- 學位論文
接受Rifapentine與Isoniazid治療之潛伏性結核病人藥物代謝酶遺傳多型性與藥物不良反應的關聯
Association of Drug Metabolic Enzyme Genetic Polymorphisms and Adverse Drug Reactions in Patients Receiving Rifapentine and Isoniazid Therapy for Latent Tuberculosis
摘要
研究目的：潛伏結核感染 (Latent tuberculosis infection, LTBI) 治療是根除結核病一項重要策略，國內已於 2016 年開始全面推廣速克伏處方的短期治療（LTBI治療處方，服用Rifapentine (PRT) 與Isoniazid (INH) 3個月，簡稱3HP），然而其藥物不良反應之發生率，尤其是類流感症狀，明顯高於西方國家之數據(8% vs. 2.2%)，且此藥物不良反應亦是導致病人中斷服藥之原因。基因多型性是討論個體間接受藥物治療反應差異最常被提及的原因，因此本研究將針對常見的藥物代謝脢之單核苷酸多型性 (single nucleotide polymorphisms, SNPs) 進行分析，找出造成藥物不良反應之關鍵因素。 研究方法：本研究為多家醫院合作之試驗，篩選接受潛伏結核感染治療的個案，給予3HP治療，於治療期間每週追蹤並記錄服藥狀況及藥物不良反應發生情形，直至完成治療後二週，並採集個案靜脈血檢體進行基因多型性試驗。最後將個案藥物不良反應發生情形與基因多型性統計分析，找出其關係。 研究結果：類流感症狀是最主要的藥物不良反應。在基因型上，cytochrome P450 (CYP) 2B6 rs8192709 帶有TC或CC基因者、CYP2E1 rs2070676帶有CG或GG 基因者、CYP2E1 rs2515641帶有CT或TT基因者、NAT2 (N-acetyltransferase 2) rs1495741 帶有AA 基因者；在等位基因 (allele) 上，CYP2E1 rs2515641 帶有 T allele 者或 NAT2 rs1495741 帶有 A allele 者，其產生藥物不良反應之危險值皆明顯較其野生型高。 結論與建議：本研究發現，使用 3HP 治療之 LTBI 個案，其 CYP2B6、CYP2E1 及 NAT2 代謝酶上之特定基因多型性與藥物不良反應相關，且有七成以上之藥物不良反應事件發生於服藥一個月內，這些藥物不良反應有近八成皆為類流感症狀。本研究的結果，可以為未來接受3HP治療的LTBI病人提供識別產生藥物不良反應的風險參考，進而改變治療策略。
並列摘要
Aims: Preventing tuberculosis (TB) disease by treating those with latent TB infection (LTBI) is a keystone of strategy for TB elimination. It has been widely executed 3HP (LTBI regimen, take INH and RPT for 3 months) short course treatment from 2016; however, the occurrence of adverse drug reactions (ADRs), flu-like syndromes especially, that resulting interrupting treatment course, is obviously higher than western countries (8% vs. 2.2%). Gene polymorphism is one of the differences for individual variation. In order to figure out the key factor about ADRs resulted by 3HP regimen, we monitored the SNP of metabolic enzymes, and compared with the events of ADRs. Methods: In this observational and multi-institutional study, we invited subjects who are undergoing LTBI 3HP treatment. In routine medical blood sampling, the more blood sampling will be done for SNPs performance. Clinical responses after taking the regimen will be conducted weekly. All data will be statistically analyzed and the correlation between the various ADRs and gene polymorphism will be discussed. Results: The most ADRs are flu-like syndromes. The individuals having TC genotype of CYP2B6 rs8192709, or CG genotype of CYP2E1 rs2070676, or CT genotype of CYP2E1 rs2515641, or AA genotype of NAT2 (N-acetyltransferase 2) rs1495741 possess higher risk of ADRs. The risk of having T allele of CYP2E1 rs2515641, or A allele of NAT2 rs1495741 are also higher. Conclusion and recommendations: We find that if individuals who received 3HP treatment have specific genotype or allele on the specific SNP of the CYP2B6, CYP2E1 and NAT2 metabolic enzymes, they would have higher risk of ADRs after receiving 3HP treatment. About 70% ADRs occurred within four weeks, and almost 80% ADRs were flu-like syndromes. The results of this study can provide an improved strategy for identifying people with increased TB risk.