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Interferon-α-n1

A Review of its Pharmacological Properties and Therapeutic Efficacy in the Management of Chronic Viral Hepatitis

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Summary

Synopsis

Interferon- α- n1 (lymphoblastoid interferon- α) is a nonrecombinant ‘natural’ interferon derived from lymphoblastoid cells exposed to Sendai virus. In common with endogenous and recombinant interferon- α molecules, interferon- α- n1 has antiviral, immunomodulatory and antiproliferative properties.

Interferon- α- n1 shows some efficacy in immunocompetent adults with well- compensated chronic viral hepatitis B. Rates of complete virological response (defined as an absence of detectable hepatitis B virus- DNA in the serum) ranged from 5 to 79% of adults who received various dosage regimens of interferon- α- n1 in monotherapy trials. Clearance of hepatitis B ‘e’ antigen was reported in 5 to 70% of patients treated with the drug. Spontaneous virological responses occurred in 0 to 48% of untreated patients.

The clinical efficacy of interferon- α- n1 in patients with chronic hepatitis B is not improved by concomitantly administered deflazacort, zidovudine or levamisole, but may be increased by a course of corticosteroid pretreatment in some patients.

Interferon- α- n1 also shows therapeutic benefit in adults with chronic hepatitis C. Complete biochemical responses (defined as normalisation of serum ALT levels) were achieved in 27 to 60% of adult patients treated with the drug, whereas spontaneous normalisation of serum ALT levels occurred in up to 11% of untreated patients. Responses to interferon- α- nl were temporary in 27 to 78% of treatment responders but were sustained in 6 to 40% of patients. Emerging data delineating baseline factors predictive of a positive response to interferon- a- nl treatment may aid in the selection of patients with hepatitis B or C most likely to benefit from treatment with this drug.

Most patients receiving interferon- a- nl experience a transient ‘influenza- like ’ syndrome during the first week of treatment. The syndrome, which is dose related and alleviated by paracetamol (acetaminophen), is characterised by fever, chills, and arthralgia. Dose- limiting adverse effects occurring during longer term interferon- a- n1 therapy include fatigue, myalgia, headache, depression, pruritus and seizures. Neutropenia and thrombocytopenia may also occur during interferon- α- nl treatment. Autoimmune thyroid disease may develop in up to 9% of patients treated with interferon- α- nl for ≥ 6 months.

At present, interferon- α- n1 and the recombinant forms of interferon- α are the only drugs available for the treatment of adults with well-compensated hepatitis B or C. Interferon- α- nl produces moderate response rates in adults with well-compensated chronic hepatitis B or C. Thus, it is positioned alongside recombinant interferon- a products as a useful first-line treatment option for patients with chronic hepatitis B or C.

Pharmacological Properties

Interferon-α-n1 is a nonrecombinant mixture of ‘natural» interferon-α subtypes. It is produced in vitro from human lymphoblastoid cells exposed to Sendai virus and thus is also referred to as lymphoblastoid interferon-α.

The drug produces antiviral effects by inducing the production of ≥20 effector proteins (notably 2′,5′-oligoadenylate synthetase and protein kinase), which block viral replication in the host cell. Interferon-α-n1 also inhibits the intracellular accumulation of replicative hepatitis B virus (HBV)-RNA.

Increased expression of cell membrane components, macrophage activation and modulation of natural killer and cytotoxic T cell activity are among the numerous documented immunomodulatory properties of interferon-a-nl. Interferon-α-n1 also has antiproliferative activity in vitro and in vivo. Evidence for an antitumour effect of interferon-α-nl in murine xenograft models is conflicting.

Interferon-α-n1 has a lower propensity than either interferon-α-2a or interferon -α-2b to stimulate the production of neutralising antibodies in patients with chronic hepatitis B or C.

Inhibition of hepatic regenerative activity was more marked in rats exposed to interferon-α-2a than in animals exposed to either interferon-α-n1 or interferon-α- 2b and was seen only with higher dose equivalents of interferon-α-n1 or interferon-α-2b than those used clinically.

The pharmacokinetics of interferon-α-n1 are similar after subcutaneous and intramuscular administration. Maximum serum interferon-α-n1 concentrations of 200 to 300 IU/ml occur after multiple doses of up to 15MU administered intramuscularly or subcutaneously 3 times weekly. Maximum serum drug concentrations are usually observed 4 to 8 hours after subcutaneous or intramuscular administration. Interferon-α-n1 is not usually detectable in the urine, although it may be present in the urine of patients with severe renal disease.

