Guidelines for the diagnosis and treatment of Helicobacter pylori infection in Korea, 2013 revised edition.

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doi:10.1111/jgh.12607

REVIEW

Guidelines for the diagnosis and treatment of Helicobacter pylori infection in Korea, 2013 revised edition Sang Gyun Kim,* Hye-Kyung Jung,† Hang Lak Lee,‡ Jae Young Jang,§ Hyuk Lee,¶ Chan Gyoo Kim,** Woon Geon Shin,†† Ein Soon Shin,‡‡,§§ Yong Chan Lee¶ and Korean College of Helicobacter and Upper Gastrointestinal Research *Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, †Department of Internal Medicine, Ewha Womans University School of Medicine, ‡Department of Internal Medicine, Hanyang University College of Medicine, §Department of Internal Medicine, Kyung Hee University College of Medicine, ¶Department of Internal Medicine, Yonsei University College of Medicine, †† Department of Internal Medicine, Hallym University College of Medicine, §§Steering Committee for Clinical Practice Guideline, Korean Academy of Medical Science, Seoul, **Center for Gastric Cancer, National Cancer Center, Goyang and ‡‡Department of Preventive Medicine and Public Health, Ajou University School of Medicine, Suwon, Korea

Key words adaptation, diagnosis, guideline, Helicobacter pylori, treatment. Accepted for publication 14 March 2014. Correspondence Dr Yong Chan Lee, Department of Internal Medicine, Yonsei University College of Medicine, Sinchon-dong 134, Seodaemun-gu, Seoul 120-752, Korea. Email [email protected] Conflicts of interest: None. Financial support: This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A102065). Authorship statement: Sang Gyun Kim and Hye-Kyung Jung have contributed in writing the paper equally as first author. Hang Lak Lee, Jae Young Jang, Hyuk Lee, Chan Gyoo Kim, Woon Geon Shin have contributed in the systematic review and the extraction of recommendations. Ein Soon Shin has contributed in the development of guideline as the methodology expert. Yong Chan Lee has designed the development of guideline as the chairman of the committee.

Abstract The Korean College of Helicobacter and Upper Gastrointestinal Research first developed guidelines for the diagnosis and treatment of Helicobacter pylori (H. pylori) infection in 1998, and revised guidelines were proposed in 2009 by the same group. Although the revised guidelines were based on a comprehensive review of published articles and the consensus of expert opinions, the revised guidelines were not developed using an evidencebased process. The new guidelines presented in this study include specific changes regarding indication and treatment of H. pylori infection in Korea, and were developed through the adaptation process using an evidence-based approach. After systematic review of the literature, six guidelines were selected using the Appraisal of Guidelines for Research and Evaluation (AGREE) II process. A total of 21 statements were proposed with the grading system and revised using the modified Delphi method. After the guideline revisions, 11 statements about indication of test and treatment, four statements about diagnosis, and four statements about treatment of H. pylori infection were developed. The revised guidelines were reviewed by external experts before receiving official endorsement from the Korean College of Helicobacter and Upper Gastrointestinal Research, and disseminated to physicians and other medical professionals for use in clinical practice in Korea. The guidelines will continue to be updated and revised periodically.

Introduction Background. The rate of Helicobacter pylori (H. pylori) infection is higher in Korea than in other regions, and thus the Korean H. pylori study group (the former society of the Korean College of Helicobacter and Upper Gastrointestinal Research) published guidelines entitled “Diagnosis and treatment of H. pylori infection in Korea,” written by expert consensus in

1998.1 Studies have shown that H. pylori is one of the primary causes of upper gastrointestinal disease, and the diagnosis and treatment of H. pylori infection is now one of the most important health issues in Korea.2 In Korea, the H. pylori infection rate is reportedly decreasing in individuals younger than 40 years old. Serology tests from 5732 healthy subjects in 1998 showed that the H. pylori infection rate was 46.6% (66.9% in adults and 17.2% in subjects younger than

Journal of Gastroenterology and Hepatology 29 (2014) 1371–1386 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

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15 years old).3 Serologic tests from a population of 15 916 healthy adults in 2005 revealed an H. pylori infection rate of 59.6%, indicating that the infection rate is decreasing in adults.2 In 2009, the revised “Diagnosis and treatment guidelines for Helicobacter pylori infection in Korea” was announced by the Korean College of Helicobacter and Upper Gastrointestinal Research and Korean Society of Gastroenterology.4 These revised guidelines combined expert opinions with an extensive literature review. The guidelines described re-infection, diagnosis, and treatment targets in detail, and made recommendations for H. pylori infection management in Korea. However, the revised guidelines were limited in that a systematic review was not performed, the guidelines were lacking multidisciplinary involvement, and they did not include an objective assessment of expert consensus. Since the first revision of these guidelines, the annual H. pylori re-infection rate has been reported to be 0.5–2.5% in the West, but higher in Asia (4.3–13.0%) and in Korea specifically (2.9–9.1%).5 In a 37.1-month (18–95 months) follow-up study of 970 patients who received the standard triple therapy from 2003 to 2010, the annual re-infection rate was 3.5%, and it was higher in males and in lower-income individuals.5 In Korea, gastric cancer is one of the most common malignancies.6 A meta-analyses of the effect of H. pylori on gastric cancer found that the H. pylori-positive group had 1.7–5.3 times higher relative risk of gastric cancer than the H. pylori-negative group.7–9 In another cohort study that included 1790 patients with 9.7 years of follow up from 1992 to 1998, gastric cancer did not occur in the H. pylori-negative group, and the incidence of gastric cancer was 10.9 times higher in the H. pylori-positive group with intestinal metaplasia than in the group without intestinal metaplasia.10 This recent decline in H. pylori infection, a relatively low re-infection rate, and the strong correlation between H. pylori and gastric cancer have created a need for the revision of guidelines in Korea. In February 2012, the newly proposed guidelines were awarded national funding by the Clinical Guidelines Development Project, supported by the National Strategic Coordinating Center for Clinical Research in Korea. The Clinical Guidelines Development Committee was launched and led by the Korean College of Helicobacter and Upper Gastrointestinal Research along with the Korean Society of Gastroenterology, the Korean Society of Clinical Microbiology, and the Korean Society of Pathologists. The revised guidelines for the diagnosis and treatment of H. pylori presented in this study include a systematic search and review of the literature to scientifically assess existing results. The newly revised guidelines were developed using the adaptation process as described below. The adaptation process is a systematic approach to endorsing and/or modifying guidelines produced in one cultural and organizational setting for application in a different context. Adaptation may be used as an alternative to de novo guideline development, such as when customizing existing guidelines to suit the local context. The adaptation process recognizes and responds to legitimate differences in organizational, regional, or cultural circumstances that could lead to variations in recommendations that are supported by the same evidence.11 Recently, the adaptation process has been recommended and disseminated for guideline development, resulting in the formation of the ADAPTE Collaboration Committee, which in turn proposed the development of principles and a standardized process in order to achieve systematic and 1372

consistent guideline adaptations. The ADAPTE process was used for guideline development in the present study.12 Target population and purpose. The target population consists of adults infected with H. pylori, and the revised guidelines are based on analysis of the latest scientific evidence, with the goal of helping clinicians and patients make informed decisions regarding the management of H. pylori infections. Therefore, the guidelines are also intended to help primary physicians and general health professionals make management decisions in the fields of gastroenterology, laboratory medicine, and pathology. In revising the guidelines, the authors attempted to provide alternative options for the treatment of H. pylori, summarize the pros and cons of each treatment, assess the probable outcomes, and propose specific guidelines based upon the aforementioned information. The revised guidelines were designed to be a guide for management principles as well as educational materials for medical students, residents and health professionals. These guidelines can also help patients better understand the provided services and make better decisions based on the most current information. Scope of the revised guidelines. The guidelines in this study are comprehensive and practical recommendations for the diagnosis and treatment of H. pylori infection in adults. Any controversial information that was not supported by scientific evidence was excluded from the newly revised guidelines. When necessary, experts reached a consensus using the Delphi method. In addition, a literature search was conducted to better understand the values and preferences of patients and the general public. A web search using the key words “patient’s satisfaction” and “H. pylori” was performed using MEDLINE and Google Scholar search engines to understand the factors that determine the patients’ preferences, and the results are reflected in the new guidelines in an effort to improve patients’ satisfaction. For example, one report claimed that Asian populations prefer upper gastrointestinal endoscopy rather than the urea breath test for diagnosing H. pylori infection, since Asian people have a higher rate of organic diseases such as gastric cancer compared with North American or European populations.13

