MMF for HIV Reservoir Reduction

Study Overview
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Brief Summary
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This is an open label, randomized Phase II study to determine whether Mycophenolate mofetil (MMF) given over 22 months meaningfully decreases the size of participants' HIV reservoir. In addition to primary safety endpoints, the following hypotheses regarding drug efficacy will be tested: MMF will be well tolerated and will not decrease adherence to or antiviral efficacy of ART. Peripheral CD4+ T-cell counts and percentages will not meaningfully decrease during treatment with MMF and ART. There will be no excess risk of opportunistic infections in MMF-treated study participants. MMF therapy will lead to a progressive decrease in reservoir size over 22 months of treatment. MMF therapy will lead to a continual shift in HIV reservoir composition from primarily effector memory CD4+ T cells (TEM) and central memory CD4+ T cells (TCM), to primarily stem cell like memory (TSCM) and naïve (TN) CD4+ T cells. MMF will eliminate detectable measures of the HIV reservoir, including by cell-associated DNA/mRNA and quantitative viral outgrowth. MMF will not decrease the humoral immune response to routine annual influenza vaccination.

Detailed Description
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This is an open-label, randomized pilot trial to determine whether MMF given over 22 months meaningfully decreases the size of the HIV reservoir. At the University of Washington in Seattle, investigators will enroll 5 study participants who have been on ≥2 years of suppressive ART. Study participants will be followed closely for at least 22 months with safety labs and serial measurements of the HIV reservoir (specifically, cell-associated HIV DNA and mRNA (ca-DNA & ca-RNA), quantitative viral outgrowth assay (QVOA), and single copy plasma viral load (scVL)). A go/no-go decision will occur after 12 months based on pre-defined thresholds of reduction in the HIV reservoir measured with ca-DNA. All participants will be offered enrollment in a sub-study in which an anoscopy with rectum biopsies is performed on 3 occasions to assess the reservoir in the gastrointestinal lymphatic tissue (GALT). Investigators will vaccinate study participants with the annual influenza vaccine and analyze their humoral response to this vaccine approximately one month later with a routine blood draw done in conjunction with a safety labs blood draw. Investigators hypothesize that low doses of MMF will be well tolerated among healthy HIV-infected study participants who have fully ART-suppressed HIV. Investigators hypothesize that the incidence of opportunistic infections will not exceed that of comparable larger cohorts of HIV-treated patients. Of note, certain opportunistic infections such as herpes zoster or HSV-2 recurrence continue to occur despite suppressive ART, while pneumocystis pneumonia, CMV end organ disease, cryptococcus and many other opportunistic infections are much less common in this context. Therefore, in the event of an infection, Investigators will confer with the data safety management (DSM) panel to discuss whether this event is directly attributable to MMF. Finally, investigators hypothesize that peripheral blood CD4+ and CD8+ T cell counts will remain unchanged throughout MMF therapy, and that HIV replication will remain controlled on ART with addition of MMF. Investigators hypothesize at least a 0.25-log reduction in cell-associated HIV DNA at one-year intervals in study participants who have a demonstrated anti-proliferative response to MMF treatment. Investigators hypothesize that cell-associated HIV DNA will undergo a shift from predominant residence in TCM and TEM to predominant residence in TN and TSCM. In regards to our sub-study, investigators predict that reservoir depletion will occur with equivalent rates in blood and GALT.

Official Title
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Mycophenolate Mofetil Therapy for Reduction of the HIV Reservoir

Conditions
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Human Immunodeficiency Virus I Infection

Intervention / Treatment
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* Drug: Mycophenolate Mofetil 500Mg Tab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed HIV infection, by two different positive antibody tests and/or detectable plasma HIV RNA on two different dates ≥18 and ≤65 years of age Continuous ART during the last two years, with current ART preferably including an integrase inhibitor HIV RNA <40 copies / mL on four occasions during continuous ART of ≥ 2 years with no more than one blip of <1000 HIV RNA copies / mL CD4+ T cell count > 350/mm3 within the past 365 days Karnofsky score ≥80 Plan to reside in area 2 years Consents to study Tolerability of MMF during one week dose escalation lead-in phase of 500 mg once daily Demonstrated anti-proliferative effect of MMF 500 mg twice daily Exclusion Criteria: Active malignancy including skin cancer, myelodysplastic syndrome, or myeloproliferative disease within 24 weeks prior to study entry Prior organ or bone marrow transplantation Diagnosed autoimmune disease Medical need for ongoing treatment with an immunosuppressive drug Diagnosis of AIDS (defined as any AIDS-defining opportunistic infection or cancer, or a history of blood CD4+ T cell count < 200/µL) Active opportunistic infection Using disallowed medications (see 4.3) Vomiting or diarrhea which prohibits consistent use of study drugs Pregnant, intention to become pregnant, or breastfeeding Woman of child bearing age who are NOT using two forms of birth control OR practicing complete abstinence Excessive ingestion of ethanol, determined by an AUDIT score of >8 Substance abuse History of medical non-compliance Quantiferon TB positive The following laboratory values (< 30 days before enrollment): Hemoglobin < 8.5 mg/dL Absolute neutrophil count < 1000 cells/mm3 ALT > 2 x upper limit of normal Platelet count < 100,000/uL Creatinine clearance < 60 mL/min

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Intervention Model: Single Group Assignment
Interventional Model Description: This is an open-label, randomized pilot trial to determine whether MMF given over 22 months meaningfully decreases the size of the HIV reservoir. Study participants will be followed closely for at least 22 months with safety labs and serial measurements of the HIV reservoir (specifically, cell-associated HIV DNA and mRNA (ca-DNA & ca-RNA), quantitative viral outgrowth assay (QVOA), and single copy plasma viral load (scVL)). Go/no-go decision will occur after 12 months based on pre-defined thresholds of reduction in the HIV reservoir measured with ca-DNA.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mycophenolate mofetil<br>Mycophenolate Mofetil 500mg Tablets once per day for one week as a lead in to limit drug-related side effects. Provided they are tolerating the drug at lower dose, they will then initiate Mycophenolate Mofetil 500mg Tablets twice daily orally for 22 months | Drug: Mycophenolate Mofetil 500Mg Tab<br>* 500 mg once daily for one week. If tolerating the drug, then initiate twice daily for 22 months<br>* Other names: Mycophenolate Mofetil Tablets USP Roxane Laboratories;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cell-associated HIV DNA (Ca-DNA) Levels Per 10^6 T Cells Over 12 Months | Regression slope of change in cell-associated HIV DNA (ca-DNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 4 time points between 0 & 12 months | 12 months | 
| Change in Cell-associated HIV DNA (Ca-DNA) Levels Per 10^6 Effector Memory CD4+ T Cells Over 12 Months | Regression slope of change in cell-associated HIV DNA (ca-DNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 3 time points between 0 & 12 months | 12 months | 
| Change in Cell-associated Intact HIV DNA (Ca-iDNA) Levels Per 10^6 T Cells Over 12 Months | Regression slope of change in cell-associated intact HIV DNA (ca-iDNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 4 time points between 0 & 12 months | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood CD4+ T Cells Per mm^3 Blood | Frequency of participants with any time point with <200 CD4+ T cells per mm^3 from 4 sampled time points between 0 & 12 months | 12 months | 
| Incidence of Opportunistic Infection | Number of participants experiencing opportunistic infection | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Antiretroviral treatment, Mycophenolate mofetil, Cure, Latency, Reservoir, CD4 T cell, Anti-proliferation