Mycophenolate Mofetil in Antiretroviral Naïve Patients 2 (MAN2 Study)

The purpose of the study is to evaluate whether mycophenolate mofetil (MMF) can treat the chronic hyperactivation of the immune system and (partly) prevent the decrease of the CD4+ T-cell count in chronically HIV-1 infected patients who are not treated with antiretroviral therapy (ART). The researchers also want to know what the effect is of treatment with MMF on plasma HIV-1 RNA; progression of disease (occurrence of AIDS defining events or reaching the indication to start ART); and the safety of treatment with MMF in this patient group.

Study Overview

• Status: Unknown
• Conditions: HIV Infection
• Intervention / Treatment: Drug: mycophenol mofetil (MMF, Cellcept®) 500 mg BID

Detailed Description

*Background: During chronic HIV-1 infection the immune system is chronically hyperactivated. This hyperactivation is considered as the main cause of CD4+ T-cell loss. Furthermore, HIV replicates most efficiently in activated CD4+ T-cells. In this study we try to inhibit the activation of the immune system with mycophenolate mofetil (MMF). Previous studies in which HIV-1 infected patients have been treated with MMF in addition to antiretroviral treatment (ART) have not shown any additional effect, compared to ART alone. In this study MMF will be used without antiretroviral medication.

*Objectives: Primary objective of the study is the evaluation of the effect of MMF on the chronic hyperactivation of the immune system and the decrease of the CD4+ T-cell count in chronically HIV-1 infected patients who are not treated with antiretroviral therapy (ART). Secondary objectives include the evaluation of the effect of MMF on plasma HIV-1 RNA; progression of disease/ reaching of indication to start ART; and the safety of treatment with MMF in this patient group.

*Study Design: This is a multi center, randomized, open-label study, in which patients will be randomized to treatment with mycophenolate mofetil (MMF) 500 mg BID during 48 weeks versus no treatment. In a subgroup of 20 patients ("immunology group", the first 20 patients in the AMC hospital, Amsterdam, the Netherlands) a number of additional immunological measurements will be performed.

The study duration is 60 weeks (48 weeks of treatments with 1 additional visit 12 weeks after cessation of treatment).

*Study Population: Potential participants are adult chronically HIV-1 infected patients, who have never been treated with ART and who according to the present criteria do not need to be treated. CD4+ T lymphocyte count has to be > 250 and <= 450 * 106/L, plasma HIV-1 RNA (viral load) < 10.000 copies/ mL.

*Intervention: Patients will be randomized (1:1) to mycofenolate mofetil (MMF) 500 mg BID versus no treatment.

*Endpoints: Primary endpoints are change over time (baseline - week 48) in CD4+ T cell count and peripheral blood lymphocyte (PBMC) activation markers.

Secondary endpoints are changes over time (baseline - week 48) in plasma HIV-1 RNA, time to reach indication to start ART (separated in three groups: 1. two consecutive measurements of CD4+ T cell count below 250 * 106 cells/ L with at least 4 weeks interval; 2. the occurrence of a CDC class B or C event; 3. any other reason); safety data.

• Study Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jan M Prins, MD PhD; Phone Number: +31 20 5669111; Email: j.m.prins@amc.uva.nl

Study Locations

• Netherlands
  • NH
    • Amsterdam, NH, Netherlands, 1091AC
      • Not yet recruiting
      • OLVG
      • Contact: Lucie Schrijnders-Gudde; Phone Number: 4626 +31 20 5999111; Email: L.Schrijnders-Gudde@olvg.nl
      • Principal Investigator: Kees Brinkman, MD PhD
      • Sub-Investigator: H. M. Weigel, MD
      • Sub-Investigator: P. H. Frissen, MD PhD
      • Sub-Investigator: W. E. Schouten, MD PhD
    • Amsterdam, NH, Netherlands, 1105 AZ
      • Recruiting
      • Academic Medical Center
      • Contact: Jan M Prins, MD PhD; Phone Number: +31 20 566 9111; Email: j.m.prins@amc.uva.nl
      • Principal Investigator: Jan M Prins, MD PhD
      • Sub-Investigator: Joost N Vermeulen, MD
    • Haarlem, NH, Netherlands, 2035RC
      • Not yet recruiting
      • Kennemer Gasthuis, location EG
      • Contact: Robin Soetekouw, MD; Phone Number: +31 23 5453545; Email: soetekou@KG.NL
      • Principal Investigator: Robin Soetekouw, MD
  • ZH
    • Rotterdam, ZH, Netherlands, 3015GD
      • Recruiting
      • Erasmus Medical Center
      • Contact: Iman Padmos; Phone Number: +31 (0)10-4635737; Email: i.padmos@erasmusmc.nl
      • Principal Investigator: Ineke van der Ende, MD PhD
    • The Hague, ZH, Netherlands, 2545 CH
      • Not yet recruiting
      • HAGA hospital, location Leyenburg Hospital
      • Contact: Robert H Kauffmann, MD PhD; Phone Number: +31 70-3592007; Email: r.kauffmann@leyenburg-ziekenhuis.nl
      • Contact: Anneke van IJperen; Phone Number: +31 70-3592414; Email: j.maat@leyenburg-ziekenhuis.nl
      • Principal Investigator: Robert H Kauffman, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient is ≥ 18 years of age;
• Patient has a proven HIV-1 infection (with antibodies against HIV-1 and a detectable plasma HIV-1 RNA measured for the first time at least 6 months prior to inclusion);
• Patient is HIV-1 treatment naïve;
• CD4+ T lymphocyte count > 250 and <= 450 * 106/L;
• No signs or history of AIDS defining events;
• No use of other medications that might possibly influence the effects of MMF;
• Male; or female sex and willingness to practice effective contraception during the study.

