Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chia-Yi Christ ian Hospital, Chiayi City, Taiwan.
Lancet Gastroenterol Hepatol. 2023 Jul;8(7):623-634. doi: 10.1016/S2468-1253(23)00097-3. Epub 2023 May 10.
Helicobacter pylori infection is an important causal factor of gastric cancer and peptic ulcer disease and is associated with immune thrombocytopenic purpura and functional dyspepsia. In H pylori strains, point mutations in the 23S rRNA and gyrA genes are associated with clarithromycin resistance and levofloxacin resistance, respectively. Whether the efficacy of molecular testing-guided therapy is non-inferior to that of susceptibility testing-guided therapy for H pylori eradication is unclear. Therefore, we aimed to compare the efficacy and safety of molecular testing-guided therapy and traditional culture-based susceptibility testing-guided therapy in first-line and third-line treatment of H pylori infection.
We did two multicentre, open-label randomised trials in Taiwan. In trial 1 (done at seven hospitals), treatment-naive individuals infected with H pylori who were aged 20 years or older were eligible for study inclusion. In trial 2 (done at six hospitals), individuals aged 20 years or older who failed treatment after two or more eradication therapies for H pylori infection were eligible for enrolment. Eligible patients were randomly assigned (1:1) to receive either molecular testing-guided therapy or susceptibility testing-guided therapy. The randomisation sequence was generated by computer using permuted block randomisation with a block size of 4. All investigators were masked to the randomisation sequence. Clarithromycin and levofloxacin resistance were determined by agar dilution test for measuring minimum inhibitory concentrations in the susceptibility testing-guided therapy group, and by PCR and direct sequencing for detection of 23S rRNA and gyrA mutations in the molecular testing-guided therapy group. Study participants received clarithromycin sequential therapy, levofloxacin sequential therapy, or bismuth quadruple therapy according to the resistance status to clarithromycin and levofloxacin. The C-urease breath test was used to determine the status of H pylori infection at least 6 weeks after eradication therapy. The primary outcome was the eradication rate by intention-to-treat analysis. The frequency of adverse effects was analysed in patients with available data. The prespecified margins for non-inferiority were 5% for trial 1 and 10% for trial 2. The trials are ongoing for post-eradication follow-up and registered with ClinicalTrials.gov, NCT03556254 for trial 1, and NCT03555526 for trial 2.
Between March 28, 2018, and April 23, 2021, 560 eligible treatment-naive patients with H pylori infection were recruited and randomly assigned to the molecular testing-guided therapy group or the susceptibility testing-guided therapy group in trial 1. Between Dec 28, 2017, and Oct 27, 2020, 320 eligible patients with refractory H pylori infection were recruited and randomly assigned to the molecular testing-guided therapy group or the susceptibility testing-guided therapy group in trial 2. 272 men and 288 women were recruited for trial 1, and 98 men and 222 women were recruited for trial 2. In first-line H pylori treatment, infection was eradicated in 241 (86%, 95% CI 82-90) of 280 patients in the molecular testing-guided therapy group and 243 (87%, 83-91) of 280 patients in the susceptibility testing-guided therapy group by intention-to-treat analysis (p=0·81). In third-line H pylori treatment, infection was eradicated in 141 (88%, 83-93) of 160 patients in the molecular testing-guided therapy group and 139 (87%, 82-92) of 160 patients in the susceptibility testing-guided therapy group by intention-to-treat analysis (p=0·74). The difference in the eradication rate between the molecular testing-guided therapy group and the susceptibility testing-guided therapy group was -0·7% (95% CI -6·4 to 5·0; non-inferiority p=0·071) in trial 1 and 1·3% (-6·0 to 8·5; non-inferiority p=0·0018 in trial 2 by intention-to-treat analysis. We found no difference in adverse effects across both treatment groups in trial 1 and trial 2.
Molecular testing-guided therapy was similar to susceptibility testing-guided therapy in first-line therapy and non-inferior to susceptibility testing guided therapy in third-line treatment of H pylori infection, supporting the use of molecular testing-guided therapy for H pylori eradication.
