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

This study has been completed.
Sponsor:
Information provided by:
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
ClinicalTrials.gov Identifier:
NCT00518154
First received: August 17, 2007
Last updated: April 16, 2009
Last verified: April 2009
  Purpose

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.


Condition Intervention Phase
HIV Infections
Drug: Pyridostigmine tablets
Phase 2

Study Type: Interventional
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.

Resource links provided by NLM:


Further study details as provided by Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran:

Primary Outcome Measures:
  • CD4+ cell count change between basal and week 12 of additive treatment [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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 ]

Enrollment: 7
Study Start Date: September 2007
Study Completion Date: January 2009
Primary Completion Date: November 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Mestinon

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 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00518154

Locations
Mexico
Departments of Immunology, and Infectious Diseases, INNSZ
Mexico City, DF, Mexico, 14000
Sponsors and Collaborators
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Investigators
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
  More Information

Additional Information:
No publications provided

Responsible Party: Juan Sierra-Madero, MD, Instituto nacional de Ciencias Médicas y Nutrición Salvador Zubirán
ClinicalTrials.gov Identifier: NCT00518154     History of Changes
Other Study ID Numbers: Ref. 1663
Study First Received: August 17, 2007
Last Updated: April 16, 2009
Health Authority: Mexico: Ethics Committee
Mexico: Ministry of Health
Mexico: National Council of Science and Technology

Keywords provided by Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran:
AIDS
Immunological non-responders
Neuroimmune modulation
Pyridostigmine
Treatment Experienced

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Pyridostigmine Bromide
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 30, 2014