Pharmacogenetic determinants of efavirenz exposure and the effect of tuberculosis co-treatment in Ethiopians: A systematic review and meta-analysis

Aim: This systematic review and meta-analysis aimed to evaluate the effects of genetic variants in CYP2B6, CYP3A5, UGT2B7, SLCO1B1, and ABCB1 on efavirenz exposure among Ethiopians with HIV and whether CYP2B6 genotype modifies the effect of concomitant tuberculosis treatment on efavirenz exposure. Methods: The review was conducted in accordance with the PRISMA guidelines. PubMed, Embase, Scopus, Web of Science, and Cochrane CENTRAL were searched. Random-effects meta-analyses were used to estimate pooled genotype effects on efavirenz plasma concentrations. An exploratory meta-regression evaluated the interaction between CYP2B6 genotype and concomitant tuberculosis treatments. Results: Eight studies involving 1,534 Ethiopian participants were included. A clear gene-dose association between CYP2B6 *6 and increased efavirenz exposure was observed. Compared with the CYP2B6 *1/*1 genotype, efavirenz concentrations were 34% higher among *1/*6 heterozygotes (geometric mean ratio [GMR] = 1.34; 95% CI: 1.22–1.48) and 2.46-fold higher among *6/*6 homozygotes (GMR = 2.46; 95% CI: 2.01–3.02). Among participants on concurrent rifampicin-isoniazid- based tuberculosis treatment, *6/*6 homozygotes exhibited up to 6.46-fold higher in efavirenz exposure (GMR = 6.46, 95% CI: 5.26–7.93). Meta-regression indicated that tuberculosis co-treatment significantly increased efavirenz exposure only among CYP2B6 *6/*6 homozygotes (β = 0.93, 95% CI: 0.62–1.24; p < 0.001). Genetic variants in CYP3A5, UGT2B7, ABCB1, and SLCO1B1 had little or inconsistent influence. Conclusion: CYP2B6 *6 variant was the principal genetic determinant of efavirenz exposure in Ethiopians. These findings identify subgroups at high risk of excessive drug exposure and support further evaluation of CYP2B6-guided efavirenz dosing and genotype-dependent interactions with tuberculosis treatments.