Updating the guidelines The Guideline Committee. The Guideline Steering Committee consisted of the President and cabinet members of the Korean College of Helicobacter and Upper Gastrointestinal Research. The Guideline Steering Committee established the guideline development strategy, appointed a chairperson, and reviewed and approved the project budget. In addition, the committee reviewed the recommended revisions, implemented the final approval and publication of the new guidelines, ensured that stakeholders were allowed to participate in the revision, and confirmed that the editing process was conducted independently. The Guideline Development and Writing Committee consisted of members of the Korean College of Helicobacter and Upper Gastrointestinal Research, including the chairman (Yong Chan Lee), the secretary (Sang Gyun Kim), six general members (HyeKyung Jung, Hang Lak Lee, Woon Geon Shin, Jae Young Jang,


SG Kim et al.

Chan Gyoo Kim, and Hyuk Lee), one methodology expert (Ein Soon Shin), and one coordinator. Guideline development was a multidisciplinary process and the following societies participated: the Korean Society of Gastroenterology, the Korean Society of Clinical Microbiology, and the Korean Society of Pathologists. The Guideline Development and Writing Committee determined the purpose of the guidelines, managed the detailed adaptation process, compiled existing data, formulated recommendations, and drafted the revised guidelines. Four workshops were conducted while developing the revised guidelines as follows: (1) Use of the adaptation process for guideline development (June 21, 2012); (2) Quality evaluation of the literature according to appraisal of guidelines for research & evaluation (AGREE) II (July 12, 2012); (3) Practical evaluation of guidelines using AGREE II (August 13, 2012); and (4) Method of data extraction methods/evidence inventory table (October 11, 2012). The Guideline Development Committee met eight times and the Steering Committee met twice during guideline development. The adaptation process. Guideline development was based upon the adaptation process and performed for Korean situations. Ein Soon Shin, a methodology expert from the Korean Academy of Medical Science, guided the development process through scientific and standardized methods. Clinical questions. Clinical questions were extracted from existing guidelines using the PICO method: P (population) was defined as content related to clinical characteristics of H. pyloriinfected individuals; I (intervention) was defined as diagnostic or therapeutic intervention; C (comparison) was defined as the control group; and O (outcome) was defined as the effectiveness of the diagnosis or treatment outcome. The clinical questions determined the priority. Web search. Various electronic databases were searched for relevant information and existing guidelines including MEDLINE, MEDLINE Systematic Review, MEDLINE Clinical Study, Ovid MEDLINE, EMBASE, the Web of Science, the Cochrane Library, KoreaMed, the Korean Medical Database, the Korean National Assembly Library, the Korean Education and Research Information Service, Google Scholar, Scopus, the National Guideline Clearinghouse, the International Guideline Library, and the Canadian Medical Association Infobase. The search words were H. pylori-related index words (“Helicobacter pylori” OR “Helicobacter” OR “pylori”) and guideline-related index words (“eradication” OR “clinical protocols” OR “regimen” OR “indication” OR “therapeutics” OR “therapy” OR “therapeutic use” OR “Therap*” OR “diagnosis” OR “guideline” OR “guidelines as topic” OR “guideline adherence” OR “practice guideline” OR “practice guideline as topic” OR “clinical guideline” OR “clinical practice guideline” OR “consensus” OR “recommendation” OR “workshop”) (Appendix I). The selection criteria for existing guidelines were as follows: (1) evidence-based, (2) written in Korean or English, (3) published between January 1995 to July 2012, (4) targeted at adult populations, (5) latest revised version, and (6) agreed upon by experts and external review.


Exclusion criteria were as follows: (1) not supported by scientific evidence, (2) only applicable to hospitalized patients, (3) outdated, (4) already went through the adaptation process, and (5) includes the use of over-the-counter drugs (Fig. 1). The first literature review was performed by medical librarian Eun-Ae Jeong, who is an expert in systematic literature review. Duplicate documents were removed and the results of this first review were organized using Endnote (Endnote X3®, Thomson Reuters, NY, USA) and Excel (Excel 2010®, Microsoft, Redmond, WA, USA). A second literature review was performed by reviewing titles and abstracts from the first review to confirm that all papers met both selection and exclusion criteria. Two independent reviewers then reviewed the complete text, and a paper was selected if both reviewers agreed that it was suitable for this adaptation. If the two reviewers could not reach an agreement, a chairperson helped them reach consensus. Ultimately, six existing guidelines were selected as seed guidelines (Fig. 1). Evaluation and selection of seed guidelines. AGREE II was used to evaluate the quality of the seed guidelines. AGREE II has six domains including scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence. It comprises 23 structured key items and two items for general assessment, all of which are scored using a 7-point Likert scale. Each seed guideline was evaluated by two reviewers based upon the Korean-AGREE II developed by the Steering Committee for Clinical Practice Guidelines of the Korean Academy of Medical Science. The Korean-AGREE II was tested for its validity through a formal consensus, and its practicality was demonstrated through the actual guideline assessment.14 Prior to the evaluation in this study, a workshop for the implementation of AGREE II was held during which guideline development expert Ein Soon Shin reduced point modifications between reviewers as much as possible. During the workshop, one guideline was selected for practice, and all evaluators assessed the guideline using AGREE II. The practice assessments were then compared with an assessment by an experienced member of the Steering Committee for Clinical Practice Guidelines of the Korean Academy of Medical Science and adjusted based on the member’s feedback. Finally, two individuals assessed each guideline, and a re-assessment was performed if there were five or more items with a score difference of three or higher. A standardized score for each domain was calculated and a distribution chart was created, and then six seed guidelines were selected by comparing the scores of each domain (Fig. 2). Rigor of development was considered the most important selection criteria, and only guidelines with a rigor score greater than the scaled final score of 50% ADAPTE were selected. Although all 2009 guidelines from Canada, the American College of Gastroenterology, and Korea scored less than 50 in terms of rigor, two guidelines from each source were included as representatives of each country.4,15,16 Extraction of recommendations. Upon final selection of the seed guidelines, a recommendation matrix for data extraction was created to extract recommendations from each subheading based on the clinical questions (PICO) (Table 1). These recommendations were then unified into a single recommendation proposal.


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Figure 1 Flow chart of study selection. OTC, over-the-counter.

Figure 2 Appraisal results of candidate guidelines by AGREE II. Selected guidelines number: 1, Canadian; 2, American College of Gastroenterology (ACG); 3, Japan; 4, Asian-Pacific (AP); 5, Korean College of Helicobacter and Upper Gastrointestinal Research (Korea); 6, Maastricht.

