Evolving Concepts in Helicobacter pylori Management.

Helicobacter pylori is the most common chronic bacterial infection worldwide and the most significant risk factor for gastric cancer, which remains a leading cause of cancer-related death globally. H pylori and gastric cancer continue to disproportionately impact racial and ethnic minority and immigrant groups in the United States. The approach to H pylori case-finding thus far has relied on opportunistic testing based on symptoms or high-risk indicators, such as racial or ethnic background and family history. However, this approach misses a substantial proportion of individuals infected with H pylori who remain at risk for gastric cancer because most infections remain clinically silent. Moreover, individuals with chronic H pylori infection are at risk for gastric preneoplastic lesions, which are also asymptomatic and only reliably diagnosed using endoscopy and biopsy. Thus, to make a significant impact in gastric cancer prevention, a systematic approach is needed to better identify individuals at highest risk of both H pylori infection and its complications, including gastric preneoplasia and cancer. The approach to H pylori eradication must also be optimized given sharply decreasing rates of successful eradication with commonly used therapies and increasing antimicrobial resistance. With growing acceptance that H pylori should be managed as an infectious disease and the increasing availability of susceptibility testing, we now have the momentum to abandon empirical therapies demonstrated to have inadequate eradication rates. Molecular-based susceptibility profiling facilitates selection of a personalized eradication regimen without necessitating an invasive procedure. An improved approach to H pylori eradication coupled with population-level programs for screening and treatment could be an effective and efficient strategy to prevent gastric cancer, especially in minority and potentially marginalized populations that bear the heaviest burden of H pylori infection and its complications.

Gastric Intestinal Metaplasia: Real Culprit or Innocent Bystander as a Precancerous Condition for Gastric Cancer?

Gastric intestinal metaplasia (GIM), which denotes conversion of gastric mucosa into an intestinal phenotype, can occur in all regions of the stomach, including cardiac, fundic, and pyloric mucosa. Since the earliest description of GIM, its association with gastric cancer of the differentiated (intestinal) type has been a well-recognized concern. Many epidemiologic studies have confirmed GIM to be significantly associated with subsequent gastric cancer development. Helicobacter pylori, the principal etiologic factor for gastric cancer, plays the most important role in predisposing to GIM. Although the role of GIM in the stepwise progression model of gastric carcinogenesis (the so-called "Correa cascade") has come into question recently, we review the scientific evidence that strongly supports this long-standing model and propose a new progression model that builds on the Correa cascade. Eradication of H pylori is the most important method for preventing gastric cancer globally, but the effect of eradication on established GIM, is limited, if any. Endoscopic surveillance for GIM may, therefore, be necessary, especially when there is extensive corpus GIM. Recent advances in image-enhanced endoscopy with integrated artificial intelligence have facilitated the identification of GIM and neoplastic lesions, which will impact preventive strategies in the near future.

AGA Clinical Practice Update on the Management of Refractory Helicobacter pylori Infection: Expert Review.

The purpose of this CPU Expert Review is to provide clinicians with guidance on the management of Helicobacter pylori after an initial attempt at eradication therapy fails, including best practice advice on specific regimen selection, and consideration of patient and systems factors that contribute to treatment efficacy. This Expert Review is not a formal systematic review, but is based upon a review of the literature to provide practical advice. No formal rating of the strength or quality of the evidence was carried out. Accordingly, a combination of available evidence and consensus-based expert opinion were used to develop these best practice advice statements.

Helicobacter pylori Antibiotic Resistance in the United States Between 2011 and 2021: A Systematic Review and Meta-Analysis.

INTRODUCTION: Antimicrobial resistance among Helicobacter pylori strains has been rising globally, leading to declining eradication rates. We performed a systematic review and meta-analysis of the resistance patterns of H. pylori strains in the United States between 2011 and 2021. METHODS: Ovid MEDLINE, Embase, CINAHL, and Cochrane CENTRAL databases were searched for manuscripts and conference abstracts published between 2011 and 2021 reporting H. pylori antibiotic resistance. A mixed-effects model estimated pooled rates of resistance to clarithromycin, amoxicillin, metronidazole, tetracycline, rifabutin, levofloxacin, or a combination of these, with 95% confidence intervals (CIs). RESULTS: A total of 19 studies including 2,660 samples, met inclusion criteria. The pooled rate of resistance to metronidazole was 42.1% (95% CI 27.3%-58.6%), levofloxacin 37.6% (95% CI 26.3%-50.4%), clarithromycin 31.5% (95% CI 23.6%-40.6%), amoxicillin 2.6% (95% CI 1.4%-5.0%), tetracycline 0.87% (95% CI 0.2%-3.8%), rifabutin 0.17% (95% CI 0.00%-10.9%), and dual clarithromycin and metronidazole 11.7% (95% CI 0.1%-94.0%). Considerable data heterogeneity was evident for pooled resistance prevalence rates (I 2 > 50%), with the exception of rifabutin resistance. DISCUSSION: Metronidazole, levofloxacin, and clarithromycin resistance rates each exceed 30%; thus, choosing an empiric antibiotic regimen without knowledge of the likely pattern of antibiotic resistance is not appropriate. Resistance to tetracycline, rifabutin, and amoxicillin remains low. Given the scarcity of available data with considerable heterogeneity among studies, continued surveillance, ideally with a more systematic approach to data collection, is an increasingly important goal in H. pylori management.

