Pyridostigmine as Immunomodulator in People Living With HIV

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Brief Title

Pyridostigmine as Immunomodulator in People Living With HIV

Official Title

Study of the Role of Peripheral Acetylcholinesterase Inhibitor Pyridostigmine as Immunomodulators in a Population of Patients Living With Human Immunodeficiency Virus Infection.

Brief Summary

      Human immunodeficiency virus (HIV) infection is characterized by persistent immune activation
      and a constant turnover of T cells. This leads to a precipitous fall in the number of T
      cells, as well as to an early immunosenescence. This results in increased susceptibility to
      opportunistic infections. In these patients, modulation of the immune response represents a
      promising mechanism to maintain immunological homeostasis and prevent the development of
      pathology. We hypothesize that the addition of pyridostigmine to the regular combined
      antiretroviral therapy will result in a decrease in T cell overactivation and a reduction in
      circulating inflammatory markers.
    

Detailed Description

      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 a constant turnover of T
      cells. This leads to a precipitous fall in the number of CD4+ and CD8+ T cells, as well as to
      early immunosenescence. This immunosenescence results in increased 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 posible that a reduced immune activation -rather than accelerating the progression of
      infection- may be an important factor in controlling infection and delaying the progression
      from chronic infection to acquired immunodeficiency syndrome (AIDS).

      The administration of combined antiretroviral therapy (cART) 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 countries 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. The
      nervous system has evolutionary mechanisms of reflex control of the inflammatory response,
      such as cholinergic anti-inflammatory pathway. 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)-γ 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 virologic 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; Valdés-Ferrer
      SI, et al., Frontiers in Immunology, 2017). 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 (180mg,
      once per day, P.O.) 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
      additional 12 weeks (placebo-to-pyridostigmine, and pyridostigmine-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 can be easily
      extrapolated to clinical practice, as there is enough long-term evidence of utility and
      safety of the drug.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

CD4+ T cell count

Secondary Outcome

 soluble CD14 receptor

Condition

HIV-1-infection

Intervention

Pyridostigmine Bromide

Study Arms / Comparison Groups

 Pyridostigmine
Description:  Pyridostigmine 180mg/d slow-release formulation

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

60

Start Date

July 1, 2019

Completion Date

June 30, 2022

Primary Completion Date

June 30, 2021

Eligibility Criteria

        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 a participant is female, pregnancy or breast-feeding

          4. Exposure to an investigational agent, chemotherapy or radiotherapy within the previous
             28 days

          5. Currently taking or planning to take treatment for Tuberculosis

          6. Being unable to follow or comply with the protocol interventions

          7. The participant is receiving immunosuppressive treatment, including corticosteroids
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Juan Sierra-Madero, MD, , 

Location Countries

Mexico

Location Countries

Mexico

Administrative Informations


NCT ID

NCT03312244

Organization ID

Ref. 1873


Responsible Party

Principal Investigator

Study Sponsor

Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran


Study Sponsor

Juan Sierra-Madero, MD, Study Director, INNSZ


Verification Date

April 2020