Official Title: “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.

Study Type: Interventional

Study Design: Treatment, Open Label, Uncontrolled, Single Group Assignment, Efficacy Study

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 This in turn enhances its coupling to nicotinic receptors in macrophages that, according to our previous study (unpublished data), improves the T-cell milieu, diminishes T-cell activation (a well known trigger for apoptosis), and enhances T-reg proliferation.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.

Intervention(s) in this Clinical Trial

• Drug: Pyridostigmine tablets
  • Patients will take 30mg tid PO for 12 weeks

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: A
  • Patients will be taking oral Pyridostigmine 30mg tid, as well as their usual antiretroviral treatment

Primary Measures

• CD4+ cell count change between basal and week 12 of additive treatment
  • Time Frame: 12 weeks
    

Secondary Measures

• - Percentage of T-reg cells - Activation of CD4+ cells - Proliferation of CD4+ cells
  • Time Frame: 12 weeks
    

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
• 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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Overall Clinical Trial Officials and Contacts

Juan Sierra-Madero, MD Study Chair Dept. of Infectious Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán  

Overall Contact: Sergio I Valdés-Ferrer, MD +52-55-5487-0900 sivaldes@quetzal.innsz.mx

Information obtained from ClinicalTrials.gov on January 08, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00518154

Study ID Number: Ref. 1663

ClinicalTrials.gov Identifier: NCT00518154

Health Authority: Mexico: Ethics Committee

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