Autonomic Neuropathy, GI Motility, and Inflammation in HIV

Early Phase 1

Completed

Conditions: HIV Disease

Interventions: Drug: Pyridostigmine

Registration Number: NCT02850276

Lead Sponsor: Icahn School of Medicine at Mount Sinai

Brief Summary: The purpose of this study is to explore a possible link between the autonomic nervous system and immune function in patients with HIV. Sometimes HIV can cause these nerves to function abnormally, this is called HIV-associated autonomic neuropathy (HIV-AN). HIV-AN is a condition that is different from person to person. In some people it causes no symptoms and is not harmful, in others it may cause symptoms such as dizziness or lightheadedness, nausea, vomiting, diarrhea, constipation, or problems urinating. Most people with HIV-AN don't know that they have it. One of the important nerves in the autonomic nervous system is the vagus nerve. Abnormal function of the vagus nerve may cause stomach and intestinal slowing, which could lead to an overgrowth of bacteria. The body senses these bacteria and tries to fight them, leading to inflammation.

In this study the researchers will test whether abnormal function of the vagus nerve in HIV is associated with stomach slowing and overgrowth of bacteria, and if a drug called pyridostigmine can help.

Detailed Description: HIV-infected patients commonly develop autonomic neuropathy (HIV-AN), which is a heterogeneous disorder characterized by varying degrees of both sympathetic and vagal dysfunction. We hypothesize that the vagal component of HIV-AN contributes to chronic inflammation, both directly via loss of cholinergic activity, and indirectly via effects on the GI tract, and that these effects will be treatable using the acetylcholinesterase inhibitor pyridostigmine. The autonomic nervous system controls the inflammatory response to lipopolysaccharide (LPS) via the cholinergic anti-inflammatory pathway. This pathway is mediated by the vagus nerve, and is therefore likely impaired in HIV-AN with vagal dysfunction. Vagal dysfunction also causes slowed GI transit, which could exacerbate LPS-driven inflammation by promoting bacterial overgrowth. However, the anti-inflammatory impact of cholinergic pathways is almost completely unstudied in HIV, despite the known importance of inflammation in HIV disease progression. Therefore, in this exploratory pilot, we seek to establish associations between vagal dysfunction, GI motility and inflammation in virally suppressed, CART-treated individuals with HIV-AN.

Specific Aim 1: To determine whether vagal dysfunction is associated with immune activation in CART-treated participants with HIV-AN, and if so to estimate the extent to which this association is mediated by GI effects (i.e. slowed motility, bacterial overgrowth, microbial translocation) versus direct effects of vagal dysfunction.

Specific Aim 2: In a subset of participants who have both vagal and GI dysfunction, to investigate whether 8 weeks of pyridostigmine: a) reduces immune activation, and b) improves GI motility; and if the immune effect depends on the GI effect.

To achieve these aims, participants with HIV-AN and GI symptoms will be assessed for: vagal dysfunction (heart rate variability); GI dysmotility (gastric emptying scintigraphy); small intestinal bacterial overgrowth (breath testing); microbial translocation (LPS and sCD14); and immune activation (IL-6 and CRP). Participants meeting threshold criteria for both vagal and GI dysfunction will then be treated with pyridostigmine for 8 weeks, after which GI and immune measures will be reassessed.

Objectives Specific Aim 1: To determine whether vagal dysfunction is associated with immune activation in HIV-infected participants treated with combination antiretroviral therapy (CART), and if so to estimate the extent to which this association is mediated by GI effects (i.e. slowed motility, bacterial overgrowth, microbial translocation) versus direct effects of vagal dysfunction.

