TY - JOUR
T1 - Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent
AU - Yuan, Jing
AU - Guo, Sheng
AU - Hall, David
AU - Cammett, Anna M.
AU - Jayadev, Supriya
AU - Distel, Manuel
AU - Storfer, Stephen
AU - Huang, Zimei
AU - Mootsikapun, Piroon
AU - Ruxrungtham, Kiat
AU - Podzamczer, Daniel
AU - Haas, David W.
AU - AUTHOR GROUP
AU - Benetucci, Jorge
AU - Ortega, Gerardo
AU - Cahn, Pedro
AU - Cesar, Carina
AU - Cassetti, Isabel
AU - Bissio, Emiliano
AU - Lupo, Sergio
AU - Chuah, John
AU - Workman, Cassy
AU - Rees, Vanessa
AU - Cooper, David A.
AU - Hickey, Rebecca
AU - Anderson, Jonathan
AU - Moore, Richard
AU - Hoy, Jennifer
AU - Downs, Cath
AU - Finlayson, Robert
AU - Bodsworth, Neil
AU - Eu, Beng
AU - Lau, Helen
AU - Montaner, Julio
AU - Harris, Marianne
AU - Walmsley, Sharon
AU - d'Aquila, Adrianna
AU - Conway, Brian
AU - Tossonian, Harout
AU - Morlat, Philippe
AU - Louis, Isabelle
AU - Yazdanpanah, Yazdan
AU - Ajana, Faiza
AU - Bollens, Diane
AU - Girard, Pierre-Marie
AU - May, Thierry
AU - Pialoux, Gilles
AU - Slama, Laurence
AU - Lyavanc, Thomas
AU - Piketty, Christophe
AU - Reiss, Peter
PY - 2011
Y1 - 2011
N2 - Nevirapine is widely prescribed for HIV-1 infection. We characterized relationships between nevirapine-associated cutaneous and hepatic adverse events and genetic variants among HIV-infected adults. We retrospectively identified cases and controls. Cases experienced symptomatic nevirapine-associated severe (grade III/IV) cutaneous and/or hepatic adverse events within 8 weeks of initiating nevirapine. Controls did not experience adverse events during more than 18 weeks of nevirapine therapy. Cases and controls were matched 1: 2 on baseline CD4 T-cell count, sex, and race. Individuals with 150 or less CD4 T cells/μl at baseline were excluded. We characterized 123 human leukocyte antigen (HLA) alleles and 2744 single-nucleotide polymorphisms in major histocompatibility complex (MHC) and drug metabolism and transport genes. We studied 276 evaluable cases (175 cutaneous adverse events, 101 hepatic adverse events) and 587 controls. Cutaneous adverse events were associated with CYP2B6 516G→T (OR 1.66, all), HLA-Cw*04 (OR 2.51, all), and HLA-B*35 (OR 3.47, Asians; 5.65, Thais). Risk for cutaneous adverse events was particularly high among Blacks with CYP2B6 516TT and HLA-Cw*04 (OR 18.90) and Asians with HLA-B*35 and HLA-Cw*04 (OR 18.34). Hepatic adverse events were associated with HLA-DRB*01 (OR 3.02, Whites), but not CYP2B6 genotypes. Associations differed by population, at least in part reflecting allele frequencies. Among patients with at least 150 CD4 T cells/μl, polymorphisms in drug metabolism and immune response pathways were associated with greater likelihood of risk for nevirapine-related adverse events. Results suggest fundamentally different mechanisms of adverse events: cutaneous, most likely MHC class I-mediated, influenced by nevirapine CYP2B6 metabolism; hepatic, most likely MHC class II-mediated and unaffected by such metabolism. These risk variants are insensitive for routine clinical screening
AB - Nevirapine is widely prescribed for HIV-1 infection. We characterized relationships between nevirapine-associated cutaneous and hepatic adverse events and genetic variants among HIV-infected adults. We retrospectively identified cases and controls. Cases experienced symptomatic nevirapine-associated severe (grade III/IV) cutaneous and/or hepatic adverse events within 8 weeks of initiating nevirapine. Controls did not experience adverse events during more than 18 weeks of nevirapine therapy. Cases and controls were matched 1: 2 on baseline CD4 T-cell count, sex, and race. Individuals with 150 or less CD4 T cells/μl at baseline were excluded. We characterized 123 human leukocyte antigen (HLA) alleles and 2744 single-nucleotide polymorphisms in major histocompatibility complex (MHC) and drug metabolism and transport genes. We studied 276 evaluable cases (175 cutaneous adverse events, 101 hepatic adverse events) and 587 controls. Cutaneous adverse events were associated with CYP2B6 516G→T (OR 1.66, all), HLA-Cw*04 (OR 2.51, all), and HLA-B*35 (OR 3.47, Asians; 5.65, Thais). Risk for cutaneous adverse events was particularly high among Blacks with CYP2B6 516TT and HLA-Cw*04 (OR 18.90) and Asians with HLA-B*35 and HLA-Cw*04 (OR 18.34). Hepatic adverse events were associated with HLA-DRB*01 (OR 3.02, Whites), but not CYP2B6 genotypes. Associations differed by population, at least in part reflecting allele frequencies. Among patients with at least 150 CD4 T cells/μl, polymorphisms in drug metabolism and immune response pathways were associated with greater likelihood of risk for nevirapine-related adverse events. Results suggest fundamentally different mechanisms of adverse events: cutaneous, most likely MHC class I-mediated, influenced by nevirapine CYP2B6 metabolism; hepatic, most likely MHC class II-mediated and unaffected by such metabolism. These risk variants are insensitive for routine clinical screening
U2 - https://doi.org/10.1097/QAD.0b013e32834779df
DO - https://doi.org/10.1097/QAD.0b013e32834779df
M3 - Article
C2 - 21505298
SN - 0269-9370
VL - 25
SP - 1271
EP - 1280
JO - AIDS (London, England)
JF - AIDS (London, England)
IS - 10
ER -