Safety and Efficacy of Antiviral Therapy for Prevention of Cytomegalovirus Reactivation in Immunocompetent Critically Ill Patients: A Randomized Clinical Trial

Abstract

Importance: Latent cytomegalovirus (CMV) infection is present in more than half the adult population, and a viral reactivation (ie, when the virus becomes measurable in body fluids such as blood) can occur in up to one-third of these individuals during episodes of critical illness.

Objective: To determine whether antiviral therapy is safe and effective for preventing CMV reactivation in a general population of critically ill patients.

Design, setting, and participants: A single-center, open-label, randomized, controlled clinical trial recruited 124 CMV-seropositive patients undergoing mechanical ventilation for at least 24 hours in the intensive care unit between January 1, 2012, and January 31, 2014. The mean baseline Acute Physiology and Chronic Health Evaluation II score of all patients was 17.6.

Interventions: Patients were randomized to receive anti-CMV prophylaxis with valacyclovir hydrochloride (n = 34) or low-dose valganciclovir hydrochloride (n = 46) for up to 28 days to suppress viral reactivation, or to a control group with no intervention (n = 44).

Main outcomes and measures: Time to first CMV reactivation in blood within the 28-day follow-up period following initiation of the study drug.

Results: Among the 124 patients in the study (46 women and 78 men; mean [SD] age, 56.9 [16.9] years), viral reactivation in the blood occurred in 12 patients in the control group, compared with 1 patient in the valganciclovir group and 2 patients in the valacyclovir group (combined treatment groups vs control: hazard ratio, 0.14; 95% CI 0.04-0.50). Although this trial was not powered to assess clinical end points, the valacyclovir arm was halted prematurely because of higher mortality; 14 of 34 patients (41.2%) had died by 28 days, compared with 5 of 37 (13.5%) patients in the control arm at the point of the decision to halt this arm. Other safety end points showed similar outcomes between groups.

Conclusions and relevance: Antiviral prophylaxis with valacyclovir or low-dose valganciclovir suppresses CMV reactivation in patients with critical illness. However, given the higher mortality, a large-scale trial would be needed to determine the clinical efficacy and safety of CMV suppression.

Trial registration: clinicaltrials.gov Identifier: NCT01503918.

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.. Trial Flowchart

Following randomization, the number of deaths and numbers having study drug stopped for each group are shown between planned sampling time points. aPalliative care initiated (died on the same day). bLow platelet count (died on the same day). cLow platelet count (died 10 days later), rash (discharged 20 days later), or drug stopped at request of the family. dRash (died 4 days later) or rash (discharged). eAllergic reaction to study drug (discharged 12 days later).

Figure 2.. Cytomegalovirus (CMV) Viral Load in Blood

A, Combined valacyclovir and valganciclovir arms. B, Control group. Each line represents a single patient. Orange lines represent patients who had CMV viremia on the day of enrollment and thus were excluded from the primary analysis of time to CMV reactivation. All enrolled patients are included in graphs to show differences in viral load over time with or without antiviral prophylaxis.

Figure 3.. Time to Cytomegalovirus (CMV) Viral Reactivation in Blood

A, Time to CMV viral reactivation in blood in combined treatment groups (valacyclovir and valganciclovir arms) vs control group (hazard ratio, 0.14; 95% CI, 0.04-0.50). B, Time to CMV viral reactivation in blood in valganciclovir group vs control group (hazard ratio, 0.08; 95% CI, 0.01-0.58).