Acyclovir‐Resistant Herpes Simplex Virus in Pediatric Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplant: A Case Series

BACKGROUND: Herpes simplex virus (HSV) infection is a significant risk in hematopoietic stem cell transplant (HSCT) recipients, and antiviral resistance poses many clinical challenges. METHODS: A retrospective case series of eight pediatric patients with acyclovir-resistant HSV infection, determined via genotypic sequencing, post allogeneic HSCT between 2012 and 2025. RESULTS: Indications for HSCT included primary immunodeficiency, sickle cell disease, myelodysplastic syndrome (MDS), and relapsed/refractory leukemia. All patients received acyclovir prophylaxis. TK mutations were most common (n = 7, 87.5%). Infections manifested as mucocutaneous disease, pneumonitis, keratitis, enterocolitis, and blood viremia. A total of 87.5% of patients (n = 7) were treated with second-line antivirals (foscarnet and/or cidofovir), and three patients were treated with third-line antivirals (pritelivir). Treatment was complicated by nephrotoxicity (n = 3, 37.5%). Adjunct treatments included intravenous immunoglobulin (n = 3, 37.5%) and donor lymphocyte infusion (n = 1, 12.5%). Poor outcomes were seen across the cohort, including death (n = 3, 37.5%). T-cell depletion was used in 50% of patients (n = 4). Concomitant immunosuppressive therapy was used in 100% of patients (n = 8) and high-dose steroids were used in 50% of patients (n = 4). Graft versus host disease occurred in four patients (50%). Secondary complications included transplant-associated thrombotic microangiopathy (n = 3, 37.5%), idiopathic pulmonary syndrome (n = 3, 37.5%), and graft failure (n = 1, 12.5%). CONCLUSION: Acyclovir-resistant HSV infection in pediatric HSCT recipients is associated with high morbidity and mortality, limited therapeutic options, and significant treatment-related nephrotoxicity. Early recognition, early resistance testing, prompt initiation of second-line therapy, and weaning of immunosuppression are critical. Emerging therapies, such as helicase-primase inhibitors and adoptive T-cell therapy, hold promise but remain limited by access and pediatric data.