Current Consensus and Remaining Questions Regarding the Diagnosis and Treatment of Helicobacter pylori Infection

The first key point in Kenneth E. L. McColl’s article in The New England Journal of Medicine regards the clear indications for eradicating Helicobacter pylori infection.¹ As McColl notes, there is general agreement in this area between the European guidelines, published in the Maastricht III Consensus Report, and the US guidelines, published by the American College of Gastroenterology.^1–3 Both guidelines recommend H. pylori eradication in the following groups.

Numerous studies have clearly demonstrated that eradication of H. pylori infection is beneficial in patients with gastric or duodenal ulcers, both in terms of facilitating ulcer healing and, more importantly, in terms of preventing ulcer recurrence. One recent study that supports this conclusion is a multicenter, collaborative, follow-up study of 1,000 patients with H. pylori-related peptic ulcer bleeding.⁴ All of the patients in this study underwent eradication therapy for H. pylori infection, and eradication was confirmed by appropriate follow-up testing. Sixty-nine percent of these patients had a duodenal ulcer, 27% had a gastric ulcer, and 4% had a pyloric ulcer. Over 2 years of follow-up, only 5 patients experienced ulcer rebleeding following H. pylori eradication, for a rebleeding incidence of only 0.15% per patient-year of follow-up. This study shows that H. pylori eradication alters the natural history of peptic ulcer disease and peptic ulcer—related complications such as bleeding.

Another group of patients who clearly benefit from eradication of H. pylori infection are those with mucosa-asso-ciated lymphoid tissue (MALT) lymphomas of the stomach. H. pylori infection has been closely linked to the pathogenesis of this type of neoplasm, and eradication of H. pylori has revolutionized the treatment of these lesions. In the past, MALT lymphomas were treated with radiation or chemotherapy, but treatment now focuses primarily on eradicating H. pylori infection. Among patients with low-grade MALT lymphomas, a substantial proportion of patients—upward of 70—80%—will achieve complete remission following eradication of H. pylori infection, and some preliminary data suggest that a subset of patients with high-grade MALT lymphomas might also benefit from eradication of H. pylori infection.

A third group that should receive H. pylori eradication therapy includes patients who have undergone endoscopic resection of early gastric cancer. Several studies from the Far East have shown that eradication of H. pylori infection in this population markedly diminishes the likelihood of gastric cancer recurrence.

Functional dyspepsia is perhaps the most common indication for H. pylori eradication in developed countries and possibly worldwide. This term describes patients who have unexplained upper abdominal pain or discomfort and normal findings on upper endoscopy. Data suggest that eradicating H. pylori in patients with functional dyspepsia offers a small but statistically significant benefit compared to either a short course of proton pump inhibitor (PPI) therapy or placebo. One possible explanation for the benefits of H. pylori eradication is that some patients with functional dyspepsia actually have peptic ulcer disease that was missed or inactive at the time of their upper endoscopy. Alternatively, it is possible that the improvements in gastritis that accompany eradication of H. pylori infection might lead to symptom-related benefits even in the absence of peptic ulcer disease.

While the benefits of H. pylori eradication in the aforementioned groups are well recognized, treatment of other groups remains controversial. For example, some interesting data suggest that idiopathic thrombocytopenic purpura may resolve in some individuals after eradication of H. pylori infection, but more data are needed to confirm this benefit. Another very controversial area is the potential role of H. pylori infection as a cause of unexplained iron-deficiency anemia, but the data in this area are inconclusive. Finally, the McColl article states that H. pylori infection does not play a role in gastroesopha-geal reflux disease (GERD), but this remains a confusing topic.¹ Some data suggest that a subset of patients with GERD symptoms may improve after eradication of H. pylori infection, while other studies suggest that some individuals with GERD symptoms may actually worsen after eradication of H. pylori infection. Most often, H. pylori eradication leads to no significant change in GERD symptoms. Whether patients with GERD symptoms improve, worsen, or stay the same following eradication of H. pylori infection probably depends to a large extent on the type of gastritis caused by the infection and its attendant effects on gastric acid secretion.

Diagnosis of Helicobacter pylori Infection

As reviewed by McColl, several tests are available that can aid in the diagnosis of H. pylori infection.¹ Nonendo-scopic tests include serology tests, urea breath testing, and fecal antigen tests; endoscopic tests include urease-based tests, histologic assessment, and culture of biopsy samples.

Serology testing has a very good negative predictive value, but its positive predictive value is poor when used in populations with a low prevalence of H. pylori infection. In such areas—including most of the United States—the positive predictive value of serology testing is around 50%. Thus, physicians who use serology testing can feel fairly confident that a negative result is accurate, but a positive result is not very helpful, as there is only a 50% chance that it represents a true positive result.

