Rifaximin as a Modulator of Microbial Translocation and Immune Activation

Study Overview
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Brief Summary
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This study is being done to see whether rifaximin, an antibiotic that works in the intestines, can lower the amount of germs in the intestines of HIV infected persons. It is possible that when the amount of these germs is lowered, an HIV-infected person's immune system will become less active and will have a better chance of recovering. Also, the study will evaluate the safety of using rifaximin in HIV-infected subjects.

Detailed Description
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A5286 is a randomized, open-label, two-arm, pilot (phase II) study that evaluated whether 4 weeks of treatment with rifaximin, a non-absorbable antibiotic, decreases markers of immune activation and levels of translocated gut microbial products in HIV-1 infected subjects virally suppressed on ART with CD4+ T-cells < 350 cells/mm^3. Rifaximin were admistered to subjects for 3 weeks. Follow-up continued to week 12. The total sample size was 73 subjects. Subjects were randomized at a 2:1 ratio (rifaximin: no study treatment), using permuted blocks, without institutional balancing. Subjects were seen through week 12 for clinical and laboratory evaluations, including plasma HIV-1 RNA, CD4+ T-cell count, and safety laboratories. Subjects had 2 baseline visits -- at pre-entry and entry. Study visits were scheduled at weeks 2, 4, 8, and 12. CD4+ T-cell counts and HIV-1 RNA were measured at all weeks; measures of activations, gut-homing markers, and soluble biomarkers were also performed at all weeks.

Official Title
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A Pilot Study of Rifaximin as a Modulator of Gut Microbial Translocation and Systemic Immune Activation in HIV-Infected Individuals With Incomplete CD4+ T-cell Recovery on Antiretroviral Therapy

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Rifaximin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection On ART for at least 96 weeks prior to study entry with a regimen that includes three or more antiretroviral medications. (Ritonavir ≤ 400 mg/day will not be considered a separate antiretroviral agent.) No plans to change the antiretroviral regimen at least in the next 3 months after study entry. CD4+ cell count < 350 cells/mm3 obtained within 120 days prior to study entry at any laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent. All previous CD4+ cell counts should be < 350 cells/mm3 for at least 96 weeks prior to study entry while subjects were on ART. (A single CD4+ cell count ≥ 350 cells/mm3 is permitted within 96 weeks prior to study entry while subjects were on ART.) Documentation of HIV-1 RNA below the limit of detection (e.g., < 50 copies/mL on Roche Amplicor HIV-1 Monitor assay, < 75 copies/mL on the Versant HIV-1 RNA assay by branched DNA, < 400 copies/mL on a standard Roche Amplicor assay, < 40 copies/mL on the Abbott m2000sp/m2000rt real-time PCR test, < 48 copies/mL on the COBAS AmpliPrep/TAQMAN HIV-1 assay) verified by at least two measurements prior to study entry, one of which must be at least 48 weeks prior to study entry and one measurement that was obtained between 121 days and 48 weeks prior to study entry. Screening HIV-1 RNA below the limit of detection obtained within 120 days prior to study entry using a FDA -approved assay (e.g., < 50 copies/mL on Roche Amplicor HIV-1 Monitor assay, < 75 copies/mL on the Versant HIV-1 RNA assay by branched DNA, < 40 copies/mL on the Abbott m2000sp/m2000rt real-time PCR test, < 48 copies/mL on the COBAS AmpliPrep/TAQMAN HIV-1 assay). (The virologic assay must have a lower limit of detection of ≤ 75 copies/mL.) All other plasma HIV-1 RNA measurements in the 48 weeks prior to study entry must be below the limit of detection. (A single detectable measurement