biopsies done on 820 patients with chronic hepatitis C after liver transplantation; 14 [1.7%] had granulomas [usually small, only one found and lobular in location] in posttransplant, but not pretransplant liver, 9 had received peginterferon including 4 with a sustained response).
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    (18 patients with metastatic melanoma received peginterferon adjuvant therapy for an average of 8 months; ALT elevations occurred in 72%, which were >5 times ULN in 11%, 1 requiring drug discontinuation).
  • Di Bisceglie AM, Shiffman ML, Everson GT, Lindsay KL, Everhart JE, Wright EC, Lee WM, et al.; HALT-C Trial Investigators. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med 2008; 359: 2429-41. [PMC free article: PMC2606037] [PubMed: 19052125]
    (Among 1050 adults with chronic hepatitis C who were nonresponders to a course of peginterferon and ribavirin and were then followed on no treatment or on low dose peginterferon alone for 3.5 years, there were no differences in rates of clinical outcomes between the two groups, but serum ALT levels were lower with peginterferon treatment and there was no evidence of hepatotoxicity).
  • Di Bisceglie AM, Stoddard AM, Dienstag JL, Shiffman ML, Seeff LB, Bonkovsky HL, Morishima C, et al.; HALT-C Trial Group. Excess mortality in patients with advanced chronic hepatitis C treated with long-term peginterferon. Hepatology 2011; 53: 1100-8. [PMC free article: PMC3073857] [PubMed: 21480316]
    (Among 1050 adult nonresponders with chronic hepatitis C [Di Bisceglie 2008] who were followed on no treatment or treated for 3.5 years with low dose peginterferon, further follow up showed an excess mortality in peginterferon treated subjects [20% vs 15% at 7 years], but the difference was attributable to non-liver related causes).
  • Bruix J, Poynard T, Colombo M, Schiff E, Burak K, Heathcote EJ, Berg T, et al; EPIC3 Study Group. Maintenance therapy with peginterferon alfa-2b does not prevent hepatocellular carcinoma in cirrhotic patients with chronic hepatitis C. Gastroenterology 2011; 140: 1990-9. [PubMed: 21419770]
    (Among 626 patients with chronic hepatitis C treated with low dose maintenance peginterferon or followed on no treatment for up to 5 years, there were no differences in time to first liver related complication, hepatocellular carcinoma or death while ALT elevations above 5 times baseline arose in 4 peginterferon treated vs 5 controls [1.3% vs 1.6%]).
  • Kowdley KV, Lawitz E, Crespo I, Hassanein T, Davis MN, DeMicco M, Bernstein DE, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naïve patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet 2013; 381 (9883): 2100-7. [PubMed: 23499440]
    (Among 316 previously treated patients with chronic hepatitis C, genotypes 1, 4, 5 or 6, treated with 12 or 24 weeks with sofosbuvir, peginterferon and ribavirin, SVR rates were 87-89%, ALT elevations above 5 times ULN occurred in 4 patients [1%], and 1 patient developed an autoimmune hepatitis, but these abnormalities were attributed to peginterferon).
  • Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, Afdhal NH, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis 2013; 13: 401-8. ( [PubMed: 23499158]
    Among 122 previously untreated patients with chronic hepatitis C, genotypes 1, 2 or 3, who received sofosbuvir [200 or 400 mg daily] or placebo for 12 weeks combined with peginterferon and ribavirin for 12 to 28 weeks, SVR rates were 90-92% with sofosbuvir and 58% with placebo; ALT and AST elevations occurred in 5 patients on sofosbuvir within 4 weeks of starting therapy, remaining elevated during treatment and resolving once peginterferon was stopped).
  • Hézode C, Fontaine H, Dorival C, Larrey D, Zoulim F, Canva V, de Ledinghen V, et al.; CUPIC Study Group. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme(ANRS CO20-CUPIC) - NCT01514890. J Hepatol 2013; 59: 434-41. [PubMed: 23669289]
    (Among 497 patients with chronic hepatitis C, genotype 1, and cirrhosis treated in a French early access program with 48 weeks of peginterferon and ribavirin with either boceprevir or telaprevir, serious adverse events occurred in 197 patients [40%], hepatic decompensation in 12 [2.4%], severe infection in 24 [4.8%], and 6 patients died [1.5%], the serious complications typically arising in the first 12 weeks of therapy).
  • Antiviral drugs. Treat Guidel Med Lett 2013; 11 (127): 19-30. [PubMed: 23459414]
    (Review of status of antiviral agents for prevention and treatment of viral infections including hepatitis B and C; discussion of interferon as therapy of hepatitis B and the combination of peginterferon with ribavirin and a protease inhibitor [telaprevir or boceprevir], including side effects of serum aminotransferase elevations, autoantibody formation and induction of autoimmune chronic hepatitis).
  • Everson GT, Terrault NA, Lok AS, Rodrigo del R, Brown RS Jr, Saab S, Shiffman ML, et al; Adult-to-Adult Living Donor Liver Transplantation Cohort Study. A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis C after liver transplantation. Hepatology 2013; 57: 1752-62. [PMC free article: PMC3510348] [PubMed: 22821361]
    (Among 79 patients with advanced chronic hepatitis C awaiting liver transplantation who were treated with peginterferon and ribavirin or observed without treatment, 22% of treated subjects achieved a sustained virologic response, but side effects were frequent and sometimes severe, although rates of liver related adverse events were similar with vs without peginterferon treatment).
  • Muir AJ, Arora S, Everson G, Flisiak R, George J, Ghalib R, Gordon SC, et al; EMERGE study group. A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection. J Hepatol 2014; 61: 1238-46. [PubMed: 25064437]
    (Among 525 patients with chronic hepatitis C treated with 3 different doses of interferon lambda or standard doses of peginterferon alfa and ribavirin for 24 [genotypes 2 or 3] or 48 weeks [genotypes 1 or 4], response rates were similar in the four groups while ALT elevations above 5 times ULN occurred in 12% treated with peginterferon and 2-22% treated with interferon lambda).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 12 were attributed to antiviral agents, but all were antiretroviral agents and no case was attributed to interferon not to the oral direct acting agents used to treat hepatitis B and C).
  • Okajima A, Yamaguchi K, Taketani H, Hara T, Ishiba H, Seko Y, Nishimura T, et al. Drug-induced liver injury in a chronic hepatitis C patient treated by peginterferon, ribavirin and simeprevir. Hepatol Res 2015; 45: E156-60. [PubMed: 25581068]
    (56 year old man with chronic hepatitis C and multiple nonresponses to therapy had a rapid virologic response to the combination of simeprevir, peginterferon and ribavirin, followed by a flare of disease at week 6 [bilirubin 1.2 mg/dL, ALT 796 U/L, Alk P 233 U/L, INR 0.8], which resolved rapidly with stopping all 3 drugs, the injury attributed to simeprevir).