Rifaximin for Chronic Immune Activation in People With HIV
- Registration Number
- NCT01866826
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
* 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.
Objectives:
- To see if Rifaximin can reduce bacteria-related inflammation in people with HIV.
Eligibility:
- Individuals at least 18 years of age who have HIV infection and are taking medications to treat it.
Design:
* 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.
- Detailed Description
The introduction of antiretroviral therapy (ART) has resulted in dramatic reductions in acquired immune deficiency syndrome (AIDS) related morbidity and mortality. Therapy is not curative, however, and the nature of human immunodeficiency virus (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 cluster of differentiation (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 lipopolysaccharides (LPS) levels leading to reductions in immune aced persons receiving Activation, 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 46
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description HIV Infected Subjects Placebo Placebo HIV infected subjects with viral suppression on ART. Double-blinded/placebo controlled trial with cross-over design. Placebo HIV Infected Subjects Rifaximin Human immunodeficiency virus (HIV) infected subjects with viral suppression on antiretroviral (ART). Double-blinded/placebo controlled trial with cross-over design. Rifaximin
- Primary Outcome Measures
Name Time Method Changes in Soluble Cluster of Differentiation 14 (sCD14) Levels Between the Placebo and Rifaximin Phases of the Study Between Day 28 of Treatment Phase 1 and Day 28 of Treatment Phase 2 One sample Wilcoxon statistic was applied to evaluate the difference on treatment phases between the placebo and Rifaximin.
- Secondary Outcome Measures
Name Time Method Changes in Cellular Markers of Immune Activation Between the Placebo and Rifaximin Phases of the Study Between Day 28 of Treatment Phase 1 and Day 28 of Treatment Phase 2 Changes in cellular markers of immune activation (IA) is defined as changes in the percentage of cluster of differentiation 4 (CD4) + or cluster of differentiation 8 (CD8)+ T cells that express human leukocyte antigen - antigen D Related (HLA-DR) and cluster of differentiation 38 (CD38). Differences will be tested by using both the Wilcoxon and the t-test.
Number of Participants With Viral (HIV-1)-Ribonucleic Acid (RNA) Elevated by Greater Than 50 Copies/ml Plasma at the End of the Rifaximin or Placebo Phase Between Day 28 of Treatment Phase 1 and Day 28 of Treatment Phase 2 HIV-1-RNA levels were assessed by using the single copy assay or the traditional HIV Branched Deoxyribonucleic Acid bDNA assay to determine elevations in HIV-1 RNA \>50 copies/ml plasma at the end of the Rifaximin or placebo phase. Differences were tested by using both the Wilcoxon and the t-test.
Changes in Soluble Markers of Inflammation Between the Placebo and Rifaximin Phases of the Study Between Day 28 of Treatment Phase 1 and Day 28 of Treatment Phase 2 Changes in soluble marker of inflammation Interleukin 6 (IL6) between the placebo and rifaximin phases of the study. Differences will be tested by using both the Wilcoxon and the t-test.
Number of Participants With Serious and Non-Serious Adverse Events From baseline until up to approximately 14 weeks The number of participants with serious and non-serious adverse events that were possibly related to Rifaximin or Placebo as assessed by the Division of Acquired Immune Deficiency Syndrome (AIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0 A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Trial Locations
- Locations (3)
University of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
Walter Reed National Medical Center
🇺🇸Bethesda, Maryland, United States
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States