title: Valaciclovir to prevent Cytomegalovirus mediated adverse modulation of the immune system in ANCA-associated vasculitis (CANVAS): study protocol for a randomised controlled trial.
abstract: The ANCA-associated vasculitides (AAV) are systemic autoimmune inflammatory disorders characterised by necrotising inflammation affecting small to medium-sized blood vessels. Despite improvements in survival, infection and cardiovascular disease remain leading causes of morbidity and mortality. Considerable evidence suggests that CD4 + CD28null T-cell expansions, predominantly seen in Cytomegalovirus (CMV) seropositive individuals, are associated with systemic dysregulation of immune function leading to a heightened risk of infection and cardiovascular disease. In patients with AAV, CD4 + CD28null expansions are driven by CMV and are associated with an increased risk of infection and mortality. The aim of this study is to explore in detail the ways in which CMV modulates the immune system and to determine whether treatment with valaciclovir blocks subclinical CMV reactivation in CMV seropositive AAV patients and ameliorates the CMV-induced adverse effects on the immune system.
  
  
  
  CANVAS is a single-centre prospective open-label randomised controlled proof-of-concept trial of 50 adult CMV seropositive patients with stable AAV. Participants will be randomly allocated to receive valaciclovir orally (2 g QDS or reduced according to renal function) or no additional treatment for 6 months with an additional 6-month follow-up period. The primary outcome is the proportion of patients with CMV reactivation, as assessed by measurable viral load on quantitative blood and urine CMV polymerase chain reaction. The secondary outcomes are safety, change in the proportion of CD4+ CMV-specific T-cell population (defined as CD4 + CD28null cells) and change in soluble markers of inflammation from baseline to 6 months. Further tertiary and exploratory outcomes include persistence of the effect of valaciclovir on the proportion of CD4 + CD28null cells at 6 months post completion of treatment, change in the immune phenotype of CD4+ T cells and change in blood pressure and arterial stiffness parameters from baseline to 6 months.
  
  
  
  The results of this study will enable larger studies to be conducted to determine whether by controlling subclinical CMV reactivation, we can improve clinical endpoints such as infection and cardiovascular disease. The potential impact of this study is not limited to AAV, as CD4 + CD28null cells have been linked to adverse outcomes in other inflammatory conditions and in the context of an ageing immune system.
  
  
  
  ClinicalTrials.gov Identifier NCT01633476 (registered 29 June 2012).
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Chanouzas
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Lovesh
authors.initials: L
authors.lastname: Dyall
authors.affiliation: Wolfson Computer Laboratory, Queen Elizabeth Hospital Birmingham, Birmingham, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Nightingale
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Ferro
authors.affiliation: School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Moss
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Matthew David
authors.initials: MD
authors.lastname: Morgan
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. l.harper@bham.ac.uk.
authors.forename: Lorraine
authors.identifier: 0000-0003-1343-9234
authors.initials: L
authors.lastname: Harper
mesh_terms: D000212:Acyclovir / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D002985:Clinical Protocols; D003587:Cytomegalovirus / Q000187:drug effects* / Q000276:immunology / Q000472:pathogenicity; D003586:Cytomegalovirus Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D004739:England; D054884:Host-Pathogen Interactions; D006801:Humans; D000075082:Proof of Concept Study; D011446:Prospective Studies; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome; D000077483:Valacyclovir; D014633:Valine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019562:Viral Load; D014775:Virus Activation / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir