Clinical trial NCT00518154: Pilot Study of Pyridostigmine Upon Immune Activation in HIV-1 Patients Who Have an Inadequate Immune Response
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: AIDS
Immunological non-responders
Neuroimmune modulation
Pyridostigmine
Treatment Experienced
Lead sponsor: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Sponsor class: OTHER
First posted: 2007-08-20
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: CD4+ Cell Count Change Between Basal and Week 16 of Additive Treatment
timeFrame: 16 weeks after initiation of pyridostigmine
Secondary outcomes:
Other outcomes:
Locations:
city: Tlalpan
country: Mexico
facility: Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
state: Ciudad De México
city: Mexico City
country: Mexico
facility: Sergio I. Valdés-Ferrer
state: DF
Study officials:
affiliation: Dept. of Infectious Diseases, INNSZ
name: Juan Sierra-Madero, MD
role: STUDY_CHAIR
affiliation: Dept. of Immunology, INNSZ
name: Jorge Alcocer-Varela, MD
role: STUDY_DIRECTOR
affiliation: Dept. of Neurology, INNSZ
name: Sergio I Valdés-Ferrer, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Valdes-Ferrer SI, Crispin JC, Belaunzaran-Zamudio PF, Rodriguez-Osorio CA, Cacho-Diaz B, Alcocer-Varela J, Cantu-Brito C, Sierra-Madero J. Add-on Pyridostigmine Enhances CD4+ T-Cell Recovery in HIV-1-Infected Immunological Non-Responders: A Proof-of-Concept Study. Front Immunol. 2017 Oct 18;8:1301. doi: 10.3389/fimmu.2017.01301. eCollection 2017.