CYP2B6 genetic variants are associated with nevirapine pharmacokinetics and clinical response in HIV-1-infected children

Background:Cytochrome P450 2B6 (CYP2B6)-G516T genotype is associated with altered activity of hepatic CYP2B6 and efavirenz pharmacokinetics, but the relationship between the CYP2B6-G516T genotype and nevirapine (NVP) pharmacokinetics in plasma and cerebrospinal fluid (CSF) is limited. Methods:In 126 children who received NVP and protease inhibitors from PACTG 366 and 377 cohorts, CYP2B6 and ATP-binding cassette, sub-family B, member 1 (ABCB1) gene polymorphisms were analyzed using real-time PCR. Plasma NVP pharmacokinetics and clinical data were collected and levels of NVP in CSF were evaluated in children with HIV-related neurologic diseases. Results:NVP oral clearance in children with the CYP2B6-516-T/T genotype (homozygous variant, n = 14) was 1.6 l/h per m2, which was significantly decreased compared to 2.3 l/h per m2 in those with the -G/G (wild type, n = 49, P = 0.002) and 2.1 l/h per m2 in those with the -G/T genotype (heterozygous variants, n = 63, P = 0.008). Furthermore, children with the -T/T genotype had a significant increase in CD4+ T-cell percentage (+9.0%) compared with those with the -G/G (+3.2%, P = 0.01) and -G/T genotype (+5.0%, P = 0.04) from baseline to week 12. The same trend continued at week 24. Although ABCB1-C3435T genotypes did not affect plasma NVP pharmacokinetics (P = 0.39), the NVP CSF: plasma ratios were significantly higher in children with the ABCB1-3435-C/T or -T/T genotypes (0.62, n = 9) in comparison with those with the ABCB1-3435-C/C genotype (0.43, n = 5) (P = 0.01). Conclusions:The CYP2B6-G516T genotype alters NVP pharmacokinetics and the immunologic response to NVP-containing HAART regimens in children. These data suggest that the CYP2B6-G516T is an important genetic variant that alters the pharmacokinetics and response to HAART regimens containing NVP.

[1]  S. Spector,et al.  Efavirenz Pharmacokinetics in HIV-1-Infected Children Are Associated With CYP2B6-G516T Polymorphism , 2007, Journal of acquired immune deficiency syndromes.

[2]  V. Natarajan,et al.  Cytochrome P450 2B6 (CYP2B6) G516T influences nevirapine plasma concentrations in HIV‐infected patients in Uganda , 2007, HIV medicine.

[3]  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.

[4]  J. Haines,et al.  Drug transporter and metabolizing enzyme gene variants and nonnucleoside reverse-transcriptase inhibitor hepatotoxicity. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[5]  M. Lederman,et al.  Pharmacogenetics of nevirapine-associated hepatotoxicity: an Adult AIDS Clinical Trials Group collaboration. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[6]  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.

[7]  K. Tashima,et al.  Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[8]  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.

[9]  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.

[10]  S. Khoo,et al.  Intracellular and plasma pharmacokinetics of efavirenz in HIV-infected individuals. , 2005, The Journal of antimicrobial chemotherapy.

[11]  S. Khoo,et al.  Intracellular and plasma pharmacokinetics of nevirapine in human immunodeficiency virus‐infected individuals , 2005, Clinical pharmacology and therapeutics.

[12]  D. Mayers,et al.  Appropriate use of nevirapine for long-term therapy. , 2005, The Journal of infectious diseases.

[13]  G. Montepiedra,et al.  Immune reconstitution after receipt of highly active antiretroviral therapy in children with advanced or progressive HIV disease and complete or partial viral load response. , 2005, The Journal of infectious diseases.

[14]  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.

[15]  S. Spector,et al.  An MDR1-3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children , 2005, AIDS.

[16]  C. Moore,et al.  Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*0101 and abrogated by low CD4 T-cell counts , 2005, AIDS.

[17]  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.

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

[19]  S. Hammer,et al.  Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. , 2004, The New England journal of medicine.

[20]  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.

[21]  Dorothy Bray,et al.  Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial , 2003, The Lancet.

[22]  S. Hayashi,et al.  Nelfinavir pharmacokinetics in stable human immunodeficiency virus-positive children: Pediatric AIDS Clinical Trials Group Protocol 377. , 2003, Pediatrics.

[23]  A. Badley,et al.  Induction of Apoptosis by a Nonnucleoside Human Immunodeficiency Virus Type 1 Reverse Transcriptase Inhibitor , 2002, Antimicrobial Agents and Chemotherapy.

[24]  D. Greenblatt,et al.  Differential Modulation of P-Glycoprotein Expression and Activity by Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors in Cell Culture , 2002, Pharmaceutical Research.

[25]  R. de Groot,et al.  Efficacy of highly active antiretroviral therapy in HIV-1 infected children. , 2002, The Lancet. Infectious diseases.

[26]  Jacques Fellay,et al.  Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study , 2002, The Lancet.

[27]  U. Hofmann,et al.  Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. , 2001, Pharmacogenetics.

[28]  R H Levy,et al.  Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[29]  Dorothy Bray,et al.  Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial , 1999, The Lancet.

[30]  T. Macgregor,et al.  Disposition and biotransformation of the antiretroviral drug nevirapine in humans. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[31]  I. Pastan,et al.  Biochemical, cellular, and pharmacological aspects of the multidrug transporter. , 1999, Annual review of pharmacology and toxicology.