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Level of evidence and grade of recommendation. A level of evidence evaluation was conducted for the planning method, quality and consistency of the study based on Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria for high overall quality of evidence across outcomes (Table 2) and consisted of three levels as follows. High quality (A) was defined as a recommendation where the results were supported using randomized trials or meta-analysis, and the estimated value of the effect was not significantly different in follow-up studies. Moderate quality (B) was defined as a recommendation from a well-designed controlled or uncontrolled non-randomized study that may not have been reproducible by follow-up studies. Low quality (C) was defined as a recommendation where the estimated value of the effect was uncertain. C-level information included non-randomized studies, case reports, expert opinions, guidelines, experts’ consensus, and recommendations based on clinical experience of the guideline developers.17 Grade of recommendation was either strong (1) or weak (2). A strong recommendation was defined as a recommendation that was significantly more effective, could be applied to most patients in

Table 1

most circumstances, and would be reproducible in future studies. A weak recommendation was defined as a recommendation with inconsistent results that might not be reproducible in future studies.

Expert consensus. A panel of experts was selected from members of the Guideline Steering Committee, current and former board members, and members of the Korean College of Helicobacter and Upper Gastrointestinal Research, the Korean Society of Gastroenterology, the Korean Society of Pathologists, and the Korean Society of Clinical Microbiology. The Delphi technique was used to help these experts reach a consensus concerning final recommendations. The first draft consisted of 21 recommendations: 12 concerning the indication of diagnosis and treatment of H. pylori, four regarding diagnosis, and five regarding treatment of H. pylori infection. The recommendations and related documentation were emailed to the panel 1 week before the vote so that the panel could review the information in detail. A total of 31 doctors participated in the first round of Delphi consensus, including 28 gastroenterologists and

Data extraction form/evidence inventory form for first-line Helicobacter pylori eradication

Item

Guideline/Country/Synopsis of Recommendations

First-line Helicobacter pylori eradication

G1 (Korean) Triple therapy for 1–2 weeks G4 (AP) Triple therapy for 1 week, bismuth-based quadruple as alternative G6 (Japan) Triple therapy for 1 week, 10 days sequential therapy G8 (Canada) Quadruple therapy for 10–14 days G9 (Maastricht) Triple therapy for 1–2 weeks, bismuth-based quadruple as alternative G10 (ACG) Triple or quadruple therapy for 2 weeks.

Supporting evidence SR/MA

NR

RCT

NRCS

CS

G

Other

0

0

2

1

0

0

0

2

0

1

0

0

0

0

1

0

6

7

0

4

0

4

2

1

4

0

1

0

0

1

0

0

0

1

0

2

2

5

3

0

0

0

Helicobacter pylori, H. pylori; CS, case series study; G, guideline; SR/MA, systemic review/meta-analysis; NR, non-systematic, narrative review; NRCS, non-randomized comparative study; RCT, randomized controlled trial.

Table 2

Level of evidence and grade of recommendation

Items Level of evidence A. High-quality evidence B. Moderate-quality evidence

C. Low-quality evidence

Strength of recommendation 1. Strong recommendation 2. Weak recommendation

Definitions

Further research is unlikely to change our confidence in the estimate of effect. Consistent evidence from RCTs without important limitations or exceptionally strong evidence from observational studies. Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Evidence from RCTs with important limitations (inconsistent results, methodologic flaws, indirect or imprecise), or very strong evidence from observational studies. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Evidence for at least one critical outcome from observational studies, case series, or from RCTs with serious flaws, or indirect evidence, or expert’s consensus. Recommendation can apply to most patients in most circumstances. The best action may differ depending on circumstances or patient or society values. Other alternatives may be equally reasonable.

RCTs, randomized controlled trials.


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three pathologists. After members of the Development Committee explained the basis of the literature review and announced the level of evidence and grade of recommendation, panel members voted for each recommendation using a keypad that ensured anonymous voting. Degree of agreement on the draft recommendations was determined using a 5-point Likert scale as follows: 1, completely agree; 2, mostly agree; 3, partially agree; 4, mostly disagree; 5, completely disagree; 6, not sure. If at least two-thirds of the panel members completely or mostly agreed with a recommendation, it was considered an agreement on the draft. Of the 21 recommendations, 14 were selected, five were dismissed, and two were rejected. The Guideline Development Committee adjusted seven recommendations that were dismissed in the first Delphi meeting and conducted the second Delphi meeting via email. The second meeting focused on the level of agreement for the newly revised recommendations. There were 27 respondents. Of the seven revised recommendations, six were approved and one was rejected, providing a total of 20 recommendations. Upon review by the Guideline Development Committee, one additional recommendation was rejected, and thus a total of 19 recommendations were selected by Delphi consensus. Internal and external review methods. A six-person editorial supervision committee was created, and three of the members (Yong Chan Lee, Sang Gyun Kim, and Hye-Kyung Jung) edited the first draft of the guidelines. Then, methodology expert Ein Soon Shin completed the first draft assessment based on the AGREE II standards, made revisions based on this assessment, and re-evaluated the draft. Two external experts (Young Woon Jang and Nayoung Kim) conducted independent peer reviews for verification purposes, with the goal of improving the balance and completeness of the guidelines. The revised guidelines were announced at the 21st Conference of the Korean College of Helicobacter and Upper Gastrointestinal Research, which was attended by general practitioners, gastroenterologists, surgeons, and family doctors (December 1, 2012). Limitations and future recommendations of the guideline development Limitations. There were some difficulties in developing guidelines based on the scientific method because of insufficient evidence-based studies in Korea, although experts did not expect that Korean-specific guidelines would be significantly different from existing guidelines. However, it was not possible to justify directly adopting guidelines from abroad, where the medical system and environment are different from Korea. Furthermore, there still exists a large gap in epidemiological, clinical, and ethical settings. Therefore, additional financial and policy support is needed for guideline development in Korea. Principles and methods of guideline revision. The revised guidelines were published in the Korean Journal of Gastroenterology and are also accessible on the Korean College of Helicobacter and Upper Gastrointestinal Research website (http://hpylori.or .kr).18 The Korean College of Helicobacter and Upper Gastrointestinal Research plans to print and distribute the revised guidelines in a small booklet, along with the original guidelines, and will con1376

tinue to promulgate them at relevant academic conferences, seminars, and workshops. These guidelines will be revised every 3–5 years as needed, to account for new data, methods, and treatments. Independent revision process. These guidelines were selected as a clinical guideline development project supported by the National Strategic Coordinating Center for Clinical Research, but the financial supporters had absolutely no influence over the process of guideline development. Moreover, no member who participated in the guideline development process had any personal interest or potential conflicts of interest.

Recommended guidelines for diagnosis and treatment of H. pylori infection (Table 3) Is H. pylori eradication indicated for peptic ulcer diseases? Statement 1. Eradication is indicated for H. pylori-positive peptic ulcer diseases. • Level of evidence A, Grade of recommendation 1 • Experts’ opinions: completely agree (100%), mostly agree (0%), partially agree (0%), mostly disagree (0%), completely disagree (0%), not sure (0%) It was expected that the prevalence of peptic ulcer diseases might be reduced by the recent decline of H. pylori infection rate, but the incidence rate of peptic ulcer diseases was not reduced by the aging population and increased use of non-steroidal antiinflammatory drugs including aspirin.2,19 H. pylori eradication is effective in the treatment and prevention of recurring gastroduodenal ulcers.20 The recurrence rate of duodenal ulcer is as high as 60–100% in individuals with persistent H. pylori infection, but decreases to 5% or lower with H. pylori eradication. In a meta-analysis of 21 randomized controlled studies, ulcer recurrence rate during a 12-month follow up of the eradication failure group was 39.1% for gastric ulcers and 42.5% for duodenal ulcers.20 Gastroduodenal ulcers have a tendency to recur upon completion of treatment, and thus H. pylori eradication is necessary even

Table 3

Indications of Helicobacter pylori eradication

Peptic ulcer disease Marginal zone B-cell lymphoma After endoscopic resection of early gastric cancer Atrophic gastritis/intestinal metaplasia Family history of gastric cancer Functional dyspepsia Long-term low-dose aspirin user with a history of peptic ulcer Idiopathic thrombocytopenic purpura

