Improving treatment outcomes and prognosticating gastric cancer risk in patients with Helicobacter pylori infection

Abstract

Helicobacter pylori (H. pylori) infection causes chronic gastritis and is strongly associated with the development of gastric cancer, peptic ulceration and mucosa-associated lymphoid tissue (MALT) lymphoma. Up to 90% of gastric cancer, which is the fourth leading cause of cancer mortality globally, is attributable to H. pylori infection. Treatment for people with H. pylori infection aims to eradicate the organism to reduce the risk of morbidity and mortality. Eradication of H. pylori has been shown to improve clinical outcomes; however, rates of eradication have been falling in the setting of rising antimicrobial resistance. A contemporary and robust understanding of antimicrobial resistance patterns in a local and global setting is essential for prescribing H. pylori eradication therapy. In addition, an understanding of the risk factors associated with poor outcomes of H. pylori infection as well as treatment failure is required, to identify those most a risk of adverse outcomes and to prioritise testing and eradication therapy accordingly. This will lead to optimisation of eradication therapy and ultimately lower the morbidity and mortality associated with this common infectious bacteria. Taking a broader view, H. pylori has co-evolved with humans over tens of thousands of years, and numerous studies have found an association with immune mediation. It plays important roles in immune signalling and its presence is inversely associated with gastro oesophageal reflux disease (GORD) and oesophageal adenocarcinoma. In the face of rising antimicrobial resistance, the difficulty of eradicating H. pylori is increasing. Treatment algorithms need to be individualised, including consideration of whether H. pylori eradication is needed and which combination of medications to select. Aims The aims of this thesis were to: •Explore antimicrobial resistance patterns of H. pylori in Australia •Characterise the prevalence, geographical origins and temporal trends of antimicrobial resistant H. pylori in Australia •Assess risk factors for adverse clinical outcomes from H. pylori infection and guide best practice for eradication therapy Methods A systematic review and meta-analysis of resistance patterns in Australia and New Zealand was performed. Following this, a retrospective observational study was undertaken on resistance patterns locally over the last 20 years at a single tertiary hospital in Adelaide, South Australia. A multifactorial geospatial analysis was performed on the distribution of resistance in order to characterise the geographic factors associated with resistance. A multi-centre, prospective observational study was undertaken to provide updated national patterns of resistance as a guide to decision-making for antimicrobial eradication therapy. Prospective, whole genome sequencing of isolates was carried out to characterise genomic patterns of antimicrobial resistance and determine concordance with phenotypic resistant profile. Finally, genetic mutation analysis was used to determine the genetic region of origin of isolates and the virulence factors associated with adverse clinical outcomes, most notably gastric cancer. Results A paucity of recent H. pylori antimicrobial resistance data was identified in the systematic review and meta-analysis. Despite this, based on the best available information, rising rates of antimicrobial resistance were found, but there were few data over the last decade to guide clinical decision-making. A retrospective analysis of local South Australian data found that rates of resistance had increased markedly over 20 years. In particular, rates of antimicrobial resistance to clarithromycin were at odds with current recommendations for its use in first-line antimicrobial therapy, bringing into question the need to revise current guidelines. Further analysis of geographical trends demonstrated clustering of antimicrobial resistance within migrant populations, emphasising the need for updated antimicrobial resistance data to guide appropriate eradication therapy in these groups. Moreover, the identification of populations that are at elevated risk of unsuccessful eradication therapy allows for a more individualised, rather than empiric, approach to eradication therapy. A multi-centre study of contemporary rates of antimicrobial culture-based resistance from patients in Australia identified a high prevalence of antimicrobial resistance nationally, suggesting that current antimicrobial guidelines are unlikely to achieve adequate eradication rates and should be revisited. Concerningly, rates levofloxacin resistance were above 20%, and similar between two geographical regions in Australia, illustrating that levofloxacin may be an inappropriate choice for empirical use in patients with refractory H. pylori infection. Prospective capture of whole genome sequencing from H. pylori isolates undergoing antimicrobial culture analysis demonstrated that genetic markers associated with antimicrobial resistance to clarithromycin and levofloxacin correlate strongly with phenotypic resistance. Phylogenetic origins determined by single-nucleotide polymorphisms (SNPs) revealed that the majority of strains originated from Europe and East Asia genetic ancestry, reflecting population migration trends in Australia over recent decades. H. pylori virulence factors associated with increased gastric cancer risk were present in the majority of isolates, especially those from East Asia. Correlations with pathological findings on histology from gastric biopsies obtained during endoscopy demonstrated that most patients with histological precursors for the development of gastric cancer contained mutations in cagA. Conclusions Rates of H. pylori antimicrobial resistance have been increasing in Australia, yet remain largely unrecognised. Currently recommended antimicrobial therapies for H. pylori are unlikely to achieve adequate eradication rates. Guidelines should therefore be revisited in order to reduce the morbidity and mortality associated with H. pylori infection. Clarithromycin and levofloxacin should no longer be used in first- and second-line empiric eradication respectively in Australia, in the populations studied. Antimicrobial resistance was found to be clustered in migrant populations, which represent a growing sector of the community at increased risk for treatment failure. Resistance was associated with migration from countries with a high prevalence of resistance, most notably East Asia and Europe. Whole genome sequencing of isolates confirmed a strong correlation between phenotypic and genetically predicted antimicrobial resistance for levofloxacin and clarithromycin. As such, genetic testing for H. pylori resistance from faecal samples may be a simple and relatively cost-effective approach to guiding therapy is higher risk groups such as in migrant populations. Individualisation of patient risk, based on both host and genetically determined isolate factors, may enable risk factor stratification and guide optimal management of eradication. Looking forward, protocolised genetic testing and tracking of H. pylori resistance profiles is essential as a coordinated national effort to guide empirical therapy and best practice for eradicating H. pylori infection. Revised antimicrobial guidelines and recognition of risk factors associated with resistance are needed to improve the quality of care in people with H. pylori infection.