Danielle El-Haddad1, Firas El Chaer2, Jackapat Vanichanan1, Dimpy P Shah1, Ella J Ariza-Heredia1, Victor E Mulanovich1, Alison M Gulbis3, Elizabeth J Shpall4, Roy F Chemaly5. 1. Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 2. Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX, USA. Electronic address: elchaer.firas@gmail.com. 3. Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 4. Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 5. Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: rfchemaly@mdanderson.org.
Abstract
BACKGROUND: The emergence of resistance to available antiviral drugs may cause higher Cytomegalovirus (CMV)-associated morbidity and mortality in hematopoietic cell transplant (HCT) recipients. Few novel antiviral drugs are being developed with potential effect against refractory or resistant CMV infections. Brincidofovir, an oral nucleotide analog and prodrug of cidofovir, has shown in vitro activity against CMV. METHODS: We reviewed data of 4 cancer patients with resistant CMV or herpes simplex virus (HSV) infections and were treated with brincidofovir under emergency IND application. RESULTS: Three out of the 4 patients with resistant CMV or HSV infections responded to brincidofovir. Brincidofovir achieved virological response in 2 patients with confirmed UL97 mutation (ganciclovir-resistant CMV infection), but failed to control CMV when a specific UL54 mutation was present (conferring resistance to foscarnet and cidofovir), as seen with patient 3. Furthermore, brincidofovir was effective for treatment of acyclovir resistant HSV infection, as described in patient 4 which is in alignment with the high in vitro potency of brincidofovir (about 100-fold more than acyclovir) for inhibition of HSV replication. Only one patient had brincidofovir-related diarrhea without any evidence of concurrent gastrointestinal GVHD. CONCLUSION: Without the nephrotoxicity of cidofovir, brincidofovir could be an effective alternative for CMV-resistant and HSV-resistant infections. Combination therapy of brincidofovir with other antiviral agent, at a conventional or a lower dose, could be considered to potentiate efficacy and minimize side effects of the approved antiviral agents.
BACKGROUND: The emergence of resistance to available antiviral drugs may cause higher Cytomegalovirus (CMV)-associated morbidity and mortality in hematopoietic cell transplant (HCT) recipients. Few novel antiviral drugs are being developed with potential effect against refractory or resistant CMV infections. Brincidofovir, an oral nucleotide analog and prodrug of cidofovir, has shown in vitro activity against CMV. METHODS: We reviewed data of 4 cancerpatients with resistant CMV or herpes simplex virus (HSV) infections and were treated with brincidofovir under emergency IND application. RESULTS: Three out of the 4 patients with resistant CMV or HSV infections responded to brincidofovir. Brincidofovir achieved virological response in 2 patients with confirmed UL97 mutation (ganciclovir-resistant CMV infection), but failed to control CMV when a specific UL54 mutation was present (conferring resistance to foscarnet and cidofovir), as seen with patient 3. Furthermore, brincidofovir was effective for treatment of acyclovir resistant HSV infection, as described in patient 4 which is in alignment with the high in vitro potency of brincidofovir (about 100-fold more than acyclovir) for inhibition of HSV replication. Only one patient had brincidofovir-related diarrhea without any evidence of concurrent gastrointestinal GVHD. CONCLUSION: Without the nephrotoxicity of cidofovir, brincidofovir could be an effective alternative for CMV-resistant and HSV-resistant infections. Combination therapy of brincidofovir with other antiviral agent, at a conventional or a lower dose, could be considered to potentiate efficacy and minimize side effects of the approved antiviral agents.
Authors: Claire J Detweiler; Sarah B Mueller; Anthony D Sung; Jennifer L Saullo; Vinod K Prasad; Diana M Cardona Journal: J Pediatr Hematol Oncol Date: 2018-08 Impact factor: 1.289