Level of evidence

Grade of recommendation

A A A

1 1 1

C C A C

2 2 2 1

A

1


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for cured peptic ulcers. Especially for bleeding peptic ulcers, the recurrence of bleeding can be prevented by H. pylori eradication.21 Is H. pylori eradication indicated for marginal zone B-cell lymphoma? Statement 2. H. pylori eradication is indicated for marginal zone B-cell lymphoma (MALT type). • Level of evidence A, Grade of recommendation 1 • Experts’ opinions: completely agree (78.6%), mostly agree (17.9%), partially agree (3.6%), mostly disagree (0%), completely disagree (0%), not sure (0%) Sixty to ninety percent of marginal zone B-cell lymphoma (MALT type) in the stomach is known to be related to H. pylori infection. As H. pylori eradication induces remission of lymphoma, and the endoscopic and histologic improvements up to 60–80%, it should be used as the primary treatment for marginal zone B-cell lymphoma confined to the mucosa or submucosa.22 It is difficult to conduct a large-scale study for marginal zone B-cell lymphoma because it is not a prevalent disease. H. pylori eradication has been recommended as the primary treatment in previous guidelines despite the fact that there is little evidence to support this recommendation. In a study consisting of 90 Korean patients, complete remission was achieved in 94.4% of patients with H. pylori eradication.23 Although H. pylori eradication is effective for marginal zone B-cell lymphoma that is confined to the mucosa or submucosa, H. pylori eradication alone might not be enough for treatment of the disease with tumor invasion beyond the submucosal layer. The remission rate is related to H. pylori infection, depth of tumor invasion, andAPI2-MALT1 gene mutation, and complete remission was achieved by eradication even in some H. pylori-negative patients.24,25 In cases of failed remission despite H. pylori eradication, surgical resection, chemotherapy, or radiation therapy could be attempted independently or in combination.26 Is H. pylori eradication indicated after endoscopic resection of early gastric cancer? Statement 3. H. pylori eradication is indicated after endoscopic resection for H. pylori-positive early gastric cancer (EGC). • Level of evidence A, Grade of recommendation 1 • Experts’ opinions: completely agree (35.7%), mostly agree (46.4%), partially agree (14.3%), mostly disagree (3.6%), completely disagree (0%), not sure (0%) Chronic gastritis due to longstanding H. pylori infection plays a significant role in gastric carcinogenesis. The risk of gastric cancer increased threefold for the H. pylori-infected group compared with the non-infected group. In some studies, the incidence rate of metachronous gastric cancer decreased with H. pylori eradication after endoscopic resection of EGC.27,28 In a multicenter study of 544 patients with endoscopic resection of EGC, the incidence rate of metachronous gastric cancer was significantly reduced in the H. pylori eradication group compared with the non-eradication group. However, another retrospective study of 268 patients with endoscopic resection of EGC showed contradictory results, in that there was no significant difference in metachronous gastric cancer


between the eradication group and the non-eradication group.29,30 Considering the high incidence of gastric cancer in Korea, H. pylori eradication is necessary to prevent metachronous gastric cancer after endoscopic resection of EGC. Information is lacking about the role of H. pylori eradication in preventing metachronous gastric cancer after partial gastrectomy rather than endoscopic resection of EGC.

Is H. pylori eradication helpful for the prevention of gastric cancer in patients with atrophic gastritis/intestinal metaplasia? Statement 4. H. pylori eradication is helpful for the prevention of gastric cancer in some patients with atrophic gastritis/intestinal metaplasia. • Level of evidence C, Grade of recommendation 2 • Experts’ opinions: completely agree (14.8%), mostly agree (70.4%), partially agree (11.1%), mostly disagree (3.7%), completely disagree (0%), not sure (0%) H. pylori plays an important role in gastric carcinogenesis; in particular, it is an important cause of 71–95% of non-cardiac gastric cancers.31 H. pylori colonizes the gastric mucosa and triggers a series of inflammatory reactions leading to cancer. The current model for gastric carcinogenesis begins with chronic gastritis, proceeds to mucosal atrophy, followed by intestinal metaplasia, dysplasia, and finally, carcinoma.32 In H. pylori-positive patients with severe atrophic gastritis, the incidence rate of gastric cancer is 4.9 times higher than H. pyloripositive patients without atrophic gastritis and 14.5 times higher than H. pylori-negative patients without atrophic gastritis.33,34 In addition, in H. pylori-positive patients with intestinal metaplasia, the incidence of gastric cancer was 6.4 times greater than in H. pylori-positive patients without intestinal metaplasia, and 10.9 times greater in the Korean study.10 Therefore, atrophic gastritis and intestinal metaplasia are considered important precancerous lesions in gastric carcinogensis.33 In a Korean study, the mean prevalence of atrophic gastritis in the antrum and body was 42.5% and 20.1%, while the mean prevalence of intestinal metaplasia was 28.6% and 21.2%, respectively.35,36 In other studies, the age-adjusted prevalence of atrophic gastritis was 42.7% for men and 38.1% for women, and the prevalence of intestinal metaplasia was 42.5% for men and 32.7% for women. The prevalence of atrophic gastritis and intestinal metaplasia increased significantly with age for both men and women.36 In communities with a high prevalence of H. pylori infection, atrophic gastritis, intestinal metaplasia, and gastric cancer, H. pylori eradication may have a prophylactic role on gastric carcinogenesis. Previous studies have shown that H. pylori eradication improved gastric mucosal atrophy, inhibited the progression of intestinal metaplasia, and prevented the development of gastric cancer. Thus, Japanese and European guidelines strongly recommend H. pylori eradication as a means of reducing the incidence of atrophic gastritis.26,29,37–39 Intestinal metaplasia was not improved by H. pylori eradication in most studies and may be considered as the “point of no return” in the histological cascade from chronic gastritis to adenocarcinoma.40,41 Therefore, it appears that


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H. pylori eradication does not prevent gastric cancer development in patients who have already developed advanced pre-neoplastic lesions such as intestinal metaplasia. A large-scale, double-blind randomized study in China showed that gastric cancer was still diagnosed after successful eradication of H. pylori and that eradication did not lead to a significant decrease in the incidence of gastric cancer.42,43 Thus, H. pylori eradication may represent a primary chemopreventive strategy for patients with atrophic gastritis and intestinal metaplasia.

early endoscopy.49 However, early endoscopy is recommended as an initial approach to uninvestigated dyspepsia instead of a testand-treat strategy of H. pylori infection in Asia (including Korea, China, and Japan), where the prevalence rate of gastric cancer is very high (0.9–3.4%) and the average age of incidence is low.50,51 The optimal cut-off age for early endoscopy as an initial approach for patients with uninvestigated dyspepsia varies according to region and ethnicity.50,52 In Korea, further studies are needed to determine the appropriate cut-off age for early endoscopy as an initial approach in patients with uninvestigated dyspepsia.

Does H. pylori eradication help prevent gastric cancer in cases with family history?

Does H. pylori eradication help long-term symptom improvement in patients with functional dyspepsia?

