Rifaximin for Chronic Immune Activation in People With HIV

The introduction of antiretroviral therapy (ART) has resulted in dramatic reductions in
AIDSrelated morbidity and mortality. Therapy is not curative, however, and the nature of 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 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 LPS levels leading to reductions in immune aced persons receiving
Ativation, 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.

- 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 HIV infection, 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 HIV RNA viral load, rapid HIV test or any other licensed 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 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 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. Hemoglobingreater 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. INR less than or equal to the 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 patient s 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 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.