Pilot Study of Pyridostigmine Upon Immune Activation in HIV-1 Patients Who Have an Inadequate Immune Response
Pilot Study of Pyridostigmine Upon Immune Activation in HIV-1 Patients Who Have an Inadequate 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 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 to nicotinic receptors in macrophages that, according to our previous study (unpublished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.
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