Interaction of Buprenorphine With HIV Medications and Tuberculosis Medications

The overall objective of this project, RO1 DA 13004 "Opioids and HIV Medications: Interactions in Drug Abusers" and the supplement "Interaction of Buprenorphine and TB Medications," is to continue to improve the clinical care of human immunodeficiency virus (HIV)-infected, substance-abusing patients by identifying significant interactions that may occur between drugs commonly used to treat HIV disease or tuberculosis and buprenorphine, the newest opioid used for maintenance treatment of opioid dependence and an important addition to existing substance abuse pharmacotherapies because its use is not restricted to specialized opiate treatment programs. The research funded by this grant over the past years has shown the presence of significant and clinically important drug interactions between methadone and LAAM in combination with antiretroviral medications. Understanding these drug interactions will allow physicians to safely and more effectively treat HIV disease in opioid-dependent patients. The following specific aims are yet to be completed for this project which has another 2 years of a 5 year funding period: 1. Continuation of studies to determine whether the pharmacokinetics of buprenorphine are affected by coadministration of any of the following HIV medications fosamprenavir/ritonavir, darunavir or the TB medications, rifampin or rifabutin. This will be done by comparing the pharmacokinetics of buprenorphine in the absence and presence of each HIV medication using a within subjects study design with participants who are opioid-dependent, without HIV infection, and receiving medication maintenance treatment with buprenorphine/naloxone (please note that naloxone absorption is negligible and is added to the buprenorphine preparation by the drug manufacturer to diminish the likelihood of diversion of the drug to injected abuse). These studies will allow an answer to a major question of concern to patients and their clinicians: Could starting one of these HIV medications or TB medications result in opioid overdose or withdrawal? These studies will determine whether buprenorphine accumulation and toxicity might occur or whether buprenorphine concentrations at standard medication doses will be subtherapeutic and/or expose the patient to the risk of opioid withdrawal symptoms during conjoint HIV or TB therapy. 2. Continuation of studies to determine whether the pharmacokinetics of the HIV medications fosamprenavir/ritonavir or darunavir, are affected by coadministration of buprenorphine. This will be done in between-subjects studies by comparing the pharmacokinetics of each HIV medication in groups of patients treated with buprenorphine and in a control group without opioid dependence or HIV infection. It will be important to identify any interaction leading to increased exposure to an HIV therapeutic with a concomitant increase in side-effects and toxicities. In addition to unnecessary discomfort and hazard, this may lead to non-adherence and/or increased substance abuse particularly if side effects are interpreted as opioid withdrawal. Equally important, substantial decreases in levels of HIV drugs could lead to subtherapeutic levels, inadequate viral suppression, and the development of antiretroviral resistance and therapeutic failure. (Please note that for the TB medications supplemental studies only the within-subjects component with buprenorphine will be completed due to budgetary constraints of the supplement.) Important clinical effects related to concomitant buprenorphine/HIV therapeutic or TB medication administration are also collected including: 1. Measures of opioid withdrawal symptoms will be collected prior to and following simultaneous buprenorphine/antiretroviral administration 2. Measures of cognitive function will be collected prior to and following simultaneous buprenorphine/antiretroviral administration 3. Measures of the occurrence of adverse events will be systematically collected and chronicled prior to and following simultaneous buprenorphine/antiretroviral administration 4. Effect of buprenorphine alone and buprenorphine in combination with antiretroviral administration on cardiac conduction will be obtained with serial electrocardiograms. 5. Effect of buprenorphine alone and in combination with antiretroviral or anti-TB medication administration on hepatic function through serial collection of laboratory blood tests of liver function to gain insight into the potential of these drugs to produce hepatotoxicity. The experimental protocol allows both sets of studies (Aims 1 and 2) to be accomplished simultaneously in the same buprenorphine-maintained subjects, thereby achieving substantial efficiencies in the current project. The studies offer a cost-effective method for rapid determination of the presence and clinical significance of drug interactions between buprenorphine and pharmacotherapies for infectious diseases of great clinical importance.