Effect of Ganciclovir on IL-6 Levels Among Cytomegalovirus-Seropositive Adults With Critical Illness: A Randomized Clinical Trial

Abstract

Importance: The role of cytomegalovirus (CMV) reactivation in mediating adverse clinical outcomes in nonimmunosuppressed adults with critical illness is unknown.

Objective: To determine whether ganciclovir prophylaxis reduces plasma interleukin 6 (IL-6) levels in CMV-seropositive adults who are critically ill.

Design, setting, and participants: Double-blind, placebo-controlled, randomized clinical trial (conducted March 10, 2011-April 29, 2016) with a follow-up of 180 days (November 10, 2016) that included 160 CMV-seropositive adults with either sepsis or trauma and respiratory failure at 14 university intensive care units (ICUs) across the United States.

Interventions: Patients were randomized (1:1) to receive either intravenous ganciclovir (5 mg/kg twice daily for 5 days), followed by either intravenous ganciclovir or oral valganciclovir once daily until hospital discharge (n = 84) or to receive matching placebo (n = 76).

Main outcomes and measures: The primary outcome was change in IL-6 level from day 1 to 14. Secondary outcomes were incidence of CMV reactivation in plasma, mechanical ventilation days, incidence of secondary bacteremia or fungemia, ICU length of stay, mortality, and ventilator-free days (VFDs) at 28 days.

Results: Among 160 randomized patients (mean age, 57 years; women, 43%), 156 patients received 1or more dose(s) of study medication, and 132 patients (85%) completed the study. The mean change in plasma IL-6 levels between groups was -0.79 log10 units (-2.06 to 0.48) in the ganciclovir group and -0.79 log10 units (-2.14 to 0.56) in the placebo group (point estimate of difference, 0 [95% CI, -0.3 to 0.3]; P > .99). Among secondary outcomes, CMV reactivation in plasma was significantly lower in the ganciclovir group (12% [10 of 84 patients] vs 39% [28 of 72 patients]); absolute risk difference, -27 (95% CI, -40 to -14), P < .001. The ganciclovir group had more median VFDs in both the intention-to-treat (ITT) group and in the prespecified sepsis subgroup (ITT group: 23 days in ganciclovir group vs 20 days in the placebo group, P = .05; sepsis subgroup, 23 days in the ganciclovir group vs 20 days in the placebo group, P = .03). There were no significant differences between the ganciclovir and placebo groups in duration of mechanical ventilation (5 days for the ganciclovir group vs 6 days for the placebo group, P = .16), incidence of secondary bacteremia or fungemia (15% for the ganciclovir group vs 15% for the placebo group, P = .67), ICU length of stay (8 days for the ganciclovir group vs 8 days for the placebo group, P = .76), or mortality (12% for the ganciclovir group vs 15% for the placebo group, P = .54).

Conclusions and relevance: Among CMV-seropositive adults with critical illness due to sepsis or trauma, ganciclovir did not reduce IL-6 levels and the current study does not support routine clinical use of ganciclovir as a prophylactic agent in patients with sepsis. Additional research is necessary to determine the clinical efficacy and safety of CMV suppression in this setting.

Trial registration: clinicaltrials.gov Identifier: NCT01335932.

Figure 1.. Flow of Patients in the Ganciclovir to Prevent Reactivation of Cytomegalovirus in Adults With Critical Illness (GRAIL) Randomized Clinical Trial

^aOther reasons included out of time window, do-not-resuscitate or do-not-intubate order, no longer septic, non-English speaking, transfer to other hospital, home ventilation, and unable to perform study procedures.

Figure 2.. Cumulative Incidence of Any Cytomegalovirus (CMV) Reactivation^a and High-Grade CMV Reactivation in Plasma^b Through Day 28

Baseline positive DNA detections were excluded from this analysis. The median duration of follow-up for CMV reactivation at any level was 28 days (range, 1 to 28) for the ganciclovir group and 28 days (range, 1 to 28) for the placebo group. The median duration of follow-up for high-grade CMV reactivation was 28 days (range, 1 to 28) for the ganciclovir group and 28 days (range, 1 to 28) for the placebo group. ^aCMV DNA was quantified in specimens using a previously published polymerase chain reaction assay method. The frequency of assessment was every 3 days until day 35 for plasma; day 1 and then every fourth day while intubated for endotracheal tube aspirate samples; days 1 and 7 only for the first 10 patients for bronchoalveolar lavage; and every 3 days until day 35 for throat. ^bExcluding baseline positive DNA detection.

Figure 3.. Kaplan-Meier Curve of Mortality by Treatment Group Through Day 180

Median (interquartile range) duration of follow-up was 180 days (89-180) for the ganciclovir group and 180 days (91-180) for the placebo group.

Figure 4.. Duration of Mechanical Ventilation and Ventilator-Free Days Through Day 28^a

The P value was .16 for panel A, .06 for panel B, .05 for panel C, and .03 for panel D. ^aError bars indicate minimum and maximum values; boxes, the interquartile range; horizontal lines, median. Dots indicate individual patients.