Evaluation of diagnostic and treatment strategies for the management of Helicobacter pylori infection

Abstract

Helicobacter pylori infection is responsible for chronic gastritis and the development of gastrointestinal disorders such as gastric or duodenal ulcers, gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. Patients who are infected with H. pylori are either diagnosed by non-invasive tests, for example the urea breath test (UBT), or invasively by means of endoscopic tests, such as the rapid urease test (RUT). Clarithromycin-based triple therapy was one of the first treatments recommended for H. pylori infection. However, in recent years the success rate of this treatment has fallen below the recommended 80% intention-to-treat (ITT) rate, mainly due to the emergence of antibiotic resistant strains of H. pylori. As a result, European guidelines recommend local surveillance of H. pylori antibiotic resistance to guide clinicians in their choice of therapy.

The overall aim of this study was to evaluate strategies for the management of H. pylori infection. Firstly, to ensure the most sensitive and specific tests are used routinely for the diagnosis of H. pylori in Ireland, the accuracy of non-invasive and invasive tests was assessed. Additionally, culture-based and molecular antimicrobial susceptibility testing was performed to determine the prevalence of H. pylori antibiotic resistance. Finally, antimicrobial susceptibility-guided tailored therapy was investigated for first-line and subsequent treatment of H. pylori infection.

In terms of diagnosis, the Premier Platinum HpSA Plus stool antigen test was found to be less accurate than the UBT, both for initial diagnosis and post-treatment testing in our population. It has been suggested that the delta over baseline (DOB) value in the UBT is indicative of bacterial load in the stomach and could potentially predict treatment outcome; however in our cohort of patients, it did not. The use of combined antral and corpus biopsies is recommended for culture, as it significantly improved culture rates when compared to the use of a single biopsy. The use of Dent?s transport media significantly reduced contamination and increased bacterial yield. These methods could potentially improve the detection of antibiotic resistance.

Antibiotic resistance surveillance revealed that there has been a sharp increase in H. pylori resistance to commonly prescribed antibiotics in our centre. Specifically, primary clarithromycin and metronidazole resistance rates have increased significantly since rates were last evaluated in 2007-2009 in Ireland (36.1% and 56.9% at present by culture-based methods, respectively). A primary levofloxacin resistance rate of 16.7% was observed. In addition, resistance to amoxicillin, tetracycline and rifabutin has emerged in our patient cohort. Secondary resistance to clarithromycin was significantly higher than primary resistance, as well as the rate of dual resistance to clarithromycin and metronidazole. There is considerable variation in resistance rates across different regions. While the rates reported in this study are high, they are similar to some recent studies conducted in other countries.

The GenoType HelicoDR assay (a PCR-based molecular method) was effective in detecting H. pylori in biopsy samples. However the assay displayed suboptimal sensitivity and specificity in detecting levofloxacin and clarithromycin resistance respectively. Until a more suitable molecular test has been validated, culture-based phenotypic testing should remain the method of choice for resistance surveillance and tailoring therapy in our cohort of patients. The GenoType HelicoDR assay was inadequate in assessing antibiotic resistance in stool samples from patients infected with H. pylori. In terms of virulence of the bacterium, it was found that less virulent strains of H. pylori (CagA-negative and vacA S1/M2 genotypes) are now the most prevalent in H. pylori strains in Ireland. There was a relationship between the less virulent strains of H. pylori and primary clarithromycin resistance.

During this study, guidelines were released which recommended extending the duration of H. pylori treatment to 14 days. Although not significant at the numbers tested, treatment duration of 14 days improved the efficacy of all treatments. The efficacy of first-line 14 day tailored treatment compared to standard triple therapy was 85.7% vs 83.3% respectively (ITT), with no statistically significant difference in efficacy observed. However, unfortunately the study did not meet the required sample size. The efficacy of second-line 14 day tailored treatment was 66.6% (ITT) and for subsequent rescue treatment (>2 failed therapies), the efficacy was 85.7% (ITT).

Based on the findings presented herein, the UBT is recommended as the gold-standard non-invasive test for both H. pylori diagnosis and assessment of eradication in Ireland. To maximise success of bacterial culture, combined antral and corpus biopsies and a specialised transport media should be used. Going forward, it will be vital to continue monitoring antibiotic resistance rates and success rates of treatment regimens in larger patient cohorts. If high primary clarithromycin resistance rates prevail and eradication rates are not acceptable, empirical clarithromycin-based triple therapy should no longer be used and alternatives will need to be strongly considered. Tailored therapy should be reserved for those having failed 2 previous therapies. On-going antimicrobial susceptibility testing is essential to (i) monitor resistance rates in a population and (ii) for tailored rescue treatment of H. pylori infection.