of ≤ 200 copies/mL is permitted if RNA levels immediately before and after are below the limits of detection for the assay.) Certain fasting laboratory values obtained within 45 days prior to entry as indicated in Section 4.1.9 of the protocol. Pre-entry peripheral blood mononuclear cell (PBMC) specimen for assay of the primary immune activation endpoint (change in CD8+ T-cells activation (%HLA-DR+CD38+CD8+ T-cells) has been obtained. Sites must receive confirmation from the processing lab via phone, e-mail, or fax, that this specimen has been entered into the ACTG's Laboratory Data Management System (LDMS). Female subjects of reproductive potential must have a negative serum or urine β-HCG pregnancy test with a sensitivity of at least 50 mIU/mL performed within 24 hours prior to study entry. If participating in sexual activity that could lead to pregnancy, the female subject must agree to use one form of contraceptive as listed in section 4.1.11 of the protocol while receiving protocol-specified treatment and for 4 weeks after stopping the treatment. If the female subject is not of reproductive potential, she is eligible without requiring the use of a contraceptive. Self report is acceptable documentation of sterilization, other contraceptive methods, and menopause. Ability and willingness of subject or legally authorized representative to provide informed consent. Exclusion Criteria: Active diarrhea (3 or more unformed stools per day) within 28 days prior to study entry (except if site investigator or primary care provider attributes diarrhea to antiretroviral or azithromycin use). History of or active inflammatory bowel disease. History of or active Clostridium difficile colitis. History of significant liver disease, defined as having chronic liver disease (including chronic alcoholic liver disease, hepatitis B or C), plus either: a) ascites, b) encephalopathy, or c) a Child-Pugh Score of > 7. Receipt of antimicrobial therapy within 30 days prior to study entry. (NOTE: Antimicrobial use for prophylaxis of opportunistic infections, e.g., azithromycin or trimethoprim-sulfamethoxazole, is allowed.) Active infection requiring the use of antibiotics within 30 days prior to study entry. Known allergy/sensitivity or any hypersensitivity to components of study drug or their formulation (e.g., allergy to rifampin). Serious illness requiring systemic treatment and/or hospitalization within 14 days prior to entry. Use of any of the following medications for more than 3 consecutive days within the 60 days prior to study entry: Immunosuppressives Immune modulators Antineoplastic agents Probiotics Anticoagulants Vaccinations within 1 week prior to the pre-entry or study entry visits. (NOTE: Subjects are encouraged to get the flu vaccine prior to study pre-entry visit.) Participation on any HIV immunotherapy/therapeutic vaccination trials within 6 months prior to study entry. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. Breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Treatment with rifaximin<br>Participants were administered one 550 mg tablet of rifaximin to be taken orally two times a day for 4 weeks. | Drug: Rifaximin<br>* Participant were administered one 550 mg tablet of rifaximin to be taken orally two times a day for 4 weeks.<br>|
| No Intervention: Arm B: No study treatment<br>No study treatment for 4 weeks | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CD8+ T-cell Activation From Baseline to Week 4 | Change in CD8+ T-cell activation percent co-expressing HLA-DR and CD38 from baseline to week 4, where the baseline value is the average of pre-entry and entry values. | At baseline and 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in D-dimer From Baseline to Week 4 | Change in D-dimer from baseline to week 4, where baseline value is the average of pre-entry and entry. D-dimer is a fibrin degradation product (FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. | At baseline and 4 weeks | 
