Clinical Trial to Evaluate the Effect of Raltegravir Intensification (1.200 mg QD) on the Gut Microbiota of Chronically HIV-1 Infected Subject Over Time: THE RAGTIME STUDY

Study Overview
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Brief Summary
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The project presented here will be the first prospective, randomized evaluation of the effect of ART on the structure and function of the gut microbiome. This study provides a unique opportunity to understand the benefits of ART with high intestinal penetration on the gut microbiome. It is thus a key study to understand the bidirectional interactions between the microbiome and the host in people living with HIV/AIDS.

Detailed Description
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The gut microbiome is essential for the maturation of the neonatal immune system and the adequate development and function of adult immune responses. HIV-1 infection in children and adults exerts a rapid and severe depletion of gut-associated lymphoid tissue, which damages the intestinal barrier, allowing translocation of gut commensal bacteria into the systemic circulation. Bacterial translocation causes chronic inflammation and immune activation, which lead to immune deterioration and premature aging of HIV-1-infected subjects, including metabolic disturbances, cardiovascular diseases, cognitive disorders and HIV-associated cancers. Persistence of residual HIV-1 replication in the presence of ART has been associated to incomplete HIV-1 suppression in gut lymphatic tissues due to suboptimal tissular penetration of PI/s or NNRTIs. In previous work in our institute, the investigators have observed that HIV-1 infection is independently associated with significant reductions in the gut microbiome richness, which is, in turn, are inversely correlated with systemic inflammation. Reduced microbial richness, for example, has been associated with intestinal inflammatory diseases and well as with metabolic syndrome, diabetes and obesity and correlated with metabolic markers. Recovering bacterial richness might thus have a positive impact on immune activation, chronic inflammation and the overall health of HIV-infected individuals. However, achieving that goal will possibly require, alongside potential bacterial supplementations, the use of ART with high penetration into gut lymphoid tissue to limit as much as possible the continued damage exerted by residual HIV replication on the GALT. Antiretroviral drugs with higher intestinal penetration like raltegravir may be more effective at recovering the intestinal microbiome composition and function than those with lower gut penetration like darunavir or the NNRTIs. Thereby, raltegravir intensification could be associated with increases in intestinal microbial richness, implying an improvement on intestinal and overall health. Despite the lack of evidence on that regard, previous studies from our group and others would favor that hypothesis. Residual HIV-1 replication in plasma can be deterred by ART intensification with raltegravir, which is, in part, due to the high penetration of raltegravir in intestinal tissues. Moreover, raltegravir intensification decreases peripheral CD8 T-cell activation CD45RA (-) and creates a transient CD4 T-cell redistribution, which revert after raltegravir withdrawal. The project presented here will be the first prospective, randomized evaluation of the effect of ART on the structure and function of the gut microbiome. This study provides a unique opportunity to understand the benefits of ART with high intestinal penetration on the gut microbiome. It is thus a key study to understand the bidirectional interactions between the microbiome and the host in people living with HIV/AIDS

Official Title
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Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Effect of Raltegravir Intensification (1.200 mg QD) on the Gut Microbiota of Chronically HIV-1 Infected Subject Over Time: THE RAGTIME

Conditions
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HIV

Intervention / Treatment
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* Drug: Raltegravir
* Drug: Placebo
* Drug: Current ART


