Safety and efficacy of antiviral therapy for prevention of cytomegalovirus reactivation in immunocompetent critically ill patients: a randomized clinical trial

Nicholas Cowley, Andrew Owen, Sarah C Shiels, Joanne Millar, Rebecca Woolley, Natalie Ives, Husam Osman, Paul Moss, Julian Bion

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Importance: Latent Cytomegalovirus (CMV) infection is present in over half of the adult population and viral reactivation, where virus becomes measurable in body fluids such as blood, can occur in up to a 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: Single centre, open-label, randomised, controlled trial recruiting between January 2012 and January 2014.

Setting: Large 100 bedded intensive care unit in England, UK

Participants: 124 CMV-seropositive patients undergoing mechanical ventilation for at least 24 hours in intensive care. Baseline characteristics were similar between groups with mean age 57 years and mean APACHE II score 17.6.

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

Main Outcome Measure: Time to first CMV reactivation in blood within the 28 day follow up period following initiation of study drug.

Results: Viral reactivation in blood occurred in 12 patients randomised to the control group, compared with one reactivation in the valganciclovir group and two reactivations in the valaciclovir group (HR=0.1, 95% CI: 0.04-0.5 for combined treatment groups vs. control). Although this trial was not powered to assess clinical endpoints, the valaciclovir arm was halted prematurely because of higher mortality; 14 of 34 patients (41%) 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 endpoints showed similar outcomes between groups.

Conclusion and Relevance: Antiviral prophylaxis with valaciclovir or low dose valganciclovir suppresses CMV reactivation in the setting of 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:, NCT01503918,
Original languageEnglish
Pages (from-to)774-783
Number of pages10
JournalJAMA internal medicine
Issue number6
Early online date24 Apr 2017
Publication statusPublished - Jun 2017


  • Acyclovir/administration & dosage
  • Adult
  • Aged
  • Antiviral Agents/administration & dosage
  • Critical Illness
  • Cytomegalovirus/drug effects
  • Cytomegalovirus Infections/drug therapy
  • Drug Administration Schedule
  • Female
  • Humans
  • Male
  • Middle Aged
  • Opportunistic Infections/virology
  • Respiration, Artificial/adverse effects
  • Valine/administration & dosage
  • Virus Activation/drug effects
  • Virus Inactivation/drug effects


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