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

HIV Clinical Trial

— GLAM HIV NAFLD  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06113003
• Other study ID #: 231185
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: April 18, 2024
• Est. completion date: July 2025

Study information

• Verified date: May 2024
• Source: Vanderbilt University Medical Center
• Contact: Curtis L Gabriel, MD, PhD
• Phone: 615-322-0128
• Email: curtis.L.gabriel[@]vumc.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 63
• Est. completion date: July 2025
• Est. primary completion date: May 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 89 Years

Eligibility

Inclusion Criteria:

• One of the following:

1. One or more of the components of metabolic syndrome, defined as:

1. Diagnosis of diabetes: on medication for diabetes for at least 6 months, HbA1c >6.5%, or fasting glucose >99 mg/dL

2. Elevated fasting triglycerides: >149 mg/dL or on medication for dyslipidemia

3. Reduced HDL-C: <40 mg/dL in males, <50 mg/dL in females or on medication for dyslipidemia

4. Elevated blood pressure: >129 mm Hg systolic and/or >84 mm Hg diastolic or on medication for hypertension

5. 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

2. 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

3. 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,

• 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

• Use of prebiotic(s) including fiber supplements and/or probiotic(s) within the past 90 days

• Participant has history of hemicolectomy, colectomy, small bowel resection, bariatric surgery, gastric bypass surgery, or short bowel syndrome

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• Fatty Liver
• HIV
• HIV Infections
• Liver Diseases
• Non-Alcoholic Fatty Liver Disease

Intervention

Dietary Supplement:
• Prebiotic
Wheat dextrin fiber
• Probiotic
Probiotic packet

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Vanderbilt University Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Plasma phosphatidylcholine	Plasma phosphatidylcholine abundance is measured	24 weeks
Secondary	Proton Density Fat Fraction	Hepatic steatosis is measured using magnetic resonance imaging proton density fat fraction	24 weeks
Secondary	Simpson Index	The Simpson Index is a measure of intestinal bacterial diversity.	24 weeks
Secondary	Soluble CD14	Soluble CD14 is an indirect plasma markers of intestinal barrier function	24 weeks
Secondary	Fatty Acid Binding Protein	Fatty acid binding protein is an indirect plasma markers of intestinal barrier function	24 weeks
Secondary	CD163	CD163 is an indirect plasma markers of intestinal barrier function	24 weeks
Secondary	Firmicutes-to-Bacteroidetes Ratio	The Firmicutes-to-Bacteroidetes ratio is a measure of intestinal bacterial diversity.	24 weeks
Secondary	Shannon Index	The Shannon Index is a measure of intestinal bacterial diversity.	24 weeks