Rifaximin as a Modulator of Microbial Translocation and Immune Activation

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.

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.