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

• ClinicalTrials.gov Identifier: NCT01439841
• Recruitment Status: Completed
• First Posted: September 23, 2011
• Last Update Posted: September 28, 2017
• Sponsor: Oslo University Hospital
• Collaborators: Karolinska University Hospital; Tine
• Information provided by (Responsible Party): MariusTrøseid, Oslo University Hospital

Tracking Information

• First Submitted Date: September 16, 2011
• First Posted Date: September 23, 2011
• Last Update Posted Date: September 28, 2017
• Study Start Date: October 2011
• Actual Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 23, 2011)

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

Original Primary Outcome Measures (submitted: September 21, 2011)

• Safety [ Time Frame: 2 months ]
  Adverse events monitoring during the study period of 2 months
• Changes in measures of microbial translocation [ Time Frame: 2 months ]
  Changes in plasma leves of LPS and sCD14 from baseline to 2 months (end of study)
• Changes in markers of immune activation [ Time Frame: 2 months ]
  Changes in CD38, HLA-DR and PD-1 on CD8+ and CD4+ T cells from baseline to 2 months (end of study)

Current Secondary Outcome Measures (submitted: September 21, 2011)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: HIV-1 Infection

Intervention

• 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 Name: Brand name Biola®
• Dietary Supplement: Placebo
  Fermented and subsequently heat-treated, sterile skimmed milk

Study Arms

• 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.
  Intervention: Dietary Supplement: Multi-strain probiotic
• Placebo Comparator: Placebo
  Fermented and subsequently heat-treated, sterile skimmed milk (TINE SA) as active placebo.
  Intervention: Dietary Supplement: Placebo
• No Intervention: Control
  No intervention

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 26, 2017): 32
• Original Estimated Enrollment (submitted: September 21, 2011): 100
• Actual Study Completion Date: June 2013
• Actual Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Norway, Sweden

Administrative Information

• NCT Number: NCT01439841
• Other Study ID Numbers: ProGut1.0
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: MariusTrøseid, Oslo University Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Oslo University Hospital
• Original Study Sponsor: Same as current

Collaborators

• Karolinska University Hospital
• Tine

Investigators

• Study Director: Geir Gokstad, MD, PhD; Oslo University Hospital
• Principal Investigator: Marius Trøseid, MD, PhD; Oslo University Hospital

• PRS Account: Oslo University Hospital
• Verification Date: September 2017