Approximately one in three new HIV infections occurring outside of sub-Saharan Africa is related to injection drug use. Because this epidemic is primarily driven by the injection of opiates, several countries have initiated methadone maintenance treatment as part of their HIV prevention, treatment, and care strategy. In many of these settings more than 30% of patients entering methadone treatment are HIV+. Most will be on antiretroviral therapies (ART) at some point during their treatment with methadone. Interactions between the two most commonly used ART in the world, nevirapine (NVP) and efavirenz (EFV), and methadone are well known but poorly characterized in clinical populations. These interactions frequently lead to opiate withdrawal symptoms, patient destabilization, and return to drug use that results in a cascade of poor ART adherence and increased morbidity related to drug use and inconsistent HIV care. Adjustment of methadone dose in the setting of methadone-ART interactions can return the patient to stability. There are no clear data to help a clinician determine the extent to which a methadone dose should be adjusted following methadone-ART interactions. Currently, clinicians must guess on methadone dose adjustments until the desired clinical response is achieved. The overall goal of our work is to The following research proposal focuses on the creation of a population pharmacokinetic model of methadone in a real-world clinical setting with a high prevalence of HIV and use of NVP and EFV. This will be accomplished through two specific aims: 1) Use population pharmacokinetics in a real-world clinical setting to measure differences in methadone exposure (e.g., area under the concentration-time curve, AUC; and relationship between dose and apparent oral clearance, CL/F) between those on NVP or EFV and those not on NVP or EFV, respectively; and 2) Evaluate the influence of selected genetic polymorphisms on methadone pharmacokinetics and methadone-NVP and -EFV interactions.
Methadone treatment of opiate dependence is part of the HIV cascade of care. Retention in HIV care is jeopardized when drug-drug interactions between methadone and ART destabilize patients by inducing opiate withdrawal. This study will develop pharmacokinetic models of these interactions in a real-world clinical population in order to create rational methadone dosing recommendations.