Fecal Microbiota Transplantation in HIV

Study Overview
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Brief Summary
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Even in individuals treated for HIV, chronic immune activation persists and is associated with increased cardiovascular disease, liver disease, and mortality. HIV-infected individuals have imbalances in the community of intestinal microbes which is thought to contribute to increased and persistent inflammation. The purpose of this study is to examine the safety and durability of fecal microbiota transplant (FMT), the transfer of the bacterial community in stool from a healthy donor, in HIV+ individuals on anti-retroviral therapy. The study will also measure the effects of FMT on immune activation and inflammatory biomarkers in anti-retroviral treated HIV+ individuals.

Detailed Description
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Despite antiretroviral therapy (ART), chronic immune activation persists and is a major driver of HIV disease progression and mortality among HIV-infected individuals. Importantly, persistent inflammation is strongly associated with increased cardiovascular events, accelerated liver disease, impaired immunologic recovery (e.g. low CD4 count, low CD4 to CD8 ratio), and mortality. Therefore, addressing persistent inflammation remains a major goal to restoring health in HIV-infected individuals. Novel therapeutic strategies to decrease immune activation in treated HIV infection are needed. Marked disruption of the gut microbial composition, or dysbiosis, is characteristic of HIV-infected individuals and persists despite long-term ART. Recent studies demonstrate that the relative degree of gut microbiome disruption positively correlates with inflammatory markers (IL-6, kynurenine to tryptophan ratio). Microbial dysbiosis and its inflammatory consequences may be an attractive target for interventions to decrease immune activation in HIV+ individuals. Fecal microbiome transplantation (FMT) has proven durable and successful as a therapeutic strategy against gut dysbiosis, such as in the treatment of recurrent Clostridium difficile infection, by restructuring the composition of the gut microbiome to resemble that of the healthy donor. FMT has an established record of safety with limited adverse effects, even in the context of immunocompromised and HIV-infected subjects. Donor selection and screening will be conducted by OpenBiome. The objective of this phase I clinical trial is to establish the safety and durability of FMT in HIV+ individuals. The microbiome of recipients will be analyzed up to 8 weeks post FMT for evidence of engraftment from the donor microbiome. We will further examine the effect of FMT on markers of immune activation and inflammation in ART treated HIV-infected individuals.

Official Title
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Reconstitution of the Gut Microbiome to Reduce HIV-Associated Inflammation

Conditions
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HIV

Intervention / Treatment
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* Drug: Fecal Microbiota


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV infected men and women 18-75 years of age. On continuous anti-retroviral therapy for at least one year. Undetectable viral load for at least one year. Written informed consent obtained from the subject and ability of the subject to comply with the requirements of the study. Exclusion Criteria: CD4 T cell count less than 200 cells/mL. Recent antibiotic use in the last 3 months. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data. Active GI symptoms: inflammatory bowel disease, abdominal pain, hematochezia, or other symptoms requiring medical evaluation and intervention. Recent hospitalization or acute medical condition within preceding three months. Severe comorbidities: cirrhosis, coagulopathy, heart failure, renal failure, and respiratory failure. Testing positive for any of the stool screening test: Clostridium difficile toxin by PCR, routine bacterial culture for enteric pathogens (E coli, Salmonella, Shigella, Yersinia, Campylobacter), culture for Vibrio, fecal Giardia antigen, fecal Cryptosporidium antigen, acid-fast stain for Cyclospora and Isospora, ova and parasites, stool for Rotavirus via EIA. History of anaphylaxis. Major immunosuppressive medications (e.g., calcineurin inhibitors, exogenous glucocorticoids, biological agents, etc.) or systemic antineoplastic agents.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fecal microbiota transplant (FMT)<br>Donor fecal suspension will be delivered during colonoscopy to HIV+ individuals. | Drug: Fecal Microbiota<br>* 300 mL of fecal suspension from a healthy donor will be delivered during colonoscopy<br>* Other names: stool transplant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of FMT in HIV-infected individuals on suppressive ART. | Determine the proportion of individuals with AE/SAE. Record AE/SAE during FMT and post-FMT and determine if related to study procedure and graded for severity. Study stoppage criteria includes any serious AE that is at least possibly related to study treatment or any serious infection (e.g., bacteremia) in a sterile body site with an organism potentially acquired from the FMT product. | 0-24 weeks post-FMT | 
| Engraftment of donor microbiome in HIV-infected individuals on suppressive ART. | The weighted Canberra distance, which calculates community similarity based on shared OTU membership irrespective of phylogenetic relatedness, and weighted UniFrac which considers phylogenetic similarity of microbial communities, will both be applied to compare the microbiome of FMT recipients over time to those of the donor infusion sample. | 8 weeks post-FMT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma will be analyzed for changes in levels of markers of inflammation (e.g. IL-6, sCD14, kynurenine to tryptophan ratio) and CD4 and CD8 T cell activation | pre-FMT and 8 weeks post-FMT. | 8 weeks post-FMT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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inflammation, microbiome, immune activation, fecal microbiota transplantation, dysbiosis