The prevention of gastric cancer by Helicobacter pylori eradication.

PURPOSE OF REVIEW: Gastric cancer remains one of the most common causes of death globally. Increasing evidence suggests that many gastric cancer cases can be prevented by eradicating its most important etiological agent, Helicobacter pylori. Using the search terms 'H. pylori' and 'gastric cancer' we reviewed the scientific literature regarding the association between H. pylori and gastric cancer published from 1 January 2020 to 30 May 2021. We review the most important articles relevant to the clinical issues regarding H. pylori eradication for gastric cancer prevention. RECENT FINDINGS: In randomized trials, eradication of H. pylori is associated with an approximately 50% reduction in sporadic gastric cancer. A similar benefit was observed when screening first-degree relatives of gastric cancer cases, after resection of early gastric cancer to prevent metachronous neoplasia, and in population-based screen and treatment programs in areas of high H. pylori and gastric cancer prevalence. Even in relatively low gastric cancer countries such as the United States, gastric cancer may potentially be avoided by screening for H. pylori, especially among minority groups who are at greatest risk. SUMMARY: Gastric cancer is preventable, at least in part, by H. pylori eradication. Ongoing screening trials will help determine whether population-based H. pylori screening programs are feasible and cost-effective. Their results are likely to differ according to H. pylori and gastric cancer prevalence rates.

Association Between Obstructive Sleep Apnea and Barrett's Esophagus: A Systematic Review and Meta-Analysis.

BACKGROUND: Obstructive sleep apnea (OSA) has gastrointestinal implications as it is associated with gastroesophageal reflux disease. Less certain is an independent association between OSA and Barrett's esophagus. We performed a systematic review and meta-analysis to evaluate the association between OSA and Barrett's esophagus. METHODS: A systematic search of Ovid MEDLINE, Embase, Web of Science, CINAHL, and the Cochrane Central Register of Controlled Trials was performed. Inclusion criteria were observational studies (retrospective and case-control) assessing the association between OSA and Barrett's esophagus in adult subjects. Data from the included studies were extracted and used to calculate the pooled odds ratio of OSA with 95% confidence interval (CI) between patients with Barrett's esophagus and those without, using a random-effects model. RESULTS: Altogether six studies involving 2333 subjects met the inclusion criteria and were included in this meta-analysis. The pooled analysis found a significantly increased risk of OSA, high risk of OSA, and patient-reported OSA symptoms among patients with Barrett's esophagus versus those without Barrett's esophagus, with a pooled odds ratio (OR) of 2.19 (95% CI 1.53-3.15). A subgroup analysis for cases of definite OSA (formally diagnosed via polysomnography) and Barrett's esophagus (n = 2 studies) also demonstrated significant association (OR 2.59, 95% CI 1.39-4.84). CONCLUSION: A significantly increased risk of OSA among patients with Barrett's esophagus was demonstrated in this meta-analysis. Further investigation is warranted to determine the pathophysiology and clinical implications of this association.

Reconciliation of Recent Helicobacter pylori Treatment Guidelines in a Time of Increasing Resistance to Antibiotics.

Increasing resistance to antibiotics worldwide has adverse effects on the effectiveness of standard therapies to eradicate Helicobacter pylori infection. We reviewed guidelines developed by expert groups in Europe, Canada, and the United States for the treatment of H pylori infection. We compared the recommendations of these guidelines, reconciled them, and addressed the increasing resistance of H pylori to antibiotic therapy regimens. The guidelines recommend bismuth quadruple therapy for first-line treatment, replacing clarithromycin-based triple therapy. There is consensus for concomitant 4-drug therapy as an alternative, especially when bismuth is not available. When therapy is unsuccessful, it is likely due to resistance to clarithromycin, levofloxacin, and/or metronidazole; these drugs, if used previously, should be avoided in subsequent eradication attempts. Second-line therapies should be bismuth quadruple therapy or levofloxacin triple therapy, depending on suspected resistance, reserving rifabutin-based triple and high-dose dual amoxicillin proton pump inhibitor therapy for subsequent treatment attempts. The increasing resistance of H pylori to antibiotic therapy necessitates local availability of susceptibility tests for individuals, and establishment of regional and national monitoring programs to develop evidence-based locally relevant eradication strategies. Further studies into the development of more easily accessible methods of resistance testing, such as biomarker analysis of stool samples, are required. Options under investigation include substituting vonoprazan for proton pump inhibitors, adding probiotics, and vaccine development. Narrow-spectrum antibiotics and new therapeutic targets could be identified based on genomic, proteomic, and metabolomic analyses of H pylori.

