MRC Clinical Trials Unit at University College London, London, UK.
University of Cape Town Lung Institute, Cape Town, South Africa.
BMC Med. 2018 Mar 28;16(1):46. doi: 10.1186/s12916-018-1033-7.
Drug-induced liver injury (DILI) is a common complication of tuberculosis treatment. We utilised data from the REMoxTB clinical trial to describe the incidence of predisposing factors and the natural history in patients with liver enzyme levels elevated in response to tuberculosis treatment.
Patients received either standard tuberculosis treatment (2EHRZ/4HR), or a 4-month regimen in which moxifloxacin replaced either ethambutol (isoniazid arm, 2MHRZ/2MHR) or isoniazid (ethambutol arm, 2EMRZ/2MR). Hepatic enzymes were measured at 0, 2, 4, 8, 12 and 17 weeks and as clinically indicated during reported adverse events. Patients included were those receiving at least one dose of drug and with two or more hepatic enzyme measurements.
A total of 1928 patients were included (639 2EHRZ/4HR, 654 2MHRZ/2MHR and 635 2EMRZ/2MR). DILI was defined as peak alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal (5 × ULN) or ALT ≥ 3 × ULN with total bilirubin > 2 × ULN. DILI was identified in 58 of the 1928 (3.0%) patients at a median time of 28 days (interquartile range IQR 14-56). Of 639 (6.4%) patients taking standard tuberculosis therapy, 41 experienced clinically significant enzyme elevations (peak ALT ≥ 3 × ULN). On standard therapy, 21.1% of patients aged >55 years developed a peak ALT/aspartate aminotransferase (AST) ≥ 3 × ULN (p = 0.01) and 15% of HIV-positive patients experienced a peak ALT/AST ≥ 3 × ULN compared to 9% of HIV-negative patients (p = 0.160). The median peak ALT/AST was higher in isoniazid-containing regimens vs no-isoniazid regimens (p < 0.05), and lower in moxifloxacin-containing arms vs no-moxifloxacin arms (p < 0.05). Patients receiving isoniazid reached a peak ALT ≥ 3 × ULN 9.5 days earlier than those on the ethambutol arm (median time of 28 days vs 18.5 days). Of the 67 Asian patients with a peak ALT/AST ≥ 3 × ULN, 57 (85.1%) were on an isoniazid-containing regimen (p = 0.008).
Our results provide evidence of the risk of DILI in tuberculosis patients on standard treatment. Older patients on standard therapy, HIV-positive patients, Asian patients and those receiving isoniazid were at higher risk of elevated enzyme levels. Monitoring hepatic enzymes during the first 2 months of standard therapy detected approximately 75% of patients with a peak enzyme elevation ≥3 × ULN, suggesting this should be a standard of care. These results provide evidence for the potential of moxifloxacin in hepatic sparing.
药物性肝损伤（DILI）是结核病治疗的常见并发症。我们利用 REMoxTB 临床试验的数据，描述了在抗结核治疗中肝酶水平升高的患者中，易患因素的发生率和自然病史。
患者接受标准结核病治疗（2EHRZ/4HR），或接受 4 个月的治疗方案，其中莫西沙星替代乙胺丁醇（异烟肼组，2MHRZ/2MHR）或异烟肼（乙胺丁醇组，2EMRZ/2MR）。在报告的不良事件期间，在 0、2、4、8、12 和 17 周以及临床需要时测量肝酶。包括至少接受一剂药物且有两次或两次以上肝酶测量值的患者。
共纳入 1928 例患者（639 例接受 2EHRZ/4HR 治疗，654 例接受 2MHRZ/2MHR 治疗，635 例接受 2EMRZ/2MR 治疗）。DILI 的定义为峰丙氨酸氨基转移酶（ALT）≥5 倍正常值上限（5×ULN）或 ALT≥3×ULN 伴总胆红素>2×ULN。在 1928 例患者中（3.0%），中位时间为 28 天（四分位间距 IQR 14-56）时发现 58 例（3.0%）DILI。在接受标准结核病治疗的 639 例（6.4%）患者中，41 例出现临床显著的酶升高（峰 ALT≥3×ULN）。在标准治疗中，年龄>55 岁的患者中有 21.1%出现 ALT/aspartate aminotransferase（AST）峰≥3×ULN（p=0.01），15%的 HIV 阳性患者出现 ALT/AST 峰≥3×ULN，而 HIV 阴性患者为 9%（p=0.160）。含异烟肼的方案的中位 ALT/AST 峰高于无异烟肼的方案（p<0.05），含莫西沙星的方案低于无莫西沙星的方案（p<0.05）。接受异烟肼治疗的患者达到 ALT≥3×ULN 的峰值比乙胺丁醇组早 9.5 天（中位时间 28 天 vs 18.5 天）。在 67 例 ALT/AST 峰≥3×ULN 的亚洲患者中，57 例（85.1%）接受含异烟肼的方案（p=0.008）。
我们的结果提供了标准结核病治疗患者发生 DILI 风险的证据。标准治疗中年龄较大的患者、HIV 阳性患者、亚洲患者和接受异烟肼治疗的患者发生酶升高的风险更高。在标准治疗的前 2 个月监测肝酶可检测到约 75%的患者出现酶升高≥3×ULN，这表明这应该是一种标准治疗方法。这些结果为莫西沙星在肝脏保护方面的潜力提供了证据。
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