Please select the eligibility criteria that correspond to the clinical trial below.
Title: 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
Brief Summary: 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.


Options:
A: Inclusion Criteria:

* Diagnosis of Wegener's granulomatosis or microscopic polyangiitis, using criteria adapted by EUVAS from the disease definitions of the Chapel Hill consensus conference
* Biopsy proven, pauci-immune, necrotising and/or crescentic glomerulonephritis, in the absence of other defined glomerulopathy
* Severe renal impairment defined by: (i) oliguria (\<400ml/24hr), or (ii) intention to commence dialysis within 48 hours of admission, and (iii) creatinine \>500umol/l (5.8mg/dl).

Exclusion Criteria:

* Age under 18 or over 80 years
* Inadequate contraception in women of child-bearing age
* Pregnancy
* Previous malignancy
* Hepatitis B antigenaemia, anti-hepatitis C virus or anti-human immunodeficiency virus antibody
* Diagnosis of Churg-Strauss syndrome, Henoch-Schönlein purpura, rheumatoid vasculitis, mixed essential cryoglobulinaemia or systemic lupus erythematosus
* Circulating anti-GBM antibodies or linear IgG staining of the GBM on renal biopsy
* Life-threatening non-renal manifestations of vasculitis, including alveolar hemorrhage requiring mechanical ventilation within 24 hours of admission
* On dialysis for \> two weeks prior to entry
* Creatinine \> 200umol/l (2.3mg/dl) one year or more before entry
* A second clearly defined cause of renal failure
* Previous episode of biopsy-proven necrotising and/or crescentic glomerulonephritis
* \> two weeks treatment with cyclophosphamide or azathioprine
* \> 500mg IV methyl prednisolone
* Plasma exchange within the preceding year
* \> three months treatment with oral prednisolone
* Allergy to study medications.
B: Inclusion Criteria:

* Wegener's granulomatosis Or microscopic polyangiitis complying Or kidney-limited disease With or without detectable ANCA (anti-neutrophil cytoplasmic antibodies) at the time of diagnosis or relapse, and at remission.
* Who have achieved remission using a treatment combining corticosteroids and an immunosuppressive agent according to current French guideline, including corticosteroids, cyclophosphamide IV or oral (the use of another immunosuppressant is allowed, according to the current French guidelines, as well as plasma exchanges and/or IV immunoglobulins).
* Interval of 1 month between the end of the immunosuppressant treatment and the randomization time
* Age \> 18 years and \< 75 years when the diagnosis is confirmed.
* Informed and having signed the consent form to take part in the study.

Exclusion Criteria:

* Other systemic vasculitis
* Secondary vasculitis (following neoplastic disease or an infection in particular)·
* Induction treatment with a regimen not corresponding to that recommended in France.
* Patient who has not achieved remission.·
* Patient who has already received a treatment by biological agents (monoclonal antibody - antiCD20 or antiTNFα).
* Incapacity or refusal to understand or sign the informed consent form.
* Incapacity or refusal to adhere to treatment or perform the follow-up examinations required by the study. Non-compliance·
* Allergy, documented hypersensitivity or contraindication to the study medication (cyclophosphamide, corticosteroids, azathioprine, rituximab),
* History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies.
* Patients receiving allopurinol cannot be included if the allopurinol must absolutely be maintained.
* Pregnancy, breastfeeding. Women of childbearing age must use a reliable method of contraception throughout the duration of immunosuppressive treatment up to 1 year after the last infusion of rituximab
* Infection by HIV, HCV or HBV
* Progressive, uncontrolled infection requiring a prolonged treatment (tuberculosis, HIV infection, etc.).
* Severe infection declared during the 3 months before randomization (CMV, HBV, HHV8, HCV, HIV, tuberculosis).
* Progressive cancer or malignant blood disease diagnosed during the 5 years before the diagnosis of vasculitis. Patients suffering from non-metastatic prostate cancer or those cured of a cancer or a malignant blood disorder for more than 5 years and not taking any antineoplastic agents for more than 5 years may be included.
* patients presenting a systemic disease receiving protocolized treatments (azathioprine, rituximab) which could have unexpected and inappropriate side effects.
* Participation in another clinical research protocol during the 4 weeks before inclusion.
* Any medical or psychiatric disorder which, in the investigator's opinion, may prevent the administration of treatment and patient follow-up according to the protocol, and/or which may expose the patient to a too greater risk of an adverse effect.
* No social security
* Churg and Strauss syndrome
* viral, bacterial or fungic or mycobacterial infection uncontrolled in the 4 weeks before the inclusion
* history of deep tissue infection (fasciitis, osteomyelitis, septic arthritis)in the first year before the inclusion
* History of chronic and severe or recurrent infection or history of preexisting disease predisposing to severe infection
* Severe immunodepression
* Administration of live vaccine in the four weeks before inclusion
* severe chronic obstructive pulmonary diseases (VEMS \< 50 % or dyspnea grade III)
* chronic heart failure stade III and IV (NYHA)
* History of recent acute coronary syndrome
C: Key Inclusion Criteria:

* Clinical diagnosis Wegener's granulomatosis or microscopic polyangiitis by Chapel Hill criteria.
* Disease flare in the past 26 weeks requiring treatment with high dose corticosteroids and 1 of the following medications: rituximab, oral cyclophosphamide OR IV cyclophosphamide.
* Tested positive for anti-proteinase 3 (anti-PR3) or anti-myeloperoxidase (anti-MPO) antibodies at any time prior to enrollment.
* Achieve remission no more than 26 weeks after first dose of induction treatment. Remission is defined as a Birmingham Vasculitis Activity (BVAS) score of 0 and receiving less than 10 mg/day of oral prednisone (or equivalent) on 2 consecutive visits 21 to 35 days apart.
* Maintenance therapy on this study must start no more than 2 weeks after confirmation of remission.

Key Exclusion Criteria:

* Pregnant or nursing.
* Receipt of a B cell targeted therapy (other than rituximab) at anytime
* Receipt of an investigational biological agent within the past 60 days.
* Required management of acute or chronic infections within the past 60 days.
* Current drug or alcohol abuse or dependence.
* Current or past positive test for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.
* History of severe allergic reaction to contrast agents or biological medicines.
D: 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.

Answer: D