Ministry of Science and Technology of Taiwan, and Centre of Precision Medicine of the Higher Education Sprout Project by the Ministry of Education of Taiwan.
幽门螺杆菌感染是胃癌和消化性溃疡病的重要致病因素，与免疫性血小板减少性紫癜和功能性消化不良有关。在幽门螺杆菌株中，23S rRNA 和 gyrA 基因的点突变分别与克拉霉素耐药和左氧氟沙星耐药相关。分子检测指导的治疗在幽门螺杆菌根除中的疗效是否不如药敏试验指导的治疗尚不清楚。因此，我们旨在比较分子检测指导的治疗与传统基于培养的药敏试验指导的治疗在幽门螺杆菌感染一线和三线治疗中的疗效和安全性。
我们在台湾进行了两项多中心、开放性随机试验。在试验 1（在 7 家医院进行）中，纳入了年龄在 20 岁及以上且未经治疗的幽门螺杆菌感染患者。在试验 2（在 6 家医院进行）中，纳入了年龄在 20 岁及以上且在接受了两次或两次以上幽门螺杆菌感染根除治疗后失败的患者。符合条件的患者被随机分配（1:1）接受分子检测指导的治疗或药敏试验指导的治疗。随机序列由计算机使用区组随机化生成，区组大小为 4。所有研究者均对随机序列设盲。在药敏试验指导的治疗组中，通过琼脂稀释法测量最小抑菌浓度来确定克拉霉素和左氧氟沙星的耐药性，而在分子检测指导的治疗组中，通过 PCR 和直接测序来检测 23S rRNA 和 gyrA 突变。根据对克拉霉素和左氧氟沙星的耐药情况，研究参与者接受克拉霉素序贯治疗、左氧氟沙星序贯治疗或铋四联治疗。C-尿素酶呼气试验用于在根除治疗后至少 6 周时确定幽门螺杆菌感染的状态。主要结局是意向治疗分析的根除率。对有可用数据的患者进行不良事件频率分析。试验 1 的非劣效性预设界限为 5%，试验 2 的非劣效性预设界限为 10%。这些试验正在进行根除后随访，并在 ClinicalTrials.gov 上注册，试验 1 的注册编号为 NCT03556254，试验 2 的注册编号为 NCT03555526。
在 2018 年 3 月 28 日至 2021 年 4 月 23 日期间，纳入了 560 名年龄在 20 岁及以上且未经治疗的幽门螺杆菌感染患者，他们被随机分配到分子检测指导的治疗组或药敏试验指导的治疗组。在 2017 年 12 月 28 日至 2020 年 10 月 27 日期间，纳入了 320 名年龄在 20 岁及以上且对幽门螺杆菌感染有抗药性的患者，他们被随机分配到分子检测指导的治疗组或药敏试验指导的治疗组。试验 1 纳入了 272 名男性和 288 名女性患者，试验 2 纳入了 98 名男性和 222 名女性患者。在一线幽门螺杆菌治疗中，意向治疗分析显示，分子检测指导的治疗组中 280 名患者中有 241 名（86%，95%CI 82-90）感染被根除，药敏试验指导的治疗组中 280 名患者中有 243 名（87%，83-91）感染被根除（p=0·81）。在三线幽门螺杆菌治疗中，意向治疗分析显示，分子检测指导的治疗组中 160 名患者中有 141 名（88%，83-93）感染被根除，药敏试验指导的治疗组中 160 名患者中有 139 名（87%，82-92）感染被根除（p=0·74）。试验 1 中分子检测指导的治疗组与药敏试验指导的治疗组的根除率差异为-0·7%（95%CI-6·4 至 5·0；非劣效性 p=0·071），试验 2 中差异为 1·3%（-6·0 至 8·5；非劣效性 p=0·0018）。我们在试验 1 和试验 2 中均未发现两组治疗的不良反应存在差异。
分子检测指导的治疗在一线治疗中与药敏试验指导的治疗相似，在三线治疗中与药敏试验指导的治疗非劣效，支持使用分子检测指导的治疗进行幽门螺杆菌根除。
台湾科技部和高等教育培育新芽计划精准医学中心。
