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
Condition: HIV
Study type: Interventional
Phase: Phase 3

Summary: 
      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: 
      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
    

Intervention name(s): Raltegravir; Placebo; Current ART
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Raltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization; Placebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.; 3-drug antiretroviral treatment including PI/r/c or NNRTI
Other intervention name(s): NP; NP; NP
Intervention MeSH terms: Raltegravir Potassium
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: HIV infection; Gut microbiome; Raltegravir; Raltegravir intensification; Bacterial richness