The use of nevirapine in many developing countries has been associated with induced hypersensitivity reactions, and this is a contributory factor for patients defaulting therapy. CYP2B6 and SULT1A1 play an important may role in NVP metabolism and these variants may predispose patients to developing NVP-hypersensitivity (5, 13). CYP2B6*18 (c.983T > C) has been associated with developing of NVP-hypersensitivity in some African populations (13, 16). SULT1A1 sulfonation of 12-OH-NVP to 12-SUL-NVP, where, 12-SUL-NVP forms adducts with proteins in the liver and skin, could also be a pathway for NVP-hypersensitivity (25). We genotyped CYP2B6 and SULT1A1 variants to determine if CYP2B6*18 (c.983T > C) and SULT1A1*2 (c.638G > A) variant could influence the developing nevirapine hypersensitivity in the Ghanaian population.
For CYP2B6*18 (c.983T > C) genotyping, the extensive metabolizer genotype (CYP2B6 983T/T) was common in this studied population than the intermediate metabolizer genotype (CYP2B6 983T/C) with no poor metabolizer genotype (CYP2B6 983C/C) recorded. The absence of the poor metabolizers (CYP2B6 983C/C) in our study was not unusual as similar findings have been reported in other African populations. (12, 26). On the contrary Maseng, Tawe (27) recorded a frequency of 9.2% for poor metabolizers in Botswana whiles Kwara, Lartey (28) reported a very low genotypic frequency of 0.001 (1/701) for poor metabolizers in the Ghanaian population. This may imply that although the variant allele is prevalent in Africans, the poor metabolizers may be rare in the Ghanaian population. In the absence of therapeutic monitoring, reduction in NVP among CYP2B6*18 poor metabolizers is recommended inorder to minimize NVP-induced ADR (29). The intermediate metabolizers are associated with higher plasma NVP levels or decreased nevirapine clearance as well as a higher risk of developing NVP-hypersensitivity compared to the extensive metabolizers (12, 16, 30, 31). The CYP2B6*18 (c.983T > C) variant frequency (2.9%) observed in our study is similar to those observed in African-Americans (2.9%) and the Ghanaian populations (3.1%) (19) but a slightly lower frequency of 1.6% observed in the Guinea population (18). However, this variant was absent in Papua New Guinea, Caucasian-Americans and Asian-Americans (18). This is an indication that there is a genetic variation between Africans and Caucasians for CYP2B6 metabolizing enzymes, hence variations in response to drugs metabolized by CYP2B6. We report that, CYP2B6*18 (c.983T > C) variant was not statistically associated to developing NVP-hypersensitivity, contrary to what has been observed in other African populations (13, 16). CYP2B6 functional polymorphism 983T > C can be linked with 785A > G as a CYP2B6*16 allele, resulting in a haplotype effect (18). CYP2B6*16 is known to be common among Africans (32), hence a significant association of the CYP2B6*18 to nevirapine hypersensitivity could be a haplotype effect of CYP2B6*16. CYP2B6*6 (c.516G > T) and CYP2B6*18 (c.983T > C) together were associated with up to five-fold higher mean plasma efavirenz (EFV) plasma concentrations, suggesting an additive effect of these polymorphisms (32). Nuclear receptor genes, NR112 and NR113 that regulate the transcription of CYP2B6 may also be possible genetic risk factors of NVP-hypersensitivity, although we did not consider these regulatory genes in our study.
SULT1A1 638 G > A variant defining the SNP of SULT1A1*2 allele has been studied among patients on HIV therapy, where it significantly impact EFV plasma concentration (33, 34). The observed SULT1A1*2 (c.638G > A) frequency, 21.4% was similar to those reported in African-Americans (35). SULT1A1*2 (c.638G > A) poor metabolizers are expected to lead to a decreased reactive metabolite, 12-SUL-NVP plasma concentration, resulting in a low risk of developing NVP-hypersensitivity (20). We report that, SULT1A1*2 (c.638G > A) variant was not statistically associated to developing NVP-hypersensitivity. Likewise, in a study by Sharma, Novalen (25), the use of dehydroepiandrosterone, a SULT1A1 inhibitor, did not prevent NVP-hypersensitivity, although there was a decreased plasma concentration of 12-OH-NVP. Inactivation of 12-OH-NVP could by due to other phase II metabolizing enzymes. The 12-OH-NVP which is a substrate for SULT can also be metabolized to 4-carboxy-NVP, escaping the SULT metabolizing pathway (21). The risk of developing NVP-hypersensitivity is high in patients with combined null genotypes of glutathione S-transferase (GSTT1 and GSTM1) (36).