Statement 5. H. pylori eradication is helpful in the prevention of gastric cancer in cases with family history. • Level of evidence C, Grade of recommendation 2 • Experts’ opinions: completely agree (17.2%), mostly agree (58.6%), partially agree (17.2%), mostly disagree (3.5%), completely disagree (3.5%), not sure (0%) Several studies found that 10–15% of patients with gastric cancer had a family history of gastric cancer, and the population with a family history of gastric cancer were two to three times more likely to have gastric cancer than the general population by the exposure to similar environmental risk factors such as dietary habits, smoking habits, and H. pylori infection.44–46 Another study reported that the incidence of gastric cancer was five to eight times higher in subjects with H. pylori infection and a family history of gastric cancer than in the control group.47 The Maastricht IV consensus report recommended H. pylori eradication to prevent gastric cancer for H. pylori-positive, first-degree relatives of the patient with gastric cancer.39 However, there has been no prospective study in which the development of gastric cancer was prevented by H. pylori eradication in the first-degree relatives of a patient with gastric cancer. Therefore, further investigations are warranted to demonstrate the effect of H. pylori eradication on the prevention of gastric cancer in the first-degree relatives of a patient with gastric cancer. Is a test-and-treat strategy of H. pylori more effective than early endoscopy as an initial approach to uninvestigated dyspepsia? Statement 6. Endoscopy is recommended instead of a test-andtreat strategy of H. pylori for uninvestigated dyspepsia. • Level of evidence C, Grade of recommendation 1 • Experts’ opinions: completely agree (51.7%), mostly agree (34.5%), partially agree (6.9%), mostly disagree (3.5%), completely disagree (3.5%), not sure (0%) In Western countries, a test-and-treat strategy for H. pylori infection has been recommended as a safe, cost-effective initial approach for young patients with uninvestigated dyspepsia and without alarm symptoms.13,48 In a meta-analysis, the test-and-treat strategy for H. pylori infection as an initial approach to uninvestigated dyspepsia was more cost-effective, and not significantly different in symptom improvement when compared with an 1378

Statement 7. H. pylori eradication helps long-term symptom improvement in some patients with functional dyspepsia. • Level of evidence A, Grade of recommendation 2 • Experts’ opinions: completely agree (18.5%), mostly agree (55.6%), partially agree (22.2%), mostly disagree (3.7%), completely disagree (0%), not sure (0%) Studies have shown that an H. pylori eradication group exhibited long-term symptom improvement in functional dyspepsia compared with the placebo group.53,54 In a meta-analysis of 17 randomized studies, the risk of symptom persistence was reduced by 9% in the H. pylori eradication group compared with the placebo group, which was a statistically significant difference.55 In addition, a prospective study conducted by a primary medical facility showed that H. pylori eradication had a significant impact on symptom improvement in patients with functional dyspepsia.56 It is not clear whether H. pylori eradication improves functional dyspepsia in Asian populations. Previous studies are insufficient as they have included a small sample size or no randomization protocol.57 Although a meta-analysis showed 3.6 times greater symptom improvement in the H. pylori eradication group, H. pylori eradication is not cost-effective in all regions.58 Another analysis of 12 randomized studies showed that H. pylori eradication was a cost-effective treatment for functional dyspepsia.59 No randomized controlled studies have assessed the effect of H. pylori eradication on functional dyspepsia in Korea. In one prospective study, there was no difference in symptom improvement between the successful H. pylori eradication group and the failed group. However, another study reported that there was a significant improvement in symptoms upon H. pylori eradication.60,61 Since the H. pylori infection rate is high in Korea, H. pylori eradication for all patients with functional dyspepsia might cause antibiotics resistance or an adverse event, and the risk of treatment should be considered in addition to cost-effectiveness. Does H. pylori eradication affect the incidence and clinical outcomes of gastroesophageal reflux disease? Statement 8. H. pylori eradication does not affect the incidence and clinical outcomes of gastroesophageal reflux disease. • Level of evidence B, Grade of recommendation 2


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• Experts’ opinions: completely agree (26.9%), mostly agree (61.5%), partially agree (11.5%), mostly disagree (0%), completely disagree (0%), not sure (0%) Gastric acid secretion decreases with H. pylori-induced chronic inflammation in the gastric antrum and body, and it has been suggested that H. pylori eradication may aggravate gastroesophageal reflux disease by increased gastric acid secretion.62 In population-based observational studies, the prevalence of gastroesophageal reflux disease was inversely correlated with H. pylori infection.63 In a study of the relationship between the gastroesophageal reflux disease and H. pylori strains, the prevalence of gastroesophageal reflux disease was only significantly lower for CagA-positive H. pylori-infected patients, which prevented the progression to Barrett’s esophagus or adenocarcinoma.64 However, H. pylori eradication had no significant impact on the clinical characteristics of gastroesophageal reflux disease.65,66 One Korean observational study reported a low prevalence of H. pylori infection in the group with gastroesophageal reflux disease, while a different prospective study found that H. pylori eradication had no effect on endoscopic severity of esophagitis or clinical outcomes.67–69 Is H. pylori eradication indicated for preventing the recurrence of disease in a long-term low-dose aspirin user with a history of peptic ulcer? Statement 9. H. pylori eradication is indicated for preventing the recurrence of disease in a long-term low-dose aspirin user with a history of peptic ulcer. • Level of evidence C, Grade of recommendation 1 • Experts’ opinions: completely agree (40.7%), mostly agree (44.4%), partially agree (7.4%), mostly disagree (7.4%), completely disagree (0%), not sure (0%) Aspirin is a known risk factor for peptic ulcers, which are more common in elderly people, as well as those who are currently infected with H. pylori or have a history of bleeding peptic ulcers.70 The risk also increases when accompanied by severe systemic disease or with use of other anti-platelets, non-steroidal anti-inflammatory drugs (NSAIDs), anticoagulants, or steroids.71 In a study comparing H. pylori eradication and long-term use of proton pump inhibitor (PPI) as a means of preventing ulcers in long-term aspirin users, there was no difference in ulcer prevention between the two groups, although successful H. pylori eradication was associated with a very low bleeding risk of the recurrent peptic ulcer in long-term aspirin users.72 When the eradication only group was compared with the group who underwent both eradication and PPI maintenance, the rate of complications was significantly reduced in the eradication with PPI maintenance group.73 However, H. pylori eradication is not recommended if there is no history of peptic ulcers or other risk factors. Does H. pylori eradication reduce the risk of peptic ulcers in long-term NSAID users? Statement 10. H. pylori eradication alone does not reduce the risk of peptic ulcer in long-term NSAID users.


• Level of evidence A, Grade of recommendation 1 • Experts’ opinions: completely agree (37.9%), mostly agree (48.3%), partially agree (3.5%), mostly disagree (6.9%), completely disagree (0%), not sure (3.5%) There have been conflicting results regarding whether H. pylori eradication reduces the risk of peptic ulcers in long-term NSAID users.72,74–77 A meta-analysis reported that the use of PPI was more effective for ulcer prevention than H. pylori eradication.76 In particular, because the long-term use of NSAIDs itself might cause disease in patients with a history of peptic ulcers, H. pylori eradication alone might not be enough for ulcer prevention in long-term NSAID users.72,75 Is H. pylori eradication more effective in patients with idiopathic thrombocytopenic purpura (ITP) compared with patients who have not undergone eradication or for whom eradication was unsuccessful? Statement 11. H. pylori eradication is recommended for the patients with ITP. • Level of evidence A, Grade of recommendation 1 • Experts’ opinions: completely agree (32.1%), mostly agree (53.6%), partially agree (7.1%), mostly disagree (3.6%), completely disagree (0%), not sure (3.6%) H. pylori may be one cause of ITP, and partial or complete remission of ITP was achieved by H. pylori eradication.78,79 Crossmolecular similarity is shown in CagA protein of H. pylori and the antigen of thrombocytes in some patients with ITP, which might result in thrombocytopenia by subsequent immune response.79 Thrombocytopenia was significantly improved by H. pylori eradication in 50% or more of patients with ITP, and this result was more evident in areas with a high prevalence of H. pylori infection.80 What are the recommended non-invasive diagnostic tests for H. pylori infection? Statement 12. Urea breath, stool antigen and serology tests are recommended as non-invasive diagnostic tests of H. pylori infection. Antibiotics or PPI should be discontinued for 2 weeks before the test. • Level of evidence B, Grade of recommendation 1 • Experts’ opinions: completely agree (53.3%), mostly agree (40.0%), partially agree (3.3%), mostly disagree (0%), completely disagree (0%), not sure (3.3%) Urea breath, stool antigen and serology tests are recommended as non-invasive diagnostic tests of H. pylori infection. These tests do not cause the patient discomfort and are less expensive than other diagnostics. The urea breath test has been widely used for diagnosing H. pylori infection because it has high sensitivity and specificity (≥ 95%) and is easy to use.81 However, false-negative rates greater than 30% have been reported when antibiotics or PPI were used just prior to or at the time of the test.82 Therefore, it is recommended that antibiotics and PPI be discontinued at least 2 weeks before the test.


