The Effect of Probiotics in HIV-1 Infection

Study Overview
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Brief Summary
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HIV progression is closely associated with chronic immune activation driven by leakage of bacterial products from a damaged gut, the investigators largest immunological organ. Notably, the degree of immune activation has been suggested to be a better predictor of disease progression than plasma viral load, and markers of immune activation and gut damage have been identified as therapeutic targets per se. The major damage by HIV to the immune system is an initial massacre of gut mucosal CD4+ Th17 cells. Interestingly, a normal gut flora has been shown to induce the maturation of Th17 cells in the small intestine mucosa. Preliminary reports have shown that the gut flora is altered in HIV-1 infection compared to controls. In this project, the investigators will characterize microbial composition of gut flora in chronic HIV infection with ultradeep sequencing. Gut flora composition will be related to clinical data as well as quantitative data of circulating microbial products and activation markers. Second, in a randomized clinical trial (RCT) the effect of probiotic lactobacilli on HIV pathogenesis and progression will be tested. This Gram-positive strain is clinically tested and is able to colonize the gut.

Detailed Description
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Objectives: To explore (i) the safety and tolerability, and (ii) the efficacy of probiotics on HIV-associated microbial translocation, systemic immune activation, disease progression and composition of gut microbiota in chronic HIV-1 infection. Methodology/Study design: Approximately 50 patients without current indication for antiretroviral treatment (ART) and 50 patients receiving ART without normalised CD4 counts will be included. A controlled clinical trial will be carried out within each stratum randomised in a 2:1:1 fashion to double blinded intervention and placebo arms as well as an open, untreated control arm, respectively.

Official Title
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The Effect of Probiotics on Microbial Translocation and Immune Activation in HIV-1 Infection. A Randomised Placebo-controlled Trial

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Dietary Supplement: Multi-strain probiotic
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For patients without ART: Confirmed diagnosis of HIV infection > 6 months and CD4+ T cell count < 900 For patients on stable, effective ART: HIV RNA < 50 copies/ml > 6 months and CD4+ T cell count > 500 Signed informed consent. Exclusion Criteria: Severe illness requiring hospitalization Systemic antibiotics or probiotics the last two months Current immune modulating therapy Infectious diarrhea Inflammatory bowel disease Acute primary HIV infection Patients immigrating from Africa, Asia or Latin-America within the last 6 months.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Probiotics<br>A multi-strain Probiotic consisting of Lactobacillus rhamnosus GG, Lactobacillus acidophilus La-5 and Bifidobacterium animalis subsp. lactis Bb-12 added to fermented skimmed milk (Biola®, TINE SA, Oslo), 250 mL/day for 8 weeks. | Dietary Supplement: Multi-strain probiotic<br>* The product consists of Lactobacillus rhamnosus GG, Lactobacillus acidophilus La-5 and Bifidobacterium animalis subsp. lactis Bb-12 added to fermented skimmed milk<br>* Other names: Brand name Biola®;|
| Placebo Comparator: Placebo<br>Fermented and subsequently heat-treated, sterile skimmed milk (TINE SA) as active placebo. | Dietary Supplement: Placebo<br>* Fermented and subsequently heat-treated, sterile skimmed milk<br>|
| No Intervention: Control<br>No intervention | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety | Adverse events monitoring during the study period of 2 months | 2 months | 
| Changes in measures of microbial translocation | Changes in plasma leves of lipopolysaccharide (LPS) and soluble CD14 from baseline to 2 months (end of study) | 2 months | 
| Changes in markers of immune activation | Changes in CD38, HLA-DR and PD-1 on CD8+ and CD4+ T cells from baseline to 2 months (end of study) | 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease progression in untreated patients | Changes in CD4 count, viral load, clinical events and indication for ART from baseline to 2 months (end of study) | 2 months | 
| Immune reconstitution in ART treated patients | Changes in CD4 count from baseline to 2 months (end of study) | 2 months | 
| Gut microbiota composition | Changes in gut microbiota (454 pyrosequencing of fecal samples) from baseline to 2 months (end of study) | 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, microbial translocation, immune activation, probiotics