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

October 24, 2019 updated by: Sergio I. Valdés-Ferrer, MD, PhD, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

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.

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.

Study Overview

Status

Completed

Conditions

Intervention / 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.

Study Type

Interventional

Enrollment (Actual)

7

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Mexico
    • Ciudad De México
      • Tlalpan, Ciudad De México, Mexico, 14080
        • Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
    • DF
      • Mexico City, DF, Mexico, 14080
        • Sergio I. Valdés-Ferrer

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: A
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 Names:
  • Mestinon

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Investigators

  • Study Chair: Juan Sierra-Madero, MD, Dept. of Infectious Diseases, INNSZ
  • Study Director: Jorge Alcocer-Varela, MD, Dept. of Immunology, INNSZ
  • Principal Investigator: Sergio I Valdés-Ferrer, MD, PhD, Dept. of Neurology, INNSZ

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2007

Primary Completion (Actual)

November 1, 2008

Study Completion (Actual)

January 1, 2009

Study Registration Dates

First Submitted

August 17, 2007

First Submitted That Met QC Criteria

August 17, 2007

First Posted (Estimate)

August 20, 2007

Study Record Updates

Last Update Posted (Actual)

November 14, 2019

Last Update Submitted That Met QC Criteria

October 24, 2019

Last Verified

October 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Ref. 1663

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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