Pharmacogenetics of Efavirenz and Neuropsychiatric Side Effects in Asian Populations
Abstract
Efavirenz (EFV), a common antiretroviral drug, was the recommended first-line therapy for the treatment for human immunodeficiency virus infection until 2018. Though many high- income countries have transitioned to newer drugs due to their improved efficacy and low toxicity, EFV is still common in many low- and middle-income countries due to the high cost of alternatives. EFV is believed to cause central nervous system (CNS) toxicity and has been linked with neuropsychiatric side effects such as insomnia, hallucinations, headache, depression, and suicidality, though the causal relationship for depression and suicidality is controversial. Several single nucleotide polymorphisms (SNPs) in CYP2B6— the gene that encodes the enzyme that metabolizes EFV— have been linked with elevated plasma EFV levels that may lead to neurotoxicity and subsequent side effects. This suggests a great inter-individual genetic variability that may put patients with certain variations at a greater risk of these side effects. Two prominent polymorphisms CYP2B6*6 (516 G>T and 785 A>G) and CYP2B6*9 (516 G>T) are more common in Asians and Africans than in Europeans. The minor allele frequencies for CYP2B6*6 and CYP2B6*9 and genotype frequencies for CYP2B6*6 were analyzed to identify countries in Asia and surrounding regions with high prevalence of these genetic variations. The use of EFV, transition to alternative drugs, and the prevalence of CNS side effects in these countries were characterized. Countries with large occurrence of these SNPs were hypothesized to report frequent CNS adverse effects. These SNPs were the most prevalent in Papua New Guinea, India, Indonesia, and Pakistan, though EFV-induced CNS effects in those with these SNPs were found only in Papua New Guinea and India. Studies that incorporate both genetic and external factors may shed light on the pharmacological outcomes of EFV.