CMV Modulation of the Immune System in ANCA-associated Vasculitis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Does CMV Reactivation Cause Functional Impairment of CMV Specific CD4+ T-cells? The Potential for Valaciclovir to Prevent CMV-mediated Adverse Modulation of the Immune System in Patients With ANCA-associated Vasculitis

Conditions
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ANCA Associated Vasculitis, CMV Infection

Intervention / Treatment
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* Drug: Valaciclovir


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Valaciclovir<br>Active treatment with valaciclovir | Drug: Valaciclovir<br>* 2g q.d.s. orally for 6 months (dose adjusted according to renal function)<br>* Other names: Brand names: Valtrex, Zelitrex;|
| No Intervention: No additional treatment<br>No additional treatment | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with CMV reactivation and time to CMV reactivation | As assessed by measurable viral load on quantitative blood and urine CMV PCR. | Over 12 month period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients experiencing adverse events sufficient to stop treatment | Safety as defined by adverse events sufficient to stop treatment with trial drugs or serious adverse events and suspected unexpected serious adverse reactions (SUSARs). | Over 6 month period (treatment period) | 
| Change in the proportion of the CD4+ CMV specific T cell population from baseline to 6 months | Change in the proportion of CD3+CD4+CD28- T-cells | Baseline to 6 months | 
| Change in markers of inflammation from baseline to 6 months | Change in markers of inflammation including serum concentrations of pro and anti-inflammatory cytokines (TNF-a, IFN-g, IL-2, IL-6, IL-10, IL-17) and a marker of systemic inflammation (highly sensitive CRP). | Baseline to 6 months | 
| Persistence of valaciclovir effect on proportion of CD4+ CMV-specific T cells at 6 months post treatment (i.e. change from 6 months to 12 months) | Change in proportion of CD3+CD4+CD28- T-cells | 6 months to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CMV, ANCA associated vasculitis, CD4+CD28- T-cells, Valaciclovir