Autonomic Neuropathy, GI Motility, and Inflammation in HIV

Autonomic Neuropathy, Gastrointestinal Motility, and Inflammation in HIV

Status

Completed

Phases

Early Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02850276

Acronym

ANGI

Enrollment

Registered

2016-07-29

Start date

2015-11-30

Completion date

2018-06-01

Last updated

2019-05-29

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

HIV Disease

Keywords

HIV disease, gastrointestinal problems

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.

Interventions

DRUGPyridostigmine

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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
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.
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.
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.
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 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

Countries

United States

Participant flow

Recruitment details

Enrollment period from November 2015 to Jan 2018

Participants by arm

Arm	Count
Pyridostigmine 30mg PO three times a day for 8 weeks	76
Total	76

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Lost to Follow-up	2
Overall Study	Physician Decision	2
Overall Study	screen failure	43
Overall Study	Withdrawal by Subject	14

Baseline characteristics

Characteristic	Pyridostigmine
Adrenal sub-score >=1	55 Participants
Age, Continuous	56.9 years STANDARD_DEVIATION 6.6
Autonomic neuropathy BRS-V of <4	33 Participants
Autonomic neuropathy CASS >=3	49 Participants
Autonomic neuropathy CASS vagal subscore >=1	30 Participants
Cramping/colicky abdominal pain	41 Participants
Current CD4+ count	602 cells/mm^3
Duration of know HIV infection	21 years
Early Satiety GI symptom	43 Participants
Moderate to severe constipation	31 Participants
Moderate to severe diarrhea	30 Participants
Nadir CD4+ count	200 cells/mm^3
Nausea	53 Participants
Post-prandial bloating GI symptom	55 Participants
Post-prandial vomiting	15 Participants
Race/Ethnicity, Customized African-American	39 Participants
Race/Ethnicity, Customized Hispanic/Latino	22 Participants
Race/Ethnicity, Customized Other	1 Participants
Race/Ethnicity, Customized White	14 Participants
Sex: Female, Male Female	20 Participants
Sex: Female, Male Male	56 Participants
Sudomotor sub-score >=1	63 Participants
Total CASS >=3	49 Participants
Vagal sub-score >=1	30 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 15
other Total, other adverse events	5 / 15
serious Total, serious adverse events	0 / 15

Outcome results

Primary

Change in Breath Test

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.

Time frame: baseline and week 8

Arm	Measure	Group	Value (MEDIAN)
Pyridostigmine	Change in Breath Test	week 8	14 ppm
Pyridostigmine	Change in Breath Test	Baseline	28 ppm

Primary

Number of Participants With Reduction in Small Intestinal Bacterial Overgrowth (SIBO)

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.

Time frame: week 8

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Pyridostigmine	Number of Participants With Reduction in Small Intestinal Bacterial Overgrowth (SIBO)	13 Participants

Secondary

Change in IL-6 Plasma Level

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.