Frequency, kinetics, and clinical significance of HHV-6 DNAemia after PTCy-based hematopoietic cell transplant

Abstract The clinical significance of human herpesvirus 6 (HHV-6) after allogeneic hematopoietic cell transplant (HCT) is debated. We prospectively collected weekly whole-blood HHV-6 in 217 posttransplantation cyclophosphamide (PTCy)–based HCT recipients. Overall, 149 patients (69%) had HHV-6 detected, at a median of 21 days after HCT; in 63 (29%) patients, HHV-6 DNAemia spiked to ≥4 × log10 copies per mL (high-level HHV-6 DNAemia) at median day +27. Hematologic malignancy, myeloablative conditioning, HLA-partially mismatched donor, marrow graft, PTCy dose, and sirolimus use were univariates associated with high-level HHV-6 DNAemia. All spikes precipitously declined spontaneously, but after initial decline, 27% persisted at ≥3 × log10 copies per mL for >1 month. Those with HHV-6 spikes had lower day +28 CD4+ T-cell counts. During initial spikes, there was a strong correlation between plasma and whole-blood HHV-6 DNAemia. By contrast, in patients with HHV-6 persisting for >1 month, HHV-6 was predominantly found within CD4+ T cells but not in plasma. Only 1 patient developed HHV-6–associated encephalitis. High-level HHV-6 DNAemia was associated with significantly increased rates of otherwise unexplained fever (35% vs 21% in patients without high-level HHV-6 DNAemia), rash (27% vs 12%), transaminitis (52% vs 27%), and gastrointestinal symptoms (23% vs 7%), as well as increased risk of acute (36% vs 18%) and moderate-to-severe chronic graft-versus-host disease (GVHD; 22% vs 8%). HHV-6 detection occurs frequently in PTCy recipients but infrequently leads to classic HHV-6–related disease (encephalitis), although it associates with various self-limited clinical symptoms, may play a role in shaping immune reconstitution, and may serve as a marker for increased GVHD risk.