高劑量amoxicillin/PPI二合一療法用於一線與救援治療幽門螺旋桿菌感染之評估

Abstract

研究背景 幽門螺旋桿菌（Helicobacter pylori）感染為常見的腸胃科感染性疾病，全世界約有一半的人感染幽門螺旋桿菌。幽門螺旋桿菌感染與慢性胃炎、消化性潰瘍、十二指腸潰瘍及胃黏膜淋巴瘤有關，甚至可能發展成胃癌。因此世界衛生組織早於1994年將幽門螺旋桿菌列為第一級的胃癌致癌因子。根據美國、歐洲、亞太地區治療指引，由質子幫浦抑制劑（proton pump inhibitor）、clarithromycin與amoxicillin（或metronidazole）所組成的三合一療法目前仍為根除幽門螺旋桿菌的第一線治療；然而目前許多國家，此療法失敗率已高於兩成，最新2012年歐洲治療指引已建議高抗藥性地區以四合一療法取代現有一線治療。相繼式療法（sequential therapy）是近年來新發展的一種四合一療法，而三合一療法中以levofloxacin取代clarithromycin現階段也被廣泛用於一線治療失敗後之救援治療。此外僅使用質子幫浦抑制劑與amoxicillin的二合一療法，其治癒率隨著不同給藥頻次、劑量與不同品項之質子幫浦抑制劑有很大的變異。 研究目的 本研究主要欲探討高劑量二合一療法分別用於一線或救援治療幽門螺旋桿菌感染的療效與安全性。一線治療將與現行治療指引建議以clarithromycin為基礎的三合一療法和四合一相繼式療法比較，救援治療則與現行建議以levofloxacin為基礎的三合一療法和四合一相繼式療法比較，評估影響各種療程療效的因子，同時針對目前幽門螺旋桿菌對於各種抗生素抗藥性之盛行率與趨勢進行分析與探討。 研究材料與方法 本研究將納入經內視鏡確診患有幽門螺旋桿菌感染引發胃炎、消化性潰瘍與十二指腸潰瘍之成年病人，分為一線治療與救援治療兩部分進行隨機分派試驗。病患若尚未接受過根除治療將納入一線治療組，此部份試驗將評估高劑量二合一療法（rabeprazole 20 毫克與amoxicillin 750 毫克，每日口服四次，共十四天）、相繼式療法（前五天使用rabeprazole 20 毫克與amoxicillin 1000 毫克，每日口服兩次，後五天使用rabeprazole 20 毫克、clarithromycin 500毫克與metronidazole 500毫克，每日口服兩次，共十天）與clarithromycin為基礎的三合一療法（rabeprazole 20 毫克、clarithromycin 500毫克與amoxicillin 1000 毫克，每日口服兩次，共七天）之根除率、副作用及服藥順從性差異；病患若曾接受過根除治療且失敗將納入救援治療組，此部份試驗將評估高劑量二合一療法（同上）、相繼式療法（同上）與levofloxacin為基礎的三合一療法（rabeprazole 20 毫克、levofloxacin 250毫克與amoxicillin 1000 毫克，每日口服兩次，共七天）之根除率、副作用及服藥順從性差異。另外，利用病患經內視鏡切片細菌培養之抗生素敏感性試驗結果，分析尚未接受治療與曾經治療失敗的病患感染各種抗生素抗藥性菌株之盛行率與趨勢。 研究結果 療且失敗的幽門螺旋桿菌感染陽性病人，所有病人以平均比例隨機分配至各組療法。一線治療部分，高劑量二合一療法之根除率為95.0％（95％信賴區間：91.4─98.6）、相繼式療法之根除率為87.1％（95％信賴區間：81.6─92.7）和clarithromycin為基礎的三合一療法之根除率為81.4％（95 %信賴區間：75─87.9）；療效上，高劑量二合一療法顯著地優於相繼式療法與三合一療法（p-value= 0.021與0.0004），而副作用發生率與服藥順從性三組之間皆無顯著性差異。救援治療部分，高劑量二合一療法之根除率為88％（95％信賴區間：79.0─97.0）、相繼式療法之根除率為52％（95％信賴區間：38.2─65.8）和levofloxacin為基礎的三合一療法之根除率為78％（95 %信賴區間：66.5─89.5）。療效上，高劑量二合一療法與levofloxacin為基礎的三合一療法未達統計上顯著差異，但相繼式療法則不適合用於救援治療；副作用發生率與服藥順從性三組之間皆無顯著性差異。研究分析顯示主要影響療效之因子為感染抗藥性菌株。在前後兩部分病人感染amoxicillin、clarithromycin、metronidazole與levofloxacin抗藥性菌株比例，一線治療分別佔1.7％、16.4％、33.8％與16％；而救援治療分別佔5.4％、81.9％、54.4％與22.1％。 結論 高劑量二合一療法可有效用於一線與救援治療幽門螺旋桿菌感染。在一線治療上，高劑量二合一療法不僅療效上顯著地優於clarithromycin為基礎三合一療法，副作用發生率上也與各療法無顯著差異。在救援治療上，高劑量二合一療法也與levofloxacin為基礎的三合一療法一樣有效與安全，且高劑量二合一療法更可有效根除clarithromycin、metronidazole或levofloxacin抗藥性菌株。

