Neuropsychiatric complications of antiretroviral therapy.
ABSTRACT Neuropsychiatric adverse effects related to potent antiretroviral therapy are among the complications that can lead to poor adherence, treatment interruptions, or change of antiretroviral therapy regimens. For a historical perspective, we review early literature and case reports with CNS adverse effects attributed to antiretrovirals. The variability of the cerebrospinal fluid penetration of individual antiretrovirals may contribute to their potential for behavioural and psychiatric manifestations. The majority of neuropsychiatric complications related to potent antiretroviral therapy have been associated with the use of the efavirenz. Updates on the risk of neuropsychiatric manifestations with efavirenz use in patients with a history of psychiatric disorders or substance abuse are reviewed. We include a critical review of recently published data on the long-term CNS adverse effects with efavirenz. Special attention is given to the results of recent investigations on the relationship between the pharmacogenomics of genes responsible for efavirenz metabolism and the plasma concentration of efavirenz. It is important to note that there is no established direct correlation of efavirenz concentrations and symptoms. It is not recommended for practitioners to adjust efavirenz doses in order to prevent or alleviate CNS adverse effects. Patients may be placed at risk for virological failure and resistance if they receive suboptimal doses of efavirenz. The aim of this article is to give a concise review and an update on recent literature concerning neuropsychiatric effects of antiretroviral use in HIV-infected patients. Our intent is to present practitioners with data that can be used in a practical way to both educate and improve outcomes in the HIV-infected patient population.
- SourceAvailable from: Luciano Sposato
Article: Iatrogenic neurology.[Show abstract] [Hide abstract]
ABSTRACT: Iatrogenic disease is one of the most frequent causes of hospital admissions and constitutes a growing public health problem. The most common type of iatrogenic neurologic disease is pharmacologic, and the central and peripheral nervous systems are particularly vulnerable. Despite this, iatrogenic disease is generally overlooked as a differential diagnosis among neurologic patients. The clinical picture of pharmacologically mediated iatrogenic neurologic disease can range from mild to fatal. Common and uncommon forms of drug toxicity are comprehensively addressed in this chapter. While the majority of neurologic adverse effects are listed and referenced in the tables, the most relevant issues are further discussed in the text.Handbook of Clinical Neurology 01/2014; 121:1635-71.
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ABSTRACT: Antiretroviral drugs are associated with a variety of adverse effects on the central and peripheral nervous systems. The frequency and severity of neuropsychiatric adverse events is highly variable, with differences between the antiretroviral classes and amongst the individual drugs in each class. In the developing world, where the nucleoside reverse transcriptase inhibitor (NRTI) stavudine remains a commonly prescribed antiretroviral, peripheral neuropathy is an important complication of treatment. Importantly, this clinical entity is often difficult to distinguish from human immunodeficiency virus (HIV)-induced peripheral neuropathy. Several clinical trials have addressed the efficacy of various agents in the treatment of NRTI-induced neurotoxicity. NRTI-induced neurotoxicity is caused by inhibition of mitochondrial DNA polymerase. This mechanism is also responsible for the mitochondrial myopathy and lactic acidosis that occur with zidovudine. NRTIs, particularly zidovudine and abacavir, may also cause central nervous system (CNS) manifestations, including mania and psychosis. The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz is perhaps the antiretroviral most commonly associated with CNS toxicity, causing insomnia, irritability and vivid dreams. Recent studies have suggested that the risk of developing these adverse effects is increased in patients with various cytochrome P450 2B6 alleles. Protease inhibitors cause perioral paraesthesias and may indirectly increase the relative risk of stroke by promoting atherogenesis. HIV integrase inhibitors, C-C chemokine receptor type 5 (CCR5) inhibitors and fusion inhibitors rarely cause neuropsychiatric manifestations.CNS Drugs 12/2013; · 4.38 Impact Factor
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ABSTRACT: Background Efavirenz exhibits multiple interactions with drug-metabolizing enzymes and transporters, and for this reason efavirenz-based HIV therapy is associated with altered pharmacokinetics of coadministered drugs. Probably by the same mechanism, efavirenz-based HIV therapy affects the disposition of endogenous compounds, but this effect is difficult to directly link with efavirenz because it is used in combination with other drugs. Objectives To explore the effect of efavirenz monotherapy on biochemical laboratory values in a clinical trial of healthy volunteers. Methods Men and women (aged 18–49 years) with body mass index ≤32 who were assessed to be healthy based on medical history, physical examination, and standard laboratory screening received a single (600 mg) and multiple doses (600 mg/d for 17 days) of efavirenz orally. This trial was designed to determine the pharmacokinetics and drug interactions of efavirenz. As part of this study, analysis of serum chemistries that were measured at study entry (screening) and 1 week after completion of the multiple dose study (exit) is reported. Results Data from 60 subjects who fully completed and 13 subjects who partially completed the study are presented. Total bilirubin was substantially reduced at exit (by ~30%, with large intersubject variability) compared with screening values (P < 0.0001). The percent changes were in part explained by the intersubject differences in baseline total bilirubin because there was a significant correlation between baseline (screening) values and percent change at exit (r = 0.50; P < 0.0001). Hemoglobin and absolute neutropenia were also substantially decreased at exit compared with screening, but this may be due to intensive blood sampling rather than direct effect of efavirenz on these parameters. No significant correlation was found between percent change in hemoglobin versus percent change in bilirubin, indicating the effect of efavirenz on bilirubin is independent of its effects on hemoglobin. Conclusions Efavirenz monotherapy significantly lowers plasma total bilirubin concentration in healthy volunteers independent of its effect on hemoglobin, probably through its effects on bilirubin metabolism and transport (uptake and efflux). These findings help explain reversal by efavirenz of hyperbilirubinemia induction observed by some protease inhibitor antiretroviral drugs (eg, atazanavir). Besides its well-documented role on drug interactions, efavirenz may alter the disposition of endogenous compounds relevant in physiologic homeostasis through its interaction with drug metabolizing enzymes and/or drug transporters. ClinicalTrials.gov identifier: NCT00668395.Current Therapeutic Research 12/2014; 76:64–69. · 0.45 Impact Factor