幽門螺旋桿菌感染的一線治療與抗藥性對除菌療效的影響

Abstract

研究目的: 幽門螺旋桿菌已被證實是導致胃癌及消化性潰瘍的重要致病原因。台灣缺乏無症狀成人的幽門螺旋桿菌感染率的最新資料。我們希望通過使用碳13呼氣試驗(13C urea breath test; 13C UBT)和幽門螺旋桿菌糞便抗原（H. pylori stool antigen; HpSA）檢測來估計台灣無症狀受試者和消化不良患者幽門桿菌感染的年齡標準化患病率/人口。再者，如何優化治療療效和減少除菌治療的副作用也是很重要的，對於幽門桿菌的一線治療，非鉍劑四合一療法是否優於各種治療天數的傳統三合一療法仍存在爭議，我們希望比較非鉍劑四合一療法和不同天數的傳統三合一療法的療效與副作用，來當作臨床治療處方選擇的參考依據。此外，抗生素抗藥性對幽門桿菌的除菌效果有很大影響。安莫西林(Amoxicillin)、克拉黴素(Clarithromycin)、甲硝唑(Metronidazole)及左氧氟沙星(Levofloxacin)這四種抗生素都是用以做幽門螺旋桿菌除菌治療中常用且重要的抗生素。Clarithromycin、Metronidazole及Levofloxacin的抗藥性都已經被證實會影響除菌成功率，不過之前的研究卻很少關於Amoxicillin抗藥性對療效影響的研究，我們藉由綜合過往五個大型隨機分配試驗結果做事後分析，來了解含Amoxicillin的處方的療效是否會受Amoxicillin抗藥性的影響。 研究方法: 研究1：在2016-2017年間，使用13C UBT和HpSA對189位無症狀的成年受試者進行幽門螺旋桿菌篩檢。在2016-2018年間，針對145位有消化不良等症狀的病患，我們使用13C UBT、HpSA、血清抗體檢查、快速尿素酶試驗和切片組織學來調查幽門桿菌感染率。在這個盛行率研究中我們所使用的標準診斷工具為碳13呼氣試驗，我們藉此機會測定幽門桿菌糞便抗原【包括Diagnostec®HpSA ELISA和快速檢測試劑盒（HpSA Rapid）】的診斷準確度，以便於未來可應用於大規模幽門螺旋桿菌篩檢之用。 研究2：從PubMed，Cochran Library和Embase等資料庫進行檢索，找出合乎研究目的的隨機對照試驗，主題是比較5至14天非鉍劑四合一療法和傳統三合一療法治療一線幽門桿菌感染時的療效。利用統合分析(Meta-analysis)作為統計分析的方法，主要和次要結果分別是根據意向治療(Intention-to-treat)分析的除菌率和副作用。亞群分析則是針對這兩種處方的各種不同治療天數做療效比較。 研究3：對2007年至2016年間在台灣進行的5項大型隨機試驗做事後分析。納入所有接受含Amoxicillin治療處方的患者。使用統合分析評估Amoxicillin抗藥菌株與敏感菌株相比的除菌失敗風險比。我們進一步對使用含Clarithromycin及Amoxicillin三合一處方治療的患者進行分析，用以找出Amoxicillin抗藥性的最佳斷點。 研究結果: 研究1：幽門桿菌感染率在無症狀成人中為21.2%，在消化不良成人患者中則為37.9%（p <0.001）。台灣無症狀成人幽門桿菌的年齡標準化患病率為28.9%。做ROC分析時，HpSA ELISA測試曲線下面積為0.978，OD值的最佳斷點為0.03。 而HpSA ELISA的靈敏度，特異性和準確性分別為0.929、0.983和0.967。 研究2：做完系統回顧分析後，納入了 23個隨機對照試驗。經由統合分析，我們發現非鉍劑四合一療法優於三合一療法[風險比（RR）：1.15; 95%信賴區間（CI）：1.09-1.21; P <0.001]。然而，其中存在顯著的異質性（I2 = 74.0%，p <0.001）。在分組分析中，5天四合一治療優於5天三合一治療（RR：1.30; 95% CI：1.04-1.62; p = 0.02），5天或7天四合一治療優於7天三合一治療（RR：1.16; 95% CI：1.12-1.21; p <0.001），5天或7天或10天或14天四合一治療優於10天三合一治療（RR：1.15; 95% CI：1.08-1.23; p <0.001）。然而，5天或10天四合一治療並未優於14天三合一治療（RR：1.02; 95% CI：0.89-1.16; p = 0.796）。四合一治療的副作用發生率顯著高於三合一治療（RR：1.19; 95% CI：1.06-1.34; P = 0.004）。 研究3：研究中包括了2,339名有Amoxicillin 抗藥性資料的受試者。統合分析顯示Amoxicillin抗藥性的存在與含Amoxicillin治療處方治療失敗的風險增加有關（當斷點為0.5 mg/ L時，RR：1.41；95% CI：1.12-1.78，P = 0.004），異質性低（I2 = 0%，p = 0.615）。統合分析結果還表明Amoxicillin是造成含Clarithromycin三合一治療失敗的獨立危險因子，而當Amoxicillin抗藥性的斷點≥ 0.125mg/ L時，Amoxicillin抗藥性與療效的相關性是最好的（Kappa係數: 0.298）。 研究結論: 和1992年時相比，現在台灣幽門螺旋桿菌感染的盛行率在各年齡層都是下降的。我們的研究發現無症狀成人中幽門桿菌感染率為21.2%，消化不良成人患者中感染率為37.9%。驗證了幽門桿菌糞便抗原可準確應用於華人中用做為幽門桿菌篩檢。對於幽門螺旋桿菌一線治療中，給予5或10天的四合一療法優於3天或7天或10天的三合一療法，但不優於14天三合一療法。含有Amoxicillin處方的療效會受Amoxicillin抗藥性的影響，其最小抑制濃度(Minimum inhibitory concentration, MIC)的最佳斷點為≥0.125mg/ L。

