Incidence and Management of Early Breakthrough HSV Infection Among Allogeneic Hematopoietic Stem Cell Transplant Recipients

Background: Reactivation of herpes simplex viruses (HSV) can occur in the early post-allogeneic hematopoietic cell transplant (aHCT) period despite antiviral prophylaxis. Few studies have assessed HSV infection in the modern era, in which acyclovir/valacyclovir is recommended for up to 1 year post aHCT. We evaluated the incidence and management of breakthrough HSV during the first 100 days post-aHCT over two decades. Methods: Patients who received their first aHCT at Fred Hutchinson Cancer Center between 2002-2022 were reviewed for breakthrough HSV infection within the first 100 days on prophylaxis (acyclovir 800 mg or valacyclovir 500 mg twice daily). Cases were identified via culture, polymerase chain reaction, and/or direct fluorescent antibody testing; clinical records were reviewed for symptoms, outcomes, and prophylaxis/treatment regimens. Refractory/resistant (R/R) infections were defined according to consensus guidelines. Results: We reviewed data from 4,357 aHCT recipients aged [≥]18 years, among whom 3,749 (86%) were HSV seropositive and 23 developed breakthrough HSV infection (observed probability = 0.6%). Among those who had an infection, the median time from transplant to first positive test was 46 days (IQR: 24.0-69.5). Oral and genital mucosa were the most common sites of infection. In total, 11 of 23 (47.8%) patients with breakthrough HSV developed R/R infection. Conclusions: Breakthrough HSV infections are rare in the first 100 days after aHCT among patients receiving antiviral prophylaxis. Refractory/resistant infections were uncommon but represented almost half of breakthrough cases. Our findings highlight the sustained effectiveness of universal prophylaxis in the early post-transplant period.