The abuse of cocaine and alcohol is strongly linked to HIV infection and transmission of the virus. In some areas, the abuse of these drugs is to a significant degree, driving the epidemic. While several pharmacotherapies are approved for alcohol addiction, no pharmacotherapy has been approved for treatment of cocaine dependence. However, promising results have been obtained with the use of disulfiram (DIS), a FDA approved medication to treat alcohol dependence, for treatment of cocaine or comorbid cocaine/alcohol use disorders. DIS is an inhibitor of aldehyde dehydrogenases (ALDH) and has been reported to alter hepatic cytochrome P450 enzyme function important to metabolism of many drugs frequently used in the treatment of HIV/AIDS. Further, DIS is metabolized to its active metabolite by CYP 3A. Several antiretroviral (ARV) medications are known to alter CYP 3A activity as well. DIS could be a promising treatment for those with cocaine and/or alcohol abuse and HIV disease, but identification and understanding of clinical relevance of potential drug interactions between DIS and ARV are a critically important initial step to determine whether these medications can be used safely in clinical care. This project proposes to use a standard clinical pharmacology study design that employs a within-subject design to examine 3 drug interaction studies between DIS (62.5 mg daily or 250 mg daily) and a frequently prescribed HIV therapeutics that have substantial and clinically significant effects on the CYP 450 drug metabolizing enzyme system including the protease inhibitors (PIs) and CYP 3A4 inhibitors ritonavir and atazanavir and the non-nucleoside reverse transcriptase inhibitor (NNRTI) and CYP 3A4 inducer efavirenz to demonstrate both the effect of DIS administration on ARV pharmacokinetics and the effect of ARV administration on DIS activity (shown by ALDH activity) and DIS pharmacokinetics. Clinical data on effects of these medications alone and in combination on cardiac conduction, hepatic function, and serum lipids will also be obtained. Should results from this project determine that DIS and ARV can be co-administered safely, DIS will be an important pharmacotherapy option for those with comorbid HIV disease and cocaine and/or alcohol dependence. The development of safe and effective pharmacotherapies for cocaine and alcohol use disorders in those with HIV disease will improve the clinical course of affected individuals while decreasing risk of virus transmission. Cocaine and alcohol abuse are strongly linked to HIV infection and transmission of the virus. Disulfiram has long been approved by the US FDA for treatment of alcoholism and recent data shows it to be effective in reducing cocaine abuse. Disulfiram and antiretroviral medications are metabolized by cytochrome P450 3A and concomitant use of these drugs could potentially produce adverse drug interactions underscoring the need to identify and understand the clinical implications of these drug interactions in order to more effectively treat individuals with both HIV disease and cocaine and/or alcohol use disorders.