Double-Stranded DNA (dsDNA) Viral Infections Among Allogeneic Hematopoietic Cell Transplant (HCT) Recipients in the First Year after Transplant

Introduction: Double-stranded DNA (dsDNA) viral infections (including cytomegalovirus, adenoviruses, BK virus, and Epstein-Barr virus) can lead to significant morbidity and mortality among immunocompromised patients following allogeneic hematopoietic stem cell transplant (HCT). The lack of a broad-spectrum antiviral with the safety and tolerability to prevent viral infections poses management challenges for patients at risk of multiple dsDNA viral infections. Using a large US insurance claims database, this study describes the incidence of dsDNA viral infections and co-infections among allogeneic HCT recipients.

Methods: The MarketScan Research Databases were used to identify commercial and Medicare enrollees with an ICD-9 or CPT procedure code for an allogeneic HCT between 7/1/2009 and 6/30/2014. Eligible patients were required to have 365 days of health plan enrollment prior to HCT, but no minimum enrollment was required post-HCT. Incidence of cytomegalovirus (CMV), adenovirus (AdV), BK virus, Epstein-Barr virus, herpes simplex, varicella zoster, and other dsDNA virus infection was measured from the date of the transplant until one year post-transplant. The rates of infection with two dsDNA viral infections or three or more dsDNA viral infections were assessed, and in-hospital mortality or transfer to hospice services within one year of transplant was reported by the number of observed dsDNA viral infection.

Results: We identified 3,035 allogeneic HCT patients (mean age 47.3 years, 56.9% male), including 30.4% (n=924) with at least one dsDNA viral infection within the first year post-transplant. Of these, 69.2% had CMV infection (n=639), 5.4% had AdV infection (n=50), and 10.3% had BK virus infection (n=95). Among patients with a reported dsDNA viral infection, 17.6% (n=163) had more than one dsDNA viral infection, including 14.6% (n=135) with two dsDNA viral infections and 3.0% (n=28) with three or more viral infections. A statistically significant increase in the rate of in-hospital death or transfer to hospice within the first year post-transplant was observed for patients with reported dsDNA viral infection vs those without.  Specifically, the rate of in-hospital mortality/transfer to hospice increased from 14.9% (315/2111) for patients without a reported dsDNA viral infection to 19.2% (146/761, p=0.0060) with one dsDNA viral infection, 23.0% (31/135, p=0.0121) for patients with two dsDNA viral infections, and 35.7% (10/28, p=0.0023) for patients with three or more dsDNA viral infections.

Conclusions: A substantial proportion of allogeneic HCT recipients with a dsDNA viral infection have two or more dsDNA viral infections. Diagnoses on insurance claims may underestimate true incidence of dsDNA viral infection and co-infection. Mortality risk increases significantly with the number of dsDNA viral infections. Availability of a safe and well-tolerated broad spectrum antiviral for prevention of primary or reactivation infections could potentially reduce the morbidity and mortality associated with dsDNA viral infections and their significant sequelae.