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Pilot Study of Pyridostigmine Upon Immune Activation in HIV-1 Patients Who Have an Inadequate Immune Response

This study has been completed.
Sponsor:
Information provided by:
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
ClinicalTrials.gov Identifier:
NCT00518154
First received: August 17, 2007
Last updated: April 16, 2009
Last verified: April 2009

August 17, 2007
April 16, 2009
September 2007
November 2008   (final data collection date for primary outcome measure)
CD4+ cell count change between basal and week 12 of additive treatment [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
CD4+ cell count change between basal and week 12 of additive treatment [ Time Frame: 12 weeks ]
Complete list of historical versions of study NCT00518154 on ClinicalTrials.gov Archive Site
  • Percentage of T-reg cells [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • Activation of CD4+ cells [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • Proliferation of CD4+ cells [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
- Percentage of T-reg cells - Activation of CD4+ cells - Proliferation of CD4+ cells [ Time Frame: 12 weeks ]
Not Provided
Not Provided
 
Pilot Study of Pyridostigmine Upon Immune Activation in HIV-1 Patients Who Have an Inadequate Immune Response
Pilot Study of an ACh-E Inhibitor Upon Immune Activation Markers in HIV-1 Infected Patients Receiving Highly Active Antiretroviral Therapy (HAART) Showing an Incomplete Immune Response.

The purpose of this study is to determine whether the addition of Pyridostigmine to Highly Active Antiretroviral Therapy (HAART) increases the number of CD4+ T-cells in discordant patients in which viral load diminishes, but T-cell levels remain low after the initiation of treatment.

In HIV-1 infected patients, HAART suppresses viral replication, reflected by a reduced viral load, and a recovery in the frequency of CD4+ T-cells. The latter is associated to a reduced risk for developing opportunistic infectious diseases, and death. T-cell recovery, however, is highly variable within individuals, suggesting that virological eradication is but one factor of it.

A phenomenon known as Immune Discordance has been well known. It reflects a subpopulation -as high as 30% of patients- in whom there is an adequate suppression of viral replication, but CD4+ cell levels rise modestly (below safety levels). In this setting, patients remain susceptible to develop opportunistic infections, have disease progression, and die. Various mechanisms have been proposed, but one common factor is enhanced CD4+-cell activation, leading to cell dysfunction and apoptosis.

It is known that an inflammatory response is able to activate the antiinflammatory cholinergic pathway, in which acetylcholine (ACh) is released and in turn activates nicotinic receptors in macrophages. The result is a diminished synthesis of inflammatory cytokines such as TNF-α, and IL-1. We have recently shown in an ex-vivo, proof-of-concept study carried in HIV-infected subjects in early phases of the infection (not requiring specific treatment) that Pyridostigmine diminishes CD4+-cell activation, and an increase in the subpopulation of regulatory T-cells (T-reg).

Pyridostigmine, an ACh-esterase inhibitor, has been shown to be safe in other populations, including healthy Gulf War troopers, and patients with Myasthenia Gravis. Its hypothetical effect is by reducing the degrading rate of the naturally occurring ACh (released by the vagus nerve) by the enzyme ACh-esterase. This in turn enhances its coupling to nicotinic receptors in macrophages that, according to our previous study (unpublished data), improves the T-cell milieu, diminishes T-cell activation (a well known trigger for apoptosis), and enhances T-reg proliferation.

The purpose of this study is to determine whether the addition of Pyridostigmine to Highly Active Antiretroviral Therapy (HAART) increases the number of CD4+ T-cells in discordant patients in which viral load diminishes, but T-cell levels remain low after the initiation of treatment.

Interventional
Phase 2
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
HIV Infections
Drug: Pyridostigmine tablets
Patients will take 30mg tid PO for 12 weeks
Other Name: Mestinon
Experimental: A
Patients will be taking oral Pyridostigmine 30mg tid, as well as their usual antiretroviral treatment
Intervention: Drug: Pyridostigmine tablets
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
7
January 2009
November 2008   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • HIV-1 infected subjects 18 years of age or older
  • Receiving HAART for at least two years
  • At least a viral load determination per year since HAART initiation, all undetectable
  • Patient's status is Immunological Non Responder (InR), that is, his or her viral load is reduced, but CD4+ cell count has not raised accordingly
  • Current viral load: undetectable
  • Patient agrees and signs informed consent

Exclusion Criteria:

  • Concomitant active infectious or neoplastic disease
  • History of new AIDS-defining events during HAART
  • Pregnancy or breast-feeding
  • Patients who have been subjects of an investigational agent, chemotherapy or radiotherapy within the previous 28 days
  • Subjects requiring treatment for Tuberculosis
  • Subjects unable to follow, or comply with the protocol interventions
  • Subjects receiving immunosuppressive treatment, including corticosteroids
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
Mexico
 
NCT00518154
Ref. 1663
No
Juan Sierra-Madero, MD, Instituto nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Not Provided
Study Chair: Juan Sierra-Madero, MD Dept. of Infectious Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Study Director: Jorge Alcocer-Varela, MD Dept. of Immunology, INNSZ
Principal Investigator: Sergio I Valdés-Ferrer, MD Dept. of Neurology, INNSZ
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
April 2009

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP