Interferons

crop_square Key points

  • check_circle Interferons are expressed in mammalian cells to bacterial/viral stimuli
  • check_circle PEGylated interferons are more stable allowing for less frequent administration
  • check_circle Direct acting antivirals have replaced interferons in hepatitis C treatment
  • check_circle Overall poorly tolerated drugs with severe side effects

crop_square Background and biochemistry

Interferons are glycoproteins widely expressed in mammalian cells in response to bacterial and viral stimuli. They were first described in 1957 but it took decades until subclasses had been identified and characterised. Strong antiviral activity was seen in type I interferons (interferon alfa and interferon beta). Large scale industrial production of recombinant interferons became feasible with the scientific advances in DNA techniques. Interferon alfa-2a was the first interferon to be isolated and cloned. FDA approval was granted in 1986 for the treatment of hepatitis C and various malignancies. PEGylated (‘polyethylene glycol-conjugated’) interferon alfa-2a with increased drug stability (allowing for less frequent administration) was FDA-approved in 2001 for hepatitis C and later for hepatitis B treatment. Interferon beta is primarily used in multiple sclerosis but has been shown to be effective against viral hepatitis. Treatment of hepatitis C has recently been revolutionised by the launch of direct acting antivirals (DAAs) and drug regimens are now mostly interferon-free.

crop_square Mechanism of action

Interferon alfa binds to the type 1 interferon membrane receptor ubiquitous on human cells. This activates various intracellular pathways inducing the expression of enzymes essential for antiviral defence. As a results, virus replication is inhibited, apoptosis of infected cells increases and both innate and adapted immune cells are modulated. Treatment success rates of interferon therapy in hepatitis vary greatly and seem to be associated with specific HCV and HBV genotype. Interferons are less vulnerable to viral resistance mechanisms compared to other classes of antivirals as their mechanism of action does not target viruses directly.

crop_square Drugs and spectrum of activity

  • PEG­inter­feron alfa­-2a (Pega­sys®)

crop_square Pharmacokinetics

PEGylated interferon reaches peak serum concentration 72-96h after subcutaneous administration. Bioavailability is above 80% and elimination half-life averages at around seven days. It is hepatically metabolised and mostly cleared via the urine.

crop_square Adverse drug effects

Interferon alfa therapy is associated with severe adverse effects limiting its clinical use. Flu-like symptoms, neuropsychiatric effects and gastrointestinal symptoms are all very common.