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Interferon-α-2a is a recombinant interferon with antiviral, antitumour and immunomodulatory properties. Clinical studies have demonstrated that the drug offers therapeutic Benefit in patients with some forms of chronic viral hepatitis.
Remission, as measured by clearance of viral DNA and hepatitis B ‘e’ antigen (HBeAg), and normalisation of serum alanine aminotransferase levels, is observed in approximately 30 to 45% of patients with chronic hepatitis B receiving interferon-α-2a (2.5 to 18MU administered 3 times/week); about 5 to 15% of untreated controls remit spontaneously every year. Complete recovery [with loss of hepatitis B surface antigen (HBsAg)] is usually noted in <20% of treated individuals. Similar response rates have been reported in the relatively small number of children evaluated to date.
Although numerous studies have shown that interferon-α-2a (at various dosages) induces biochemical amelioration of chronic hepatitis C in approximately 50 to 75% of patients, relapse is common. Thus, long term remission may only be observed in about 15 to 30% of treated patients. On the other hand, this disorder remits spontaneously in only a few patients.
The role of interferon-α-2a in the treatment of chronic hepatitis D remains unclear. Although preliminary data suggest it may be beneficial, cessation of therapy is generally followed by relapse.
As with other types of interferons, most patients receiving interferon-α-2a experience an ‘influenza-like’ syndrome, which tends to diminish with continuing therapy. Other effects such as fatigue, lethargy, anorexia and weight loss are usually dose-limiting. Serum neutralising antibodies develop in approximately 10 to 20% of treated patients.
Thus, although response rates are less than optimal, interferon-α-2a is a drug of first choice amongst the limited therapeutic options available for the management of well-compensated chronic viral hepatitis B or C.
Interferon-α-2a is a recombinant form of endogenous interferon-α. By inducing the release of intracellular enzymes such as 2′5′-oligoadenylate synthetase and double-stranded RNA-dependent protein kinase, the drug causes degradation of viral messenger RNA and inhibits protein synthesis.
Interferon-α-2a has various immunomodulatory effects: increased expression of major histocompatibility complex antigens, increased natural killer and cytotoxic T cell activity, cytokine induction and production of endogenous interferons. Progression of active hepatic disease to cirrhosis appears to slow in patients responding to interferon-α-2a therapy.
Peak plasma concentrations of interferon-α-2a are attained within 3.8 and 7.3 hours after intramuscular or subcutaneous injection, respectively; greater than 80% of a given dose is absorbed following administration by these routes. At steady state, the drug has a volume of distribution of 31.4L. Total body clearance after intravenous delivery is 13 L/h and elimination occurs mainly by renal catabolism. Interferon-α-2a has a short elimination half-life ranging from 2.3 to 3.5 hours when given by intramuscular or subcutaneous injection.
The clinical efficacy of interferon-α-2a has been evaluated in patients with chronic hepatitis B, C and D. Most studies recruited between 10 and 60 patients per treatment group.
At dosages of 2.5 to 18MU administered 3 times/week, favourable responses [clearance of viral DNA and hepatitis B ‘e’ antigen (HBeAg), with normalisation of serum alanine aminotransferase (ALT) levels] were generally observed in approximately 30 to 45% of patients with chronic hepatitis B; spontaneous remissions may be reported in about 5 to 15% of untreated individuals every year. Complete recovery, as evidenced by loss of hepatitis B surface antigen (HBsAg), usually occurred in <20% of treated patients. Improvements in viral and biochemical markers were associated with clinical, biochemical and histological resolution of liver disease. Similar response rates were observed in the relatively small number of children assessed to date.
Numerous controlled studies (using varying dosage regimens) indicate that interferon-α-2a also induces biochemical amelioration of chronic hepatitis C; approximately 50 to 75% of treated patients attain normal ALT levels. Viral RNA was cleared in ≥50% of patients with persistent ALT normalisation, and these changes were associated with histological improvements of the liver. Despite these initial beneficial effects, 40 to 60% of responders generally relapse after treatment cessation. Thus, long term remission may be observed in about 15 to 30% of treated patients. Untreated patients with hepatitis C rarely exhibit spontaneous remission.
Preliminary data suggest that interferon-α-2a may be beneficial in patients with chronic hepatitis D. However, cessation of therapy is generally followed by relapse.
Adverse effects occur frequently with interferons, but are generally mild and reversible at dosages <5 MU/day. The severity of adverse effects is dose-dependent. Most patients treated with interferon-α-2a experience an ‘influenza-like’ syndrome within 2 to 8 hours of drug administration. Although tolerance to these effects develops within a few weeks of treatment, symptoms may be alleviated by concurrent use of paracetamol (acetaminophen). Other effects such as fatigue, lethargy, anorexia and weight loss are usually dose-limiting.
Less commonly, interferon-α-2a may induce or exacerbate autoimmune reactions (e.g. thyroid disorders or psoriasis) in patients with chronic hepatitis B or C. Haematological (leucopenia and thrombocytopenia), CNS (visual disturbances, insomnia), endocrine (hypertriglyceridaemia, reductions in total and high density lipoprotein cholesterol), and cardiovascular (atrioventricular block, ECG changes) effects have also been observed. Hepatic decompensation occurs rarely. Treatment withdrawal due to intolerable adverse effects may occur in up to 17% of individuals.
Interferon-α-2a induces the formation of serum neutralising antibodies in approximately 10 to 20% of treated patients. It is, however, unclear whether these compromise the clinical outcome of the disease.
Dosage and Administration
Dosage recommendations are currently available for use of interferon-α-2a in patients with chronic hepatitis B, C or D. The role of interferon-α-2a in hepatitis D, however, remains unclear. The drug may be administered by intramuscular or subcutaneous injection 3 times/week at dosages of: (i) hepatitis B — 2.5 to 5 MU/m2 for up to 6 months, titrated to response; (ii) hepatitis C — 6MU for 3 months, reduced to 3MU for a further 3 months in treatment responders only; and (iii) hepatitis D — 9MU for 1 year.
KeywordsHepatitis Interferon Chronic Hepatitis Chronic Active Hepatitis Interferon Therapy
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