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years old Documented HIV infection Stable 3-drug antiretroviral treatment including PI/r/c or NNRTI for at least 6 months. Plasma HIV-1 RNA load <50 copies/mL for at least 12 months. Signed Informed Consent Exclusion Criteria: PI/r monotherapy INSTI therapy during the previous 6 months Evidence of previous INSTI resistance Creatine clearance <50 mL/min Child- Pugh B or C History of active uncontrolled GI disorders or diseases including: 6.1. Major surgery of the GI tract, with the exception of cholecystectomy and appendectomy, in the previous 5 years. 6.2. Any major bowel resection at any time. 6.3. Any chronic digestive disease such as peptic ulcer, Crohn's disease, ulcerative colitis, coeliac disease, confirmed intolerance to lactose or indeterminate colitis. 6.4. Persistent infectious gastroenteritis, colitis or gastritis; persistent or chronic diarrhea of unknown etiology; Clostridium difficile infection (recurrent) or Helicobacter pylori infection (untreated) 6.5. Irritable bowel syndrome (moderate-severe) 6.6. Chronic constipation 6.7. Active proctitis Antibiotic therapy within the previous 2 months In women, pregnancy or breastfeeding*. Female subjects of childbearing potential must not be pregnant, not be planning a pregnancy or breast-feeding. Sexually active women must be willing to use two approved methods of contraception (including condoms, diaphragm, spermicides, hormonal methods and/or intrauterine devices) from baseline until the end of the clinical trial. Sexually active men in heterosexual relationships must be willing to use two approved method of contraception with their partners from baseline until the end of the clinical trial. condom use is considered as an additional method of contraception only and cannot be the only method of contraception used as not been considered an effective method by the Clinical Trial Facilitation Group (CTFG) guidelines.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Current ART + Raltegravir<br>Current ART + Raltegravir | Drug: Raltegravir<br>* Raltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization<br>* Other names: NP;Drug: Current ART<br>* 3-drug antiretroviral treatment including PI/r/c or NNRTI<br>* Other names: NP;|
| Placebo Comparator: Current ART + placebo<br>Current ART + placebo | Drug: Placebo<br>* Placebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.<br>* Other names: NP;Drug: Current ART<br>* 3-drug antiretroviral treatment including PI/r/c or NNRTI<br>* Other names: NP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| bacterial richness (observed species). Analysis of the composition, structure and function of the intestinal microbiome. * | -* Structure and composition of the microbiome. DNA will be extracted and purified from fecal samples and cryopreserved at -80ºC until amplification. The purified DNA will be amplified using Illumina-tagged primers to amplify the V3 and V4 16S ribosomal DNA (rDNA) regions. PCR reactions will be performed in triplicate to preserve diversity. Pooled triplicates will be sequenced ensuring adequate sampling depth. -Function of the bacteriome. The gene content will be inferred from the abundance of each bacteria in the intestinal bacteriome according to the 16S rDNA information | From baseline to 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Association of the gut microbiome composition and richness with inflammation | IL-6, IP-10 | From baseline to 48 weeks | 
| Association of the gut microbiome composition and richness with coagulation | D-Dimer | From baseline to 48 weeks | 
| Association of the gut microbiome composition and richness with Enterocyte damage | Intestinal Fatty Acid Binding Protein (I-FABP) | From baseline to 48 weeks | 
| Association of the gut microbiome composition and richness with Bacterial translocation and monocyte activation | LPS-binding protein (LBP), soluble CD14 | From baseline to 48 weeks | 
| Association of the gut microbiome composition and richness with Maturation, activation, exhaustion and immune senescence in CD4+ and CD8+ T-cells | CD3+, CD4+, CD8+, CD45RA, CCR7, CD28, CD27, HLA-DR, CD38, PD-1, CD57 | From baseline to 48 weeks | 
| Association of the gut microbiome composition and richness with CD4 and CD8+ counts and ratio. | CD4 and CD8+ counts and ratio | From baseline to 48 weeks | 
| Gut bacterial composition* | Longitudinal changes | From baseline to 48 weeks | 
| Gut bacterial function* | Longitudinal changes | From baseline to 48 weeks | 
| Other estimators of richness and diversity | 1/Simpson | From baseline to 48 weeks | 
| Other estimators of richness and diversity | ACE | From baseline to 48 weeks | 
| Other estimators of richness and diversity | Shannon | From baseline to 48 weeks | 
| In case of changes in the microbiome, the quantification of viral reservoir will be done in PBMCs | quantification of viral reservoir | From baseline to 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV infection, Gut microbiome, Raltegravir, Raltegravir intensification, Bacterial richness