Because of this limitation, physicians may want to consider using either a urea breath test or a fecal antigen test in populations with a low prevalence of H. pylori infection, as both of these tests have excellent positive and negative predictive values. For clinicians who choose to start with a serology test, a negative result is accurate and requires no additional testing, but a positive result should be confirmed by either a urea breath test or a fecal antigen test before offering the patient antibiotic therapy.

A final point to remember is that serologic testing is not a reliable means of proving H. pylori eradication. If a patient initially tests positive but later tests negative, then the latter result can be helpful. However, serologic tests can remain positive for months, even years, following successful eradication of H. pylori infection. For this reason, either a urea breath test or a fecal antigen test should be used when clinicians want to prove that the infection has been eradicated after a course of antibiotics. As McColl notes, testing should be done at least 4 weeks after the completion of antibiotic therapy.¹

When to Treat Patients for Helicobacter pylori Infection

When deciding which patients to test and treat for H. pylori infection, clinicians need to have a clear idea as to why they are testing a particular patient and whether they are committed to treatment. If a patient has one of the aforementioned indications for H. pylori eradication, testing should be pursued. However, testing should not be pursued unless the clinician is prepared to offer treatment for a positive result. Once clinicians commit to testing for H. pylori, they are obligated to discuss the potential consequences of the infection with the patient. After hearing how H. pylori infection is associated with peptic ulcer disease, gastric malignancy, and dyspeptic symptoms, nearly all patients will elect to pursue treatment.

The reason I emphasize this point is that gastroen-terologists are increasingly being confronted with patients who have failed an initial course of antibiotic therapy. Sometimes, patients have been given 2 or even 3 courses of antibiotic therapy in an effort to eradicate H. pylori infection. When dealing with such a patient, the first question to critically ask is whether the indication for eradication therapy is appropriate. For example, patients with GERD symptoms or irritable bowel syndrome symptoms are unlikely to experience benefit from H. pylori eradication and thus do not warrant an initial attempt at antibiotic therapy, let alone repeated attempts at treatment. A simple way to think about this situation is that the benefits of treating should always outweigh the potential risks.

Further Research

While guidelines, including the recently published Maastricht IV Consensus Report, are available to aid in the management of patients with H. pylori infection, further research is needed in several areas.⁵ First, there is a need for large-scale, randomized, controlled trials conducted in the United States to determine the most appropriate treatment regimen for US patients with H. pylori infection. Concern has been growing that the first-line therapy most commonly used in the United States—standard triple therapy consisting of a PPI, clarithromycin, and amoxicillin—appears to have lost some of its effectiveness over time. One possible explanation for this trend is the growing prevalence of clarithromycin resistance among H. pylori strains in the United States.

Taking these trends into consideration, there has been much discussion about the potential role of sequential therapy for the treatment of H. pylori infection. Sequential therapy typically consists of a 5-day course of a PPI plus amoxicillin, followed by a 5-day course of a PPI, clarithromycin, and an imidazole antibiotic. Data from southern Europe and parts of Asia have suggested that sequential therapy yields significantly better eradication rates than triple therapy: Meta-analyses of randomized, controlled trials report over 90% eradication with sequential therapy compared to less than 80% with standard triple therapy.⁶ In small numbers of patients for whom antimicrobial sensitivity data are available, sequential therapy appears to be particularly beneficial for patients infected with clarithromycin-resistant strains of H. pylori.

While studies from Italy and Taiwan have touted the benefits of sequential therapy, other recent studies have not replicated these results.^7–10 For example, a recent, very large, randomized, controlled trial conducted in 7 Latin American countries yielded different results.^7,11 The Latin American study found that a 14-day course of triple therapy performed better than a 10-day course of sequential therapy or a 5-day course of concomitant therapy (giving all 4 drugs together rather than sequen-tially).⁷ Thus, we currently have data from Europe and the Far East suggesting that sequential therapy is more effective than triple therapy, while data from Latin America suggest that triple therapy is at least as effective, and perhaps more effective, than sequential therapy. In addition, although the recent study from Latin America found a short course of concomitant therapy to be the least effective of the 3 regimens evaluated, others have found longer courses of concomitant therapy to be highly effective for eradicating H. pylori infection. As the data emerge, it is growing increasingly clear that a variety of factors influence the efficacy of H. pylori treatment regimens, including compliance, tolerability, levels of antimicrobial resistance, and duration of therapy.

The disparity among recently published studies raises important questions as to the validity of making treatment recommendations for US patients based on data generated in other countries. Until additional treatment studies—or, at a minimum, data on antimicrobial resistance—are collected in the United States, controversy and confusion will likely remain as to which regimen is the most appropriate first-line treatment for pylori infection.