A Double Blind Randomized Placebo Controlled Study Examining the Effects of a Non-Absorbable (Rifaximin) Antibiotic on the Chronic Immune Activation Observed In HIV-infected Subjects
The introduction of antiretroviral therapy (ART) has resulted in dramatic reductions in
AIDSrelated morbidity and mortality. Therapy is not curative, however, and the nature of HIV
replication during therapy remains unclear. Understanding mechanisms involved in HIV
persistence will be useful in identifying effective strategies for HIV eradication. Immune
activation (IA) plays a central role in the pathogenesis of HIV-infection, and may play a
critical role in HIV persistence during therapy. In comparison with the levels detected in
HIV uninfected subjects, both cellular markers of activation and biomarkers of inflammation
are elevated in HIV-infected individuals. Levels of inflammatory cytokines and cellular
markers of activation independently correlate with disease progression in HIV-infected
subjects. Chronic, persistent IA is associated with the observed CD4 depletion in untreated
subjects and among ART- treated and virologically suppressed subjects and may contribute to
the failure to reconstitute CD4 counts. IA also plays a role in the pathogenesis of non-AIDS
related complications such as chronic kidney and coronary artery disease (CAD).
Although chronic persistent IA may play a role in HIV persistence, the source of immune
activation itself is unknown. Low level viremia may represent a virologic stimulus for IA.
Viremia persists at low levels during therapy, but it is not known whether HIV infection is
maintained by ongoing cycles of replication in sanctuary sites, production from long-lived
cells with integrated proviruses, or both. Using sensitive assays for HIV-1 viremia, we and
others have detected the presence of persistent HIV viremia in the majority of subjects
throughout prolonged antiretroviral therapy. Drug intensification studies suggest little
contribution of active replication to levels of persistent viremia, suggesting that factors
other than complete cycles of HIV replication may contribute to HIV-1 persistence.
Activation of HIV-1 from long-lived cells in reservoir sites is another potential source of
viremia, but the nature of such reservoirs is not yet well understood.
The mechanism of immune activation in HIV infection remains to be clarified and is likely
multifactorial. Additional potential mechanisms of persistence include a central role for
the gastrointestinal tract. The gastrointestinal epithelium and gut-associated lymphoid
tissue (GALT) are thought to represent important barriers to microbial translocation, but
HIV infection results in substantial destruction of both barriers. The reservoir of bacteria
in the gastrointestinal tract is substantial, and small amounts of bacterial products are
reported to translocate across the gastrointestinal tract into the bloodstream; microbial
translocation across this defective GALT is an important driver of the observed immune
activation in HIV infection. The precise effects of ART on gut microbial translocation
remain uncertain; some studies suggest that ART incompletely reverses the effects of
microbial translocation, others have failed to demonstrate any effect, yet other studies
have demonstrated complete reversal with ART.
In this study, we will examine the potential role of bacterial translocation on IA by
studying the effects of the antibiotic rifaximin on markers of microbial translocation,
immune activation, and HIV viremia in the gut reservoir in ART treated aviremic subjects.
Rifaximin is an orally administered antibiotic with potent qualitative and quantitative
effects on gut bacterial flora. Rifaximin is not systemically absorbed, and drug effects
appear to be confined to the gastrointestinal tract. Rifaximin has been studied as
maintenance therapy in both inflammatory bowel disease (IBD) and hepatic encephalopathy
(HE), disease states in which endogenous gut flora play an important role in the
pathogenesis. It is anticipated that the use of rifaximin will result in an alteration and
reduction in gut bacterial flora. We hypothesize that the reductions in gut bacterial flora
will result in a corresponding reduction in bacterial translocation and reductions in
biologically active LPS levels leading to reductions in immune aced persons receiving
Ativation, and HIV.
In this protocol, the role of gut microbial translocation in the pathogenesis of HIV
infection will be examined by performing a randomized, double-blind, placebo-controlled
study of rifaximin with a case cross-over design in virologically-suppressed HIV-infected
persons receiving ART.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
The primary objective is to compare changes in sCD14 levels during the rifaximin phase of the study and compare it with the changes in sCD14 levels during the placebo phase
Frank Maldarelli, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|
|University of Pittsburgh||Pittsburgh, Pennsylvania 15261|
|Walter Reed National Medical Center||Bethesda, Maryland 20301|