Neuropsychiatric complications of efavirenz in children with HIV infection

Efavirenz is an effective antiretroviral agent widely used as part of first-line regimen in HIV1-infected children and adults. Neuropsychiatric adverse effects are reported in up to 50% of users. These include dizziness, insomnia, abnormal dreams, headache and impaired concentration. The plasma level of efavirenz may be key in the development of these adverse effects. Even among individuals taking recommended doses for weight, the plasma levels vary widely. Genetic polymorphisms leading to different allelic variants of the CYP2B6 enzyme, making some individuals slow metabolizers may play a role. These allelic variants are highest in people of African descent. This report examines the neuropsychiatric adverse effects of efavirenz, and the strength of the data that the product may result in neuronal damage.

[1]  Richard D Moore,et al.  The Relationship Between Efavirenz as Initial Antiretroviral Therapy and Suicidal Thoughts Among HIV-Infected Adults in Routine Care , 2017, Journal of acquired immune deficiency syndromes.

[2]  B. Godman,et al.  A review of trials investigating efavirenz-induced neuropsychiatric side effects and the implications , 2016, Expert review of anti-infective therapy.

[3]  L. Kuhn,et al.  Case report: Severe central nervous system manifestations associated with aberrant efavirenz metabolism in children: the role of CYP2B6 genetic variation , 2015, BMC Infectious Diseases.

[4]  R. Chaisson,et al.  Efavirenz Pharmacokinetics and Pharmacodynamics in HIV-Infected Persons Receiving Rifapentine and Isoniazid for Tuberculosis Prevention. , 2015, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[5]  J. Esplugues,et al.  Efavirenz and the CNS: what we already know and questions that need to be answered. , 2015, The Journal of antimicrobial chemotherapy.

[6]  D. Moore,et al.  Efavirenz as a cause of ataxia in children. , 2015, South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde.

[7]  F. Vaida,et al.  Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients , 2015, Journal of NeuroVirology.

[8]  Dan J Stein,et al.  White matter micro-structural changes in ART-naive and ART-treated children and adolescents infected with HIV in South Africa , 2015, AIDS.

[9]  I. Truter,et al.  Efavirenz : a review of the epidemiology, severity and management of neuropsychiatric side-effects , 2015 .

[10]  J. Esplugues,et al.  Efavirenz alters mitochondrial respiratory function in cultured neuron and glial cell lines. , 2015, The Journal of antimicrobial chemotherapy.

[11]  D. Havlir,et al.  Combined effect of CYP2B6 and NAT2 genotype on plasma efavirenz exposure during rifampin-based antituberculosis therapy in the STRIDE study. , 2015, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[12]  H. Jessen,et al.  Cerebrospinal fluid exposure of efavirenz and its major metabolites when dosed at 400 mg and 600 mg once daily: a randomized controlled trial. , 2015, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[13]  A. Winston,et al.  Could antiretroviral neurotoxicity play a role in the pathogenesis of cognitive impairment in treated HIV disease?. , 2015, AIDS.

[14]  B. Eley,et al.  HIV Encephalopathy: pediatric case series description and insights from the clinic coalface , 2015, AIDS Research and Therapy.

[15]  K. Dooley,et al.  Pharmacokinetics of efavirenz and treatment of HIV-1 among pregnant women with and without tuberculosis coinfection. , 2015, The Journal of infectious diseases.

[16]  C. Power,et al.  The brain and HAART: collaborative and combative connections , 2014, Current opinion in HIV and AIDS.

[17]  B. Eley,et al.  Update on the key developments of the neurologic complications in children infected with HIV , 2014, Current opinion in HIV and AIDS.

[18]  J. Esplugues,et al.  Neuronal bioenergetics and acute mitochondrial dysfunction: a clue to understanding the central nervous system side effects of efavirenz. , 2014, The Journal of infectious diseases.

[19]  J. Mukonzo.  The challenge of paediatric efavirenz dosing: implications and way forward for the sub-Saharan Africa. , 2014, AIDS.

[20]  P. Sax,et al.  Association Between Efavirenz as Initial Therapy for HIV-1 Infection and Increased Risk for Suicidal Ideation or Attempted or Completed Suicide , 2014, Annals of Internal Medicine.

[21]  M. Wainberg,et al.  Has the time come to abandon efavirenz for first-line antiretroviral therapy? , 2014, The Journal of antimicrobial chemotherapy.

[22]  K. White,et al.  Week 48 results from a randomized clinical trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults , 2014, AIDS.

[23]  K. White,et al.  Rilpivirine versus efavirenz with emtricitabine/tenofovir disoproxil fumarate in treatment-naïve HIV-1-infected patients with HIV-1 RNA ≤100,000 copies/mL: week 96 pooled ECHO/THRIVE subanalysis. , 2014, AIDS patient care and STDs.

[24]  K. White,et al.  A Randomized, Double-Blind Comparison of Single-Tablet Regimen Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF Versus Single-Tablet Regimen Efavirenz/Emtricitabine/Tenofovir DF for Initial Treatment of HIV-1 Infection: Analysis of Week 144 Results , 2014, Journal of acquired immune deficiency syndromes.

[25]  B. Eley,et al.  Neurologic complications of pediatric human immunodeficiency virus: implications for clinical practice and management challenges in the African setting. , 2014, Seminars in pediatric neurology.

[26]  France Mentré,et al.  Dependence of efavirenz- and rifampicin-isoniazid-based antituberculosis treatment drug-drug interaction on CYP2B6 and NAT2 genetic polymorphisms: ANRS 12154 study in Cambodia. , 2014, The Journal of infectious diseases.

[27]  S. Khoo,et al.  Pharmacogenetic associations with plasma efavirenz concentrations and clinical correlates in a retrospective cohort of Ghanaian HIV-infected patients. , 2014, The Journal of antimicrobial chemotherapy.

[28]  P. Naidoo,et al.  Impact of CYP polymorphisms, ethnicity and sex differences in metabolism on dosing strategies: the case of efavirenz , 2014, European Journal of Clinical Pharmacology.

[29]  Javier González-Maeso,et al.  The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties , 2013, Neuropsychopharmacology.

[30]  G. Maartens,et al.  Neuronal toxicity of efavirenz: a systematic review , 2013, Expert opinion on drug safety.

[31]  D. Haas,et al.  Effects of rifampin-based antituberculosis therapy on plasma efavirenz concentrations in children vary by CYP2B6 genotype , 2013, AIDS.

[32]  L. Bertilsson,et al.  Importance of Ethnicity, CYP2B6 and ABCB1 Genotype for Efavirenz Pharmacokinetics and Treatment Outcomes: A Parallel-Group Prospective Cohort Study in Two Sub-Saharan Africa Populations , 2013, PloS one.

[33]  Y. Yazdanpanah,et al.  Durable Efficacy and Safety of Raltegravir Versus Efavirenz When Combined With Tenofovir/Emtricitabine in Treatment-Naive HIV-1–Infected Patients: Final 5-Year Results From STARTMRK , 2013, Journal of acquired immune deficiency syndromes.

[34]  B. Eley,et al.  Prevalence of Seizures in Children Infected With Human Immunodeficiency Virus , 2013, Journal of child neurology.

[35]  Iris Usach,et al.  Non-nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability , 2013, Journal of the International AIDS Society.

[36]  C. Kenyon,et al.  Severe efavirenz-induced vacuolar axonopathy complicated by fatal aspiration pneumonia. , 2012, British journal of clinical pharmacology.

[37]  Mardge H. Cohen,et al.  A single-nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in plasma and hair among HIV-infected women. , 2012, The Journal of infectious diseases.

[38]  D. Back,et al.  Efavirenz Pharmacokinetics in Cerebrospinal Fluid and Plasma over a 24-Hour Dosing Interval , 2012, Antimicrobial Agents and Chemotherapy.

[39]  A. Kekitiinwa,et al.  Safety and Tolerability of Antiretroviral Therapy Among HIV-Infected Children And Adolescents In UGANDA , 2012, Journal of acquired immune deficiency syndromes.

[40]  J. M. George,et al.  Evidence-based guideline: Antiepileptic drug selection for people with HIV/AIDS , 2012, Neurology.

[41]  N. Holford,et al.  The influence of tuberculosis treatment on efavirenz clearance in patients co-infected with HIV and tuberculosis , 2011, European Journal of Clinical Pharmacology.

[42]  L. Kuhn,et al.  Absence seizures associated with efavirenz initiation. , 2011, The Pediatric infectious disease journal.

[43]  Yusuke Nakamura,et al.  CYP2B6 genotype is a strong predictor of systemic exposure to efavirenz in HIV-infected Zimbabweans , 2011, European Journal of Clinical Pharmacology.

[44]  H. Goforth,et al.  A Systematic Review of the Psychiatric Side-Effects of Efavirenz , 2011, AIDS and Behavior.

[45]  R. Haubrich,et al.  Efavirenz concentrations in CSF exceed IC50 for wild-type HIV. , 2011, The Journal of antimicrobial chemotherapy.

[46]  P. Wintrode,et al.  Efavirenz binding site in HIV-1 reverse transcriptase monomers. , 2010, Biochemistry.

[47]  D. Clifford,et al.  Long-Term Impact of Efavirenz on Neuropsychological Performance and Symptoms in HIV-Infected Individuals (ACTG 5097s) , 2009, HIV clinical trials.

