Safety of Cidofovir in High-Risk Paediatric Patients.

Abstract Purpose: Cidofovir has efficacy in the treatment of adenovirus and cytomegalovirus (CMV) infection in immunocompromised individuals. It is licensed for the treatment of CMV retinitis in AIDS patients over the age of 12 years, and is nephrotoxic and contra-indicated with the use of other concomitant nephrotoxic agents. Its use has been further limited due to concerns regarding an individual’s ability to tolerate the hydration regimens associated with cidofovir administration. Despite this it is a valuable anti-viral agent particularly in the setting of haemapoietic stem cell transplantation. This study assessed the safety of cidofovir in a high-risk paediatric population. Methods: A retrospective review of all episodes of cidofovir administration at the Oncology Unit at the Children’s Hospital at Westmead from 2000–2005 was undertaken. The dose of cidofovir and renal function (measured by urea and creatinine) pre and post infusion were recorded, and the medical notes reviewed for adverse events and concomitant use of other nephrotoxic drugs. Results: A total of 233 cidofovir infusions in 23 patients were studied. Patients: Age range 5 months - 19 years (mean 6.6 years). Sex: male 17 (74%), female 6 (26%). Clinical setting: 16 (70%) were post allogeneic stem cell transplantation, 4 (17%) were post autologous stem cell transplation, 3 (13%) had other malignancies. Indications for cidofovir: In 20 (87%) for proven adenovirus identified in stool, urine, nasopharyngeal aspirate, CSF, or tissue biopsy; 2 (9%) for adenovirus prophylaxis as part of haplo-identical stem cell transplant conditioning, 1 (4%) for extended coverage in sepsis without an identified organism. Cidofovir doses: 111 (48%) were 1mg/kg, 75 (32%) were 3mg/kg, 47 (20%) were 5mg/kg. All episodes of cidofovir administration received the same standard recommended regimen of oral probenecid 40mg/kg at hour -3, 20ml/kg of intravenous 0.9% NaCl from hour −1 to 0, cidofovir infusion with 20ml/kg 0.9% NaCl from hour 0 to +1, maintenance intravenous fluids from hour +1 to +3, followed by oral probenecid 20mg/kg at hour +3 and +9. All patients received concomitant nephrotoxic agents: 4 (17%) received 1, 4 (17%) received 2, 5 (22%) received 3, and 10 (43%) received 4 or more agents. In 19 (83%) patients with normal renal function (defined by urea/creatinine within normal range for age), there was no evidence of nephrotoxicity (defined as >150% increase in urea/creatinine from baseline) following cidofovir therapy - mean change in urea/creatinine pre and post infusion −7.5%/+5.6%. There was no deterioration in renal function in 4 (17%) patients with pre-existing renal impairment (defined by urea/creatinine above the upper limit of normal) - mean change in urea/creatinine pre and post infusion −10.9%/+3.0%. Symptomatically cidofovir was tolerated by 20 (87%) patients without adverse events. Cidofovir therapy was associated with significant morbidity in 3 (17%) patients - 1 developed blindness and axonal degeneration of unknown aetiology, and in 2 patients, both with pre-existing pneumonitis post allogeneic stem cell transplantation, the fluid regimen precipitated a respiratory deterioration secondary to fluid overload. Conclusion: Cidofovir is a safe and well tolerated drug in a high-risk paediatric population, even with the use of concomitant nephrotoxic agents. An aggressive fluid regimen may not be necessary, with particular care required in patients with significant pulmonary disease in whom the fluid regimen may precipitate respiratory compromise.