Specific Aim 2: In a subset of participants who have both vagal and GI dysfunction, to investigate whether 8 weeks of pyridostigmine: a) reduces immune activation, and b) improves GI motility; and if both effects are present to determine whether the immune effect depends on the GI effect.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 76

Inclusion Criteria

≥18 years old
Documented evidence of HIV-1 infection
Stable CART therapy for ≥3 months Most recent HIV-1 viral load ≤100 copies/ml (value must be within the past six months)
English speaking
Able to tolerate autonomic testing (e.g. able to stand, able to perform Valsalva maneuver).
If using nicotine-containing products willing to refrain from use for 24 hours prior to all testing procedures (autonomic reflex screen, breath testing, and gastric emptying)
≥1 GI symptom on the Survey of Autonomic Symptoms (SAS)47

Exclusion Criteria

Diagnosis known to cause autonomic dysfunction other than HIV (e.g. Parkinson's disease, diabetes)
Diagnosis known to cause GI dysfunction other than HIV (e.g. peptic ulcer disease, infectious diarrhea)
Current use of any of the following classes of medications (due to potential for significant autonomic or GI effects, interaction with pyridostigmine, or interference with one or more of the testing procedures) Prokinetics (e.g. metoclopramide) Anti-diarrheals (e.g. loperamide) Antibiotics Mefloquine
Medical or psychiatric conditions precluding safe participation in study procedures or deemed likely to result in hospitalization during the study period.
The presence of one or more of the following diagnoses which render the Valsalva maneuver relatively or absolutely contraindicated: uncontrolled glaucoma, aortic stenosis, myocardial infarction in the last 6 months, other retinopathy or unclipped cerebral aneurysm.
The presence of one or more of the following diagnoses which impede interpretation of autonomic testing: cardiac arrhythmias or pacemakers.
An allergy to eggs (contraindication to gastric emptying scintigraphy)
Any of the following laboratory results:

Positive pregnancy test (administered to women of childbearing potential only) Urine toxicology screen positive for stimulants (e.g. amphetamines, cocaine) or opiates/opioids.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Pyridostigmine	Pyridostigmine	30mg PO three times a day

Primary Outcome Measures

Name	Time	Method
Change in Breath Test	baseline and week 8	Breath Test at week 8 as compared to baseline. Breath test results is the rise in the combined hydrogen and methane during the breath test.
Number of Participants With Reduction in Small Intestinal Bacterial Overgrowth (SIBO)	week 8	Number of participants with reduction in Small intestinal bacterial overgrowth (SIBO) assessed with breath testing after 8 weeks of treatment. The hydrogen breath test for the detection of small intestinal bacterial overgrowth (SIBO), obtained by having participants exhale into a plastic bag. the hydrogen content of the samples is measured using a commercially available analyzer.

Secondary Outcome Measures

Name	Time	Method
Change in sCD14 Level	Baseline and week 8	Change in sCD14 level at week 8 as compared to baseline. sCD14 is a marker of macrophage activation commonly used as an indirect measure of translocation
Medical Outcomes Study Questionnaire	Baseline and week 8	Medical Outcomes Study (MOS-HIV) quality of life questionnaire. It is a 35 item questionnaire covering 11 dimensions of health including physical functioning, role functioning, pain, social functioning, emotional well-being, energy/fatigue, cognitive functioning, general health, health distress, overall QOL, and health transition. The total scale ranges from 0-100 with a higher score representing better functioning and well-being.
Change in TNFα Level	Baseline and week 8	TNFα is a pro-inflammatory cytokine which is induced by components of translocating bacteria. Change in TNFα level at week 8 compared to baseline
Mean Percent Retention of Gastric Contents on Gastric Emptying Study	Baseline and week 8	Percent retention of gastric contents on gastric emptying study. GI dysmotility calculated from gastric emptying scintigraphy - measurement of the percent retention of gastric contents at 4 hours.
The Composite Autonomic Symptom Score (COMPASS)	Baseline and week 8	The gastrointestinal domain domain score of the COMPASS contains 12 items which reflect gastrointestinal symptoms of autonomic function. It is scored on a total scale of 0-28, with higher numbers reflecting worse symptoms.
Change in IL-6 Plasma Level	Baseline and week 8	Change in IL-6 plasma level at week 8 as compared to baseline. Plasma interleukin-6 (IL-6), an important inflammatory mediator which predicts mortality in HIV as well as multiple medical co-morbidities, presumably via inflammatory mechanisms.