Exclusion Criteria:

• Plasma HIV-1 RNA < 10.000 copies/ mL;
• Autoimmune disease;
• Active hepatitis B or C virus infection;
• Other chronic diseases;
• Recent infectious disease other than HIV-1;
• Treatment with immunomodulatory or anti-inflammatory medication in the past 6 months;
• For female patients: pregnancy and lactation;
• Any other condition, illness or use of medication which according to the investigator is not compatible with the use of the study medication or which could interfere with the evaluations required by the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Change over time (baseline - week 48) in CD4+ cell counts in peripheral blood and peripheral blood lymphocyte activation markers.

Secondary Outcome Measures

Outcome Measure
* Change over time (baseline - week 48) in plasma HIV-1 RNA, time to reach an indication to start antiretroviral treatment and safety parameters.

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Hoffmann-La Roche; Sanquin Research & Blood Bank Divisions
• Investigators: Principal Investigator: Jan M Prins, MD PhD, Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, University of Amsterdam, the Netherlands; Principal Investigator: Kees Brinkman, MD PhD, department of internal medicine, OLVG hospital, Amsterdam, the Netherlands; Principal Investigator: Robin Soetekouw, MD, department of internal medicine, Kennemer Gasthuis, Haarlem, the Netherlands; Principal Investigator: Robert Kauffmann, MD PhD, Department of Internal Medicine, HAGA hospital, location Leyenburg Hospital, The Hague, The Netherlands

Publications and helpful links

General Publications

• Chapuis AG, Paolo Rizzardi G, D'Agostino C, Attinger A, Knabenhans C, Fleury S, Acha-Orbea H, Pantaleo G. Effects of mycophenolic acid on human immunodeficiency virus infection in vitro and in vivo. Nat Med. 2000 Jul;6(7):762-8. doi: 10.1038/77489.
• Sankatsing SU, Jurriaans S, van Swieten P, van Leth F, Cornelissen M, Miedema F, Lange JM, Schuitemaker H, Prins JM. Highly active antiretroviral therapy with or without mycophenolate mofetil in treatment-naive HIV-1 patients. AIDS. 2004 Sep 24;18(14):1925-31. doi: 10.1097/00002030-200409240-00008.
• Garcia F, Plana M, Arnedo M, Brunet M, Castro P, Gil C, Vidal E, Millan O, Lopez A, Martorell J, Fumero E, Miro JM, Alcami J, Pumarola T, Gallart T, Gatell JM. Effect of mycophenolate mofetil on immune response and plasma and lymphatic tissue viral load during and after interruption of highly active antiretroviral therapy for patients with chronic HIV infection: a randomized pilot study. J Acquir Immune Defic Syndr. 2004 Jul 1;36(3):823-30. doi: 10.1097/00126334-200407010-00009.

Study record dates

Study Major Dates

• Study Start: April 1, 2005

Study Registration Dates

• First Submitted: July 11, 2005
• First Submitted That Met QC Criteria: July 15, 2005
• First Posted (Estimate): July 18, 2005

Study Record Updates

• Last Update Posted (Estimate): July 22, 2009
• Last Update Submitted That Met QC Criteria: July 21, 2009
• Last Verified: January 1, 2006

More Information

Terms related to this study

• Keywords: Treatment Naive; HIV-1 infection; immunomodulatory therapy
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Mycophenolic Acid
• Other Study ID Numbers: MAN2-study