GLAM HIV NAFLD: The Gut, Liver And Metabolome in Human Immunodeficiency Virus and Non Alcoholic Fatty Liver Disease

Sponsor

Vanderbilt University Medical Center (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06113003

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

3.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Persons with human immunodeficiency virus (HIV) have higher risk of developing fatty liver disease (NAFLD) than HIV-negative persons but the reasons for this discrepancy are not known. Changes in the intestinal microbiome may contribute to the development of NAFLD in persons with HIV (PWH) through impairment of barrier function of the intestinal wall and by producing metabolites that are harmful to the liver. This project will test the hypothesis that HIV-related NAFLD is associated with differences in the intestinal microbiome and that supplementation with probiotic and prebiotic fiber will lead to improvements in markers of NAFLD in PWH.

Condition or Disease	Intervention/Treatment	Phase
HIV Non-Alcoholic Fatty Liver Disease Metabolic-Associated Steatotic Liver Disease	Dietary Supplement: Prebiotic Dietary Supplement: Probiotic	Phase 1/Phase 2

Detailed Description

Over 1.1 million people in the United States are living with human immunodeficiency virus (HIV). Liver disease is a leading cause of mortality in persons with HIV (PWH), and PWH suffer a disproportionate burden of non-alcoholic fatty liver disease (NAFLD). While the mechanisms underlying this disparity are not well understood, harmful changes in the intestinal microbiome ("dysbiosis") and increased bacterial product movement across the intestinal lining ("leaky gut") are implicated in the pathogenesis of NAFLD in HIV-negative persons. HIV infection has been shown to alter the intestinal microbiome and promote leaky gut; however, there are few data on the microbiome among PWH with NAFLD. Our overarching hypothesis is that intestinal dysbiosis in PWH promotes NAFLD through: 1) impairment of the barrier function of the intestinal lining causing translocation of proinflammatory bacterial products to the bloodstream and 2) alteration of plasma metabolites that promote NAFLD. Specifically, HIV-associated gut dysbiosis leads to reduction in the production of short chain fatty acids, which are essential for the maintenance of a healthy intestinal lining. A reduction in butyrate production leads to breakdown of the intestinal barrier, allowing for translocation of inflammatory bacterial products into the splanchnic vasculature and the liver. These products lead to inflammation and disruption of lipid metabolism in the liver causing lipid deposition in the liver. Additionally, dysbiosis in PWH leads to lower bacterial production of lipids necessary for fat metabolism in the liver leading to NAFLD. We will test these hypotheses in a single arm pre/post feasibility and efficacy trial of an intervention designed to restore a healthy gut microbiome in PWH with NAFLD (n=63). The study will assess the effects of a probiotic containing multiple strains of bacteria supporting butyrate synthesis and prebiotic fiber among PWH at risk of NAFLD (diagnosis of metabolic syndrome, elevated BMI or elevated transaminases) without history of current excessive alcohol use, viral hepatitis or other known liver diseases.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

63 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Pre/Post TrialPre/Post Trial

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

The Gut, Liver And Metabolome in Human Immunodeficiency Virus and Non Alcoholic Fatty Liver Disease

Anticipated Study Start Date :

Dec 1, 2023

Anticipated Primary Completion Date :

May 1, 2025

Anticipated Study Completion Date :

Jul 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Probiotic and Prebiotic Fiber	Dietary Supplement: Prebiotic Wheat dextrin fiber Dietary Supplement: Probiotic Probiotic packet

Arm

Intervention/Treatment

Experimental: Probiotic and Prebiotic Fiber

Dietary Supplement: Prebiotic

Wheat dextrin fiber

Dietary Supplement: Probiotic

Probiotic packet

Outcome Measures

Primary Outcome Measures

Plasma phosphatidylcholine [24 weeks]
Plasma phosphatidylcholine abundance is measured

Secondary Outcome Measures

Proton Density Fat Fraction [24 weeks]
Hepatic steatosis is measured using magnetic resonance imaging proton density fat fraction
Simpson Index [24 weeks]
The Simpson Index is a measure of intestinal bacterial diversity.
Soluble CD14 [24 weeks]
Soluble CD14 is an indirect plasma markers of intestinal barrier function
Fatty Acid Binding Protein [24 weeks]
Fatty acid binding protein is an indirect plasma markers of intestinal barrier function
CD163 [24 weeks]
CD163 is an indirect plasma markers of intestinal barrier function
Firmicutes-to-Bacteroidetes Ratio [24 weeks]
The Firmicutes-to-Bacteroidetes ratio is a measure of intestinal bacterial diversity.
Shannon Index [24 weeks]
The Shannon Index is a measure of intestinal bacterial diversity.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 89 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

One of the following:

One or more of the components of metabolic syndrome, defined as:
Diagnosis of diabetes: on medication for diabetes for at least 6 months, HbA1c >6.5%, or fasting glucose >99 mg/dL
Elevated fasting triglycerides: >149 mg/dL or on medication for dyslipidemia
Reduced HDL-C: <40 mg/dL in males, <50 mg/dL in females or on medication for dyslipidemia
Elevated blood pressure: >129 mm Hg systolic and/or >84 mm Hg diastolic or on medication for hypertension
Prior diagnosis of hepatic steatosis or NAFLD: hepatic steatosis noted on interpretation of clinical imaging, CT scan liver density of less than 58 HU, Fibroscan CAP score >238 dB/m, MRI-PDFF ≥5%, liver biopsy showing ≥5% triglyceride content
Persistently abnormal transaminases: elevated liver enzymes defined by transaminases ≥1.5 upper limit of normal ([ULN] = 35 IU/mL) and/or gammaglutamyltransferase level ≥2 ULN (ULN = 60 IU/L) on 2 blood samples within at least a 3-month interval
BMI ≥ 30 kg/m2

Documented HIV infection
On antiretroviral therapy for at least 18 months
HIV-1 RNA <50 copies/ml for the prior 12 months
CD4 count >350 cells/microliter for the prior 12 months
Ability to be contacted by phone (home or cell)
Access to a private (i.e. accessible only to participant and immediate family or roommates) refrigerator for 6 months
Able and willing to comply with all study protocols and procedures

Exclusion Criteria:

Not fluent in English
Known allergy to the study product or its formulation
Pregnant or planning to become pregnant within the next six months
History of chronic diarrhea in the past three months
Breastfeeding
History of celiac disease
Prior diagnosis of non-NAFLD liver disease including, but not limited to, Wilson Disease, hemochromatosis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and alpha 1 antitrypsin deficiency
On medications associated with secondary NAFLD including systemic corticosteroids, tamoxifen, methotrexate, nifedipine, history of cancer chemotherapy, and short bowel syndrome
Positive hepatitis C quant or on treatment for hepatitis C within the last 12 months
History of cirrhosis or liver transplant
AUDIT-C score ≥3 women and ≥4 in men
History of inflammatory bowel disease
History of all other GI surgery within the past 12 months
Use of antibiotics in the past 30 days
Metal shrapnel, MRI incompatible hardware or claustrophobia that would preclude MRI imaging
Inability to participate in the study in the opinion of the participant's HIV treatment provider