Probiotic Visbiome for Inflammation and Translocation in HIV II (PROOV IT II)

Probiotic Visbiome for Inflammation and Translocation in HIV II (PROOV IT II)

Modern antiretroviral therapy (ART) has transformed the clinical care and lived experience of HIV infection. However, increased rates of adverse health conditions that are related to immune activation, such as cardiovascular disease (CVD) and neurodegenerative disease in ART-treated individuals persist. An important cause of this inflammation is the gut CD4 T cell loss and the "leaking" or translocation of luminal gut bacteria and other microbes across the bowel wall and into the bloodstream.

The use of complementary and alternative therapies is very common among people living with HIV, with estimates ranging from 16-60%. However, their efficacy has generally not been well demonstrated. Probiotics are live microbes that may provide a health benefit to the host and the investigators believe that the simultaneous use of probiotics along with ART will improve gut CD4 T cell restoration and function and therefore reduce microbial translocation and immune activation.

A major challenge to HIV treatment is the suboptimal CD4 T cell count despite successful HIV suppression on ART in immunologic non-responders (INRs). These individuals are at increased risk of AIDS-related deaths and non-AIDS related comorbidities that may be associated with increased immune activation and microbial translocation from the gut mucosa. With limited treatment options, alternative therapies to reduce inflammation and restore gut immunology will be important. Probiotic Visbiome consists of a high potency blend of eight different probiotics. The precise mechanism of action of Visbiome is unknown,but preclinical studies have shown that Visbiome may modulate the immune response towards an immunoregualtory phenotype with increased the levels of IL-10 and reduced levels of proinflammatory cytokines (TNFα, IL1β and IL-8). Therefore,the investigators believe that the "beneficial" bacteria from Visbiome will accelerate the normalization of gut immune cells and function in HIV-infected INRs. It is hypothesized consumption of Visbiome for 48 weeks will help restore the immune system in INRs who have suboptimal immune reconstitution to currently available ART. Resolution of gut immune cells will mean that microbial translocation and immune activation will be normalized and will reduce the rates of HIV-associated comorbidities.

Study Overview

• Status: Unknown
• Conditions: HIV-1 Infection
• Intervention / Treatment: Other: Placebo; Drug: Visbiome

• Study Type: Interventional
• Enrollment (Anticipated): 36
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Rupert Kaul, MD; Phone Number: 416-978-8607; Email: rupert.kaul@utoronto.ca
• Study Contact Backup: Name: Rodney Rousseau; Phone Number: 416-946-7054; Email: r.rousseau@mail.utoronto.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1K2
      • Recruiting
      • Maple Leaf Medical Clinic
      • Contact: Colin Kovacs, MD; Phone Number: 416-465-3252; Email: ckovacs@mlmedical.com
      • Principal Investigator: Colin Kovacs, MD
    • Toronto, Ontario, Canada, M5G 2N2
      • Recruiting
      • Toronto General Hospital, UHN
      • Contact: Sharon Walmsley, MD; Phone Number: 416-340-3871; Email: sharon.walmsley@uhn.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Documented HIV-1 infection
• Male adult (age >18 years)
• Currently on ART (>2 years but <10 years)
• Undetectable HIV-1 viral load <50 copies/ml for the past 2 years (1 viral blip below 500 copies/ml permitted in the past year)
• Last CD4 count <350 cells/μl, and >70% over the past 2 years <350 cells/μl
• Ability to provide informed consent

Exclusion Criteria:

• Current alcohol or substance use judged by the Investigator to potentially interfere with subject study compliance
• Taking pharmaceutical-grade probiotics

• Any of the following abnormal laboratory results in screening:

  • Hemoglobin <85 g/L
  • Neutrophil count <750 cells/μl
  • Platelet count <50,000 cells/μL
  • AST or ALT >5X the upper limit of normal
• Colitis
• Liver fibrosis (decompensated cirrhosis), portal hypertension or clinical hepatitis
• Other significant underlying disease (non-HIV-1) that might impinge upon disease progression or death

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Probiotic Group; Visbiome probiotic group (900 billion bacteria daily; 2 sachets daily)	Drug: Visbiome; Visbiome probiotic
Placebo Comparator: Placebo Group; Placebo comparator group	Other: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent change in blood immune activation	Percent change in blood immune activation (co-expression of CD38 and HLA-DR) on CD8 T cells at week 48 in participants randomized to probiotic Visbiome versus the placebo arm	48 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Level of microbial translocation (including LSP and sCD14)	48 weeks
Plasma level of inflammation and coagulation (including IL-6, D-dimer and CRP)	48 weeks
Number and function of gut immune cells (including CD4 T cell subsets)	48 weeks
Intestinal permeability (Lac/Mac ratio)	48 weeks
Bacterial community diversity, determined by 16s rRNA gene sequencing of penile swabs	48 weeks
Bacterial community composition, determined by 16s rRNA gene sequencing of penile swabs	48 weeks
Gut HIV DNA levels	48 weeks
Canadian Diet History Questionnaire	48 weeks
Safety assessed by AE monitoring and participant questionnaire	48 weeks
Tolerability of Visbiome assessed by AE monitoring and participant questionnaire	48 weeks
Adherence to Visbiome assessed by participant questionnaire and sachet count	48 weeks

Other Outcome Measures

Outcome Measure	Time Frame
Metabolomic measurements: vitamin D levels, glucose measurements, insulin levels and lipid profiling	48 weeks
Microbiome analysis by 16s rRNA bacterial DNA isolated from penile swabs	48 weeks

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Collaborators: CIHR Canadian HIV Trials Network

Publications and helpful links

General Publications

• Rousseau RK, Walmsley SL, Lee T, Rosenes R, Reinhard RJ, Malazogu F, Benko E, Huibner S, Kovacs CM, Singer J, Kim CJ, Kaul R. Randomized, Blinded, Placebo-Controlled Trial of De Simone Formulation Probiotic During HIV-Associated Suboptimal CD4+ T Cell Recovery. J Acquir Immune Defic Syndr. 2022 Feb 1;89(2):199-207. doi: 10.1097/QAI.0000000000002840.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Anticipated): May 1, 2019
• Study Completion (Anticipated): May 1, 2019

Study Registration Dates

• First Submitted: April 23, 2015
• First Submitted That Met QC Criteria: May 11, 2015
• First Posted (Estimate): May 12, 2015

Study Record Updates

• Last Update Posted (Actual): April 18, 2018
• Last Update Submitted That Met QC Criteria: April 17, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation
• Other Study ID Numbers: CTNPT 022B