Pharmacogenetics of efavirenz discontinuation for reported central nervous system symptoms appears to differ by race

Background Efavirenz frequently causes central nervous system (CNS) symptoms. We evaluated genetic associations with efavirenz discontinuation for CNS symptoms within 12 months of treatment initiation. Methods Patients had initiated efavirenz-containing regimens at an HIV primary care clinic in the Southeastern United States and had at least 12 months of follow-up data. Polymorphisms in CYP2B6 and CYP2A6 defined efavirenz metabolizer categories. Genome-wide genotyping enabled adjustment for population stratification. Results Among 563 evaluable patients, 99 (17.5%) discontinued efavirenz within 12 months, 29 (5.1%) for CNS symptoms. The hazard ratio (HR) for efavirenz discontinuation for CNS symptoms in slow versus extensive metabolizers was 4.9 [95% confidence interval (CI): 1.9–12.4; P=0.001]. This HR in Whites was 6.5 (95% CI: 2.3–18.8; P=0.001) and 2.6 in Blacks (95% CI: 0.5–14.1; P=0.27). Considering only slow metabolizers, the HR in Whites versus Blacks was 3.1 (95% CI: 0.9–11.0; P=0.081). The positive predictive value of slow metabolizer genotypes for efavirenz discontinuation was 27% in Whites and 11% in Blacks. Conclusion Slow metabolizer genotypes were associated significantly with efavirenz discontinuation for reported CNS symptoms. This association was considerably stronger in Whites than in Blacks.

[1]  T. Manini,et al.  Long-Term Cigarette Smoking Trajectories Among HIV-Seropositive and Seronegative MSM in the Multicenter AIDS Cohort Study , 2016, AIDS and Behavior.

[2]  A. Farr,et al.  No Evidence of an Association Between Efavirenz Exposure and Suicidality Among HIV Patients Initiating Antiretroviral Therapy in a Retrospective Cohort Study of Real World Data , 2016, Medicine.

[3]  K. Freedberg,et al.  Cost-effectiveness of CYP2B6 genotyping to optimize efavirenz dosing in HIV clinical practice. , 2015, Pharmacogenomics.

[4]  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.

[5]  H. Chu,et al.  Investigation of Efavirenz Discontinuation in Multi-ethnic Populations of HIV-positive Individuals by Genetic Analysis , 2015, EBioMedicine.

[6]  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.

[7]  D. Haas,et al.  Secondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes. , 2014, The Journal of antimicrobial chemotherapy.

[8]  B. Gazzard,et al.  Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial , 2014, The Lancet.

[9]  H. Tilson,et al.  No evident association between efavirenz use and suicidality was identified from a disproportionality analysis using the FAERS database , 2014, Journal of the International AIDS Society.

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

[11]  R. Tyndale,et al.  Ethanol self-administration and nicotine treatment induce brain levels of CYP2B6 and CYP2E1 in African green monkeys , 2013, Neuropharmacology.

[12]  Marylyn D Ritchie,et al.  Genome-wide association study of plasma efavirenz pharmacokinetics in AIDS Clinical Trials Group protocols implicates several CYP2B6 variants , 2012, Pharmacogenetics and genomics.

[13]  R. Kuchenbecker,et al.  Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1. , 2011, Annals of internal medicine.

[14]  D. Katzenstein,et al.  Atazanavir Plus Ritonavir or Efavirenz as Part of a 3-Drug Regimen for Initial Treatment of HIV-1 , 2011, Annals of Internal Medicine.

[15]  K. Sagoe,et al.  Paradoxically elevated efavirenz concentrations in HIV/tuberculosis-coinfected patients with CYP2B6 516TT genotype on rifampin-containing antituberculous therapy , 2011, AIDS.

[16]  Matthias Cavassini,et al.  Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study. , 2011, The Journal of infectious diseases.

[17]  D. Clifford,et al.  Effect of CYP2B6, ABCB1, and CYP3A5 polymorphisms on efavirenz pharmacokinetics and treatment response: an AIDS Clinical Trials Group study. , 2010, The Journal of infectious diseases.

[18]  D. Cooper,et al.  Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. , 2010, The Journal of infectious diseases.

[19]  Adriano Lazzarin,et al.  Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial , 2009, The Lancet.

[20]  C. Guillemette,et al.  Glucuronidation of the Antiretroviral Drug Efavirenz by UGT2B7 and an in Vitro Investigation of Drug-Drug Interaction with Zidovudine , 2009, Drug Metabolism and Disposition.

[21]  Huldrych F. Günthard,et al.  In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function , 2009, Pharmacogenetics and genomics.

[22]  K. Sagoe,et al.  CYP2B6 (c.516G-->T) and CYP2A6 (*9B and/or *17) polymorphisms are independent predictors of efavirenz plasma concentrations in HIV-infected patients. , 2009, British journal of clinical pharmacology.

[23]  Lynne Peeples,et al.  Class-sparing regimens for initial treatment of HIV-1 infection. , 2008, The New England journal of medicine.

[24]  T. Harrer,et al.  Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients. , 2008, The Journal of antimicrobial chemotherapy.

[25]  G. Swan,et al.  Gene–gene interactions between CYP2B6 and CYP2A6 in nicotine metabolism , 2007, Pharmacogenetics and genomics.

[26]  S. Matsushita,et al.  Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P450 2B6 *6 and *26. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[27]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[28]  Lang Li,et al.  Impact of CYP2B6 polymorphism on hepatic efavirenz metabolism in vitro. , 2007, Pharmacogenomics.

[29]  P. Binkley,et al.  Highly variable mRNA expression and splicing of L-type voltage-dependent calcium channel alpha subunit 1C in human heart tissues , 2006, Pharmacogenetics and genomics.

[30]  Christopher D Pilcher,et al.  Three- vs four-drug antiretroviral regimens for the initial treatment of HIV-1 infection: a randomized controlled trial. , 2006, JAMA.

[31]  M. Ingelman-Sundberg,et al.  Identification of a novel specific CYP2B6 allele in Africans causing impaired metabolism of the HIV drug efavirenz , 2006, Pharmacogenetics and genomics.

[32]  M. Hirsch,et al.  Pharmacogenetics of long-term responses to antiretroviral regimens containing Efavirenz and/or Nelfinavir: an Adult Aids Clinical Trials Group Study. , 2005, The Journal of infectious diseases.

[33]  F. Gutiérrez,et al.  Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

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

[35]  V. Soriano,et al.  Influence of 516G>T polymorphisms at the gene encoding the CYP450-2B6 isoenzyme on efavirenz plasma concentrations in HIV-infected subjects. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[36]  Amalio Telenti,et al.  Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients , 2005, Pharmacogenetics and genomics.

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

[38]  S. Oka,et al.  Homozygous CYP2B6 *6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimens. , 2004, Biochemical and Biophysical Research Communications - BBRC.

[39]  B. Gazzard,et al.  Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study , 2004, The Lancet.

[40]  V. Soriano,et al.  Analyzing sleep abnormalities in HIV-infected patients treated with Efavirenz. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[41]  David A. Flockhart,et al.  The Cytochrome P450 2B6 (CYP2B6) Is the Main Catalyst of Efavirenz Primary and Secondary Metabolism: Implication for HIV/AIDS Therapy and Utility of Efavirenz as a Substrate Marker of CYP2B6 Catalytic Activity , 2003, Journal of Pharmacology and Experimental Therapeutics.

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

[43]  Kiyoshi Inoue,et al.  Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes , 1999, Archives of Toxicology.