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This recommendation also applies to the stool antigen test that has yielded false-negative results in patients using PPI or antibiotics at the time of the test.83 The stool antigen test uses both polyclonal or monoclonal antibodies. The sensitivity and specificity of the stool antigen test using polyclonal antibodies ranges from 87.1–93.1% and 94.6–100%, respectively.84,85 In a meta-analysis of stool antigen test results using monoclonal antibodies, sensitivity and specificity were 94% and 97%, respectively, which were slightly higher than tests using polyclonal antibodies.86 The serology test includes blood agglutination, complement fixation, indirect immunofluorescence tests, and enzyme-linked immunosorbent assays (ELISA), which are non-invasive, less expensive, and quick and easy to conduct. In contrast to urea breath and stool antigen tests, serology tests have a low potential for false-negatives in patients using antibiotics or PPI or with hemorrhagic ulcers.87 Serology tests are not useful for determining whether H. pylori eradication is successful because it takes more than 1 year for antibodies to disappear or have reduced titers. Therefore, serology tests are useful in screening patients for infection rather than evaluating the success of H. pylori eradication.88

What are the recommended invasive diagnostic tests for H. pylori infection? Statement 13. Rapid urease test and histology are the recommended invasive diagnostic tests for H. pylori infection. • Level of evidence B, Grade of recommendation 1 • Experts’ opinions: completely agree (41.9%), mostly agree (51.6%), partially agree (3.2%), mostly disagree (0%), completely disagree (3.2%), not sure (0%) Rapid urease test, histology, and bacterial cultures are the recommended invasive diagnostic tests for H. pylori infection. As with the non-invasive tests, these methods may produce inaccurate results in patients using antibiotics or PPI.89 For the rapid urease test, a sample of gastric mucosa obtained by endoscopic biopsy is placed into a urea substrate. The presence of H. pylori is indicated by a color change, which is due to the increased pH from the ammonia created by the urease secreted by H. pylori. Test sensitivity rages from 85–98% and specificity ranges from 89–100%.90 Although histology requires a pathologist and is invasive, it provides additional information regarding mucosal inflammation, atrophy, and intestinal metaplasia, as well as the presence of H. pylori. The diagnostic accuracy of histology differs based on the distribution and density of H. pylori, the experience of the pathologist, and the applied staining method. Hematoxylin and eosin (H&E) staining has a sensitivity of 69–93% and a specificity of 87–90%. If H&E staining is combined with a special staining such as Giemsa, then the diagnostic specificity increases to 90–100%.91 Therefore, a combination of H&E and special staining methods such as Giemsa or Warthin–Starry silver is recommended if possible. In cases with a failure to eradicate H. pylori, a secondary or tertiary eradication regimen can be selected by testing for antibiotics resistance in a bacterial culture. Because such methods are complicated and time-intensive, it is impractical to use such tests for primary diagnostic purposes in the clinic. 1380

From where should biopsy samples be collected when conducting invasive diagnostic tests for H. pylori infection? Statement 14. It is preferable to obtain biopsy samples from both the gastric antrum and body for invasive diagnostic tests of H. pylori infection. If the samples are obtained from only one area, they should be obtained from the area where mucosal atrophy and intestinal metaplasia are not present or are minimal. • Level of evidence B, Grade of recommendation 1 • Experts’ opinions: completely agree (40.0%), mostly agree (56.7%), partially agree (0%), mostly disagree (3.3%), completely disagree (0%), not sure (0%) Invasive diagnostic tests for H. pylori infection can produce false-negatives based on the location of the biopsy and the number of biopsy samples because H. pylori may not be evenly distributed in the gastric mucosa.92,93 Mucosal atrophy and intestinal metaplasia are particularly unfavorable environments for the survival of H. pylori.94,95 Thus, it is preferable to obtain more than two samples from both the antrum and body for accurate diagnosis.92,93 If dual sampling is difficult as a result of increased procedure time, cost, and risk of bleeding at the biopsy sites, tissue samples should be obtained from areas where the mucosal atrophy and intestinal metaplasia are not present or are minimal. It has been reported that biopsy specimens from the gastric body had equivalent or higher diagnostic accuracy compared with those from the gastric antrum where mucosal atrophy or intestinal metaplasia were commonly present.94–96 Which tests are recommended H. pylori eradication?

to

confirm

Statement 15. Urea breath or stool antigen tests are the recommended non-invasive methods, and histology or rapid urease tests from the gastric antrum and body are the recommended invasive tests to confirm H. pylori eradication. Tests should be performed at least 4 weeks after completion of eradication or 2 weeks after PPI use. • Level of evidence B, Grade of recommendation 1 • Experts’ opinions: completely agree (22.6%), mostly agree (48.4%), partially agree (9.7%), mostly disagree (3.2%), completely disagree (9.7%), not sure (6.5%) It is recommended that any test confirming H. pylori eradication should be conducted at least 4 weeks after the completion of eradication or 2 weeks after treatment with PPI because of the possibility of a false-negative result.15,26,39,97 The urea breath test is convenient and non-invasive, with reproducibility, sensitivity, and specificity all greater than 95%, and thus is recommended as the primary confirmatory test for H. pylori eradication.81,98 The stool antigen test is also useful for confirming H. pylori eradication with a sensitivity of 89% and a specificity of 92% in children. However, it is inconvenient and has low diagnostic accuracy when polyclonal antibodies are used.99,100 Histology or rapid urease tests can be used to confirm H. pylori eradication when follow-up endoscopies are conducted to evaluate the underlying disease. Because of the reduced and uneven distribution of H. pylori colonization after eradication, two or more


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samples should be obtained from the gastric antrum and body and combined with a special stain such as Giemsa to avoid false-negatives.101 What is the recommended primary regimen for H. pylori eradication? Statement 16. Triple therapy including a standard dose of PPI, 1 g of amoxicillin and 500 mg clarithromycin twice a day for 7–14 days is the recommended primary regimen for H. pylori eradication. • Level of evidence A, Grade of recommendation 1 • Experts’ opinions: completely agree (53.6%), mostly agree (35.7%), partially agree (10.7%), mostly disagree (0%), completely disagree (0%), not sure (0%) When creating a regimen for eradication of H. pylori, the eradication rate should be over 80%.102,103 Since 1998, when regimens for H. pylori eradication were first recommended in Korea, the triple therapy of PPI, clarithromycin, and amoxicillin has been the recommended primary regimen.4,104,105 Although metronidazole was commonly used for H. pylori eradication in the past, it is not currently recommended as the primary regimen because of the high rate of antibiotics resistance, although it is occasionally used as part of the quadruple therapy explained below.106 The eradication rate of the 7-day regimen has declined in recent years, but it is not clear whether the eradication rate of the 14-day regimen is any better.107,108 Since no other regimen currently reports a superior eradication rate, the conventional triple therapy is recommended as primary eradication until a better regimen is made available. What is the recommended alternative primary regimen when clarithromycin resistance is suspected? Statement 17. Quadruple therapy including two standard doses of PPI, three doses of 500 mg metronidazole, four doses of 120 mg bismuth, and four doses of 500 mg tetracycline daily for 7–14 days is the recommended alternative primary regimen for H. pylori eradication when clarithromycin resistance is suspected. • Level of evidence A, Grade of recommendation 1 • Experts’ opinions: completely agree (17.9%), mostly agree (60.7%), partially agree (14.3%), mostly disagree (0%), completely disagree (0%), not sure (0%) In Korea, clarithromycin resistance has gradually increased over the last 10 years, and has become a main cause of the reduced H. pylori eradication rate.109 Since quadruple therapy including bismuth has an eradication rate similar to triple therapy, quadruple therapy is recommended for regions of the country with high clarithromycin resistance.15,16,39,97,110–112 What is the recommended secondary regimen for H. pylori eradication in cases of eradication failure with the conventional triple therapy? Statement 18. Bismuth-containing quadruple therapy is recommended as the secondary regimen for H. pylori eradication in

