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

NCT ID: NCT00518154

Last Updated: 2019-11-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 7 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-09-30
• Study Completion Date: 2009-01-31

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.

Conditions

HIV Infections

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

A

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

Group Type: EXPERIMENTAL

Pyridostigmine tablets

Intervention Type: DRUG

Patients will take 30mg tid PO for 12 weeks

Interventions

Pyridostigmine tablets

Patients will take 30mg tid PO for 12 weeks

Intervention Type: DRUG

Other Intervention Names

Mestinon

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

OTHER

Sponsor Role: lead

Responsible Party

Sergio I. Valdés-Ferrer, MD, PhD

Investigator, Depatment of Infectious Diseases

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Juan Sierra-Madero, MD

Role: STUDY_CHAIR

Dept. of Infectious Diseases, INNSZ

Jorge Alcocer-Varela, MD

Role: STUDY_DIRECTOR

Dept. of Immunology, INNSZ

Sergio I Valdés-Ferrer, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Dept. of Neurology, INNSZ

Locations

Sergio I. Valdés-Ferrer

Mexico City, Mexico City, Mexico

Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

Tlalpan, Mexico City, Mexico

Countries

Mexico

References

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.

Reference Type: DERIVED

PMID: 29093707 (View on PubMed)

Related Links

http://www.innsz.mx

Institute's web page

Other Identifiers

Ref. 1663

Identifier Type: -

Identifier Source: org_study_id