Immune Activation and Drug Absorption in HIV-Infected Patients
Condition: HIV Infection
MeSH terms: HIV Infections
Study type: Interventional

Summary: 
      The investigators' objective is to describe the variability of rifampicin absorption, markers
      of inflammation and gut damage, intestinal absorptive capacity, and intestinal permeability
      among HIV-infected volunteers. Rifampicin is the least well absorbed of the first-line
      anti-tuberculosis drugs. Rifampicin malabsorption is frequently observed in HIV-infected
      patients with active tuberculosis, but cannot be predicted by patient factors such as CD4+ T
      cell count, viral load, or the presence of diarrhea. The mechanisms for rifampicin
      malabsorption in HIV-infected patients are unknown. An understanding of mechanisms for
      rifampicin malabsorption could eventually lead to new therapeutic targets, with the ultimate
      goal of improving HIV/tuberculosis treatment outcomes.
    

Detailed description: 
      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.
    

Intervention name(s): Rifampicin 600 mg
Intervention type(s): Drug
Intervention description(s): The investigators will administer a single dose of rifampicin 600 mg to study subjects in order to conduct a pharmacokinetic study of rifampicin absorption.
Other intervention name(s): rifamycin
Intervention MeSH terms: Rifampin; Rifamycins
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science