Autonomic Neuropathy, GI Motility, and Inflammation in HIV

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.

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.