The primary objective of this multi-center sub-study of USPHS Study 23: "Intensive
Pharmacokinetic Study of Intermittent Rifabutin and Isoniazid with Daily Efavirenz in
Combination with Two Nucleoside Analogs for Treatment of HIV and Tuberculosis
Co-infections," is to compare the pharmacokinetics of rifabutin at 600 mg twice a week in
combination with efavirenz 600 mg daily to the pharmacokinetics of rifabutin 300 mg twice a
week without efavirenz. Secondary objectives are: (1) To describe pharmacokinetics of both
rifabutin and efavirenz in combination regimen, (2) To evaluate the safety of concomitant
efavirenz and rifabutin, (3) To assess the effect on absolute neutrophil count by changing
rifabutin dose and adding efavirenz to the regimen, (4) To develop models of optimal
sampling times for rifabutin dosed twice a week, (5) To describe the pharmacokinetics of
isoniazid in combination with efavirenz daily with two NRTIs, (6) To compare the
pharmacokinetics of isoniazid with and without efavirenz.
BACKGROUND: There are two concerns regarding rifabutin and INH pharmacokinetics in this
population: 1) Malabsorption of anti-TB medications is frequent in this population and 2)
Many antiretrovirals and other drugs frequently used in the management of HIV-infected
individuals are inhibitors of the cytochrome p450 3A4 isoform and result in increased levels
of rifabutin. Correlation of the pharmacokinetic and clinical outcomes in the setting of
these interactions is essential.
METHODS: The study will be done on the General Clinical Research Center at Duke University
Medical Center, on an inpatient basis (depending on where the patient lives). No one who is
suspected of being infectious or is infectious from TB will be enrolled on the GCRC. After
informed consent is obtained, each subject will be admitted to the GCRC twice; the first
admission will occur after at least four twice weekly doses of intermittent rifabutin and
prior to beginning antiretroviral therapy and the second admission will occur two to six
weeks following the institution of an antiretroviral regimen including efavirenz. During
Admission #1, blood will be drawn at 0, 1, 3, 5, 7, 9, and 21 hours post dosing with INH and
rifabutin. During Admission #2, blood will be drawn at 0, 2, 4, 6, 8, 10, 12, and 24 hours.
Efavirenz will be given at time points 0 and 24 hours post sampling. TB drugs will be
given at 3 hours (so that sampling times subsequent to INH/rifabutin dosing will correspond
to those of Admission #1). Patients will be interviewed regarding concomitant medications,
gastrointestinal symptoms and meals relative to study drug dosing. Sixty days following the
last dose of PK study medicines, a follow-up visit or phone call (including review of
medical record) will identify any adverse events.
DATA ANALYSIS: Frequency distributions will include plots of the data, distribution curves
to test for normality, parametric and non-parametric measures of central tendency and
dispersion, as well as the Shapiro-Wilk W test for normality. Means will be reported + the
standard deviation (SD). The percent coefficient of variation (CV) will be calculated as
(SD/mean) multiplied by 100%. Correlation analysis (JMP) will be performed across the
subject and outcome variables using non-parametric techniques (Spearman Rho, continuous data
only). The dependence of outcome variables (the pharmacokinetic parameters) upon subject
characteristics (demographic data such as age, weight, CD4 count, etc.) will be determined
by using Y by X analyses, one parameter at a time (continuous or nominal data).
Subsequently, models with multiple X variables will be constructed using forward addition
and backward deletion. Correlations between parameters and covariates will be considered
statistically significant at p 3/4 0.05.
Inclusion criteria: Eligible subjects enrolled in Study 23 or HIV-infected patients with
culture confirmed or suspected tuberculosis. Subjects must be currently receiving
tuberculosis therapy including twice weekly isoniazid and rifabutin and currently not
receiving antiretroviral therapy. Subjects must be willing to begin an antiretrovial
regimen containing efavirenz and two NRTIs (combinations defined by protocol) at the
requisite dosing. Exclusion criteria include hematocrit of less than 25%, pregnant or
lactating women, prior use of an NNRTI, or use of a protease inhibitor or select
medications defined in the protocol. Women of child-bearing potential must agree to
practice an adequate (barrier) method of birth control and submit to serum pregnancy
testing with 14 days of enrollment.