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Original Investigation
December 16, 2019

Acyclovir for Mechanically Ventilated Patients With Herpes Simplex Virus Oropharyngeal Reactivation: A Randomized Clinical Trial

Author Affiliations
  • 1Sorbonne Université, INSERM, Médecine Intensive Réanimation, Institut de Cardiologie, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Assistance Publique–Hôpitaux de Paris, Paris, France
  • 2Médecine Intensive Réanimation, Aix-Marseille Université, Hôpital Nord, Assistance Publique–Hôpitaux de Marseille, Marseille, France
  • 3Sorbonne Université, INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Département Biostatistique Santé Publique et Information Médicale, Centre de Pharmacoépidémiologie, Paris, France
  • 4Réanimation Chirurgicale, Centre Hospitalier Universitaire de Montpellier, Hôpital St-Eloi, Montpellier, France
  • 5Département de médecine periopératoire, Centre Hospitalier Universitaire Clermont-Ferrand, Clermont-Ferrand, France
  • 6Réanimation Chirurgicale, Hôpital Edouard-Herriot, Hospices Civils de Lyon, Lyon, France
  • 7Réanimation Médicale, Centre Hospitalier Universitaire Gabriel-Montpied, Clermont-Ferrand, France
  • 8Réanimation Chirurgicale Polyvalente, Département d’Anesthésie-Réanimation, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Assistance Publique–Hôpitaux de Paris, Paris, France
  • 9Sorbonne Université, INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique, AP-HP, Hôpitaux Universitaires Pitié Salpêtrière Charles Foix, Unité de Recherche Clinique, Paris, France
  • 10Pharmacie, Hôpitaux Sud, Assistance Publique–Hôpitaux de Marseille, Marseille, France
  • 11Réanimation Polyvalente, Centre Hospitalier Universitaire Dupuytren, Limoges, France
  • 12Médecine Intensive Réanimation, Centre Hospitalier Universitaire Grenoble Alpes, La Tronche, France
  • 13Médecine Intensive Réanimation, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris, Paris, France
  • 14Service de Réanimation, Hôpital Mignot, Versailles, France
  • 15Médecine Intensive Réanimation, Hôpital Européen Georges-Pompidou, Assistance Publique–Hôpitaux de Paris, Paris, France
  • 16Réanimation des Urgences et Médicale, Aix-Marseille Université, Hôpital Timone, Assistance Publique–Hôpitaux de Marseille, Marseille, France
  • 17Pneumologie, Médecine Intensive Réanimation, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Assistance Publique–Hôpitaux de Paris, Paris, France
  • 18Réanimation Chirurgicale, Centre Hospitalier Universitaire Nîmes, Nîmes, France
  • 19Médecine Intensive Réanimation, Hôpital Cochin, Assistance Publique–Hôpitaux de Paris, Paris, France
  • 20Réanimation Neurochirurgicale, Hôpital Sainte-Anne, Paris, France
JAMA Intern Med. Published online December 16, 2019. doi:10.1001/jamainternmed.2019.5713
Key Points

Question  Does preemptive treatment with acyclovir reduce the duration of mechanical ventilation in critically ill patients with herpes simplex virus oropharyngeal reactivation?

Findings  In this multicenter, randomized clinical trial of 238 adults, treatment with intravenous acyclovir vs placebo during 14 days did not significantly reduce ventilator-free days at day 60. Compared with placebo, intravenous acyclovir was not associated with higher incidence of adverse events.

Meaning  The findings of this study do not appear to support routine preemptive use of acyclovir in this setting.

Abstract

Importance  The role of herpes simplex virus (HSV) reactivation on morbidity and mortality in patients in the intensive care unit requiring mechanical ventilation remains unknown.

Objective  To determine whether preemptive treatment with intravenous acyclovir reduces the duration of mechanical ventilation in patients with HSV oropharyngeal reactivation.

Design, Setting, and Participants  A double-blind, placebo-controlled randomized clinical trial was conducted in 16 intensive care units in France. Participants included 239 adults (age, >18 years) who received mechanical ventilation for at least 96 hours and continued to receive mechanical ventilation for 48 hours or more, with HSV oropharyngeal reactivation. Patients were enrolled between February 2, 2014, and February 22, 2018.

Interventions  Participants were randomized to receive intravenous acyclovir, 5 mg/kg, 3 times daily for 14 days or a matching placebo.

Main Outcomes and Measures  The primary end point was ventilator-free days from randomization to day 60. Prespecified secondary outcomes included mortality at 60 days. Main analyses were conducted on an intention-to-treat basis.

Results  Of 239 patients enrolled and randomized, 1 patient withdrew consent, leaving 238 patients, with 119 patients in both the acyclovir and placebo (control) groups (median [IQR] age, 61 [50-70] years; 76 [32%] women) available for primary outcome measurement. On day 60, the median (IQR) numbers of ventilator-free days were 35 (0-53) for acyclovir recipients and 36 (0-50]) for controls (P = .17 for between-group comparison). Among secondary outcomes, 26 patients (22%) and 39 patients (33%) had died at day 60 (risk difference, 0.11, 95% CI, –0.004 to 0.22, P = .06). The adverse event frequency was similar for both groups (28% in the acyclovir group and 23% in the placebo group, P = .40), particularly acute renal failure post randomization affecting 3 acyclovir recipients (3%) and 2 controls (2%). Four patients (3%) in the acyclovir group vs none in the placebo group stopped the study drug for treatment-related adverse events.

Conclusions and Relevance  In patients receiving mechanical ventilation for 96 hours or more with HSV reactivation in the throat, use of acyclovir, 5 mg/kg, 3 times daily for 14 days, did not increase the number of ventilator-free days at day 60, compared with placebo. These findings do not appear to support routine preemptive use of acyclovir in this setting.

Trial Registration  ClinicalTrials.gov identifier: NCT02152358

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