Brincidofovir for the treatment of human adenovirus infection in pediatric solid organ transplant recipients: A case series

Abstract

Viral infections represent a significant cause of morbidity among pediatric recipients of SOT. 1,2 They not only induce specific disease states that are usually more severe compared with immunocompetent hosts but can also lead to the development of allograft damage and acute transplant rejection. HAdV is one viral pathogen associated with such complications in SOT patients. 3,4 In SOT patients, HAdV can be acquired as a primary infection from horizontal transmission or as a reactivation of a latent infection in the setting of immunosuppression. HAdV infections have been documented in pediatric liver, kidney, lung, and heart transplant recipients with variability in incidence based on the organ group. 5-9 Infection is most common in the immediate post-transplant time period with varying severity of infection ranging from asymptomatic disease to disseminated disease with multiorgan dysfunction, graft failure, and death. We have little evidence to guide treatment and prognosis for the limited number of pediatric SOT patients who are at risk of severe disease complications including direct infection of the graft, precipitation of rejection, or graft failure. Currently, there are no US FDA-approved drugs for the specific indication of treating HAdV infection or disease. Historically, the treatment approach to post-transplant HAdv disease has been to decrease immunosuppression to allow development of a protective antiviral immune response, ideally without rejection. 10 Antiviral therapy has been attempted in disseminated HAdv disease (affecting two or more organ systems) with varying degrees of success. 8,11 The most frequently reported experience is with the use of cidofovir

Adenovirus: Epidemiology, Global Spread of Novel Types, and Approach to Treatment

“…79,178,345,362 A cardinal strategy with AdV infections is to reduce the level of IT 124,217,346 ; antiviral therapy is reserved for severe disease or high-risk cases. 343 In a prospective study, serial blood AdV PCR specimens were obtained in 76 HSCT recipients. 354 If blood PCR was positive, IT was reduced or withdrawn.…”

“…20,222 Hexadecyloxyprophyl-cidofovir or BCV, an orally active lipophilic form of CDV, has potent activity against AdV in vitro 345 and in animal models, 357 with anecdotal successes in small clinical series. 343,[358][359][360][361] Compared with CDV, BCV has excellent oral bioavailability, achieves more than 100-fold higher intracellular concentrations of active drug, and lacks nephrotoxicity. 345 A retrospective multicenter study compared the kinetics of viremia and toxicities following preemptive treatment with BCV in 27 children with HSCTrelated adenoviremia.…”

“…No antiviral drug has been approved to treat AdV. 343 344 Reduction of the level of IT is the mainstay of treatment for AdV infections. 345 346 Antiviral agents are reserved for preventing viral diseases in high-risk cases (e.g., HSCT recipients) or for serious infections.…”

Viral Enteritis in Solid-Organ Transplantation

“…However, brincidofovir seems to be better tolerated in stem-cell and solid-organ transplant recipients [41]. In a recent report in pediatric SOT recipients (two kidneys, one kidney-liver, and one liver), treatment with brincidofovir was associated with mild GI symptoms, which resolved with completion of the therapy [42]. Brincidofovir was reported to be an effective salvage therapy in immunocompromised patients with adenovirus disease who failed CDV treatment.…”

Respiratory Viruses in Solid Organ Transplant Recipients

“…Earlier case reports described favorable outcomes when combining cidofovir with reduction of immunosuppression [106,[109][110][111]. Contemporary data, the largest series being 13 liver transplant recipients, show promising results with the use of brincidofovir as well as with its use in combination with the reduction of immunosuppression [108,[112][113][114]. Some may use IVIG, usually in addition to an antiviral drug [110].…”