Impact of isoniazid monoresistance on overall and vulnerable patient populations in Taiwan

Isoniazid is an early bactericidal anti-tuberculosis (TB) agent and isoniazid mono-resistance TB is the most prevalent drug-resistant TB worldwide. Concerns exist regarding whether resistance to isoniazid would lead to delayed culture conversion and worst outcomes. From January 2008 to November 2017, adult culture-positive pulmonary TB patients receiving isoniazid, rifampicin, pyrazinamide, and ethambutol were identified through Taiwan Center for Disease Control database and were followed until the end of 2017. Primary outcomes included time to sputum culture conversion (SCC) within two months. Secondary outcomes included death and unfavourable outcomes at the end of 2nd month. A total of 37,193 drug-susceptible and 2,832 isoniazid monoresistant pulmonary TB patients were identified. Compared with no resistance, isoniazid monoresistance was not associated with a delayed SCC (HR: 0.99, 95% CI: 0.94─1.05, p = 0.8145), a higher risk of 2-month mortality (HR: 1.19, 95% CI: 0.92─1.53, p = 0.1884), and unfavourable outcomes at 2nd month (OR: 1.05, 95% CI: 0.97─1.14, p = 0.2427). Isoniazid monoresistance was associated with delayed SCC (HR: 0.90, 95% CI: 0.83─0.98, p = 0.0099) and a higher risk of unfavourable outcomes (OR:1.18, 95% CI: 1.05─1.32, p = 0.0053) in patients aged between 20 and 65, and delayed SCC in patients without underlying comorbidities (HR: 0.90, 95% CI: 0.81─0.98, p = 0.0237). Isoniazid mono-resistant TB had a comparable outcome with drug-susceptible TB at the end of the intensive phase. Healthy, and non-elderly patients were more likely to had culture persistence, raising concerns about disease transmission in these subgroups and warranting early molecular testing for isoniazid resistance.异烟肼（Isoniazid）是一款早期杀菌性抗结核药物，异烟肼单耐药结核病是全球范围内最为常见的耐药结核病类型。目前学界对于异烟肼耐药是否会导致痰培养转阴延迟及预后不良尚存疑虑。本研究于2008年1月至2017年11月期间，通过台湾疾病管制中心数据库筛选出接受异烟肼、利福平、吡嗪酰胺及乙胺丁醇治疗的成人痰培养阳性肺结核患者，并对其随访至2017年末。本研究的主要结局指标为2个月内的痰培养转阴（sputum culture conversion, SCC）时间；次要结局指标为治疗2月末的死亡情况及不良预后结局。最终共纳入37193例药物敏感肺结核患者与2832例异烟肼单耐药肺结核患者。与药物敏感肺结核患者相比，异烟肼单耐药并未显著延迟痰培养转阴时间（HR=0.99，95%置信区间CI：0.94~1.05，P=0.8145），未显著升高2个月死亡率（HR=1.19，95%CI：0.92~1.53，P=0.1884），也未显著增加2月末不良预后风险（OR=1.05，95%CI：0.97~1.14，P=0.2427）。但在20~65岁的患者亚组中，异烟肼单耐药与痰培养转阴延迟（HR=0.90，95%CI：0.83~0.98，P=0.0099）及更高的不良预后风险（OR=1.18，95%CI：1.05~1.32，P=0.0053）相关；在无基础合并症的患者亚组中，异烟肼单耐药同样与痰培养转阴延迟相关（HR=0.90，95%CI：0.81~0.98，P=0.0237）。强化治疗期末，异烟肼单耐药结核病患者的预后与药物敏感结核病患者相当。健康、非老年的异烟肼单耐药肺结核患者更易出现痰培养持续阳性，这提示该亚组人群存在更高的疾病传播风险，因此亟需针对异烟肼耐药开展早期分子检测。