Fecal microbiota transplantation to reduce immune activation in ART-treated people with HIV with low CD4/CD8 ratio: protocol for the single-blind, randomized, placebo-controlled Gutsy study (CIHR/CTN PT038)

Abstract

Background: Despite antiretroviral therapy (ART) controlling HIV viral replication, people with HIV (PWH) remain at risk for inflammatory non-AIDS comorbidities. Factors contributing to comorbidities in PWH on ART include spontaneous release of HIV products, CMV co-infection, microbial translocation, and gut dysbiosis, each driving systemic T-cell activation. In addition to ART, novel gut microbiota-modulating therapies could reduce epithelial gut permeability, microbial translocation, and immune activation. Fecal microbiota transplantation (FMT) from healthy volunteer is a promising therapy to counteract dysbiosis, protect from gut barrier damage, and lower systemic immune activation.

Methods: The Gutsy study is a single-blind, randomized, placebo-controlled clinical trial evaluating the effects of FMT in PWH on ART for more than 3 years, with a viral load below 50 copies/mL, a CD4 count above 200 cells/mL, and a CD4/CD8 ratio below 1.0. All participants undergo a bowel cleanse before receiving FMT or placebo capsules. In the treatment group, 10 participants receive a bowel cleanse then two high doses of FMT delivered via 30 to 40 capsules twice, 3 weeks apart. The placebo group of 10 participants receive a bowel cleanse and capsules filled with microcrystalline cellulose for equivalence in weight and color, administered under the same time course. Peripheral blood mononuclear cells (PBMCs) and stool samples are collected at each visit: before bowel cleanse (baseline 1), before the first (baseline 2) and the 2nd (visit 4) FMT/placebo, 6 weeks (visit 5) and 12 weeks (visit 6) after the first FMT/placebo; colon biopsies are obtained at visits 3 and 6 in an optional sub-study. The primary objective is to assess the effect of FMT on plasma markers of gut epithelial permeability. Secondary objectives include microbial translocation, immune activation, and HIV latent reservoir biomarkers.

Discussion: We hypothesize that large-dose FMT in capsules, but not placebo capsules, will increase the abundance of beneficial microbes in the gut of PWH on ART, leading to decreased gut damage markers and reduced immune activation. The results of the Gutsy pilot study will inform for the calculation of sample size of larger definitive randomized clinical trials assessing the influence of FMT on immune activation in PWH.

Trial registration: ClinicalTrials.gov NCT06022406. Registered on 2024-08-01. https://clinicaltrials.gov/study/NCT06022406?cond=HIV&term=Gutsy&rank=1 .

Keywords: Antiretroviral therapy; Fecal microbiota transplantation; Gut microbiota; Gut mucosa; HIV; Immune activation; Inflammation; Microbial translocation; Randomized control trial.