| Change in IL-6 From Baseline to Week 4 | Change in Interleukin (IL)-6 from baseline to week 4, where baseline value is the average of pre-entry and entry | At baseline and 4 weeks | 
| Change in LPS From Baseline to Week 4 | Change in Lipopolysaccharide (LPS) from baseline to week 4, where baseline value is the average of pre-entry and entry | At baseline and 4 weeks | 
| Change in hsCRP From Baseline to Week 4 | Change in High Sensitivity C-reactive Protein (Hs-CRP) from baseline to week 4, where baseline value is the average of pre-entry and entry | At baseline and 4 weeks | 
| Change in sCD14 From Baseline to Week 4 | Change in soluble CD14 (sCD14) from baseline to week 4, where baseline value is the average of pre-entry and entry | At baseline and 4 weeks | 
| Change in Peripheral B7hi CD4+ T-cell From Baseline to Week 4 | Change in gut-homing percent B7hi+ of CD4+ from baseline to week 4, where baseline value is the average of pre-entry and entry | At baseline and 4 weeks | 
| Change in %CD38+ of CD4+ From Baseline to Week 4 | Change in advanced flow percent CD38+ of CD4+ from baseline to week 4, where baseline value is the average of pre-entry and entry | At baseline and 4 weeks | 
| Change in %CD38+ of CD8+ From Baseline to Week 4 | Change in advanced flow percent CD38+ of CD8+ from baseline to week 4, where baseline value is the average of pre-entry and entry | At baseline and 4 weeks | 
| Change in %Ki67+ of CD4+ From Baseline to Week 4 | Change in advanced flow percent Ki67+ of CD4+ from baseline to week 4, where baseline value is the average of pre-entry and entry | At baseline and 4 weeks | 
| Change in %Ki67+ of CD8+ From Baseline to Week 4 | Change in advanced flow percent Ki67+ of CD8+ from baseline to week 4, where baseline value is the average of pre-entry and entry | At baseline and 4 weeks | 
| Change in %HLA-DR+/CD38+ of CD4+ From Baseline to Week 4 | Change in CD4 activation percent co-expressing HLA-DR and CD38 from baseline to week 4, where baseline value is the average of pre-entry and entry | At baseline and 4 weeks | 
| Change in CD38+ of CD8+ MFI From Baseline to Week 4 | Change in CD38+ of CD8+ MFI (Median Fluorescence Intensity) from baseline to week 4, where baseline value is the average of pre-entry and entry. MFI measures the shift in fluorescence intensity of a population of cells. MFI values are based on control to demonstrate an increase or decrease in expression of the marker. MFI in this study was automatically calculated in FlowJo. The median is the relative intensity value below which 50% of the events are found. MFI is an arbitrary unit of relative intensity. | At baseline and 4 weeks | 
| Change in CD4 Count From Baseline to Week 4 | Change in total CD4 T-cell from baseline to week 4, where baseline value is the average of pre-entry and entry | At baseline and 4 weeks | 
| Change in CD8+ T-cell Activation From Week 4 to Week 8 | Change in CD8+ T-cell activation percent co-expressing HLA-DR and CD38 from week 4 to week 8 | At weeks 4 and 8 | 
| Change in D-dimer From Week 4 to Week 8 | D-dimer is a fibrin degradation product (FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. | At weeks 4 and 8 | 
| Change in IL-6 From Week 4 to Week 8 | Change in IL-6 from week 4 to week 8. | At weeks 4 and 8 | 
| Change in LPS From Week 4 to Week 8 | Change in LPS from week 4 to week 8. | At weeks 4 and 8 | 
| Change in hsCRP From Week 4 to Week 8 | Change in hsCRP from week 4 to week 8. | At weeks 4 and 8 | 
| Change in sCD14 From Week 4 to Week 8 | Change in soluble CD14 from week 4 to week 8 | At weeks 4 and 8 | 
| Change in Peripheral B7hi CD4+ T-cells From Week 4 to Week 8 | Change in gut homing percent B7hi+ of CD4+ from week 4 to week 8 | At weeks 4 and 8 | 
| Change in %CD38+ of CD4+ From Week 4 to Week 8 | Change in advanced flow percent CD38+ of CD4+ from week 4 to week 8 | At weeks 4 and 8 | 
