Immune Activation and Drug Absorption in HIV-Infected Patients

Overview

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.

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.