Management of Helicobacter pylori.

PURPOSE OF REVIEW: Gastroenterologists and many general internists and primary care physicians confront questions regarding the management of Helicobacter pylori on a daily basis. The subject remains of global interest and continue to generate debate and research. Using the search terms 'pylori and treatment' or 'pylori and management' we identified over 1000 relevant articles in PubMed published over the time period 1 January 2019 to 30 April 2020. We have selected the most highly clinically relevant of these to review here. RECENT FINDINGS: Clinical evidence grows regarding the benefits of H. pylori eradication on gastric cancer prevention. High rates of resistance to clarithromycin and levofloxacin, correlating with treatment failure in regimens utilizing these drugs, has stimulated interest in alternative regimens as well as the need for susceptibility testing of individual patients and populations. Although many aspects of H. pylori management are well established, implementation of appropriate testing and treatment pathways remains suboptimal throughout healthcare settings. SUMMARY: Increased emphasis on measuring H. pylori-related clinical outcomes in practice is needed to identify implementation gaps, and to suggest means to best apply the knowledge gained on H. pylori for the prevention of gastric symptoms and disease.

Structure of the human P2Y12 receptor in complex with an antithrombotic drug.

P2Y receptors (P2YRs), a family of purinergic G-protein-coupled receptors (GPCRs), are activated by extracellular nucleotides. There are a total of eight distinct functional P2YRs expressed in human, which are subdivided into P2Y1-like receptors and P2Y12-like receptors. Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo, which limits our understanding of this receptor family. P2Y12R regulates platelet activation and thrombus formation, and several antithrombotic drugs targeting P2Y12R--including the prodrugs clopidogrel (Plavix) and prasugrel (Effient) that are metabolized and bind covalently, and the nucleoside analogue ticagrelor (Brilinta) that acts directly on the receptor--have been approved for the prevention of stroke and myocardial infarction. However, limitations of these drugs (for example, a very long half-life of clopidogrel action and a characteristic adverse effect profile of ticagrelor) suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors. Here we report the 2.6 Å resolution crystal structure of human P2Y12R in complex with a non-nucleotide reversible antagonist, AZD1283. The structure reveals a distinct straight conformation of helix V, which sets P2Y12R apart from all other known class A GPCR structures. With AZD1283 bound, the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic. Along with the details of the AZD1283-binding site, analysis of the extracellular interface reveals an adjacent ligand-binding region and suggests that both pockets could be required for dinucleotide binding. The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates.

Treatment of Helicobacter pylori.

PURPOSE OF REVIEW: Helicobacter pylori eradication has become more challenging over the past decade due to increasing antimicrobial resistance, especially to clarithromycin and levofloxacin. We identified 508 recent publications on H. pylori treatment (published between January 2018 and June 2019), focusing on the most highly clinically relevant for this review. RECENT FINDINGS: Declining H. pylori eradication rates with clarithromycin triple therapy have led to most guidelines recommending 14 days bismuth-based quadruple therapy or concomitant therapy as the best initial empiric regimen. Substituting amoxicillin for tetracycline or metronidazole in quadruple therapy, and a three-in-one pill version of the regimen, also appear effective. Vonoprazan, a potent acid inhibitor, can overcome much clarithromycin resistance in triple therapy. High-dose dual therapy (proton pump inhibitor with amoxicillin) is a promising alternative approach. Reviewing resistance patterns to select suitable first-line empiric therapies is important in high resistance regions. Molecular methods to evaluate H. pylori antimicrobial susceptibility promise to be simpler than standard microbiological culture. The cost-effectiveness of antimicrobial susceptibility testing in refractory cases remains unproven. SUMMARY: Updating clinicians treating H. pylori is important to combat the emerging problems of multidrug antimicrobial resistance in H. pylori strains. Truly novel approaches to H. pylori eradication are needed.

Analysis of Accredited Gastroenterology Fellowship Internet-Available Content: Twenty-Nine Steps Toward a Better Program Website.

