Content area
Full text
Efavirenz is a potent and effective non-nucleoside reverse transcriptase inhibitor that is a preferred component of first-line antiretroviral therapy (ART) for HIV-1-infected individuals in both wealthy and resource-limited countries [1,2]. The use of efavirenz in clinical practice has further increased in recent years, especially in developing countries. It is usually prescribed at a fixed dosage of 600 mg once daily. Some patients who receive efavirenz have experienced adverse effects such as neuropsychiatric manifestations, skin rash, hepatitis and dyslipidemia [1,3]. In clinical practice, concern over neuropsychiatric adverse effects often plays a role in the decision of whether or not to include efavirenz as part of ART. Prediction of therapeutic efficacy and the likelihood of developing psychiatric disorders have been associated with plasma efavirenz concentrations [4]. The preferable mid-dosing plasma level of efavirenz is 1000-4000 ng/ml to allow for optimized antiretroviral potency and to minimize the risk of neuropsychiatric toxicity. HIV-1-infected patients who receive standard-dose efavirenz and have plasma efavirenz concentration of <1000 ng/ml appear to have a higher risk for virological failure and emergence of selective drug resistance, while those with high plasma efavirenz concentrations of >4000 ng/ml may experience adverse CNS effects more frequently [4]. Many studies have highlighted the potential for serious psychiatric complications with efavirenz, including depression, psychosis, amnesia, extreme excitability, aggressive behavior, post-traumatic stress disorder symptoms and induced suicidal effect [3,4]. However, increased neuropsychiatric adverse effects were typically reported only during the first month after starting this medication [4-6]. Clinical trials have reported CNS side effects in >50% of patients following initiation of efavirenz-based ART. In patients initiating efavirenz therapy for the first time, the development of adverse effects may negatively influence adherence and subsequent treatment failure [6]. The effect of genetic polymorphisms on efavirenz pharmacokinetics is markedly considered because the plasma concentration of efavirenz has been found to be a reliable predictor of treatment failure and risk of neurologic side effects.
CYP2B6 polymorphisms, efavirenz concentrations & CNS adverse effects
Genetic variance among individuals influences the metabolism, distribution and elimination of drugs. Higher plasma efavirenz concentrations may be a result of genetic differences in the metabolism of this drug. Efavirenz is metabolized by CYP2B6, CYP2A6 and UGT2B7 [7]. However, CYP2B6 is the major metabolizing enzyme involved in the metabolism of efavirenz,...