Pyridostigmine as Immunomodulator in People Living With HIV

HIV-1-infection Clinical Trial

Official title:

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

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT03312244
• Other study ID #: Ref. 1873
• Status: Suspended
• Phase: Phase 2
• Start date: July 1, 2019
• Est. completion date: June 30, 2022

Study information

• Verified date: April 2020
• Source: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 60
• Est. completion date: June 30, 2022
• Est. primary completion date: June 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• CD4+ T Lymphocytopenia
• HIV-1-infection
• Immune Deficiency
• Immuno-senescence
• Immunologic Deficiency Syndromes
• Infection
• Lymphopenia

Intervention

Drug:
• Pyridostigmine Bromide
Pyridostigmine 180mg/day p.o.
• Placebo
Placebo

Locations

Country	Name	City	State
Mexico	Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán	Ciudad de México	Tlalpan

Sponsors (1)

Lead Sponsor	Collaborator
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Country where clinical trial is conducted

Mexico, 

References & Publications (12)

Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, Katlama C, Debré P, Leibowitch J. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science. 1997 Jul 4;277(5322):112-6. — View Citation

Corbeau P, Reynes J. Immune reconstitution under antiretroviral therapy: the new challenge in HIV-1 infection. Blood. 2011 May 26;117(21):5582-90. doi: 10.1182/blood-2010-12-322453. Epub 2011 Mar 14. Review. — View Citation

Kaufmann GR, Perrin L, Pantaleo G, Opravil M, Furrer H, Telenti A, Hirschel B, Ledergerber B, Vernazza P, Bernasconi E, Rickenbach M, Egger M, Battegay M; Swiss HIV Cohort Study Group. CD4 T-lymphocyte recovery in individuals with advanced HIV-1 infection — View Citation

Kawashima K, Fujii T. The lymphocytic cholinergic system and its biological function. Life Sci. 2003 Mar 28;72(18-19):2101-9. Review. — View Citation

Ku NS, Song YG, Han SH, Kim SB, Kim HW, Jeong SJ, Kim CO, Kim JM, Choi JY. Short communication: factors influencing time to CD4(+) T cell counts >200 cells/mm(3) in HIV-infected individuals with CD4(+) T cell <50 cells/mm(3) at the time of starting combin — View Citation

Moore DM, Hogg RS, Yip B, Wood E, Tyndall M, Braitstein P, Montaner JS. Discordant immunologic and virologic responses to highly active antiretroviral therapy are associated with increased mortality and poor adherence to therapy. J Acquir Immune Defic Syn — View Citation

Pakker NG, Notermans DW, de Boer RJ, Roos MT, de Wolf F, Hill A, Leonard JM, Danner SA, Miedema F, Schellekens PT. Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and prolife — View Citation

Piconi S, Trabattoni D, Gori A, Parisotto S, Magni C, Meraviglia P, Bandera A, Capetti A, Rizzardini G, Clerici M. Immune activation, apoptosis, and Treg activity are associated with persistently reduced CD4+ T-cell counts during antiretroviral therapy. A — View Citation

Rosas-Ballina M, Olofsson PS, Ochani M, Valdés-Ferrer SI, Levine YA, Reardon C, Tusche MW, Pavlov VA, Andersson U, Chavan S, Mak TW, Tracey KJ. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 2011 Oct 7;334(6052) — View Citation

Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest. 2007 Feb;117(2):289-96. Review. — View Citation

Valdés-Ferrer SI, Crispín JC, Belaunzarán PF, Cantú-Brito CG, Sierra-Madero J, Alcocer-Varela J. Acetylcholine-esterase inhibitor pyridostigmine decreases T cell overactivation in patients infected by HIV. AIDS Res Hum Retroviruses. 2009 Aug;25(8):749-55. — View Citation

Valdés-Ferrer SI, Crispín JC, Belaunzarán-Zamudio PF, Rodríguez-Osorio CA, Cacho-Díaz B, Alcocer-Varela J, Cantú-Brito C, Sierra-Madero J. Add-on Pyridostigmine Enhances CD4(+) T-Cell Recovery in HIV-1-Infected Immunological Non-Responders: A Proof-of-Con — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	CD4+ T cell count	Change in total CD4+ T cel count from baseline	Change from baseline, at 12 and 24 weeks
Secondary	soluble CD14 receptor	Change in circulating (plasma) soluble CD14 receptor from baseline	Change from baseline, at 12 and 24 weeks
Secondary	CD4+ / CD8+	Change in index of CD4+ to CD8+ T cells from baseline	Change from baseline, at 12 and 24 weeks
Secondary	Inteleukin (IL)-6	Change in circulating (plasmatic) IL-6 from baseline	Change from baseline, at 12 and 24 weeks
Secondary	TREC levels	Changes in T cell receptor excision DNA circle (TREC) levels	Change from baseline, at 12 and 24 weeks