Clinical trial NCT01839734
Conditions: HIV
Keywords: CD4+
Sponsor: Ruth M. Rothstein CORE Center
Start date: 2013-06-01; Completion date: 2016-02-01
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief 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.

Arms: arm 1: 4 weeks of treatment with lubiprostone 24 mcg by mouth (PO) once-daily (Interventional Group) arm 2: No intervention
Interventions: intervention 1: Lubiprostone
Intervention descriptions: intervention 1: Lubiprostone 24 mcg by mouth (PO) once-daily

Protocol documents: