Clinical trial NCT01466595: Rifaximin as a Modulator of Microbial Translocation and Immune Activation
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV-1 Infection
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2011-11-08
Enrollment: 73
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in CD8+ T-cell Activation From Baseline to Week 4
timeFrame: At baseline and 4 weeks
Secondary outcomes:
measure: Change in D-dimer From Baseline to Week 4
timeFrame: At baseline and 4 weeks
measure: Change in IL-6 From Baseline to Week 4
timeFrame: At baseline and 4 weeks
measure: Change in LPS From Baseline to Week 4
timeFrame: At baseline and 4 weeks
measure: Change in hsCRP From Baseline to Week 4
timeFrame: At baseline and 4 weeks
measure: Change in sCD14 From Baseline to Week 4
timeFrame: At baseline and 4 weeks
measure: Change in Peripheral B7hi CD4+ T-cell From Baseline to Week 4
timeFrame: At baseline and 4 weeks
measure: Change in %CD38+ of CD4+ From Baseline to Week 4
timeFrame: At baseline and 4 weeks
measure: Change in %CD38+ of CD8+ From Baseline to Week 4
timeFrame: At baseline and 4 weeks
measure: Change in %Ki67+ of CD4+ From Baseline to Week 4
timeFrame: At baseline and 4 weeks
measure: Change in %Ki67+ of CD8+ From Baseline to Week 4
timeFrame: At baseline and 4 weeks
measure: Change in %HLA-DR+/CD38+ of CD4+ From Baseline to Week 4
timeFrame: At baseline and 4 weeks
measure: Change in CD38+ of CD8+ MFI From Baseline to Week 4
timeFrame: At baseline and 4 weeks
measure: Change in CD4 Count From Baseline to Week 4
timeFrame: At baseline and 4 weeks
measure: Change in CD8+ T-cell Activation From Week 4 to Week 8
timeFrame: At weeks 4 and 8
measure: Change in D-dimer From Week 4 to Week 8
timeFrame: At weeks 4 and 8
measure: Change in IL-6 From Week 4 to Week 8
timeFrame: At weeks 4 and 8
measure: Change in LPS From Week 4 to Week 8
timeFrame: At weeks 4 and 8
measure: Change in hsCRP From Week 4 to Week 8
timeFrame: At weeks 4 and 8
measure: Change in sCD14 From Week 4 to Week 8
timeFrame: At weeks 4 and 8
measure: Change in Peripheral B7hi CD4+ T-cells From Week 4 to Week 8
timeFrame: At weeks 4 and 8
measure: Change in %CD38+ of CD4+ From Week 4 to Week 8
timeFrame: At weeks 4 and 8
measure: Change in %CD38+ of CD8+ From Week 4 to Week 8
timeFrame: At weeks 4 and 8
measure: Change in %Ki67+ of CD4+ From Week 4 to Week 8
timeFrame: At weeks 4 and 8
measure: Change in %Ki67+ of CD8+ From Week 4 to Week 8
timeFrame: At weeks 4 and 8
measure: Change in CD4 Activation Percent From Week 4 to Week 8
timeFrame: At weeks 4 and 8
measure: Change in CD38+ of CD8+ MFI From Week 4 to Week 8
timeFrame: At weeks 4 and 8
measure: Change in CD4 Count From Week 4 to Week 8
timeFrame: At weeks 4 and 8
measure: Change in CD8+ T-cell Activation From Week 4 to Week 12
timeFrame: At weeks 4 and 12
measure: Change in D-dimer From Week 4 to Week 12
timeFrame: At weeks 4 and 12
measure: Change in IL-6 From Week 4 to Week 12
timeFrame: At weeks 4 and 12
measure: Change in LPS From Week 4 to Week 12
timeFrame: At weeks 4 and 12
measure: Change in hsCRP From Week 4 to Week 12
timeFrame: At weeks 4 and 12
measure: Change in sCD14 From Week 4 to Week 12
timeFrame: At weeks 4 and 8
measure: Change in Peripheral B7hi CD4+ T-cells From Week 4 to Week 12
timeFrame: At weeks 4 and 12
measure: Change in %CD38+ of CD4+ From Week 4 to Week 12
timeFrame: At weeks 4 and 12
measure: Change in %CD38+ of CD8+ From Week 4 to Week 12
timeFrame: At weeks 4 and 12
measure: Change in %Ki67+ of CD4+ From Week 4 to Week 12
timeFrame: At weeks 4 and 12
measure: Change in %Ki67+ of CD8+ From Week 4 to Week 12
