Lubiprostone as a Modulator of Gut Microbial Translocation in HIV With Incomplete CD4 Recovery on Antiretroviral Therapy
Condition: HIV
Study type: Interventional
Phase: Phase 2

Summary: 
      The use of lubiprostone will decrease the levels of immune activation in HIV-infected
      subjects with incomplete CD4+ T-cell recovery with antiretroviral therapy (ART).

        -  Lubiprostone will decrease levels of translocated gut microbial products in HIV-infected
           subjects with incomplete CD4+ T-cell recovery with ART.

        -  The decrease in levels of translocated gut microbial products will be associated with a
           decline in the levels of immune activation in HIV-infected subjects with incomplete CD4+
           T-cell recovery with ART.
    

Detailed description: 
      Incomplete immune recovery in HIV-infected individuals is associated with impaired immune
      response to antigens, opportunistic infections, cardiovascular disease and malignancies, and
      increased mortality. Several studies have pointed to increased microbial translocation and
      immune activation as playing a causative role in these patients with limited CD4 recovery
      with antiretroviral therapy (ART). The gut mucosa of HIV-infected individuals sustains a
      rapid and profound depletion of gut mucosal CD4+ T-cells as early as a few days after
      infection. These changes lead to defects in mucosal immune and epithelial barrier function
      that allows the translocation of gut microbial products, such as plasma LPS (endotoxin) and
      bacterial 16s DNA. Plasma endotoxin and bacterial 16s DNA are elevated in HIV-infected
      individuals and their levels are associated with increased levels of immune activation. ART
      does not readily reverse the deficits in gut mucosal CD4+ T-cells. The epithelial barrier
      composed of tight junction complexes of the GI tract is a major defense that must be breached
      in order for microbial antigens and enterotoxins expressed by pathogenic bacteria to traverse
      from the lumen of the intestine to the lamina propria of the GI tract. Given recent data
      demonstrating increased complications and mortality in HIV-infected individuals despite
      suppressed viral replication on ART, investigators have proposed that adjunctive therapies
      aimed at reducing microbial translocation and/or its inflammatory consequences could improve
      the long-term prognosis of HIV-infected individuals. An intervention that decreases the level
      of translocated gut microbial products using modulators that act at the mucosal tight
      junction barrier is a strategy that has not been studied in HIV.

      LAMBCHOP is a randomized, open-label, controlled two-arm study that will test whether 4 weeks
      of treatment with lubiprostone, an apical lumen ClC-2 chloride channel activator licensed for
      the treatment of chronic idiopathic constipation and irritable bowel syndrome with
      constipation, reduces levels of translocated gut microbial products and markers of immune
      activation in HIV-infected subjects on antiretroviral therapy with incomplete CD4 recovery.
      Lubiprostone is a potent intestinal epithelial secretagogue that has been shown to stimulate
      recovery of mucosal barrier function via the restoration of tight junction protein complexes
      in ex vivo studies of ischemic porcine intestine. This study will take advantage of
      lubiprostone's known effect in vitro to significantly decrease E. coli and S. typhimurium
      translocation in a concentration-dependent manner and in in vivo mouse studies to promote
      enhanced protection against translocated pathogenic bacteria by shifting the intestinal
      microbiota in order to study the role of translocated gut microbial products in driving
      immune activation in HIV-infected subjects. Blood samples and stool specimens will be
      collected at several time points during the study to measure markers of cellular activation,
      inflammation, gut translocation, and coagulation. Safety assessments will be performed at
      screening, entry, and several post-entry visits. The primary objectives of the study is to
      determine whether there is a significant difference in levels of immune activation and gut
      microbiome after 4 weeks of study drug in those who received lubiprostone.
    

Intervention name(s): Lubiprostone
Intervention type(s): Drug
Intervention description(s): Lubiprostone 24 mcg by mouth (PO) once-daily
Other intervention name(s): Brand name: Amitiza
Intervention MeSH terms: Lubiprostone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: CD4+