Ribavirin

Ribavirin, also known as tribavirin, is a broad-spectrum antiviral medication used in the management of selected RNA virus infections, most notably hepatitis C and several viral haemorrhagic fevers. Although widely used since the late twentieth century, its clinical value has come under increasing scrutiny due to uncertainties regarding its efficacy against a number of viral diseases for which it has historically been prescribed. Ribavirin is administered orally or via inhalation and is available as a generic medicine. Patented in 1971 and introduced into clinical practice in 1986, it is included on the World Health Organization’s Model List of Essential Medicines.

Medical Applications

Ribavirin’s primary licensed indication is chronic hepatitis C infection, for which it is employed exclusively as an adjunct rather than as monotherapy. Combination regimens may include pegylated interferon-α, sofosbuvir or simeprevir, depending on viral genotype assessments undertaken prior to treatment. The drug’s use in hepatitis C therapy has decreased with the advent of more effective direct-acting antiviral agents; however, it may still be incorporated into certain therapeutic protocols to enhance virological response.
Acute hepatitis C infection, typically occurring within six months of exposure, often resolves without intervention. When treatment is initiated, ribavirin may be included within selected combinations, although more modern antivirals tend to be preferred.
Beyond hepatitis C, ribavirin is administered for several viral haemorrhagic fevers, including Lassa fever, Crimean–Congo haemorrhagic fever, Venezuelan haemorrhagic fever and Hantavirus-related diseases. Its effectiveness appears greatest when given early in the course of illness. Evidence remains limited for many of these indications, and the drug has demonstrated poor activity against flaviviruses and filoviruses such as Ebola and Marburg, prompting restrictions on its use in these contexts. Despite such limitations, ribavirin remains the only antiviral with proven benefit for Lassa fever.
Historically, aerosolised ribavirin was used in children with respiratory syncytial virus (RSV) infection, although contemporary evidence supporting this practice is weak. The drug has occasionally formed part of experimental or compassionate treatment approaches for rabies when combined with agents such as ketamine or amantadine.

Investigational and Experimental Uses

Ribavirin has been explored experimentally in several additional virological and oncological settings. Laboratory studies have indicated potential antiviral activity against canine distemper and poxviruses. Small trials involving herpes simplex virus infection reported reduced severity of outbreaks and synergistic effects when combined with acyclovir.
In oncology, interest has centred on tumours exhibiting elevated levels of the eukaryotic translation initiation factor eIF4E. In acute myeloid leukaemia and certain head and neck cancers, ribavirin has been shown to bind eIF4E and to inhibit its functions related to RNA export, translation and oncogenic signalling. Clinical responses, including complete remissions, have been documented in early-phase trials. Resistance mechanisms identified in cancer cells include metabolic deactivation via glucuronidation and impaired intracellular drug retention.

Adverse Effects

Ribavirin is associated with a notable adverse-effect profile, leading to two boxed warnings. One concerns the risk of teratogenicity when exposure occurs before or during pregnancy in either parent; stringent contraceptive measures are advised for at least seven months during and following treatment. The second warning relates to haemolytic anaemia, which may be severe. Other common side effects include fatigue, headache, nausea, fever, myalgia and irritability. Serious reactions may involve hepatotoxicity and hypersensitivity.
Drug interactions are clinically significant. Concomitant administration with zidovudine heightens the risk of anaemia, while use with didanosine increases the likelihood of mitochondrial toxicity and is contraindicated.

Mechanisms of Action

Although ribavirin has been studied for decades, its antiviral mechanism is multifaceted and not yet fully elucidated. It acts as a guanosine analogue and undergoes intracellular metabolism to several phosphorylated forms. Proposed direct and indirect mechanisms include:

• inhibition of inosine monophosphate dehydrogenase (IMPDH), reducing intracellular GTP levels;
• acting as a mutagenic nucleoside analogue, able to pair with multiple bases due to the orientation of its carboxamide group, producing lethal mutagenesis in RNA viruses;
• interference with viral RNA synthesis and mRNA capping, thereby disrupting replication;
• modulation of host immune responses through metabolic pathways.

Reduced activity of inosine triphosphate pyrophosphatase (ITPase) in some individuals enhances ribavirin-induced mutagenesis by influencing the balance of active metabolites; around 30 per cent of people exhibit such reduced enzymatic activity.
Ribavirin’s inactivity against many DNA viruses suggests that it mimics RNA nucleosides more effectively than DNA nucleosides. Its 2′-deoxyribose analogue is inactive, reinforcing this observation.

eIF4E Targeting in Cancer

Beyond its antiviral effects, ribavirin directly interacts with the eIF4E cap-binding protein, as demonstrated through biophysical and NMR studies. In cells, ribavirin and particularly its triphosphate form bind to eIF4E with relatively high affinity. This binding inhibits eIF4E’s roles in RNA metabolism, including oncogenic activities associated with aberrant translation and mRNA export. Early clinical investigations have shown evidence of disease stabilisation and remission in patients with malignancies characterised by elevated eIF4E activity, although resistance to ribavirin has also emerged, driven by altered drug metabolism or uptake.