Figure 3 Algorithm of Helicobacter pylori eradication. Triple therapy, proton pump inhibitor (PPI) standard dose twice a day (b.i.d.), amoxicillin 1 g b.i.d., clarithromycin 500 mg b.i.d. for 7–14 days; bismuth-based quadruple therapy, PPI standard dose b.i.d., metronidazole 500 mg three times a day (t.i.d.), bismuth 120 mg four times a day (q.i.d.), tetracycline 500 mg q.i.d. for 7–14 days; Regimen including other two or more antibiotics, combination with other two or more antibiotics except metronidazole and tetracycline, which were used in first-line therapy.

cases of eradication failure with the conventional triple therapy (Fig. 3). • Level of evidence A, Grade of recommendation 1 • Experts’ opinions: completely agree (51.9%), mostly agree (33.3%), partially agree (0%), mostly disagree (0%), completely disagree (3.7%), not sure (11.1%) Bismuth-containing quadruple therapy is considered a conventional secondary regimen for H. pylori eradication.4,15,39,97 In Korea, recent randomized studies have reported 80% or higher eradication rates in intention-to-treat analysis and have shown that quadruple therapy and triple therapy have similar adverse event rates.113,114 In terms of duration of treatment, there have been contradictory reports whether the eradication rate was significantly different between the 7-day and 14-day regimens of bismuthcontaining quadruple therapy. What is the recommended secondary regimen for H. pylori eradication in cases of eradication failure with initial bismuth-containing quadruple therapy? Statement 19. A secondary regimen including two or more antibiotics that were not used in the primary regimen is recommended for H. pylori eradication in cases of eradication failure with initial bismuth-containing quadruple therapy (Fig. 3). • Level of evidence C, Grade of recommendation 1 • Experts’ opinions: completely agree (37.0%), mostly agree (55.6%), partially agree (7.4%), mostly disagree (0%), completely disagree (0%), not sure (0%) H. pylori eradication failure is associated with antibiotics resistance, patient compliance, H. pylori density, CagA status, and smoking. A secondary regimen must contain new antibiotics that have not been used in the primary regimen because of the possibility of resistance. One study showed that the expression of multidrugresistant H. pylori increased after primary eradication.115


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Various combinations of antibiotics have been proposed as secondary regimens.15,26,39,97 Potential combinations included sequential therapy, concomitant therapy, and triple therapy with a PPI and amoxicillin. However, sequential or concomitant therapy has limitations as a secondary regimen because studies have mostly focused on using these therapies as primary treatment. Even with such limitations, sequential or concomitant therapy is recommended as a secondary regimen because it is very difficult to create a secondary regimen in cases of H. pylori eradication failure when the primary treatment included both clarithromycin and nitroimidazole. Sequential therapy. Sequential therapy is composed of 5 days of treatment with PPI and amoxicillin, followed by another 5days of treatment with PPI, clarithromycin, and nitroimidazole (metronidazole or tinidazole). In one retrospective and six prospective randomized studies conducted in Korea, sequential therapy had an eradication rate of 77.8–85.9% in intention-to-treat analysis, and was more effective than clarithromycin-containing triple therapy, which reported an eradication rate of 62.2–75.0%.116–120 There are several reasons why sequential therapy has a higher eradication rate than triple therapy. First, clarithromycincontaining triple therapy has a higher eradication rate when H. pylori density is low (inoculum effect). Therefore, initial dual therapy with PPI and amoxicillin lowers H. pylori density, and likely increases the effect of subsequent triple therapy, which is composed of PPI, clarithromycin and nitroimidazole.121 Second, H. pylori moves antibiotics outside of itself to create an efflux channel of clarithromycin and prevents antibiotics from binding to ribosomes. Initial dual therapy can prevent secondary clarithromycin resistance since amoxicillin weakens the bacterial cellular wall and inhibits the development of efflux channels.121,122 Concomitant therapy. Concomitant therapy is the regimen containing nitroimidazole and additional clarithromycincontaining triple therapy. This regimen was proposed since it was unclear whether the improved H. pylori eradication rate of sequential therapy was achieved by sequential drug administration or additional use of antibiotics such as metronidazole, and the studies that showed high H. pylori eradication rate by sequential therapy were heterogeneous.123 In a randomized study, 5 days of concomitant therapy had an 80.7% H. pylori eradication rate in intentionto-treat analysis, which was not statistically different from clarithromycin-containing triple therapy.124 In addition, another study that compared sequential and concomitant therapies did not report any significant difference in H. pylori eradication rates between the two therapies.125 Triple therapy containing PPI and amoxicillin. Asia-Pacific guidelines recommend clarithromycin-containing triple therapy as a secondary regimen for H. pylori eradication in cases of eradication failure with metronidazole-containing primary regimen. These guidelines cite a study with a 75% eradication rate from intention-to-treat analysis.15,126 Maastricht IV/Florence guidelines recommend a combination of PPI, amoxicillin, and fluoroquinolone in cases of eradication failure with bismuth-containing quadruple therapy.39 However, fluoroquinolone-containing triple therapy has limitations as a sec1382

ondary regimen in Korea because the resistance to fluoroquinolone has increased dramatically in recent years and is currently at 30% or higher.106,127,128 Others. Rifabutin, which has an antibacterial action in an acidic environment and has been used for atypical tuberculosis, can also be used for triple combination therapy.129 A recent study compared rifabutin 300 mg-containing triple therapy and levofloxacincontaining triple therapy as tertiary regimens, and reported low eradication rates of 71.4% and 57.1%, respectively.130 Considering the cost of the treatment, the side-effect of bone marrow suppression, and the potential increased resistance to Mycobacterium tuberculosis, rifabutin triple combination therapy should only be considered in cases of multi-eradication failure.4 In cases of primary and secondary eradication failure, AsiaPacific guidelines recommend testing for CYP2C19 polymorphism, and the Maastricht IV/Florence guidelines recommend testing for antibiotics resistance.15,40 However, the test for CYP2C19 polymorphism is difficult to use in primary care settings, and it can be difficult to confirm antibiotics resistance because of bacterial cultural conditions, different antibiotic usage patterns for each community, regional differences in strains, the possibility of co-infection of resistant and susceptible strains, uncertainty about bacterial minimum inhibitory concentration, and differences in various antibiotic susceptibility tests.131 Currently, the agar dilution method, microdilution method, and Epsilometer (E) test are used as antibiotic susceptibility tests for H. pylori. Although the Clinical and Laboratory Standards Institute recommends the agar dilution method as the primary test of antibiotics resistance, it can be used only for research purposes.132 Recently, a simple new method has been developed for clarithromycin-resistant H. pylori using polymerase chain reaction, which can be easily implemented by primary clinics but needs further clinical data.133

Acknowledgments We would like to express our sincere gratitude to Eun-Ae Jeong, PhD of the Library of Medicine of Soonchunhyang University who searched existing guidelines during the first phase of the systematic literature review. In addition, we would like to thank Prof. Young Woon Chang (Department of Internal Medicine, Kyung Hee University College of Medicine), and Prof. Nayoung Kim (Department of Internal Medicine, Seoul National University College of Medicine) who reviewed the draft of this manuscript in the peer review process.

