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.

• Authors: Ajit P Limaye, Renee D Stapleton, Lili Peng, Scott R Gunn, Louise E Kimball, Robert Hyzy, Matthew C Exline, D Clark Files, Peter E Morris, Stephen K Frankel, Mark E Mikkelsen, Duncan Hite, Kyle B Enfield, Jay Steingrub, James O'Brien, Polly E Parsons, Joseph Cuschieri, Richard G Wunderink, David L Hotchkin, Ying Q Chen, Gordon D Rubenfeld, Michael Boeckh
• Journal: JAMA (JAMA) Vol. 318 Issue 8 Pg. 731-740 (08 22 2017) ISSN: 1538-3598 [Electronic] United States
• PMID: 28829877 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Antiviral Agents
• IL6 protein, human
• Interleukin-6
• Valganciclovir
• Ganciclovir

Topics

• Adult
• Aged
• Antiviral Agents (pharmacology, therapeutic use)
• Critical Illness (mortality)
• Cytomegalovirus (isolation & purification, physiology)
• Cytomegalovirus Infections (blood, prevention & control)
• Double-Blind Method
• Female
• Follow-Up Studies
• Ganciclovir (analogs & derivatives, pharmacology, therapeutic use)
• Humans
• Intention to Treat Analysis
• Interleukin-6 (blood)
• Length of Stay
• Male
• Middle Aged
• Respiration, Artificial (statistics & numerical data)
• Respiratory Insufficiency (etiology, therapy)
• Sepsis (blood, complications, drug therapy)
• Treatment Outcome
• Valganciclovir
• Virus Activation (drug effects)
• Wounds and Injuries (blood, complications, drug therapy)