Hu Yi, Zheng Xubin, Ning Zhu, Li Qun, Zhang Zhengdong, Hoffner Sven
Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China; Key Laboratory of Public Health Safety (Fudan University), Ministry of Education, China.
Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China; Key Laboratory of Public Health Safety (Fudan University), Ministry of Education, China.
Int J Mycobacteriol. 2016 Dec;5 Suppl 1:S34-S35. doi: 10.1016/j.ijmyco.2016.11.007. Epub 2016 Nov 22.
Despite the strong association between drug resistance and genetic mutations, the value of molecular diagnosis of drug resistance to guide the treatment of multidrug-resistant tuberculosis (MDR-TB) remains unclear. This is particularly relevant in resource-limited areas, in which it is difficult to implement the drug susceptibility test. Here, we focused on the association of drug susceptibility phenotype and genotype with treatment outcomes in patients with MDR-TB.
In a prospective cohort study, we enrolled 252 consecutive patients with confirmed MDR-TB between 2010 and 2013, and outcomes were followed-up over the 24-month treatment course in terms of clinical manifestation and sputum conversion. All the isolates were tested for phenotypic susceptibility to second-line drugs in the Mycobacteria Growth Indicator Tube based system, and genotypic mutations were assessed by DNA sequencing.
Among the 252 MDR-TB isolates, 88 (34.9%) were resistant to fluoroquinolones and/or second-line injectable drugs, of which 65 (73.9%) harbored a mutation in drug resistance-related genes (gyrA, rrs and eis). In addition, 85 individuals (33.7%) were also resistant to pyrazinamide, with 87.1% containing the pncA mutation. Of 252 MDR-TB patients, 207 (82.1%) had known outcomes and 45 (17.9%) were lost to follow-up. Among those with known outcomes, treatment succeeded in 85.8% with plain MDR-TB, 69.7% with initial resistance to either a fluoroquinolone or second-line injective drugs, 37.5% with initial resistance to pyrazinamide, 29.3% with initial extensively drug resistance. In contrast, among those with known outcomes, treatment success and culture conversion depends on the susceptibility to drug especially for pyrazinamide and fluoroquinolones. In multivariate analysis, pyrazinamide resistance and its related pncA gene mutation were independently associated with a lower risk of culture conversion on at 8weeks and treatment success, while fluoroquinolone resistance was negatively correlated with treatment success. Besides, specific treatment, patient and program variables were also associated with treatment outcome.
Drug susceptibility testing for pyrazinamide and fluoroquinolones together with genetic information appears to provide a clinically useful indicator of the treatment outcome of MDR-TB in China.
尽管耐药性与基因突变之间存在密切关联，但分子诊断耐药性以指导耐多药结核病（MDR-TB）治疗的价值仍不明确。这在资源有限的地区尤为重要，因为在这些地区难以开展药敏试验。在此，我们重点关注MDR-TB患者的药敏表型和基因型与治疗结果之间的关联。
在一项前瞻性队列研究中，我们纳入了2010年至2013年间连续确诊的252例MDR-TB患者，并在24个月的治疗过程中对其临床表现和痰菌转阴情况进行随访。所有分离株均在基于分枝杆菌生长指示管系统中进行二线药物的表型药敏试验，并通过DNA测序评估基因型突变。
在252株MDR-TB分离株中，88株（34.9%）对氟喹诺酮类和/或二线注射用药物耐药，其中65株（73.9%）在耐药相关基因（gyrA、rrs和eis）中存在突变。此外，85例患者（33.7%）也对吡嗪酰胺耐药，其中87.1%含有pncA突变。252例MDR-TB患者中，207例（82.1%）有已知结局，45例（17.9%）失访。在有已知结局的患者中，普通MDR-TB患者的治疗成功率为85.8%，初始对氟喹诺酮类或二线注射用药物耐药的患者为69.7%，初始对吡嗪酰胺耐药的患者为37.5%，初始广泛耐药的患者为29.3%。相比之下，在有已知结局的患者中，治疗成功和痰菌转阴取决于对药物的敏感性，尤其是对吡嗪酰胺和氟喹诺酮类药物。在多变量分析中，吡嗪酰胺耐药及其相关的pncA基因突变与8周时痰菌转阴风险降低和治疗成功独立相关，而氟喹诺酮类耐药与治疗成功呈负相关。此外，特定的治疗、患者和项目变量也与治疗结果相关。
吡嗪酰胺和氟喹诺酮类药物的药敏试验以及基因信息似乎为中国MDR-TB的治疗结果提供了一个临床有用的指标。
