Title: Anti-viral Prophylaxis for Prevention of Cytomegalovirus (CMV) Reactivation in Immunocompetent Patients in Critical Care
Funder: Department of Health (England)

Abstract: Background Cytomegalovirus (CMV) is a common virus which infects around half the UK population. Infection is usually mild, but after infection the virus is never completely eradicated, and may reactivate in ill health. Reactivation is most commonly seen in those with compromised immune systems, such as people with advanced HIV infection, or whilst on immunosuppression following organ transplantation. CMV reactivation in these patients can be life threatening. There is evidence to support the use of antiviral medication in these groups of immunosuppressed patients to prevent CMV reactivation, and their use is part of standard therapy. There is increasing evidence demonstrating that a third of critically ill patients will reactivate CMV, and these patients have as much as a doubled mortality. Aims This study is a proof of concept study designed to assess whether antiviral prophylaxis can effectively and safely suppress CMV reactivation in CMV seropositive high risk critically ill patients in ITU. Antiviral prophylaxis is currently not standard practice in ITU, and no previous trials of prophylaxis have been undertaken in this setting. All commonly used antiviral agents have side effects, and it is important to demonstrate their efficacy and safety in the critical care setting before undertaking a large multicentre trial powered to identify mortality or morbidity differences with prophlyaxis. Plan of Investigation This is a prospective, randomised, open-label single centre study. Patients admitted to the Queen Elizabeth Hospital Birmingham ITU, and identified by study criteria to be at high risk of CMV reactivation will be assessed for inclusion into the study. Blood will be analysed for CMV antibodies to establish eligibility. Recruited patients will be randomised to receive high dose aciclovir/valaciclovir, or low dose ganciclovir/valganciclovir for the duration of their ICU stay, for a maximum of 28 days, or to enter the control group receiving standard care. CMV viral load by PCR will be measured in blood twice weekly, and in sputum and urine weekly. Blood will also be taken to assess the immune response to herpesviruses at day 14 using functional T cell assays and ELISA. Potential Impact Latent CMV infection is common, affecting around half of all adults in the UK. Evidence demonstrates that a third of these patients will reactivate leading to CMV viraemia when critically ill. Epidemilogical data from multiple independant groups have identified a doubling in mortality in this group, although a causal link between CMV reactivation and mortality without a trial of antiviral drugs can not be assumed. From these figures, it is estimated that 16.5% of critically ill patients (current mortality rates of around 40%) may benefit from antiviral prophyaxis. Almost no patients are receiving prophylaxis or screening for reactivation worldwide in this group. Demonstration of mortality or morbidity improvements would potentially change worldwide intensive care practice.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION