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Pyridostigmine as Immunomodulator in People Living With HIV

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ClinicalTrials.gov Identifier: NCT03312244
Recruitment Status : Active, not recruiting
First Posted : October 17, 2017
Last Update Posted : October 17, 2017
Sponsor:
Information provided by (Responsible Party):
Sergio I. Valdes-Ferrer, MD, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

April 1, 2017
October 17, 2017
October 17, 2017
October 1, 2017
June 30, 2019   (Final data collection date for primary outcome measure)
CD4+ T cell count [ Time Frame: Change from baseline, at 12 and 24 weeks ]
Change in total CD4+ T cel count from baseline
Same as current
No Changes Posted
  • soluble CD14 receptor [ Time Frame: Change from baseline, at 12 and 24 weeks ]
    Change in circulating (plasma) soluble CD14 receptor from baseline
  • CD4+ / CD8+ [ Time Frame: Change from baseline, at 12 and 24 weeks ]
    Change in index of CD4+ to CD8+ T cells from baseline
  • Inteleukin (IL)-6 [ Time Frame: Change from baseline, at 12 and 24 weeks ]
    Change in circulating (plasmatic) IL-6 from baseline
  • TREC levels [ Time Frame: Change from baseline, at 12 and 24 weeks ]
    Changes in T cell receptor excision DNA circle (TREC) levels
Same as current
Not Provided
Not Provided
 
Pyridostigmine as Immunomodulator in People Living With HIV
Study of the Role of Peripheral Acetylcholinesterase Inhibitor Pyridostigmine as Immunomodulators in a Population of Patients Living With Human Immunodeficiency Virus Infection.

Human immunodeficiency virus (HIV) infection is a public health problem with enormous personal, and social losses. According to the National Mexican HIV/AIDS survey, more than 235,000 new cases of HIV infection were reported in Mexico between 1983 and 2015.

HIV infection is characterized by persistent immune activation and constant turnover of T cells. This leads to a precipitous fall in the number of CD4 + and CD8 + T cells, as well as to an early immunosenescence phenomenon that conditions susceptibility to opportunistic infections and a profound decrease in circulating and mucosal T cells. In these patients, modulation of the immune response represents a promising mechanism to maintain immunological homeostasis and prevent the development of pathology. From this perspective, it is feasible that lesser immune activation - rather than accelerating the progression of infection - may be an important actor in controlling infection and delaying the progression from chronic infection to acquired immunodeficiency syndrome (AIDS) .

The administration of highly active antiretroviral therapy (ART) has resulted in a reduction in the mortality of these patients, although the occurrence of late morbidity due to both infection and treatment has increased. Unfortunately, even in cluntries with complete coverage for HIV-infection, a large group of patients do not start treatment until late stages, in which immunosenescence is profound and the possibilities of immunological recovery (increase in T cell counts CD4 +, normalization of the CD4 + / CD8 + index, decrease in susceptibility to opportunists, normalization in the cellular response to vaccines) are very low. In this context, finding new immuno-modulatory strategies that are both easily applicable and potentially improving survival and quality of life is crucial.

The therapeutic use of neuroimmune regulators in HIV infection has been poorly explored. In brief, the nervous system has evolutionary mechanisms of reflex control of the inflammatory response, such as cholinergic anti-inflammatory reflex (RCA). Cholinergic stimulation through the use of nicotinic agonists has shown promising effects in murine and cellular models of systemic inflammation. Since cholinergic agonists are rapidly degraded or cause side effects, we performed a pilot study using pyridostigmine (Mestinon®), an acetylcholinesterase inhibitor (ACh-E), in HIV-infected patients. We observed that administration of pyridostigmine decreases the activation and proliferation of HIV-infected T cells, reduces the production of interferon (IFN) -gamma and increases that of interleukin (IL) -10 (Valdés-Ferrer SI et al., AIDS Research And Human Retrovir 2009). In a second open-label pilot study in seven chronically infected patients with full virological suppression but without concomitant elevation of CD4+ T cell counts, we found that the addition of pyridostigmine to ART led to a sustained and significant increase in the number of CD4 + T cells (PRS record: NCT00518154; in preparation for publication). These results suggest that the addition of pyridostigmine to antiretroviral therapy may be beneficial in achieving and maintaining immunological homeostasis in patients with HIV.

The present study will address the potential effectiveness of add-on pyridostigmine (90mg, once per day, per oris) on CD4+ T cell counts, CD4+/CD8+ ratio, as well as ex-vivo markers of T cell phenotype and activity. The study is designed as a 24-week crossover study where patients will start a 12-week of pyridostigmine or placebo, and then crossing-over for an aditional 12 weeks (placebo-to-pyridostigmine, and pyrodistigmine-to-placebo).

Since pyridostigmine is a commonly used drug for both myasthenia gravis and as a preventive in biological warfare cases, if our hypotheses are correct, the results will be easily extended to clinical practice, as there is enough long-term evidence of utility and safety of the drug.

