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.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Limaye reports personal fees from Merck and Helocyte; serving on the advisory board for Artemis; and being a site investigator for trials with Astellas and Oxford Immunotech. Dr Files reports being a principal investigator for Ferring Pharmaceuticals. Dr O’Brien reports being an investor in Quorum Therapeutics and receiving personal fees from Quorum Therapeutics, GenEndeavor, Tenax, Abbott, General Electric, and the Medical Simulation Corporation. Dr Hotchkin reports receiving personal fees from Intermune and Boehringer Ingelheim. Dr Boeckh reports receiving personal fees from Merck, Chimerix, Shire, and Artemis and grant funding from Chimerix and Shire. No other disclosures were reported.

Figures

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) Reactivationa and High-Grade CMV Reactivation in Plasmab 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 28a

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.