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

The clinical significance of human herpesvirus-6 (HHV-6) after allogeneic hematopoietic cell transplantation (HCT) is debated. We prospectively collected weekly whole-blood HHV-6 in 217 PTCy-based HCT recipients. One-hundred forty-nine (69%) patients had at least one detection, at a median of 21 days post-HCT, and 63 (29%) spiked ≥4*log10 copies/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 associated on univariate analysis with high-level HHV-6 DNAemia. All spikes precipitously declined spontaneously, but after initial decline, 27% persisted at ≥3*log10 copies/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 (Spearman's ρ=0.85, p<0.0001). By contrast, in patients with HHV-6 persisting >1 month, HHV-6 was predominantly found within CD4+ T-cells, but not in plasma. Only one patient developed HHV-6-associated encephalitis, but high-level HHV-6 DNAemia was associated with increased rates of otherwise unexplained fever (35% vs 21% in patients without high-HHV-6 DNAemia, p=0.036), rash (27% vs 12%, p=0.009), transaminitis (52% vs 27%, p=0.001), and gastrointestinal symptoms (23% vs 7%, p=0.0036) as well as increased risk of acute (36% vs 18%, p=0.007) and moderate-to-severe chronic (22% vs 8%, p=0.01) graft-versus-host disease. 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. (NCT04959175, NCT05436418, NCT02579967, NCT03983850, NCT03922724, NCT03663933).