timeFrame: At weeks 4 and 12
measure: Change in CD4 Activation Percent From Week 4 to Week 12
timeFrame: At weeks 4 and 12
measure: Change in CD38+ of CD8+ MFI From Week 4 to Week 12
timeFrame: At weeks 4 and 12
measure: Change in CD4 Count From Week 4 to Week 12
timeFrame: At weeks 4 and 12
measure: Primary Adverse Events
timeFrame: from study enrollment until study completion at 12 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS (5801)
state: Alabama
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS (601)
state: California
city: Palo Alto
country: United States
facility: Stanford CRS (501)
state: California
city: San Francisco
country: United States
facility: Ucsf Aids Crs (801)
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS (6101)
state: Colorado
city: Washington
country: United States
facility: Georgetown University CRS (GU CRS) (1008)
state: District of Columbia
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS (901)
state: Florida
city: Atlanta
country: United States
facility: The Ponce de Leon Center CRS (5802)
state: Georgia
city: Chicago
country: United States
facility: Northwestern University CRS (2701)
state: Illinois
city: Chicago
country: United States
facility: Rush Univ. Med. Ctr. ACTG CRS (2702)
state: Illinois
city: Baltimore
country: United States
facility: IHV Baltimore Treatment CRS (4651)
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS (101)
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hosp. ACTG CRS (107)
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med. Ctr., ACTG CRS (103)
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington U CRS (2101)
state: Missouri
city: Newark
country: United States
facility: New Jersey Medical School-Adult Clinical Research Ctr. CRS (31477)
state: New Jersey
city: New York
country: United States
facility: Cornell CRS (7804)
state: New York
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS (401)
state: New York
city: New York
country: United States
facility: HIV Prevention & Treatment CRS (30329)
state: New York
city: Rochester
country: United States
facility: AIDS Care CRS (1108)
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS (1101)
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs (3201)
state: North Carolina
city: Durham
country: United States
facility: Duke Univ. Med. Ctr. Adult CRS (1601)
state: North Carolina
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS (2401)
state: Ohio
city: Cleveland
country: United States
facility: Case CRS (2501)
state: Ohio
city: Cleveland
country: United States
facility: Metro Health CRS (2503)
state: Ohio
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS (2301)
state: Ohio
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS (6201)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Pittsburgh CRS (1001)
state: Pennsylvania
city: Providence
country: United States
facility: The Miriam Hosp. ACTG CRS (2951)
state: Rhode Island
city: Seattle
country: United States
facility: University of Washington AIDS CRS (1401)
state: Washington
city: San Juan
country: Puerto Rico
facility: Puerto Rico-AIDS CRS (5401)
Study officials:
affiliation: Rush University Medical Center
name: Allan R. Tenorio, M.D.
role: STUDY_CHAIR
References:
citation: Tenorio AR, Chan ES, Bosch RJ, Macatangay BJ, Read SW, Yesmin S, Taiwo B, Margolis DM, Jacobson JM, Landay AL, Wilson CC; A5286 Team. Rifaximin has a marginal impact on microbial translocation, T-cell activation and inflammation in HIV-positive immune non-responders to antiretroviral therapy - ACTG A5286. J Infect Dis. 2015 Mar 1;211(5):780-90. doi: 10.1093/infdis/jiu515. Epub 2014 Sep 11.