CMV Modulation of the Immune System in ANCA-associated Vasculitis
CMV Modulation of the Immune System in ANCA-associated Vasculitis
The purpose of this study is to determine whether Cytomegalovirus (CMV) reactivation in
 ANCA-associated vasculitis (AAV) patients can be effectively and safely reduced using an
 antiviral agent (valaciclovir) and whether this in turn improves the function of the immune
 system thereby also improving the body's ability to fight other infections.

 The primary hypothesis is that repeated episodes of CMV reactivation in AAV patients drive
 the expansion and functional impairment of CMV-specific T-cells, with increased
 susceptibility to infection. Inhibition of CMV replication with valaciclovir will block
 further stimulation of CMV specific T-cells and increase the functional capacity of the
 immune system.
Infection is the commonest cause of death in patients with ANCA-associated vasculitis (AAV).
 The investigators have shown that the expansion of CD4+CD28- T-cells present in patients with
 AAV is driven by CMV and this expansion is associated with increased infection risk. It is
 suggested that these cells are driven by CMV reactivation and express markers of T-cell
 exhaustion with reduced cytokine production and inhibitory receptor expression. However the
 phenotype of CMV-specific T cells in those with extreme expansions of CD4+CD28- T-cells has
 not been explored.

 The investigators aim to investigate the phenotype of CMV-specific T-cells comparing those
 patients with extreme expansions of CD4+CD28- T-cells to those with smaller expansions and
 relate this to CMV reactivation. The investigators will monitor CMV reactivation in urine and
 blood monthly by qPCR. This will be correlated with the expansion of CD4+CD28- T-cells and
 the phenotype of these cells, specifically looking at cytokine production and inhibitory
 receptor expression. The investigators will identify CMV-specific T-cells by MHC class II
 tetramers or by stimulating with CMV lysate. The investigators will proceed to undertake a
 randomised controlled trial with valaciclovir or no treatment to investigate whether the
 reduction of CMV reactivation improves the phenotype of CD4+CD28- T-cells in these patients.
Inclusion Criteria:

 -  Documented diagnosis of Wegener's granulomatosis (now called Granulomatosis with
 Polyangiitis), microscopic polyangiitis or renal limited vasculitis according to
 Chapel Hill Consensus Conference criteria.

 -  In stable remission (no documented clinical disease activity) for at least 6 months
 prior to entry.

 -  On maintenance immunosuppression with prednisolone, mycophenolate mofetil or
 azathioprine alone or in combination (maximum 2 agents).

 -  Documented evidence of CMV infection (CMV-specific immunoglobulin G detected in
 peripheral blood).

 -  Documentation that female patients of child bearing potential are not pregnant and
 using an appropriate form of contraception.

 -  Written informed consent for study participation

 Exclusion Criteria:

 -  Stage 5 chronic kidney disease (eGFR<15ml/minute/1.73m2).

 -  Other significant chronic infection (HIV, HBV, HCV, TB).

 -  B-cell or T-cell depleting therapy within 12 months.

 -  Treatment with anti-CMV therapies in last month

 -  Underlying medical conditions, which in the opinion of the Investigator place the
 patient at unacceptably high risk for participating in the study.

 -  Inability to fully or appropriately participate in the study.