Kinetic Features of Double Stranded DNA Virus Detection after Allogeneic Hematopoietic Cell Transplantation

Background:

Double stranded DNA (dsDNA) viruses frequently reactivate after hematopoietic cell transplantation (HCT). Improved understanding of virus kinetics and associated risk factors is important for the study of novel therapeutic strategies.

Methods:

We identified allogeneic HCT recipients at our center from 2007-2014 who had ≥60% of possible weekly plasma samples available to day 100 post-HCT (or death if at <100 days). We tested samples for human herpesvirus 6B (HHV-6B), HHV-6A, BK polyomavirus (BKV), adenovirus (AdV), and Epstein-Barr virus (EBV) using quantitative PCR. We abstracted weekly cytomegalovirus (CMV) results from clinical records. Average area under the curve (AUC) was calculated per virus. Virus episodes were defined as ≥2 consecutive positive tests with a negative test pre and post. A single positive test was defined as a blip. We used Cox regression to evaluate the association of each virus’ time-dependent and day 100 AUC with overall mortality at day 100 and day 100 through day 365, respectively. Logistic regression was used to identify risk factors associated with persistent virus episodes.

Results:

In a cohort of 404 allogeneic HCT recipients, we tested 4,960 samples (median, 13 samples/patient). We demonstrated that higher average AUC for each virus was independently associated with day 100 and/or day 365 overall mortality post-HCT (Fig. 1). There were 494 episodes of CMV, 254 of BKV, 195 of HHV-6B, 39 of AdV, and 40 of EBV. We showed that mean viral load increased with episode duration (Fig. 2A). Mean viral load of blips was significantly lower than average viral loads during episodes of any duration (Fig. 2B). Among subjects with a positive test, higher viral load at time of first positive was significantly associated with that positive test being the beginning of an episode for all viruses (Fig. 3).

Conclusion:

We demonstrate that dsDNA virus AUC through day 100 post-HCT is independently associated with overall mortality through day 365. Given that episodes have greater quantity and duration of virus detection, and therefore higher AUC, strategies to prevent episodes (e.g. prophylactic medications, T-cell immunotherapy, vaccines) may improve post-HCT outcomes.