The Effect of Probiotics in HIV-1 Infection (ProGut)

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

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.

Study Overview

• Status: Completed
• Conditions: HIV-1 Infection
• Intervention / Treatment: Dietary supplement: Multi-strain probiotic; Dietary supplement: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway, 0407
    • Oslo University Hospital
• Sweden
  • Stockholm, Sweden, 14186
    • Karolinska University Hospital Huddinge

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
NO_INTERVENTION: Control; No intervention
EXPERIMENTAL: Probiotics; 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; The product consists of Lactobacillus rhamnosus GG, Lactobacillus acidophilus La-5 and Bifidobacterium animalis subsp. lactis Bb-12 added to fermented skimmed milk; Other Names: Brand name Biola®
PLACEBO_COMPARATOR: Placebo; Fermented and subsequently heat-treated, sterile skimmed milk (TINE SA) as active placebo.	Dietary supplement: Placebo; Fermented and subsequently heat-treated, sterile skimmed milk

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: Karolinska University Hospital; Tine
• Investigators: Study Director: Geir Gokstad, MD, PhD, Oslo University Hospital

Publications and helpful links

General Publications

• Stiksrud B, Nowak P, Nwosu FC, Kvale D, Thalme A, Sonnerborg A, Ueland PM, Holm K, Birkeland SE, Dahm AE, Sandset PM, Rudi K, Hov JR, Dyrhol-Riise AM, Troseid M. Reduced Levels of D-dimer and Changes in Gut Microbiota Composition After Probiotic Intervention in HIV-Infected Individuals on Stable ART. J Acquir Immune Defic Syndr. 2015 Dec 1;70(4):329-37. doi: 10.1097/QAI.0000000000000784.

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (ACTUAL): April 1, 2013
• Study Completion (ACTUAL): June 1, 2013

Study Registration Dates

• First Submitted: September 16, 2011
• First Submitted That Met QC Criteria: September 21, 2011
• First Posted (ESTIMATE): September 23, 2011

Study Record Updates

• Last Update Posted (ACTUAL): September 28, 2017
• Last Update Submitted That Met QC Criteria: September 26, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: HIV; probiotics; immune activation; microbial translocation
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Disease Attributes; HIV Infections; Infections; Communicable Diseases
• Other Study ID Numbers: ProGut1.0