Pharmacokinetics and Safety of Intravenous Cidofovir for Life-Threatening Viral Infections in Pediatric Hematopoietic Stem Cell Transplant Recipients

Abstract

fChildren undergoing hematopoietic stem cell transplantation (HSCT) are at risk for life-threatening viral infections. Cidofovir is often used as a first-line agent for adenovirus infections, despite the absence of randomized controlled trials with HSCT patients, and as a second-line agent for resistant herpesvirus infections. The frequency and severity of adverse effects, particularly nephrotoxicity, in pediatric HSCT recipients are unclear, and pharmacokinetics (PK) of cidofovir in children have not previously been reported. This study was an open-label, nonrandomized, single-dose pilot study to determine the safety and PK of cidofovir in pediatric HSCT recipients with symptomatic adenovirus, nucleoside-resistant cytomegalovirus (CMV) or herpes simplex virus (HSV), and/or human papovavirus infections. Subsequent dosing and frequency were determined by clinical response and side effects, as assessed by the treating physician. Blood and urine samples were obtained from patients for PK studies and assessment of toxicity and virologic response. Twelve patients were enrolled (median age, 9 years; 33.5 days posttransplantation). Four of seven patients with adenovirus infection were successfully treated and eventually cleared their infections. Four of twelve patients died of disseminated viral disease and multiorgan failure. Two of twelve patients had evidence of acute kidney injury after the first dose, and one of these patients developed chronic kidney disease; two other patients developed late nephrotoxicity. The mean drug half-life was 9.5 h. There was no correlation between nephrotoxicity and plasma maximum concentration, clearance, or half-life. PK were similar to those reported for adults, although the drug half-life was significantly longer than that for adults. Cidofovir was well tolerated in the majority of patients. However, effective therapeutic strategies are urgently needed to support patients until immune reconstitution is achieved.A utologous and allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignant and nonmalignant hematological and immunological disorders results in a variable period of compromised immunity (1). T-lymphocyte numbers and function are decreased by chemotherapeutic conditioning regimens, certain stem cell processing techniques, and immunosuppressive agents used to prevent or treat graft-versus-host disease (GVHD) in allogeneic HSCT recipients (1). In addition, the graft source, such as cord blood, peripheral blood stem cells, or marrow, impacts the pace and quality of immune reconstitution. Consequently, children undergoing HSCT are at profound risk for serious and potentially fatal viral infections. Viruses that commonly complicate HSCT include adenoviruses, cytomegalovirus (CMV), herpes simplex virus (HSV), human herpesvirus 6 (HHV-6), BK virus, and other community-acquired respiratory and gastrointestinal (GI) viruses (2-6). Furthermore, the need for protracted antiviral therapy due to impaired immune clearance increases the risk of antiviral resis...

Fatal systemic adenoviral infection superimposed on pulmonary mucormycosis in a child with acute leukemia

“…Despite administration of cidofovir, 43% to 50% of allogeneic HCT recipients with ADV viremia die: early administration of cidofovir reportedly improves the prognosis of ADV infections. [ 18 , 19 ] Although our patient had not received allogeneic HCT and T-cell-specific immune suppressants, uncontrolled underlying ALL, concurrent fungal pneumonia, and delayed cidofovir administration could have led to the grave outcome. Fatal ADV infections in allogeneic HCT recipients with concurrent bacterial and fungal coinfections have been reported, although the ADV DNA titers from blood samples were low.…”

Progress in treatment of viral infections in children with acute lymphoblastic leukemia

“…ADV, and several other viruses are also treated with cidofovir, which in those cases might be better tolerated than in CMV infections. 91 Alternatively, treatment with a modified dosing regimen of cidofovir was well tolerated and high-risk ADV infections resolved in seven pediatric allogeneic hematopoietic progenitor cell transplant recipients. 92 …”

Use of cidofovir with extracorporeal membrane oxygenation to treat adenovirus‐associated acute respiratory distress syndrome in paediatric patients— a case series

“…Cidofovir has been shown to effectively manage adenoviral infections in several studies. An open label, nonrandomized, single pilot study concluded that cidofovir could be safely used in paediatric hematopoietic stem cell transplant recipients 6 . Cidofovir is a nucleoside analog that prevents DNA polymerization and DNA replication of viruses.…”