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Improvement of therapy regimens for Helicobacter pylori eradication in children

par Kotilea, Kallirroi
Président du jury Casimir, Georges
Promoteur Bontems, Patrick
Publication Non publié, 2024-08-27

Thèse de doctorat

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Summary Background Forty years ago, Warren and Marshal published the first article referring to Helicobacter pylori (H. pylori) in the Lancet. This Gram-negative spiral-shaped bacterium affects half of the world’s population. It is estimated that among H. pylori-infected individuals, approximately 90% will likely remain asymptomatic. However, H. pylori is causing chronic gastritis, peptic ulcers, and gastric cancer. The burden is considerable as those last two gastric diseases represent over a million global deaths annually. Complications of the infection occur predominantly in adults rather than children, as persistence of colonization is critical for their development. Although less frequent than in adults, H. pylori-associated gastroduodenal ulcers are also responsible for abdominal pain and upper gastrointestinal bleeding in children. In addition, research shows that differences in mucosal and humoral immune responses might also explain differences in the frequency of mucosal lesions between children and adults. As a result, knowledge from adults cannot be extrapolated in children, especially regarding the indication of diagnosis and treatment choice. Despite the high-quality research conducted and the decrease in the worldwide prevalence of H. pylori infection and H. pylori-related complications, the efficacy of treatment schemes remains unsatisfactory, with the problem of antimicrobial resistance rising to threatening levels. Thus, indisputable diagnosis and optimal treatment strategies with regular updates is needed.Aim This thesis aims to improve H. pylori eradication schemes in children and, as a result, improve the eradication rates in clinical practice. To do so, we aimed to: 1) Provide an updated review of the literature regarding H. pylori in children, particularly the advances in treatment options. 2) Analyze the factors affecting eradication success in children. 3) Propose a novel therapeutic scheme that could be used as an alternative first-line option or when standard therapeutic schemes have failed.Achievements My doctoral thesis represents the culmination of extensive clinical research from 2018 to 2023. It encompasses 2 narrative review ( papers II and VI, where I served as the 1st author), 1 interventional trial (paper III, where I was the primary investigator and 1st author), 3 observational retrospective studies (papers I, IV and V, where I was the 1st co-author for two, 2nd author for the third one), two multicenter studies, and national guidelines (papers VII, VIII and IX, where I was the 3rd author). My research was centered on the comprehensive design, data collection, management, maintenance, and analysis (including statistical analysis) of a pediatric H. pylori database, including more than 650 children diagnosed with H. pylori infection from gastric biopsies from a single tertiary center in Brussels, Belgium. In addition, I conducted a challenging therapeutic study with Bismuth subcitrate, a medication albeit well-known but currently unavailable and not commercially marketed in Belgium in the desired form, at the time of the study. Our results, published in peer-reviewed journals and widely shared in the expert community, highly contributed to improving therapy regimens for Helicobacter pylori eradication in children (from around 70% to >90%) in 10 years in our center. Our conclusions and recommendations are now part of the updated European and North American pediatric guidelines, which will soon be published. * The term narrative review is used as this 2 review articles, although they implemented detailed and broad litterature searches, did not follow Cochrane’s (PRISMA or ROSE statements) systematic review protocol following the formulation of a PICO question but rather provided authors’ perspectives on a focused but broader topic. In reality, the methodology of a scoping review was used for both works but the results are presented in a more user-friendly format.Results - ContributionIn 2018, we conducted a narrative review (paper II) to comment on the last updated pediatric guidelines for diagnosing and treating H. pylori infection in children (Jones et al., 2017). The following points were underlined: adequate management of symptomatic children requires an upper gastrointestinal endoscopic exam with mucosal biopsy samples for histology and culture or Polymerase Chain Reaction (PCR) as a minimum. When indicated, eradication treatment