Pilot Study of Pyridostigmine Upon Immune Activation in HIV-1 Patients Who Have an Inadequate Immune Response
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
|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.|
- CD4+ cell count change between basal and week 12 of additive treatment [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
- 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 ]
|Study Start Date:||September 2007|
|Study Completion Date:||January 2009|
|Primary Completion Date:||November 2008 (Final data collection date for primary outcome measure)|
Patients will be taking oral Pyridostigmine 30mg tid, as well as their usual antiretroviral treatment
Drug: Pyridostigmine tablets
Patients will take 30mg tid PO for 12 weeks
Other Name: Mestinon
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00518154
|Departments of Immunology, and Infectious Diseases, INNSZ|
|Mexico City, DF, Mexico, 14000|
|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|