Immune Activation and Drug Absorption in HIV-Infected Patients

The dosing scheme for rifampicin for the treatment of tuberculosis was developed in the
pre-HIV era, and achieving target concentrations at the site of infection is important for a
successful outcome. Rifampicin is the least well absorbed of the first-line anti-TB drugs and
may depend on active transport across the intestinal barrier. Rifampicin malabsorption is
frequently observed in HIV/tuberculosis patients, but cannot be predicted by patient factors
such as CD4+ T cell count, viral load, or the presence of diarrhea. Most importantly, loss of
rifampicin absorptive capacity in the setting of HIV infection would explain the inferior
treatment outcomes that are characteristic of HIV-associated tuberculosis, including early
mortality, relapse after the completion of therapy, and the development of
rifampicin-resistant infection during anti-tuberculosis therapy.

The gut-associated lymphoid tissue is the site of early and dramatic lymphocyte depletion in
HIV+ patients, with near complete loss of intestinal CCR5+ CD4+ T cells within the first few
weeks of infection. Lymphocyte depletion is accompanied by the loss of intestinal epithelial
barrier integrity, and recent attention has focused on potential role of bacterial
translocation across the damaged ("leaky") intestinal barrier. In support of this model,
systemic immune activation markers have been shown to predict HIV progression better than
CD4+ T cell count or HIV viral load. Independent of the potential role of bacterial
translocation, the damage to gut epithelium may have other profound consequences for the
HIV-infected patient.

The impact of this disease progression on the enterocyte's capacity to absorb specific drugs
and nutrients has not been adequately explored. Loss of rifampicin absorptive capacity in the
setting of HIV infection would explain the inferior treatment outcomes that are
characteristic of HIV-associated tuberculosis, including early mortality, relapse after the
completion of therapy, and the development of rifampicin resistant infection during
anti-tuberculosis therapy. Therefore, we propose a pilot study of the relationship between
immune activation, rifampicin absorption, and intestinal capacity for carrier-mediated
transport and permeability, which will lay the foundation for a K23 Career Development Award
application to the Division of AIDS, NIAID.

Rifampicin is an-antibacterial compound from the rifamycin family that is used for the
treatment of certain bacterial infections, and is the cornerstone of the first-line treatment
regimen for tuberculosis. Polymorphisms in a specific drug uptake transporter gene, SLCO1B1,
lead to significant variability in the pharmacokinetics of rifampicin. Other host factors
that negatively influence rifampicin absorption are not well understood, particularly in the
high-risk group of HIV-infected patients with active tuberculosis.

Long-term use of rifampicin is rarely associated with adverse effects that include a flu-like
illness and anemia. Both of these effects cease after termination of the drug. Neither of
these effects has been reported after a single dose administration. Hypersensitivity
reactions presenting with rash have also been reported after prolonged use of rifampicin, but
would be rare after a single-dose administration. The risks associated with rifampicin have
been minimized by studying pharmacokinetics after administration of a single dose, rather
than after prolonged use. Rifampicin is a potent inducer of the cytochrome p450 enzyme system
that is involved in the metabolism of many commonly used therapeutic compounds. For this
reason, we will exclude participants who are receiving any prescription medications with
clinically significant drug-drug interactions with rifampicin.

Inclusion Criteria:

- HIV-infected males and females, between the ages of 21 and 45 years.

- Naïve to antiretroviral therapy

- T cell count greater than 350 cells/mm3

- Body Mass Index (BMI) greater or equal to 19 and less than or equal to 33.

- Weight greater than 60 kilograms.

- Ability and willingness to provide informed consent.

- Ability to swallow oral medications

Exclusion Criteria:

- Breastfeeding.

- Allergy or sensitivity to rifampicin.

- Prior history of documented active tuberculosis infection.

- Receipt of any investigational therapy, chemotherapy, or immune modulatory agents
within 42 days prior to study entry.

- The following laboratory values obtained within 42 days prior to study entry:

Hemoglobin < 12.0 g/dL; Females: Hemoglobin < 11.0 g/dL Platelet count < 100,000/mm3 AST,
ALT, and bilirubin > 5x ULN An estimated creatinine clearance < 80 mL/min based on the
Cockroft-Gault equation

- Positive blood test for latent tuberculosis infection (T-SPOT)

- Female participants of reproductive potential must have a negative serum or urine
pregnancy test performed with 28 days prior to study entry.

"Female participants of reproductive potential" is defined as women who have reached
menarche or who have not been post-menopausal for at least 24 consecutive months (i.e. who
have had menses within the preceding 24 months) or who have not undergone surgical
sterilization (e.g. hysterectomy, or bilateral oophorectomy or salpingectomy).

- Female participants of reproductive potential that are using oral contraceptive pills
(OCPs) must be willing to use barrier precautions for contraception for at least 7
days following each study visit.

- Use of any of the following prescription medications within 30 days prior to study
entry, which may have drug-drug interactions with rifampicin, including (but not
limited to):

- Anti-coagulants (warfarin)

- Cardiac drugs (digoxin, quinidine, verapamil, nifedipine, metoprolol, atenolol,
carvedilol)

- Hypoglycemics (rosiglitazone, pioglitazone, glipizide, repaglinide)

- Proton pump inhibitors (omeprazole, esomeprazole,

- Immune modulators (tacrolimus, cyclosporine)

- Corticosteroids (dexamethasone, prednisone, hydrocortisone)

- H2 blockers (ranitidine, cimetidine)

- HMG CoA reductase inhibitors (atorvastatin, pravastatin, simvastatin)

- Benzodiazepines (alprazolam, diazepam, midazolam, triazolam)

- CNS-acting drugs (amitriptyline, buproprion, clozapine, phenytoin)

- Evidence of current ongoing tobacco use, illicit drug use, or average alcohol use of
greater than 2 drinks per day.

- Any illness that, in the opinion of the study investigator, might confound the results
of the study, or pose an additional risk to the subject by his or her participation in
the study.