Refractory and/or Resistant Herpes Simplex Virus Mucocutaneous Infections in Adult Transplantation and Cellular Therapy Patients: A Single-Center Experience.

Purpose and methods Refractory and/or resistant herpes simplex virus (R/R HSV) mucocutaneous infections are an emerging challenge in immunocompromised hosts. A single-center retrospective study of R/R HSV mucocutaneous infections in allogeneic hematopoietic cell transplantation (HCT) was conducted on cases identified between 2023 and 2025. Cases were categorized using the 2025 consensus definitions. We collected data on the clinical presentation, risk factors, and outcomes and investigated the genetic mechanisms of resistance. Results Five cases of R/R HSV following HCT were identified. Four patients had documented UL23 gene resistance mutations. The median time from HCT to R/R HSV was 642 days. All the patients were recipients of unrelated or mismatched donors. Three (60%) had relapsed hematological disease. The CD4 lymphopenia (<200 cells/µL) and hypogammaglobulinemia (IgG <600 mg/dL) were present in three patients (60%) and four patients (80%), respectively. The median cumulative exposure to (val)acyclovir prior to R/R HSV was 30 months (range: 18 to 51 months). Foscarnet was used in all patients as initial therapy. Viremia was present in four (80%) cases, with clearance of viremia in response to antiviral therapy in only two. Acute renal failure and electrolyte disturbances related to antiviral therapy occurred in two patients (40%) and four patients (80%), respectively. Despite protracted courses of antivirals (lasting up to nine weeks), no patient achieved complete healing. Three-month mortality was 80% (n=4), although none of the deaths were directly attributed to the HSV infection. Conclusion Refractory and/or resistant herpes simplex virus is a rare but serious complication of HCT. Current antivirals for R/R HSV infections have suboptimal efficacy and safety profiles.