[48]  L. Milani,et al.  A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans. , 2009, British journal of clinical pharmacology.

[49]  G. Maartens,et al.  Effect of Rifampicin on Efavirenz Pharmacokinetics in HIV-Infected Children With Tuberculosis , 2009, Journal of acquired immune deficiency syndromes.

[50]  G. Maartens,et al.  Effect of rifampicin-based antitubercular therapy and the cytochrome P450 2B6 516G>T polymorphism on efavirenz concentrations in adults in South Africa , 2008, Antiviral therapy.

[51]  T. Tenhave,et al.  Slow efavirenz metabolism genotype is common in Botswana. , 2008, Journal of acquired immune deficiency syndromes.

[52]  A. Kwara,et al.  Status epilepticus resulting from severe efavirenz toxicity in an HIV-infected patient. , 2008, The AIDS reader.

[53]  M. Kurowski,et al.  Antiviral efficacy, tolerability and pharmacokinetics of efavirenz in an unselected cohort of HIV-infected children. , 2008, The Journal of antimicrobial chemotherapy.

[54]  M. Hughes,et al.  Long-term Safety and Efficacy of a Once-Daily Regimen of Emtricitabine, Didanosine, and Efavirenz in HIV-Infected, Therapy-Naive Children and Adolescents: Pediatric AIDS Clinical Trials Group Protocol P1021 , 2007, Pediatrics.

[55]  Virginia Cafaro,et al.  Depressive symptoms predict increased incidence of neuropsychiatric side effects in patients treated with efavirenz. , 2006, Journal of acquired immune deficiency syndromes.

[56]  J. Cassuto,et al.  Use of efavirenz is not associated with a higher risk of depressive disorders: a substudy of the randomized clinical trial ALIZE-ANRS 099. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[57]  B. Gazzard,et al.  Changes in sleep quality and brain wave patterns following initiation of an efavirenz‐containing triple antiretroviral regimen , 2006, HIV medicine.

[58]  A. Maeland,et al.  Can efavirenz be taken in the morning? , 2006, Scandinavian journal of infectious diseases.

[59]  C. Königs,et al.  Effect of first line therapy including efavirenz and two nucleoside reverse transcriptase inhibitors in HIV-infected children. , 2005, European journal of medical research.

[60]  M. Eichelbaum,et al.  Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional variants, and possible implications for anti-HIV therapy with efavirenz , 2005, Pharmacogenetics and genomics.

[61]  K. Tashima,et al.  Impact of Efavirenz on Neuropsychological Performance and Symptoms in HIV-Infected Individuals , 2005, Annals of Internal Medicine.

[62]  R. Haubrich,et al.  Comparison of Neuropsychiatric Side Effects in an Observational Cohort of Efavirenz- and Protease Inhibitor-Treated Patients , 2005, HIV clinical trials.

[63]  B. Clotet,et al.  Long-Term Neuropsychiatric Disorders on Efavirenz-Based Approaches: Quality of Life, Psychologic Issues, and Adherence , 2005, Journal of acquired immune deficiency syndromes.

[64]  Catia Marzolini,et al.  Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study , 2004, AIDS.

[65]  Derick R. Peterson,et al.  Effects of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults , 2004, Antimicrobial Agents and Chemotherapy.

[66]  J. Gatell,et al.  Comparison of Once-Daily Atazanavir With Efavirenz, Each in Combination With Fixed-Dose Zidovudine and Lamivudine, As Initial Therapy for Patients Infected With HIV , 2004, Journal of acquired immune deficiency syndromes.

[67]  G. McComsey,et al.  Impact of protease inhibitor substitution with efavirenz in HIV-infected children: results of the First Pediatric Switch Study. , 2003, Pediatrics.

[68]  J. Pachón,et al.  Pharmacokinetic Interactions Between Efavirenz and Rifampicin in HIV-Infected Patients with Tuberculosis , 2002, Clinical pharmacokinetics.

[69]  Michael D. Johnson,et al.  Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cDNA and oligonucleotide expression arrays. , 2001, The Journal of pharmacology and experimental therapeutics.

[70]  P. Quartier,et al.  Tolerance of efavirenz in children , 2001, AIDS.

[71]  A. Telenti,et al.  Efavirenz Plasma Levels Can Predict Treatment Failure and Central Nervous System Side Effects in Hiv-1-infected Patients , 2022 .

[72]  K. Tashima,et al.  Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. , 1999, The New England journal of medicine.

[73]  M. Gersten,et al.  Combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors in children infected with human immunodeficiency virus type 1. Pediatric AIDS Clinical Trials Group 382 Team. , 1999, The New England journal of medicine.

[74]  K. Tashima,et al.  Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) suppression and efavirenz drug concentrations in HIV-1-infected patients receiving combination therapy. , 1999, The Journal of infectious diseases.