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

Study Overview
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Brief Summary
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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.

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 This in turn enhances its coupling to nicotinic receptors in macrophages that, according to our previous study (unpublished data), improves the T-cell milieu, diminishes T-cell activation (a well known trigger for apoptosis), and enhances T-reg proliferation.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

Official Title
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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.

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Pyridostigmine tablets


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>Patients will be taking oral Pyridostigmine 30mg tid, as well as their usual antiretroviral treatment | Drug: Pyridostigmine tablets<br>* Patients will take 30mg tid PO for 12 weeks<br>* Other names: Mestinon;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD4+ Cell Count Change Between Basal and Week 16 of Additive Treatment | Change in total CD4+ T-cell number from baseline to addition of pyridostigmine | 16 weeks after initiation of pyridostigmine | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AIDS, Immunological non-responders, Neuroimmune modulation, Pyridostigmine, Treatment Experienced