Therapeutic Efficacy

Chronic Hepatitis B. Complete virological responses (defined as an absence of detectable levels of HBV-DNA in the serum) occurred in 5 to 79% of recipients of interferon-α-n1 either at treatment completion, or up to 12 months after discontinuation of treatment. Complete virological responses were also evident in 0 to 48% of patients receiving placebo or no treatment. The drug was generally administered in maintenance dosages of 2.5 to 5 MU/m2 3 times weekly for up to 6 months. Serum hepatitis B ‘e’ antigen (HBeAg) was cleared in 5 to 70% of patients with chronic hepatitis B receiving interferon-α-n1, compared with 0 to 39% of placebo recipients or untreated controls, suggesting spontaneous responses in some untreated patients.

The efficacy of interferon-α-n1 in patients with chronic hepatitis B is not improved by concomitantly administered zidovudine, levamisole or deflazacort. However, results of one double-blind trial indicated that a 1-month course of prednisolone treatment before initiation of interferon-α-n1 therapy significantly improved response rates, compared with interferon-α-n1 alone.

Chronic Hepatitis C. Results of numerous trials conducted in adults with chronic hepatitis C showed that interferon-α-n1 produced complete responses (defined as normalisation of serum ALT levels by the end of the treatment period) in 27 to 60% of patients. Spontaneous normalisation of serum ALT levels occurred in 0 to 11% of untreated patients. Rates of sustained response ranged from 6 to 40%; a proportion of treatment responders (27 to 78%) relapsed after treatment discontinuation (most within 2 to 3 months of finishing treatment).

Preliminary results from a large clinical trial involving more than 1000 patients indicate that interferon-α-n1 treatment may produce higher sustained response rates than interferon-α-2b. However, sustained response rates were similar for patients receiving interferon-α-n1 and interferon-α-2a in another trial.

The onset of hepatitis C ‘breakthrough’ (defined as an increase in serum ALT levels after a period of interferon-α-induced normalisation) is attributed to interferon-α-specific cell receptor down-regulation, the appearance of anti-interferon-α neutralising antibodies and the emergence of viral mutants resistant to the drug.

Interferon-α-n1 may restore therapeutic response in patients who do not respond to treatment with interferon-α-2a or -2b because of the development of neutralising antibodies.

Evidence from several clinical trials indicates that interferon-α-n1 treatment may contribute towards preventing the development of hepatocellular carcinoma in patients with chronic viral hepatitis.

Predictors of Response

Low baseline serum HBV-DNA levels, high serum ALT levels and active hepatic disease with fibrosis appear to be the best predictors of a positive response to interferon-α treatment in patients with chronic hepatitis B. Response predictors in patients with hepatitis C include low baseline viral RNA levels, minimal fibrosis, the absence of cirrhosis and the absence of hepatitis C virus genotype 1b.

Tolerability

The tolerability profile of interferon-α-n1 is typical of the interferons-α as a class. Adverse effects occur frequently and are associated with the dosage and duration of interferon-α-n1 treatment. Patients with cirrhosis are more likely to experience adverse effects than noncirrhotic patients.

A transient dose-related ‘influenza-like’ illness, manifest as fever, myalgia, headache, chills and arthralgia, is experienced by most patients during the first week of treatment with the drug. These symptoms are usually ameliorated by paracetamol (acetaminophen). Adverse effects of interferon-α-n1 occurring during longer term treatment (≥2 weeks) include fatigue, myalgia, headache, depression, anorexia, pruritus, seizures and hair loss. Haematological suppression, such as neutropenia and thrombocytopenia, occurs in some recipients of interferon-α-n1. Although tolerance to some adverse effects may develop, dosage reduction is required for some patients.

Some autoimmune diseases are triggered during long term treatment with interferon-α-n1. Autoimmune thyroid disease may develop in up to 9% of patients during ≥6 months’ interferon-α-n1 treatment. After treatment discontinuation, thyroid dysfunction persists in some patients but resolves in others.

Dosage and Administration

Interferon-α-n1 is administered either subcutaneously or intramuscularly; rotation of the site of injection is advised.

In clinical trials conducted in adult patients with well-compensated chronic hepatitis B, interferon-α-n1 was generally administered in induction dosages of 1.25 to 6 MU/m2 /day (for 1 to 4 weeks) followed by maintenance dosages of 2.5 to 5 MU/m 3 times weekly for up to 6 months. The manufacturer recommends a dosage of 10 to 15MU (to a maximum of 7.5 MU/m ) 3 times weekly for 12 weeks. Alternatively, a lower dosage of 5 to 10MU 3 times weekly may be given for up to 6 months.

The dosage of interferon-α (subtype not specified) recommended by the US National Institutes of Health for the initial treatment of patients with chronic hepatitis C is 3MU 3 times daily for 12 months. The manufacturer of the drug currently recommends a dosage of 3 to 5MU 3 times weekly for up to 48 weeks.

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    Caroline M. Perry & Antona J. Wagstaff

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Perry, C.M., Wagstaff, A.J. Interferon-α-n1. BioDrugs 9, 125–154 (1998). https://doi.org/10.2165/00063030-199809020-00004

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