must be given only if good adherence is expected and should be tailored to susceptibility testing. Treatment schemes recommended for H. pylori eradication in children are triple-tailored treatment with Proton Pump Inhibitor-Amoxicillin-Clarithromycin (PAC) or Proton Pump Inhibitor-Amoxicillin-Metronidazole (PAM) for 14 days, Proton Pump Inhibitor (PPI) – Clarithromycin (CLA) – Metronidazole (MET) in the rare case of allergy to Amoxicillin (AMO), and in case of double resistance to CLA and MET, either a PAM could be proposed, or a bismuth-based quadruple scheme acknowledging the fact that data regarding bismuth based schemes in children were lacking at that time. A few months later, we published a second review (paper VI) emphasizing the epidemiology, the risk factors and the diagnosis of H. pylori. In the meantime, we conducted a retrospective analysis over 23 years (paper V), tracing the proportion of gastroduodenal ulcers in our population and analyzing the relationship with H. pylori infection. Data indicate that, despite a decreasing prevalence of H. pylori infection over time, in our pediatric population, the proportion of ulcers without H pylori infection has not changed over the past two decades. H. pylori infection was not a risk factor for gastric ulcers but can be considered an independent risk factor for duodenal ulcers, duodenal erosions, and gastric erosions. In another cohort study (paper I), we analyzed 145 children (67 girls/78 boys, median age 9.7 years) treated for H. pylori infection according to local protocols and European guidelines applicable at the time of the study. One hundred eighteen were infected with a strain susceptible to both CLA and MET, 10 with a CLA resistant (CLA-R), and 17 with a MET resistant (MET-R) strain. Follow-up data were available for 130/145, and successful eradication was observed in 105. The Intention to Treat (ITT) eradication rate was then 72% (95% Confidence Interval - CI 65%-79%) and Full Analysis Set (FAS) eradication rate was 81% (95%CI 73%-87%). Concordance of more than 90% between the prescribed and the ingested drugs was observed in 109 children, between 50 and 90% in 8, and less than 50% in 11. Successful eradication was achieved for 89.9% of patients who received at least 90% of the prescribed drugs, whereas the eradication rate for nonadherent patients was 36.6%. Adherence above 90% was significantly higher in the absence of chronic concomitant disease and in the absence of reported adverse events. This was the first time adherence had been assessed as an independed factor affecting H. pylori eradication success in children.The fifth study (paper III) was a pilot, monocentric, one-arm, prospective clinical trial aiming to evaluate the efficacy and safety of a 10-day quadruple therapy containing colloidal bismuth sub-citrate (CBS), esomeprazole (ESO), AMO and MET for H. pylori eradication in 36 children. Eight (22.2%) had a prior H. pylori eradication treatment. Thirteen (36.1%) patients were infected by a MET-R strain, and 8 (22.2%) by a strain resistant to both MET and CLA (CLA/MET-R). In the ITT population, eradication was achieved in 35/36 patients (95%CI: 85%−99%). Twenty-three children reported at least one adverse event (63.8%), primarily mild (nausea, vomiting, abdominal pain, diarrhea, dark stool, metallic taste, headache, and rash). However, the treatment adherence rate was high, with 30 (83.3%) patients taking >90% of the treatment. This was a preliminary study, the first one in Europe studying a bismuth-based quadruple treatment for eradication of H. pylori in children. This treatment is now proposed (in the upcoming guidelines) as one of the first-line treatment options in children when antimicrobial susceptibility testing is not available. The sixth study (paper IV) consists of an analysis of our cohort over 9 years, including 565 children infected with H. pylori who underwent upper GI endoscopy. Culture and antimicrobial susceptibility testing were available for every patient. Strains susceptible to all antibiotics were detected in 64.2%. Primary resistance rates for CLA, MET, Levofloxacin (LEV), Tetracycline (TET) and AMO were, respectively, 11%, 22.9%, 6.9%, 0.4% and 0% and secondary resistance rates were 20.4%, 29.4%, 9.3%, 0% and 0%. Heteroresistance was present in untreated children in 2%, 7.1%, 0.7%, 0.7% and 0% for CLA, MET, LEV, TET and AMO. Patients were treated according to protocols applicable at each given time, but treatment tailored to antimicrobial susceptibility was the standard of care in our unit throughout the period studied. First-line eradication rates were 78.5% in ITT, 88.3 % in FAS and 94.1% in per protocol (PP). Eradication rates significantly increased from 70.4% in ITT to 85.9% throughout