Impact of glutathione transferases genes polymorphisms in nevirapine adverse reactions: a possible role for GSTM1 in SJS/TEN susceptibility

• Published in: European journal of clinical pharmacology Vol. 73; no. 10; pp. 1253 - 1259
• Main Authors: Ciccacci, Cinzia, Latini, Andrea, Politi, Cristina, Mancinelli, Sandro, Marazzi, Maria C., Novelli, Giuseppe, Palombi, Leonardo, Borgiani, Paola
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2017; Springer Nature B.V
• Subjects: Alleles; Anti-HIV Agents - adverse effects; Anti-HIV Agents - pharmacokinetics; Antiretroviral drugs; Biomedical and Life Sciences; Biomedicine; Case-Control Studies; Developing countries; Enzymes; Genetic Predisposition to Disease; Genotype; Glutathione; Glutathione Transferase - genetics; GSTM1 protein; GSTT1 protein; Hepatotoxicity; Humans; LDCs; Liver; Mozambique; Multivariate analysis; Nevirapine; Nevirapine - adverse effects; Nevirapine - pharmacokinetics; Pharmacogenetics; Pharmacogenomic Variants; Pharmacology/Toxicology; Risk factors; Side effects; Skin diseases; Stevens-Johnson syndrome; Stevens-Johnson Syndrome - etiology; Stevens-Johnson Syndrome - genetics; Toxic epidermal necrolysis; Toxicity; Stevens-Johnson syndrome; Toxic epidermal necrolysis; NVP adverse reactions; Glutathione S-transferases; Polymorphisms
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-017-2295-2

Purpose Nevirapine (NVP) is used in developing countries as first-line treatment of HIV infection. Unfortunately, its use is associated with common serious adverse drug reactions, such as liver toxicity and the most severe and rare Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). GSTT1 and GSTM1 genes code for enzymes involved in the metabolism of a wide range of drugs. We hypothesized that this gene variability could be implicated in NVP adverse reactions. Methods We analyzed the GSTM1 and GSTT1 null genotypes by multiplex PCR in a population of 181 patients from Mozambique, treated with NVP. A case/control association study was performed. We also counted the number of risk alleles in SJS/TEN patients and in controls, including the GSTM1 null genotype and four previously identified risk alleles in CYP2B6 , HCP5 , and TRAF3IP2 genes. Results Among patients, 27 had developed SJS/TEN and 76 had developed hepatotoxicity during the treatment. The GSTM1 null genotype was more frequent in the cases with SJS/TEN than in the controls (OR = 2.94, P  = 0.027). This association is also observed when other risk factors are taken into account, by a multivariate analysis ( P  = 0.024 and OR = 3.58). The risk allele counting analysis revealed a significantly higher risk for SJS/TEN in patients carrying three or four risk alleles. Moreover, all subjects with five or six risk alleles developed SJS/TEN, while subjects without any risk alleles were present only in the control group. Conclusions We observed an association between GSTM1 and SJS/TEN susceptibility. Moreover, GSTM1 contributes to the definition of a genetic risk profile for SJS/TEN susceptibility.