Maseng Monkgomotsi J, Tawe Leabaneng, Thami Prisca K, Seatla Kaelo K, Moyo Sikhulile, Martinelli Axel, Kasvosve Ishmael, Novitsky Vladimir, Essex Max, Russo Gianluca, Gaseitsiwe Simani, Paganotti Giacomo M
School of Allied Health Professions, Faculty of Health Sciences, University of Botswana, Gaborone, Botswana.
Botswana-Harvard AIDS Institute Partnership, Gaborone, Botswana.
Pharmgenomics Pers Med. 2021 Mar 16;14:335-347. doi: 10.2147/PGPM.S289471. eCollection 2021.
CYP2B6 liver enzyme metabolizes the two non-nucleoside reverse transcriptase inhibitors Efavirenz (EFV) and Nevirapine (NVP) used in the antiretroviral therapy (ART) regimens for HIV-infected individuals. Polymorphisms of the gene influence drug levels in plasma and possibly virological outcomes. The aim of this study was to explore the potential impact of genotype and haplotype variation on the risk of developing EFV/NVP drug resistance mutations (DRMs) in HIV-1 patients receiving EFV-/NVP-containing regimens in Botswana.
Participants were a sub-sample of a larger study (Tshepo study) conducted in Gaborone, Botswana, among HIV-infected individuals taking EFV/NVP containing ART. Study samples were retrieved and assigned to cases (with DRMs) and controls (without DRMs). Four single-nucleotide polymorphisms (SNPs) in the gene (-82T>C; 516G>T; 785A>G; 983T>C) were genotyped, the haplotypes reconstructed, and the metabolic score assigned. The possible association between drug resistance and several independent factors (baseline characteristics and genotypes) was assessed by Binary Logistic Regression (BLR) analysis. EFV/NVP resistance status and haplotypes were also analyzed using Z-test, chi-square and Fisher's exact test statistics.
Two hundred and twenty-seven samples were analysed (40 with DRMs, 187 without DRMs). BLR analysis showed an association between EFV/NVP resistance and 516G allele (OR: 2.26; 95% CI: 1.27-4.01; =0.005). Moreover, haplotype analysis revealed that the proportion of EFV/NVP-resistant infections was higher among fast than extensive/slow metabolizers (30.8% vs 16.8%; 0.035), with the 516G allele more represented in the haplotypes of fast than extensive/slow metabolizers (100.0% vs 53.8%; <0.001).
We demonstrated that the 516G allele, and even more when combined in fast metabolic haplotypes, is associated with the presence of EFV/NVP resistance, strengthening the need to assess the genetic profiles in HIV-infected patients in order to improve the virologic outcomes of NNRTI containing ART.
细胞色素P450 2B6（CYP2B6）肝酶可代谢用于人类免疫缺陷病毒（HIV）感染者抗逆转录病毒治疗（ART）方案中的两种非核苷类逆转录酶抑制剂依非韦伦（EFV）和奈韦拉平（NVP）。该基因的多态性会影响血浆中的药物水平，并可能影响病毒学结局。本研究的目的是探讨在博茨瓦纳接受含EFV/ NVP方案治疗的HIV-1患者中，CYP2B6基因型和单倍型变异对发生EFV / NVP耐药突变（DRM）风险的潜在影响。
参与者是在博茨瓦纳哈博罗内进行的一项更大规模研究（特绍波研究）的子样本，研究对象为接受含EFV / NVP的ART治疗的HIV感染者。检索研究样本并分为病例组（有DRM）和对照组（无DRM）。对CYP2B6基因中的四个单核苷酸多态性（SNP）（-82T>C；516G>T；785A>G；983T>C）进行基因分型，重建单倍型，并指定代谢评分。通过二元逻辑回归（BLR）分析评估耐药性与几个独立因素（基线特征和CYP2B6基因型）之间的可能关联。还使用Z检验、卡方检验和费舍尔精确检验统计量分析EFV / NVP耐药状态和CYP2B6单倍型。
共分析了227个样本（40个有DRM，187个无DRM）。BLR分析显示EFV / NVP耐药性与CYP2B6 516G等位基因之间存在关联（比值比：2.26；95%置信区间：1.27 - 4.01；P = 0.005）。此外，单倍型分析显示，在CYP2B6快速代谢者中，EFV / NVP耐药感染的比例高于广泛/缓慢代谢者（30.8%对16.8%；P = 0.035），516G等位基因在快速代谢者的单倍型中比在广泛/缓慢代谢者中更常见（100.0%对53.8%；P<0.001）。
我们证明CYP2B6 516G等位基因，尤其是在快速代谢单倍型中，与EFV / NVP耐药性的存在相关，这进一步表明有必要评估HIV感染患者的CYP2B6基因谱，以改善含非核苷类逆转录酶抑制剂的ART的病毒学结局。
