Clinical trial NCT01866826: Rifaximin for Chronic Immune Activation in People With HIV
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV
Keywords: HIV
Eradication Strategies
Immune Activation
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: University of Pittsburgh
name: Walter Reed National Military Medical Center
First posted: 2013-06-03
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: * PARTICIPANT INCLUSION CRITERIA:

Patients who have agreed in the course of other research studies to have their records reviewed will have the following elements evaluated from their existing records: age, history of human immunodeficiency virus (HIV) infection, antiretroviral therapy (ART) history and viral loads prior to informed consent, or else these elements will be assessed after informed consent. All blood draws to assess eligibility will be completed after obtaining informed consent. To participate in this study the criteria listed below will need to be met.

1. Subjects must be 18 years of age or older.
2. Able and willing to provide written informed consent
3. Must have a history of documented HIV infection.
4. HIV infection if not previously documented at host institutions will need to be documented by a plasma human immunodeficiency virus (HIV) ribonucleic acid (RNA) viral load, rapid HIV test or any other licensed enzyme-linked immunosorbent assay (ELISA) test and confirmed by another test using a different method such as a rapid HIV test, Western Blot, HIV culture, HIV antigen, HIV pro-viral deoxyribonucleic acid (DNA) at any time prior to study entry.
5. ART- treated subjects who are virologically suppressed for greater than or equal to 3 years (1095 days). To meet this criteria all documented viral loads in the 3 years (1095 days) prior to the screening visit must be below the lower limit of detection \[LLD\] using Food and Drug Administration (FDA)-approved standard assays (i.e. \<50 copies/mL) with the following clarification: In each of the three prior years, subjects experiencing a single blip \[i.e. viral loads above the lower limit of detection, LLD\] may be included provided they satisfy the following criteria: the blips are below 200 copies/ml, and the blip is surrounded (i.e the preceding and succeeding viral loads) by undetectable HIV-1 RNA level measurements. That is all viral loads must be below LLD EXCEPT for up to one blip. In any 12 month period.
6. Viral RNA level \< 50 c/ml at Screen 1.
7. A minimum of 2 HIV-1 RNA levels that are below the lower limit of detection using standard assays will be required during the 12 month period prior to their screening visit. As assay characteristics across the sites can vary, LLD for the assay will be used to define whether or not a subject is suppressed.
8. Stable dose of statin therapy for 6 months if receiving statin therapy.
9. No known allergy or contraindication to the use of rifamycin compounds such as rifampin, rifabutin or rifaximin. .
10. The effect of rifaximin on the developing human fetus are unknown, therefore subjects must be willing to use two methods of contraception (one of which must be a barrier method) during the study period. Adequate methods of birth control include: tubal ligation, hysterectomy, condoms (male or female) with or without a spermicide; diaphragm or cervical cap with spermicide; intrauterine device; any of the methods that require a prescription (such as contraceptive pills or patch, Norplant, Depo-Provera, and others) or a male partner who has previously undergone a vasectomy.

The following elements will be assessed with a blood draw and after obtaining informed consent.

1. Absolute Neutrophil count (ANC) greater than or equal to 750/mm(3)
2. Hemoglobin greater than or equal to 10.0 g/dL for women and Hemoglobin 11.0 g/dl for men
3. Platelet count greater than or equal to 75,000/mm(3)
4. Estimated Glomerular Filtration Rate (eGFR) \>60 mL/min, eGFR will be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
5. Confirmed serum glutamate pyruvate transaminase (SGPT)/serum glutamate oxaloacetate transferase (SGOT) less than or equal to 3 times the upper limit of normal (ULN)
6. International Normalized Ratio (INR) less than or equal to the upper limit of normal (ULN) for the assay
7. Negative urine pregnancy test of child bearing potential at randomization
8. No evidence of active hepatitis B or hepatitis C (active hepatitis B will be defined as a positive hepatitis B surface antigen present on a single determination, whereas a positive result on hepatitis C RNA will be considered as evidence of active hepatitis C)

All routine laboratory testing used to determine safety will be completed within the 70 days prior to randomization.

EXCLUSION CRITERIA:

1. Known bleeding diathesis (for example a diagnosis of hemophilia or Von Willebrand disease)
2. Active drug use or alcohol abuse/dependence, which in the opinion of the investigators will interfere with the patients ability to participate in the study
3. Serious illness requiring systemic treatment and/or hospitalization within 30 days of screening into the study
4. Evidence of active opportunistic infections or neoplasms (excluding cutaneous basal cell carcinoma and squamous cell carcinoma) in the 6 months prior to randomization
5. History of inflammatory bowel disease (Crohn's Disease, ulcerative colitis)
6. Positive urine pregnancy test at screening (of child bearing potential).
7. Breastfeeding
8. Current imprisonment
9. Concurrent immunomodulatory agents, including systemic corticosteroids in the 12 weeks prior to randomization. Topical, nasal or inhaled corticosteroid use is allowed
10. Concomitant use of probiotics except yogurt
11. Chronic antibiotic use such as tetracyclines for acne
12. Vaccinations within 6 weeks of randomization
13. Concomitant use of anticoagulants (other than aspirin and nonsteroidal anti-inflammatory drugs (NSAIDS)) is an exclusion criterion for subjects opting in for the colonoscopy. Aspirin and NSAIDs will be discontinued per each institutions requirement before the procedure.
14. Child-Pugh Class C disease
15. A prior history of Clostridium difficile colitis
16. Any condition that precludes the safe administration of conscious sedation for endoscopy (such as decompensated lung or heart disease) will not be able to participate in the colonoscopy aspect of the protocol.

Primary outcomes:
measure: Changes in Soluble Cluster of Differentiation 14 (sCD14) Levels Between the Placebo and Rifaximin Phases of the Study
timeFrame: Between Day 28 of Treatment Phase 1 and Day 28 of Treatment Phase 2
Secondary outcomes:
measure: 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
timeFrame: Between Day 28 of Treatment Phase 1 and Day 28 of Treatment Phase 2
measure: Changes in Soluble Markers of Inflammation Between the Placebo and Rifaximin Phases of the Study
timeFrame: Between Day 28 of Treatment Phase 1 and Day 28 of Treatment Phase 2
measure: Changes in Cellular Markers of Immune Activation Between the Placebo and Rifaximin Phases of the Study
timeFrame: Between Day 28 of Treatment Phase 1 and Day 28 of Treatment Phase 2
measure: Number of Participants With Serious and Non-Serious Adverse Events
timeFrame: From baseline until up to approximately 14 weeks
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: Walter Reed National Medical Center
state: Maryland
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
Study officials:
affiliation: National Cancer Institute (NCI)
name: Frank Maldarelli, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Deeks SG. Immune dysfunction, inflammation, and accelerated aging in patients on antiretroviral therapy. Top HIV Med. 2009 Sep-Oct;17(4):118-23.
citation: Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, Ledergerber B, Lundgren J, Neuhaus J, Nixon D, Paton NI, Neaton JD; INSIGHT SMART Study Group. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008 Oct 21;5(10):e203. doi: 10.1371/journal.pmed.0050203.
citation: Hunt PW, Martin JN, Sinclair E, Bredt B, Hagos E, Lampiris H, Deeks SG. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis. 2003 May 15;187(10):1534-43. doi: 10.1086/374786. Epub 2003 Apr 23.