Background and Objective: Helicobacter pylori has been proved to be an important predisposing factor for gastric cancer and peptic ulcer. An updated prevalence Helicobacter pylori (H. pylori) infection in asymptomatic adults is lacking in Taiwan. We hope to assess the updated age-standardized prevalence of H. pylori infection in asymptomatic subjects and in patients with dyspepsia in Taiwan. Besides, optimizing treatment and reducing side effects are also very important. Whether concomitant therapy is superior to triple therapy of various treatment lengths for the first-line treatment of H. pylori remains controversial. We hope to compare the efficacy of concomitant therapy and triple therapy given for 5 to 14 days. Antimicrobial resistance has great impact on eradication efficacy of H. pylori. The antibiotic’s resistance of clarithromycin, metronidazole and levofloxacin has been shown to affect the eradication efficacy; however, the impact of amoxicillin resistance on eradication efficacy remains unknown. It’s worthy to investigate whether the efficacy of amoxicillin containing regimen is affected by amoxicillin resistance. Methods: Study1: Asymptomatic adult subjects (N=189) were screened for H. pylori infection using HpSA, serology, and 13C-Urea Breath Test (13C-UBT) in 2016-2017. Adult patients with dyspepsia (N=145) were screened for H. pylori using 13C-UBT, HpSA, serology, rapid urease test, and histology during 2016-2018. In the present study, the 13C-UBT was used as the gold standard diagnostic tool for identification of H. pylori infection. Study 2: Randomized control trials (RCTs) comparing the efficacy of concomitant therapy for 5 to 14 days and proton pump inhibitor-amoxicillin-clarithromycin (PAC) based triple therapy for 5 to 14 days in the first-line treatment of H. pylori infection published from 1990 to January 2018 were searched from the PubMed, Cochrane Library and Embase. The primary and secondary outcomes were the eradication rate according to the intention-to-treat analysis and the adverse effects, respectively. Subgroup analyses were also performed according to treatment length. Study 3: This was one analysis of five randomized trials conducted in Taiwan from 2007 to 2016. Patients who received amoxicillin-containing regimens were recruited. Meta-analysis was performed to assess the risk ratio of eradication failure in amoxicillin resistant strains compared to susceptible strains of seven different regimens. Then, pooled analysis and logistic regression in patients treated with clarithromycin triple therapy were performed to identify the optimal breakpoint of amoxicillin resistance. Results: Study1: The un-adjusted prevalence of H. pylori was 21.2% in asymptomatic adults and 37.9% in patients with dyspepsia (p<0.001). The age-standardized prevalence of H. pylori was 28.9% in asymptomatic adults in Taiwan. Of the 334 patients included for analysis, the area under the curve of HpSA ELISA test was 0.978, and the optimal cut-off value of OD was 0.03. The sensitivity, specificity, and accuracy of the HpSA ELISA were 0.929, 0.983, and 0.967, respectively. Study 2: Of the 639 articles identified, 23 RCTs including 3,305 patients in the concomitant therapy group and 3,327 patients in the triple therapy group were eligible. Overall, concomitant therapy was superior to triple therapy [Risk ratio (RR): 1.15; 95% confidence interval (CI):1.09-1.21; p<0.001]. However, there were significant heterogeneity (I2=74.0%, p<0.001). In the subgroup analysis, 5-day concomitant therapy was superior to 5-day triple therapy (RR: 1.30; 95% CI:1.04-1.62; p=0.02), 5-or 7-day concomitant therapy was superior to 7-day triple therapy (RR: 1.16; 95% CI: 1.12-1.21; p<0.001), and 5- or 7- or 10- or 14-day concomitant therapy was superior to 10-day triple therapy (RR: 1.15; 95% CI: 1.08-1.23; p<0.001). However, 5- or 10-day concomitant therapy was not superior to 14-day triple therapy (RR: 1.02; 95% CI: 0.89-1.16; p=0.796). The frequency of adverse effects was significantly higher in concomitant therapy than triple therapy (RR: 1.19; 95% CI: 1.06-1.34; P=0.004). Study 3: A total of 2,339 patients with available data of amoxicillin MICs were enrolled. Meta-analysis showed that the presence of amoxicillin resistance was consistently associated with increased risk of treatment failure of amoxicillin-containing regimens at different breakpoints (Risk ratio: 1.41, 95% confidence interval: 1.12-1.78, P= 0.004 when cut at 0.5 mg/L). The heterogeneity was low (I2=0%, p=0.615). Pooled analysis also showed that amoxicillin resistance was an independent risk factor of treatment failure of clarithromycin triple therapy at different breakpoints. The best correlation was observed when the breakpoint of amoxicillin resistance was ≧0.125 mg/L (Kappa coefficient: 0.298), at which the resistance rate was 11.1% (110/990). Conclusions: The reported prevalence of Helicobacter pylori (H. pylori) infection in Taiwan was 54.4% in 1992. Compared with the study in 1992, our study found that prevalence of H. pylori has decreased in all age groups in Taiwan. HpSA test is an accurate tool for screening of H. pylori for Chinese population. Concomitant therapy given for 5 or 10 days was superior to 5- or 7- or 10-day PAC based triple therapy, but was not superior to 14-day triple therapy. The efficacies of amoxicillin containing regimens are affected by amoxicillin resistance and the optimal breakpoint of MIC is ≧0.125 mg/L.