Background Helicobacter pylori infection is a common infectious disease and is highly associated with a variety of gastrointestinal disorders. Standard triple therapy consisted of a proton pump inhibitor, clarithromycin and amoxicillin (or metronidazole) has been recommended as first-line treatment for H. pylori infection for many years. However, with the increasing resistance rates to clarithromycin and metronidazole, the eradication rate of standard triple therapy is less than 80% in many countries. Therefore, alternative treatments, such as sequential therapy, are recently recommended as alternative treatment in the areas with high clarithromycin resistance rate according to Maastricht IV guideline. Compared to clarithromycin and metronidazole resistance, primary resistance rate to amoxicillin is usually less than 1%. Yet, the eradication rate of high dose amoxicillin/PPI dual therapy varies among different studies. Objectives The objectives of this study was to compare the efficacy, adverse events and patient adherence of high dose dual therapy (HD), sequential therapy (ST) and clarithromycin-based (CLA-T) triple therapy as the first-line treatment for H. pylori infection and those of HD, ST and levofloxacin-based triple therapy (LEV-T) as the rescue treatment. Also, factors affecting the studied regimens and the prevalence of antimicrobial resistance were investigated. Materials and Methods This prospective randomized study recruited H. pylori-positive patients (≧18 years of age). Treatment na&iuml;ve patients were randomly assigned to one of the following regimens: (1) HD group-rabeprazole 20 mg + amoxicillin 750 mg four times daily for 14 days, (2) ST group- rabeprazole 20 mg + amoxicillin 1 g twice daily for first 5 days and following by rabeprazole 20 mg, clarithromycin 500 mg and metronidazole 500 mg twice daily for next 5 days, or (3) CLA-T group- rabeprazole 20 mg, clarithromycin 500 mg and amoxicillin 1 g twice daily for 7 days. Patients who had a history of treatment failure were randomly assigned to one of the following regimens: (1) HD group, (2) ST group or (3) LEV-T group- rabeprazole 20 mg, levofloxacin 250 mg and amoxicillin 1 g twice daily for 7 days. Primary end point is the eradication rates of studied regimens, and secondary end point are adverse event rates and patient adherence. Results Between Oct, 2010 and April, 2013, 420 treatment na&iuml;ve patients and 150 patients who had a history of treatment failure were included. In the first-line treatment, the eradication rates were 95.0% (95% CI=91.4-98.6) in HD group, 87.1% (95% CI=81.6-92.7) in ST group, and 81.4% (95% CI=75-87.9) in CLA-T group. The efficacy of HD group is significantly superior to that of ST group and CLA-T group (p=0.021 and 0.0004). In the rescue treatment, the eradication rates were 88% (95% CI=79-97) in HD group, 52% (95% CI=38.2-65.8) in ST group, and 78% (95% CI=66.5-89.5) in LEV-T group. The efficacy of ST group is significantly worse than that of HD and LEV-T group (p<0.0001). There were no significant difference in the total adverse event rates and in patient adherence between three groups in the first-line and the rescue treatment. Conclusions High dose dual therapy is a well-tolerated and highly effective regimen as the first-line and the rescue treatment for H. pylori infection. In first-line treatment, high dose dual therapy is superior to clarithromycin-based triple therapy. In rescue treatment, high dose dual therapy is also as effective as levofloxacin-based triple therapy, of which both are better than sequential therapy.