GOAL: To assess publicly available content derived from official websites of accredited gastroenterology fellowship programs, specifically evaluating data pertinent to prospective applicants. BACKGROUND: The Internet provides access to key information for applicants applying to gastroenterology fellowship, particularly as competition drives applicants to apply to a large number of programs. Thus, it is important for fellowship program websites to be up to date and contain accurate and pertinent information. METHODS: Twenty-nine variables, determined as important website content on the basis of prior published website analyses and from surveys of preferences, were extracted from the relevant websites of all accredited gastroenterology fellowships in the USA. Results were binary-i.e., a website either contained or did not contain each item. RESULTS: A total of 178 websites were evaluated. The mean number of online content items was 14.1(± 3.2 SD) out of a possible 29 (47.1%). Program coordinator contact information, application information, and the number of current fellows were accessible on > 80% of websites. In contrast, the typical number and types of procedures performed by fellows and number of hospitals covered by fellows on call were found on < 10% of websites. Analysis revealed that 23.2% of lifestyle, 48.3% of training, and 59.6% of program variables were met. CONCLUSIONS: Gastroenterology fellowship websites lacked important content. Websites had a lower mean percentage of lifestyle content compared to training and program-related items. An organized website containing relevant information may not only attract qualified applicants but also avert unnecessary email inquiries and inappropriate applications. This study may provide guidance to gastroenterology fellowship programs seeking to improve their websites for applicants.

Retrospective Analysis Confirms Tetracycline Quadruple as Best Helicobacter pylori Regimen in the USA.

BACKGROUND: Declining Helicobacter pylori (H. pylori) eradication rates have prompted a switch in first-line therapy from standard triple (PPI, clarithromycin, and amoxicillin) to bismuth-based quadruple therapy. A caveat of the ACG 2017 H. pylori treatment guidelines was a paucity of recent US eradication data. AIM: To determine Rhode Island H. pylori eradication data, in the largest US study from the last two decades. METHODS: Electronic records were queried for patients with H. pylori infection diagnosed by pathology, urea breath test, or stool antigen from 2015 to 2017. Demographics, diagnostic test, treatment regimen, and test of cure were extracted. Eradication rates were calculated, and treatment regimens were compared. RESULTS: A total of 1710 patients were identified (64% female): 825 (46%) diagnosed by breath test, 755 (42%) by biopsy, and 191 (12%) by stool antigen. Full data were obtained on 1101 patients. Seven regimens were used: quadruple (64%), triple (25%), doxycycline quadruple (5%), and miscellaneous (6%). Quadruple was superior to triple: (85% vs. 75%, P = 0.002), quadruple 14 days versus triple 14 days (87% vs. 79%, P = 0.0052), quadruple 10 days versus triple 10 days (77% vs. 67%, P = 0.33). Increased therapy length improved eradication (quadruple 14 days  vs. 10 days, 87% vs. 77%, P = 0.002; triple 14 days  versus 10 days 79% vs. 67%, P = 0.13). Finally, substituting doxycycline for tetracycline yielded lower eradication (85% vs. 67%, P = 0.006). CONCLUSION: Quadruple therapy is superior to triple therapy within the Rhode Island population. Fourteen-day therapy achieves superior eradication compared to 10-day therapy, and doxycycline is inferior to tetracycline for quadruple therapy. Our findings support adherence to ACG and international guidelines advising 14-day quadruple therapy.

Houston Consensus Conference on Testing for Helicobacter pylori Infection in the United States.

Despite guidelines for detection and treatment of Helicobacter pylori infection, recommendations to test patients before and after therapy are commonly not followed in the United States. At the Houston Consensus Conference, 11 experts on management of adult and pediatric patients with H pylori, from different geographic regions of the United States, met to discuss key factors in diagnosis of H pylori infection, including identification of appropriate patients for testing, effects of antibiotic susceptibility on testing and treatment, appropriate methods for confirmation of infection and eradication, and relevant health system considerations. The experts divided into groups that used a modified Delphi panel approach to assess appropriate patients for testing, testing for antibiotic susceptibility and treatment, and test methods and confirmation of eradication. The quality of evidence and strength of recommendations were evaluated using the GRADE system. The results of the individual workshops were presented for a final consensus vote by all panel members. After the Expert Consensus Development meeting, the conclusions were validated by a separate panel of gastroenterologists, who assessed their level of agreement with each of the 29 statements developed at the Expert Consensus Development. The final recommendations are provided, on the basis of the best available evidence, and provide consensus statements with supporting literature to implement testing for H pylori infection at health care systems across the United States.

Correction: ACG Clinical Guideline: Treatment of Helicobacter pylori Infection.

Since the publication of this manuscript it was realised that reference 14 was provided incorrectly. The correct reference is provided here.