Microbiota Restoration Therapy in HIV With Repeated Low-Dose Interventions (REFRESH)

A Phase I/II Randomized, Double-Blind, Placebo Controlled Study of Repeated Low-Dose Fecal Microbiota Restoration in HIV-Infected Subjects. The REFRESH Study

Altered interplay between gut mucosa and dysbiotic bacteria during HIV infection seems to contribute to chronic immune dysfunction. Manipulation of the intestinal microbiota with nutritional interventions exert limited immunologic effects, but a deep understanding of how these interventions could ameliorate gut dysbiosis and influence health among HIV-infected individuals remain unexplored. In this Phase I clinical trial, 30 HIV-infected subjects on effective ART with evidence of persistent immune dysfunction, indicated by a CD4/CD8 ratio<1 will be included and randomized to either repeated low-dose oral fecal microbiota transplantation or placebo during 8 weeks. The primary outcome will be safety. Secondary outcomes will include changes in CD4+ T cell counts, CD8+ T cell counts, CD4/CD8 ratio, inflammatory markers, T cell activation and markers of enterocyte barrier function through week 48. Engraftment on host microbiota will be examined using Illumina sequencing of the V3-V4 16S RNA, and changes in bacterial metabolism and in the plasma metabolite fingerprint will be studied by combination of untargeted mass spectrometry and two different and complementary separation techniques in bacterial and plasma samples.

Fecal microbiota capsules (provided by Openbiome). Dosage: Induction: 10 capsules (single dose) Maintenance: 5 capsules, weekly, during 7 weeks.

Placebo capsules (provided by Openbiome). Dosage: Induction: 10 capsules (single dose) Maintenance: 5 capsules, weekly, during 7 weeks.

Inflammation: interleukin (IL)-6, high sensitivity C reactive protein (hs-CRP), interferon gamma-induced protein (IP)-10. Monocyte/macrophage activation: sCD14, SCD163, Gut epithelial integrity: zonulin-1, intestinal fatty acid binding protein (IFABP). Bacterial translocation: lipoteichoic acid (LTA) Indolamine deoxygenase-1 induction: kynurenine/tryptophan ratio Coagulation: D-dimers

Inflammation: interleukin (IL)-6, high sensitivity C reactive protein (hs-CRP), interferon gamma-induced protein (IP)-10. Monocyte/macrophage activation: sCD14, SCD163, Gut epithelial integrity: zonulin-1, intestinal fatty acid binding protein (IFABP). Bacterial translocation: lipoteichoic acid (LTA) Indolamine deoxygenase-1 induction: kynurenine/tryptophan ratio Coagulation: D-dimers

Inclusion Criteria: On stable antiretroviral therapy with plasma HIV RNA <20 copies/mL during at least 48 weeks. CD4/CD8 ratio <1 Exclusion Criteria: Pregnancy Gastrointestinal diseases, including cirrhosis Active infections, including HCV EBV and/or CMV negative patients (donors are not screened for EBV/CMV). Planned used of chemotherapy or antibiotics Allergy to sodium chloride or glycerol (the former components are capsule ingredients Generally Recognized As Safe (GRAS) Current or planned use of antimicrobial agents (including prophylactic treatments against P. jiroveci) other than ART. Neutropenia <500 cells/uL or CD4 counts <350 cells/uL Patients unable to give informed consent Patients unable to comply with the protocol requirements Predicted death within time period of follow-up Any other condition for which the treating physician thinks the treatment may pose a health risk Dysphagia: oropharyngeal, esophageal, functional, neuromuscular (e.g. stroke, multiple sclerosis, ALS) History of aspiration History of gastroparesis

Serrano-Villar S, Talavera-Rodriguez A, Gosalbes MJ, Madrid N, Perez-Molina JA, Elliott RJ, Navia B, Lanza VF, Vallejo A, Osman M, Dronda F, Budree S, Zamora J, Gutierrez C, Manzano M, Vivancos MJ, Ron R, Martinez-Sanz J, Herrera S, Ansa U, Moya A, Moreno S. Fecal microbiota transplantation in HIV: A pilot placebo-controlled study. Nat Commun. 2021 Feb 18;12(1):1139. doi: 10.1038/s41467-021-21472-1.