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Immune Activation and Drug Absorption in HIV-Infected Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Drexel University
ClinicalTrials.gov Identifier:
NCT01845298
First received: April 29, 2013
Last updated: February 28, 2017
Last verified: February 2017

April 29, 2013
February 28, 2017
June 2014
March 2016   (Final data collection date for primary outcome measure)
Rifampicin Absorption (Ka) [ Time Frame: Baseline ]
The investigators will perform a pharmacokinetic study to assess rifampicin absorption among study subjects. Pharmacokinetic modeling will be used to assess the absorption rate constant (Ka) for each subject.
Same as current
Complete list of historical versions of study NCT01845298 on ClinicalTrials.gov Archive Site
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Immune Activation and Drug Absorption in HIV-Infected Patients
Immune Activation and Drug Absorption in HIV-Infected Patients
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.

Interventional
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Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Basic Science
HIV Infection
Drug: Rifampicin 600 mg
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 Name: rifamycin
Experimental: HIV-infected subjects
HIV-infected subjects who have not yet initiated highly active antiretroviral therapy (HAART). All enrolled subjects will receive a single dose of rifampicin 600 mg.
Intervention: Drug: Rifampicin 600 mg

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
7
March 14, 2016
March 2016   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
21 Years to 45 Years   (Adult)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01845298
TMC114HIV4076
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No
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Drexel University
Drexel University
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Principal Investigator: Christopher Vinnard, MD Faculty
Drexel University
February 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP