Cytomegalovirus load at treatment initiation is predictive of time to resolution of viremia and duration of therapy in hematopoietic cell transplant recipients

Abstract

Background Preemptive antiviral therapy relies on viral load measurements and is the mainstay of cytomegalovirus (CMV) prevention in hematopoietic cell transplant (HCT) recipients. However, optimal CMV levels for the initiation of preemptive therapy have not been defined. Objectives To evaluate the relationship between plasma CMV DNA levels at initiation of preemptive therapy with time to resolution of viremia and duration of treatment. Study Design Retrospective analysis of HCT recipients undergoing serial CMV PCR testing between June 2011 and June 2014 was performed. Results 221 HCT recipients underwent preemptive therapy for 305 episodes of CMV viremia. Median time to resolution was shorter when treatment was initiated at lower CMV levels (15 days at 135-440 international units (IU)/mL, 18 days at 441-1000 IU/mL, and 21 days at >1000 IU/mL, P <.001). Prolonged viremia lasting >30 days occurred less frequently when treatment was initiated at 135-440 IU/mL compared to 441-1000 IU/mL and >1000 IU/mL (1%, 15%, 24%, P<.001). Median treatment duration was also shorter in the lower viral load groups (28, 34, 37 days, P <.001). Conclusion Initiation of preemptive therapy at low CMV levels was associated with shorter episodes of viremia and courses of antiviral therapy. These data support the utility of initiating preemptive CMV therapy at viral loads as low as 135 IU/mL in HCT recipients.

Spontaneously‐resolving episodes of cytomegalovirus DNAemia in allogeneic hematopoietic stem cell transplant recipients: Virological features and clinical outcomes

“…It should be highlighted that both this approach and ours spare the need for PET administration in a notable percentage of patients who are capable of controlling CMV replication by themselves, thus potentially reducing the toxicity inherent in the use of nucleoside analog anti‐CMV drugs. Other studies, in contrast, advocate initiating PET at very low CMV DNA loads (<150 IU/mL) aimed at reducing the length of antiviral treatment needed to clear CMV DNAemia . Unfortunately, a direct comparison between these studies and ours is not straightforward because of a number of factors, including the use of different PCR assays and criteria for initiation of PET and patients’ baseline and post‐transplant characteristics in each cohort.…”

“…9 These data suggest that PET should be started as soon as possible to keep CMV DNA loads to a minimum. Two recent reports support the suitability of this approach 3,8 ; Tan and colleagues 3 showed that initiation of PET at low CMV DNA loads results in shorter episodes of CMV DNAemia and courses of antiviral therapy. In turn, Camargo et al 8 concluded that CMV DNA peak levels ≥ 150 IU/mL associate with a drastically reduced probability of spontaneous CMV DNAemia clearance.…”

“…Currently, PET consists of administrating antivirals with intrinsic activity against CMV upon detection of a certain CMV DNA load level in the blood compartment, as quantified by real‐time polymerase chain reaction (RT‐PCR) assays. CMV DNA load thresholds for PET initiation vary widely across centers, usually ranging between 25 to 1500 IU/mL when plasma is the chosen specimen type . Recently published data point to an association between very low CMV DNA loads (≥250 IU/mL) and increased risk of overall and nonrelapse mortality within the first year of allo‐HSCT, particularly in the early days (day 0–60) after the transplantation .…”

“…Demographic and baseline clinical characteristics of patients only experiencing self-resolving episodes of CMV DNAemia and those who had CMV DNAemia and received one or more courses of PET Risk factors for overall mortality through day 365 after allo-HSCT in patients experiencing one or more episodes of self-resolving CMV DNAemia ,8 in contrast, advocate initiating PET at very low CMV DNA loads (<150 IU/mL) aimed at reducing the length of antiviral treatment needed to clear CMV DNAemia 3. Unfortunately, a direct comparison between these studies3,8 and ours is not straightforward because of a number of factors, including the use of different PCR assays and criteria for initiation of PET and patients' baseline and post-transplant characteristics in each cohort.…”

How to Best Manage Cytomegalovirus Infection in the Allogeneic Stem Cell Transplant Setting: Future Prospects

“…These data are difficult to reconcile with earlier findings demonstrating that prophylactic administration of ganciclovir at engraftment and delaying the start of ganciclovir until high-grade antigenemia resulted in similar survival rates [11], and thus must be confirmed in multicenter prospective studies. Likewise, the idea that early initiation of pre-emptive therapy (at viral loads as low as 135 IU/ml) may result in shorter courses of antiviral therapy [12] merits further research. Until then, to limit drug overexposure and thus toxicity, the focus must be placed on treating as few patients as possible, without compromising their safety, and using antiviral treatment courses as short as possible, without increasing the patient's risk of relapsing/recurrent episodes and late end-organ disease.…”