Human adenoviruses can cause serious disseminated
infections including death in immunosuppressed patients, especially pediatric allogeneic hematopoietic stem cell transplant (allo-HSCT) patients. There are no drugs approved to treat such
infections.
Cidofovir is used intravenously in many transplant clinics, probably with some effect, but controlled trials have not been completed.
Cidofovir is an acyclic
nucleoside phosphonate analog of
cytidine monophosphate. Following conversion to its
diphosphate form within cells,
cidofovir is a preferred substrate for the adenovirus
DNA polymerase, leading to
viral DNA chain termination. Problems with
cidofovir include poor cellular uptake and nephrotoxicity.
Brincidofovir, a
lipid-linked derivative of
cidofovir which is active against five families of
double-stranded DNA viruses, represents a major advance in anti-adenovirus
therapy. It is administered orally, taken up readily by cells followed by release of
cidofovir within cells, and is not nephrotoxic.
Brincidofovir, under development by Chimerix, Inc., is being evaluated against
adenovirus infections in transplant patients including allo-HSCT patients in a phase III clinical trial (AdVise Study). Preliminary results indicate that
brincidofovir is safe and very effective at decreasing adenovirus
viremia and adenovirus-induced pathogenicity and mortality. Anti-adenovirus adoptive T cell
therapy is another very promising approach to treating allo-HSCT patients as demonstrated in clinical studies.