Treatment of Low Dose IL-2 and Ganciclovir in Cytomegalovirus Infection

Study Overview
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Brief Summary
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Cytomegalovirus (CMV) infections is a severe infection in patients of rheumatic disease treated with corticosteroid and immunosuppressive agents. Ganciclovir is the main therapy in CMV infection, accompanied with diverse side effects, including neutropenia, anemia, disorder of renal function and so on, which are also common symptoms of rheumatic diseases. Additionally, prolonged antiviral treatment may delay recovery of virus, specific immune responses, resulting in an increasing of late-onset CMV disease. IL-2 is a pleotropic cytokine which can promote the proliferation and function of CD8+ T cells and NK cells through the combination with IL-2 receptor. Recently, several studies have revealed that low dose IL-2 is an effective and safe therapy for autoimmune disease. In systemic lupus erythematous patients, additionally, patients treated with low-dose IL-2 had lower incidence of infection with increased percentages of natural killer (NK) cells. In this prospective clinical trial, we propose to assess the effective and safety of low-dose IL-2 combined with ganciclovir in the treatment of CMV infection. Meanwhile, we will assess the immune response of after IL-2 treatment.

Detailed Description
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In rheumatic diseases, CMV infection are more frequent in patients after corticosteroid pulse treatment and long-term treatment of corticosteroid and immunosuppressor. If patients are eligible, which CMV-DNA are more than 10^3 copies, it will be randomly distributed in low-dose IL-2 and ganciclovir group, or ganciclovir group. Low-dose IL-2 is defined as 1 million IU per day subcutaneously, The CMV-DNA levels will be monitored until it turned out to be negative. In this period, we will simultaneously monitor the immune response in regard to CMV infection, including innate immune response, such as IFN-γ, TNF-α, natural killer cells, and adaptive immune response, such as CMV specific CD8+ T cells, T helper cells and so on. We will follow these patients for at least 3 months after drug withdrawal. If patient belonging to any of these two groups develops a viral infection, then the patient will receive treatment with ganciclovir.

Official Title
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The Efficiency and Safety of Low Dose IL-2 and Ganciclovir in Treatment of Cytomegalovirus Infection: an Open Label, Prospective and Control Trial

Conditions
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Cytomegalovirus Infections

Intervention / Treatment
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* Drug: Low-dose IL-2 and ganciclovir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Rheumatic disease by the Criteria ; Patients have current CMV infection, CMV-DNA are positive. Apply corticosteroid less than 1.0mg/kg/d. Exclusion Criteria: CMV-DNA is negative. Other infection, such as bacteremia, hepatitis B and C viruses, HIV, syphilis, bacteremia, Epstein-Barr virus and so on. Known allergies, hypersensitivity, or intolerance to IL-2 or its excipients. Severe comorbidities: including 1) Heart failure (≥ grade III NYHA); 2) Renal insufficiency (creatinine clearance ≤30 ml/min); 3) Hepatic insufficiency (serum ALT or AST >3 times the ULN, or total bilirubin >ULN for the central laboratory conducting the test); 4) Other disease including hematopathy, gastrointestinal disease, endocrinopathy, pulmonary, neuropathy. Malignancy. Had uncontrolled psychiatric or emotional disorder. Pregnant or breast-feeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: We distribute the patients with CMV infection into two groups, one group will be treated with low-dose IL-2 and ganciclovir, another group will be only treated with ganciclovir.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment of low-dose IL-2 and ganciclovir<br>If patients are eligible, which CMV-DNA are more than 10^3 copies, it will be randomly distributed in low-dose IL-2 and ganciclovir group and low-dose IL-2 is defined as 1 million IU per day subcutaneously. | Drug: Low-dose IL-2 and ganciclovir<br>* If patients are eligible, which CMV-DNA are more than 10^3 copies, it will be randomly distributed in low-dose IL-2 and ganciclovir group, or ganciclovir group. Low-dose IL-2 is defined as 1 million IU per day subcutaneously.<br>|
| Placebo Comparator: Treatment of ganciclovir<br>If patients are eligible, which CMV-DNA are more than 10^3 copies, it will be randomly distributed in ganciclovir treatment group. | Drug: Low-dose IL-2 and ganciclovir<br>* If patients are eligible, which CMV-DNA are more than 10^3 copies, it will be randomly distributed in low-dose IL-2 and ganciclovir group, or ganciclovir group. Low-dose IL-2 is defined as 1 million IU per day subcutaneously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline of NK cells cytotoxicity after treatment | NK cells cytotoxicity will be detected by flow cytometry | Days 7 after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The total dose for anti-viral drugs. | The total dose of ganciclovir | Day for drug withdrawal. | 
| The change of cytokine after low-dose IL-2 treatment. | Detect by flow cytometry and ELISA. | Day after anti-viral treatment and 3 months. | 
| The change of NK cell subsets. | Detect by flow cytometry. | Day after anti-viral treatment and 3 months. | 
| The change of level of CMV immunoglobulin M (IgM) | Detect by EILSA. | Day for drug withdrawal and 3 months. | 
| The change of level of CMV immunoglobulin G (IgG) | Detect by EILSA. | Day for drug withdrawal and 3 months. | 
| The day for CMV infection patients convert into negative. | CMV-DNA will be detected by PCR | Days when CMV-DNA are less than 10^3 copies. |