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5 Kim MS, Kim N, Kim SE et al. Long-term follow-up Helicobacter pylori reinfection rate and its associated factors in Korea. Helicobacter 2013; 18: 135–42. 6 Park B, Choi KS, Lee YY, Jun JK, Seo HG. Trends in cancer screening rates among Korean men and women: results from the Korean National Cancer Screening Survey (KNCSS), 2004–2011. Cancer Res. Treat. 2012; 44: 113–20. 7 Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut 2001; 49: 347–53. 8 Chang WK, Kim HY, Kim DJ et al. Association between Helicobacter pylori infection and the risk of gastric cancer in the Korean population: prospective case-controlled study. J. Gastroenterol. 2001; 36: 816–22. 9 Cho SJ, Choi IJ, Kim CG et al. Helicobacter pylori seropositivity is associated with gastric cancer regardless of tumor subtype in Korea. Gut Liver 2010; 4: 466–74. 10 Kim N, Park RY, Cho SI et al. Helicobacter pylori infection and development of gastric cancer in Korea: long-term follow-up. J. Clin. Gastroenterol. 2008; 42: 448–54. 11 Fervers B, Remy-Stockinger M, Graham ID et al. Guideline adaptation: an appealing alternative to de novo guideline development. Ann. Intern. Med. 2008; 148: 563–4, author reply 564–565. 12 The ADAPTE Collaboration. ADAPTE framework. Cited 13 Jul 2010. Available from URL: http://www.adapte.org 13 Mahadeva S, Chia YC, Vinothini A, Mohazmi M, Goh KL. Cost-effectiveness and satisfaction with a Helicobacter pylori “test and treat” strategy compared with prompt endoscopy in young Asians with dyspepsia. Gut 2008; 57: 1214–20. 14 Steering Committee for Clinical Practice Guideline. Adaptation Process for Developing Korean Clinical Practice Guideline, 1st edn. Seoul: Minister of Health & Welfare, Korean Academy of Medical Science, 2011. 15 Chey WD, Wong BC, Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am. J. Gastroenterol. 2007; 102: 1808–25. 16 Hunt R, Fallone C, van Zanten SV et al. Canadian Helicobacter Study Group Consensus Conference: update on the management of Helicobacter pylori—An evidence-based evaluation of six topics relevant to clinical outcomes in patients evaluated for H. pylori infection. Can. J. Gastroenterol. 2004; 18: 547–54. 17 Schunemann HJ, Oxman AD, Brozek J et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ 2008; 336: 1106–10. 18 Kim SG, Jung HK, Lee HL et al. Guidelines for the diagnosis and treatment of Helicobacter pylori infection in Korea, 2013 revised edition. Korean J. Gastroenterol. 2013; 62: 3–26. 19 Kim JI, Kim SG, Kim N et al. Changing prevalence of upper gastrointestinal disease in 28 893 Koreans from 1995 to 2005. Eur. J. Gastroenterol. Hepatol. 2009; 21: 787–93. 20 Leodolter A, Kulig M, Brasch H et al. A meta-analysis comparing eradication, healing and relapse rates in patients with Helicobacter pylori–associated gastric or duodenal ulcer. Aliment. Pharmacol. Ther. 2001; 15: 1949–58. 21 Chan FK, Ching JY, Suen BY, Tse YK, Wu JC, Sung JJ. Effects of Helicobacter pylori infection on long-term risk of peptic ulcer bleeding in low-dose aspirin users. Gastroenterology 2013; 144: 528–35. 22 Wotherspoon AC, Dogolioni C, Diss TC et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 1993; 342: 575–7.


23 Hong SS, Jung HY, Choi KD et al. A prospective analysis of low-grade gastric MALT lymphoma after Helicobacter pylori eradication. Helicobacter 2006; 11: 569–73. 24 Inagaki H, Nakamura T, Sugiyama T et al. Gastric MALT lymphoma are divided into three groups based on responsiveness to H. pylori eradication and detection of API2-MALT1 fusion. Am. J. Surg. Pathol. 2004; 28: 1560–7. 25 Park HS, Kim YJ, Yang WI, Suh CO, Lee YC. Treatment outcome of localized Helicobacter pylori-negative low-grade gastric MALT lymphoma. World J. Gastroenterol. 2010; 16: 2158–62. 26 Asaka M, Kato M, Takahashi S et al. Guidelines for the management of Helicobacter pylori in Japan: 2009 revised edition. Helicobacter 2010; 15: 1–20. 27 Uemura N, Mukai T, Okamoto S et al. Effect of Helicobacter pylori eradication on subsequent development of cancer after endoscopic resection of early gastric cancer. Cancer Epidemiol. Biomarkers Prev. 1997; 6: 639–42. 28 Nakagawa S, Asaka M, Kato M et al. Helicobacter pylori eradication and metachronous gastric cancer after endoscopic mucosal resection of early gastric cancer. Aliment. Pharmacol. Ther. 2006; 2: 214–8. 29 Fukase K, Kato M, Kikuchi S et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomized controlled trial. Lancet 2008; 372: 392–7. 30 Maehata Y, Nakamura S, Fujisawa K et al. Long-term effect of Helicobacter pylori eradication on the development of metachronous gastric cancer after endoscopic resection of early gastric cancer. Gastrointest. Endosc. 2012; 75: 39–46. 31 Ekström AM, Held M, Hansson LE, Engstrand L, Nyrén O. Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. Gastroenterology 2001; 121: 784–91. 32 Correa P. Human gastric carcinogenesis: a multistep and multifactorial process—First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 1992; 52: 6735–40. 33 Uemura N, Okamoto S, Yamamoto S et al. Helicobacter pylori infection and the development of gastric cancer. N. Engl. J. Med. 2001; 345: 784–9. 34 Ohata H, Kitauchi S, Yoshimura N et al. Progression of chronic atrophic gastritis associated with Helicobacter pylori infection increases risk of gastric cancer. Int. J. Cancer 2004; 109: 138–43. 35 Kim N, Park YS, Cho SI et al. Prevalence and risk factors of atrophic gastritis and intestinal metaplasia in a Korean population without significant gastroduodenal disease. Helicobacter 2008; 13: 245–55. 36 Kim HJ, Choi BY, Byun TJ et al. The prevalence of atrophic gastritis and intestinal metaplasia according to gender, age and Helicobacter pylori infection in a rural population. J. Prev. Med. Public Health 2008; 41: 373–9. 37 van Grieken NC, Meijer GA, Kale I et al. Quantitative assessment of gastric antrum atrophy shows restitution to normal histology after Helicobacter pylori eradication. Digestion 2004; 69: 27–33. 38 Lu B, Chen MT, Fan YH, Liu Y, Meng LN. Effects of Helicobacter pylori eradication on atrophic gastritis and intestinal metaplasia: a 3-year follow-up study. World J. Gastroenterol. 2005; 11: 6518–20. 39 Malfertheiner P, Megraud F, O’Morain CA et al. Management of Helicobacter pylori infection—the Maastricht IV/Florence Consensus Report. Gut 2012; 61: 646–64. 40 Satoh K, Kimura K, Takimoto T, Kihira K. A follow-up study of atrophic gastritis and intestinal metaplasia after eradication of Helicobacter pylori. Helicobacter 1998; 3: 236–40.


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Supporting information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Appendix S1 Formulate research question.


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