the study period and from 80.4% to 96.8% in FAS. Factors affecting eradication success were the duration of treatment when the triple-tailored treatment was used, the number of daily administration doses of amoxicillin, 3 daily doses leading to better eradication rates vs. 2 doses, and the patient's adherence to treatment. Analysis of this database provided valuable results and recommendations endorsed by the scientific community and the continuation of this surveillance work is the key to quality of care. Thanks to fruitful collaborations with Belgian and European experts, our data were also published in multicenter studies with interesting conclusions: In the Belgian study analyzing antimicrobial resistance from children and adults in 2021 (paper VIII), resistance to LEV is twice as high in adults compared to children (26.8% vs. 13.9%; p = 0.028). This is related to the limited indication for using fluoroquinolones in pediatric patients. We also observed a higher resistance rate for CLA in adults than in children (19% vs. 13.9%, p = 0.388), but this difference is not statistically significant. Heteroresistance cases were more frequent in children than in adults (32.6% vs. 15.8%, P = 0.124) but did not reach statistical significance. In the pediatric European H. pylori cohort (EuroPedHP-Registry), with data from 30 centers from members of the ESPGHAN’s Helicobacter Pylori-Special Interest Group from 2017 to 2020 (paper VII), resistance to MET was present in 21% (17.7% in naïve patients, 40.2% after one treatment failure), CLA in 28.8% ( 25% in naive, 51.4% after treatment failure), and both in 7.1% (3.8% naive, 26.5% after treatment failure). Regarding treatment, guideline-conform 2-weeks triple therapy tailored to antibiotic susceptibility (PAM or PAC) achieves primary eradication of ≥ 90%. Despite tailored treatment, higher failure rates in single-resistant strains are underlined. Finally, our team contributed to the publication of the 2023 Belgian guidelines for the management of H. pylori infection (paper IX) as part of the Belgian Helicobacter pylori and Microbiota Study Group (BHMSG). Discussion To improve H. pylori eradication treatment in children, we must identify and address the factors affecting treatment efficacy. Several points are underlined through the different works of this thesis, and advances are made, leading to a better understanding of the role of the microbial, host and systems factors. Antibiotic resistance is identified as follows (papers IV, VII and VIII): in the European setting, primary resistance to CLA is 25%, and to MET is 17.7%. The resistance profile, in our center’s cohort study differs, with primary CLA resistance at 11% and MET resistance at 22.9%. Secondary resistance, heteroresistance and multidrug resistance are also identified. Despite AST and tailored treatment schemes, eradication rates were still low before the start of this thesis. Treatment adherence was subsequently identified as an independent factor significantly affecting eradication rates in 3 of our studies. Today, when instructing the indication of an eradication treatment with the children and the parents, we make it clear that strict adherence to the prescribed drugs is mandatory (>90%). Regarding the choice of the treatment scheme, our works (papers IV and VII) underscore existing pediatric guidelines for H. pylori eradication, confirming the better efficacy of the longer duration (14 days) triple-tailored treatment with optimized doses. We now have data to promote (paper IV) the administration of AMO in 3 daily doses as it significantly enhances the efficacy of the treatment. The 10-day bismuth quadruple treatment scheme (CBS-EAM) was shown to be safe and effective and could be an alternative to the 14-day triple-tailored scheme (paper III). Conclusion With constant surveillance, regular updates, and re-evaluation of our practices, we significantly improved our H. pylori eradication rates and reached the objective of 90% (as shown in paper IV). An ideal treatment regimen for H. pylori infection does not exist in children nor in adults. This occurs because of differences in drug availability and antimicrobial resistance of H. pylori in different regions and differences in resources, practices, and recommendations. Nevertheless, we know now that successful eradication depends on several factors that can be modified, aiming for excellent eradication rates. As a result, we propose the diagnostic algorithms, therapeutic schemes and doses that are efficient, available, and safe in the time being and for our pediatric population in our tertiary center in Brussels, Belgium, with a commitment to pursue a regular evaluation and evolution of our practices to provide care of excellent quality.