Rifaximin for Chronic Immune Activation in People With HIV
- Human immunodeficiency virus (HIV) treatment can control the amount of virus in the blood, but it does not provide a cure. The reasons why HIV treatment does not cure the infection are not well understood. HIV persists in blood cells for years, even if people receive treatment for it. In addition, HIV infection leads to an activated immune system, which can cause other problems.
- One theory for why HIV infection causes immune activation involves the intestinal tract. HIV infects immune cells the intestine soon after infection and damages their immune barrier. This damage lets bacteria cross into the bloodstream, leading to ongoing inflammation. Even when a person with HIV feels well, this chronic inflammation may affect the immune system. Researchers want to see if the antibiotic Rifaximin can reduce this inflammation. Rifaximin is designed to stay inside the digestive system, so it affects only bacteria in the intestines.
- To see if Rifaximin can reduce bacteria-related inflammation in people with HIV.
- Individuals at least 18 years of age who have HIV infection and are taking medications to treat it.
- Participants will be screened with a physical exam, blood test, and medical history.
- Participants will take either Rifaximin or a placebo for 4 weeks. They will have no medication for 4 to 6 weeks, and then take the other drug for 4 more weeks.
- During the study, participants will have frequent blood and urine tests. They will also provide stool samples. Liver and kidney function tests will be performed. HIV viral load (the amount of virus in the blood) will also be studied.
- Participants will have a final follow-up visit after an additional 4 weeks.
- Two additional tests are optional for study participants:
- Two blood draws: one on the third day after starting Rifaximin, and one on the third day after starting the placebo.
- Up to three colonoscopies of the lower intestine and biopsies of the intestine. These studies will collect samples of the intestinal tract to look at the effects of Rifaximin in the study.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
|Official Title:||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 primary objective is to compare the changes in sCD14 levels between the placebo and phases of the study [ Time Frame: End of Study Phase 2 ] [ Designated as safety issue: No ]
- To compare the changes in HIV-1-RNA levels (using the single copy assay or the traditional HIV bDNA assay) between the placebo and the rifaximin phases of the study. [ Time Frame: End of Phase 2 ] [ Designated as safety issue: No ]
- To compare changes in soluble markers of inflammation between the placebo and rifaximin phases of the study. [ Time Frame: End of Phase 2 ] [ Designated as safety issue: No ]
- To compare the changes in cellular markers of IA (changes in the proportion ofCD4+ or CD8+ T cells that express HLA-DR and/or CD38) during the rifaximin phase of the study and compare it with the changes in cellular markers of activation during ... [ Time Frame: End of Phase 2 ] [ Designated as safety issue: No ]
|Study Start Date:||January 2013|
|Estimated Study Completion Date:||May 2018|
|Primary Completion Date:||June 2016 (Final data collection date for primary outcome measure)|
Experimental: HIV Infected Subjects
HIV infected subjects with viral suppression on ART.Double-blinded/placebo controlled trial with cross-overdesign.
Drug: Rifaximin/ Placebo
subject will receive either three capsules of rifaximin (183.3 mg each) by mouth twice daily (total 1100 mg Daily) or will receive three capsules of placebo by mouth twice daily.
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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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01866826
|United States, Maryland|
|Walter Reed National Medical Center|
|Bethesda, Maryland, United States, 20301|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|United States, Pennsylvania|
|University of Pittsburgh|
|Pittsburgh, Pennsylvania, United States, 15213|
|Principal Investigator:||Frank Maldarelli, M.D.||National Cancer Institute (NCI)|