| Change in %CD38+ of CD8+ From Week 4 to Week 8 | Change in advanced flow percent CD38+ of CD8+ from week 4 to week 8 | At weeks 4 and 8 | 
| Change in %Ki67+ of CD4+ From Week 4 to Week 8 | Change in advanced flow percent Ki67+ of CD4+ from week 4 to week 8 | At weeks 4 and 8 | 
| Change in %Ki67+ of CD8+ From Week 4 to Week 8 | Change in advanced flow percent Ki67+ of CD8+ from week 4 to week 8 | At weeks 4 and 8 | 
| Change in CD4 Activation Percent From Week 4 to Week 8 | Change in CD4 activation percent co-expressing HLA-DR and CD38 from week 4 to week 8 | At weeks 4 and 8 | 
| Change in CD38+ of CD8+ MFI From Week 4 to Week 8 | Change in CD38+ of CD8+ median fluorescence intensity (MFI) from week 4 to week 8. MFI measures the shift in fluorescence intensity of a population of cells. MFI values are based on control to demonstrate an increase or decrease in expression of the marker. MFI in this study was automatically calculated in FlowJo. The median is the relative intensity value below which 50% of the events are found. MFI is an arbitrary unit of relative intensity. | At weeks 4 and 8 | 
| Change in CD4 Count From Week 4 to Week 8 | Change in total CD4 T-cell count from week 4 to week 8 | At weeks 4 and 8 | 
| Change in CD8+ T-cell Activation From Week 4 to Week 12 | Change in CD8+ T-cell activation percent co-expressing HLA-DR and CD38 from week 4 to week 12 | At weeks 4 and 12 | 
| Change in D-dimer From Week 4 to Week 12 | D-dimer is a fibrin degradation product (FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. | At weeks 4 and 12 | 
| Change in IL-6 From Week 4 to Week 12 | Change in IL-6 from week 4 to week 12. | At weeks 4 and 12 | 
| Change in LPS From Week 4 to Week 12 | Change in LPS from week 4 to week 12. | At weeks 4 and 12 | 
| Change in hsCRP From Week 4 to Week 12 | Change in hsCRP from week 4 to week 12. | At weeks 4 and 12 | 
| Change in sCD14 From Week 4 to Week 12 | Change in soluble CD14 from week 4 to week 12 | At weeks 4 and 8 | 
| Change in Peripheral B7hi CD4+ T-cells From Week 4 to Week 12 | Change in gut homing percent B7hi+ of CD4+ from week 4 to week 12 | At weeks 4 and 12 | 
| Change in %CD38+ of CD4+ From Week 4 to Week 12 | Change in advanced flow percent CD38+ of CD4+ from week 4 to week 12 | At weeks 4 and 12 | 
| Change in %CD38+ of CD8+ From Week 4 to Week 12 | Change in advanced flow percent CD38+ of CD8+ from week 4 to week 12 | At weeks 4 and 12 | 
| Change in %Ki67+ of CD4+ From Week 4 to Week 12 | Change in advanced flow percent Ki67+ of CD4+ from week 4 to week 12 | At weeks 4 and 12 | 
| Change in %Ki67+ of CD8+ From Week 4 to Week 12 | Change in advanced flow percent Ki67+ of CD8+ from week 4 to week 12 | At weeks 4 and 12 | 
| Change in CD4 Activation Percent From Week 4 to Week 12 | Change in CD4 activation percent co-expressing HLA-DR and CD38 from week 4 to week 12 | At weeks 4 and 12 | 
| Change in CD38+ of CD8+ MFI From Week 4 to Week 12 | Change in CD38+ of CD8+ median fluorescence intensity (MFI) from week 4 to week 12. MFI measures the shift in fluorescence intensity of a population of cells. MFI values are based on control to demonstrate an increase or decrease in expression of the marker. MFI in this study was automatically calculated in FlowJo. The median is the relative intensity value below which 50% of the events are found. MFI is an arbitrary unit of relative intensity. | At weeks 4 and 12 | 
| Change in CD4 Count From Week 4 to Week 12 | Change in total CD4 T-cell count from week 4 to week 12 | At weeks 4 and 12 | 
| Primary Adverse Events | Primary adverse events include all SAEs, defined according to ICH guidelines and targeted protocol events (grade 2 or higher signs and symptoms, grade 2 or higher laboratory abnormality, all diagnoses identified by the ACTG criteria for clinical events, and all events that led to a change in treatment regardless of grade). | from study enrollment until study completion at 12 weeks |