Kanestri Veronika, Mironov Konstantin, Kravchenko Alexey, Pokrovskaya Anastasiya, Dribnohodova Olga, Dunayeva Elena, Tsiganova Galina, Harbutly Marina, Goliusova Marina, Konnov Vladislav, Kozirina Nadezhda, Shahgildyan Vasiliy, Kuimova Ulyana, Popova Anna, Efremova Oksana, Konnov Danila
Central Scientific Research Institute of Epidemiology, Russian AIDS Federal Center, Moscow, Russian Federation.
Department of Genetic Polimorphisms, Central Scientific Research Institute of Epidemiology, Moscow, Russian Federation.
J Int AIDS Soc. 2014 Nov 2;17(4 Suppl 3):19579. doi: 10.7448/IAS.17.4.19579. eCollection 2014.
The UGT1A128 (rs8175347) polymorphism is associated with hyperbilirubinemia. The presence of 6 TA-repeats in the UGT1A1 gene promoter region corresponds to normal UGT1TA1 activity. A detection of 7 TA-repeats in hetero- or homozygous individuals [(TA)6/(TA)7 and (TA)7/(TA)7] is associated with lower UGT1TA1 activity, which may eventually result in the development of Gilbert syndrome and/or modified individual response to drugs metabolized by this enzyme. ATV contributes to the decreased levels of UGT1A1, which may lead to elevations of indirect bilirubin, jaundice and even to therapy discontinuation. We evaluated the prevalence of the UGT1A128 among HIV-infected patients and the dependence of the frequency and severity of AE during ATV treatment on individual genetic characteristics.
47 HIV-infected patients was screen for UGT1A1 genotype and the presence of UGT1A1*28. All patients received ATV in the HAART regimen for 48 weeks. Changes in the total, direct and indirect bilirubin, ALT, AST, GGT and jaundice were evaluated. Statistical analysis was performed using Microsoft Office Excel for Windows XP Professional 2007 and Biostat.
All patients were followed up in the AIDS Center (males 72.3%, median age 33 years, median CD4+ count-282 cells/µl (19.5%)). HBV/HCV was in 36.2% patients. Ten patients had risk factors that could affect bilirubin turnover (chronic cholecystitis, biliary dyskinesia, etc.). Genotype (TA)6/(TA)6 was found in 42.6% patients, (TA)6/(TA)7-42.6% and (TA)7/(TA)7-14.9%. Overall prevalence of UGT1A128 was 57.4%, and homozygous allele frequency was 14.9%. G3/4 of indirect bilirubin were detected in 36.2% patients [(TA)6/(TA)6 in 10-20%, (TA)6/(TA)7-25-40%, (TA)7/(TA)7-72-86%], and significant jaundice in 10.6% [80% with (TA)7/(TA)7]. The OR for hyperbilirubinemia>40 µmol/L in patients with heterozygous UGT1A128 was increased 3 times over patients without this allele (OR 3.07, 95% CI 1.54-4.6) and 34 times as compared with homozygotes (OR 33.9, 95% CI 31.45-36.35). The presence of additional risk factors increased the probability of G3/4 hyperbilirubinemia. No significant changes in the ALT, AST, and GGT levels were observed.
The risk of severe hyperbilirubinemia during ATV treatment is minimal for patients without UGT1A128 and no more than one additional risk factor and for patients with UGT1A128 and no additional risk factors; patients with homozygous genotype UGT1A1*28 are at the highest risk.
UGT1A128（rs8175347）多态性与高胆红素血症相关。UGT1A1基因启动子区域存在6个TA重复序列对应正常的UGT1TA1活性。在杂合或纯合个体中检测到7个TA重复序列[（TA）6/（TA）7和（TA）7/（TA）7]与较低的UGT1TA1活性相关，这最终可能导致吉尔伯特综合征的发生和/或个体对该酶代谢的药物的反应改变。阿扎那韦会导致UGT1A1水平降低，这可能导致间接胆红素升高、黄疸，甚至导致治疗中断。我们评估了HIV感染患者中UGT1A128的患病率以及阿扎那韦治疗期间不良事件的频率和严重程度对个体遗传特征的依赖性。
对47例HIV感染患者进行UGT1A1基因型和UGT1A1*28存在情况的筛查。所有患者在高效抗逆转录病毒治疗方案中接受阿扎那韦治疗48周。评估总胆红素、直接胆红素、间接胆红素、谷丙转氨酶、谷草转氨酶、γ-谷氨酰转移酶和黄疸的变化。使用适用于Windows XP Professional 2007的Microsoft Office Excel和Biostat进行统计分析。
所有患者均在艾滋病中心接受随访（男性占72.3%，中位年龄33岁，中位CD4+细胞计数为282个/μl（19.5%））。36.2%的患者感染了乙肝病毒/丙肝病毒。10例患者有可影响胆红素代谢的危险因素（慢性胆囊炎、胆道运动障碍等）。42.6%的患者基因型为（TA）6/（TA）6，（TA）6/（TA）7为42.6%，（TA）7/（TA）7为14.9%。UGT1A128的总体患病率为57.4%，纯合等位基因频率为14.9%。36.2%的患者检测到间接胆红素G3/4[（TA）6/（TA）6为10 - 20%，（TA）6/（TA）7为25 - 40%，（TA）7/（TA）7为72 - 86%]，10.6%的患者出现明显黄疸[（TA）7/（TA）7的患者中80%出现黄疸]。UGT1A128杂合患者中高胆红素血症>40 μmol/L的比值比是无此等位基因患者的3倍（比值比3.07，95%置信区间1.54 - 4.6），与纯合子相比增加了34倍（比值比33.9，95%置信区间31.45 - 36.35）。存在其他危险因素会增加G3/4高胆红素血症的发生概率。未观察到谷丙转氨酶、谷草转氨酶和γ-谷氨酰转移酶水平有显著变化。
对于无UGT1A128且不超过一个其他危险因素的患者以及有UGT1A128但无其他危险因素的患者，阿扎那韦治疗期间发生严重高胆红素血症的风险最小；UGT1A1*28纯合基因型患者风险最高。