Human immunodeficiency virus (HIV) infection is a public health problem with enormous personal, and social losses. According to the National Mexican HIV/AIDS survey, more than 235,000 new cases of HIV infection were reported in Mexico between 1983 and 2015.

HIV infection is characterized by persistent immune activation and constant turnover of T cells. This leads to a precipitous fall in the number of CD4 + and CD8 + T cells, as well as to an early immunosenescence phenomenon that conditions susceptibility to opportunistic infections and a profound decrease in circulating and mucosal T cells. In these patients, modulation of the immune response represents a promising mechanism to maintain immunological homeostasis and prevent the development of pathology. From this perspective, it is feasible that lesser immune activation - rather than accelerating the progression of infection - may be an important actor in controlling infection and delaying the progression from chronic infection to acquired immunodeficiency syndrome (AIDS) .

The administration of highly active antiretroviral therapy (ART) has resulted in a reduction in the mortality of these patients, although the occurrence of late morbidity due to both infection and treatment has increased. Unfortunately, even in cluntries with complete coverage for HIV-infection, a large group of patients do not start treatment until late stages, in which immunosenescence is profound and the possibilities of immunological recovery (increase in T cell counts CD4 +, normalization of the CD4 + / CD8 + index, decrease in susceptibility to opportunists, normalization in the cellular response to vaccines) are very low. In this context, finding new immuno-modulatory strategies that are both easily applicable and potentially improving survival and quality of life is crucial.

The therapeutic use of neuroimmune regulators in HIV infection has been poorly explored. In brief, the nervous system has evolutionary mechanisms of reflex control of the inflammatory response, such as cholinergic anti-inflammatory reflex (RCA). Cholinergic stimulation through the use of nicotinic agonists has shown promising effects in murine and cellular models of systemic inflammation. Since cholinergic agonists are rapidly degraded or cause side effects, we performed a pilot study using pyridostigmine (Mestinon®), an acetylcholinesterase inhibitor (ACh-E), in HIV-infected patients. We observed that administration of pyridostigmine decreases the activation and proliferation of HIV-infected T cells, reduces the production of interferon (IFN) -gamma and increases that of interleukin (IL) -10 (Valdés-Ferrer SI et al., AIDS Research And Human Retrovir 2009). In a second open-label pilot study in seven chronically infected patients with full virological suppression but without concomitant elevation of CD4+ T cell counts, we found that the addition of pyridostigmine to ART led to a sustained and significant increase in the number of CD4 + T cells (PRS record: NCT00518154; in preparation for publication). These results suggest that the addition of pyridostigmine to antiretroviral therapy may be beneficial in achieving and maintaining immunological homeostasis in patients with HIV.

The present study will address the potential effectiveness of add-on pyridostigmine (90mg, once per day, per oris) on CD4+ T cell counts, CD4+/CD8+ ratio, as well as ex-vivo markers of T cell phenotype and activity. The study is designed as a 24-week crossover study where patients will start a 12-week of pyridostigmine or placebo, and then crossing-over for an aditional 12 weeks (placebo-to-pyridostigmine, and pyrodistigmine-to-placebo).

Since pyridostigmine is a commonly used drug for both myasthenia gravis and as a preventive in biological warfare cases, if our hypotheses are correct, the results will be easily extended to clinical practice, as there is enough long-term evidence of utility and safety of the drug.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
12x12 weeks of pyridostigmine or placebo followed by crossing-over to the other arm of intervention
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
All participants will be blinded. The steering committee will have the authority to open the blinding in case of adverse effects
Primary Purpose: Treatment
  • HIV-1-infection
  • CD4+ T Lymphocytopenia
  • Immune Deficiency
  • Immuno-senescence
  • Drug: Pyridostigmine Bromide
    Pyridostigmine 90mg/day p.o.
  • Drug: Placebo
    Placebo
  • Experimental: Pyridostigmine
    Pyridostigmine 90mg/d
    Intervention: Drug: Pyridostigmine Bromide
  • Placebo Comparator: Placebo
    Placebo
    Intervention: Drug: Placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
60
Same as current
June 30, 2020
June 30, 2019   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  1. HIV-1 infected subjects 18 years of age or older
  2. Receiving stable ART for at least six months
  3. At least two undetectable viral load determinations in the previous six months
  4. Patient agrees to participate and signs informed consent

Exclusion Criteria:

  1. Concomitant active infectious or neoplastic disease
  2. History of new AIDS-defining events in the previous six months
  3. If particiant is female, pregnancy or breast-feeding
  4. Expossure to an investigational agent, chemotherapy or radiotherapy within the previous 28 days
  5. Currently taking or planing to take treatment for Tuberculosis
  6. Being unable to follow or comply with the protocol interventions
  7. Participant is receiving immunosuppressive treatment, including corticosteroids
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
Mexico
 
 
NCT03312244
Ref. 1873
Yes
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Plan to Share IPD: Yes
Plan Description: All data will be freely available to all research parties involved
Sergio I. Valdes-Ferrer, MD, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Not Provided
Not Provided
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
October 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP