Introduction by Camille Kotton

Human Respiratory Syncytial Virus (RSV) is a member of the Paramyxoviridae family and is well recognized to cause a spectrum of illness ranging from mild respiratory symptoms to severe lower respiratory tract infections including bronchiolitis, pneumonia and respiratory failure, with a mortality of 10-20%. In the setting of lung transplantation, the development of bronchiolitis obliterans with long term loss of lung function and reduced survival has been associated with RSV infection. Ribavirin, a guanosine analogue with a broad spectrum of activity against DNA and RNA viruses was licensed for use in 1986 for aerosol treatment of RSV in infants, and the oral formulation was approved for treatment of hepatitis C in 1998. Small uncontrolled case series have suggested ribavirin improves the outcome in lung transplant recipients infected with RSV. However ribavirin has significant associated toxicity, in particular haemolytic anaemia, and is potentially teratogenic. Surprisingly, the optimum dosing for RSV infection is yet to be determined.

Ribavirin administration in RSV infection: the issues

Nebulized ribavirin is prohibitively expensive, difficult to administer, requires special facilities and is mutagenic, tumorigenic and gonadotoxic. In addition, it is often associated with respiratory symptoms such as wheeze, cough and dyspnoea.

Intravenous ribavirin is available in some countries. While it is simpler to administer, staff involved in preparation and administration are required to handle it as a cytotoxic drug. Small case series suggest it may be effective in the treatment of RSV in lung transplantation.

Oral ribavirin is widely used in the treatment of hepatitis C at a dose of 800-1200mg per day in conjunction with interferon-y.  Recently, some centres have reported on the efficacy of oral ribavirin in the treatment of RSV. However there is no standard dosing regimen. The literature suggests that ribavirin is renally cleared to a variable degree in normal volunteers. There is no information on the clearance mechanism in solid organ transplant recipients. In addition, a number of lung transplant recipients have underlying cystic fibrosis. It is highly likely that these patients have altered clearance of ribavirin and would therefore require a different dosing schedule but there is no data available to confirm this.
Globally, there is no literature reporting on therapeutic drug monitoring of ribavirin in the solid organ transplant setting despite the increasing use of this potentially toxic and mutagenic agent. A small amount of literature exists for therapeutic drug monitoring of ribavirin in hepatitis C treatment where a strong association is seen between serum levels of ribavirin and haemoglobin. However this is not applicable to solid organ transplant recipients as the dosing schedule is dissimilar, the concomitant medications and therefore potential for pharmacokinetic and pharmacodynamic drug interactions are very different, and renal and hepatic function may not be comparable.
Preliminary therapeutic drug monitoring data for ribavirin

Ribavirin concentrations have been monitored in a preliminary study of transplant recipients infected with RSV (n=17). Ribavirin concentrations were highly variable (range 0.6 – 23 mg/L) and extremely high in some patients with a concurrent fall in haemoglobin even with short-term therapy.

These findings suggest the current protocol is not satisfactory for all patients and there is an urgent need to investigate new therapeutic strategies.