Treating Helicobacter pylori Infection Reduces Gastric Cancer Risk

As the only bacterium deemed a class I carcinogen by the World Health Organization, Helicobacter pylori infection is a risk factor for gastric cancer.¹ Experts have emphasized the importance of H pylori treatment in decreasing gastric cancer risk, and study findings suggest that adequate rates of H pylori eradication may reduce gastric cancer diagnoses by at least 50%.^2-4

In a 2022 meta-analysis of 4 randomized controlled trials, comprising 10 to 26.5 years of follow-up data captured from healthy, asymptomatic individuals with H pylori infection, researchers observed gastric cancers in 2.6% of those who received eradication therapy compared with 4.8% in those who received placebo or no treatment.³

In a prospective randomized trial published in 2020, researchers examined the risk for gastric cancer following H pylori eradication in first-degree relatives of patients with gastric cancer. After a median follow-up period of 9.2 years, patients in the treatment group showed a 55% lower risk for gastric cancer compared with those in the placebo group.⁴

Despite the important role of H pylori eradication in gastric cancer prevention, more than 20% of patients with H pylori infection experience treatment failure, most commonly due to antimicrobial resistance (AMR).⁵ For example, clarithromycin and levofloxacin resistance reduces treatment success rates by up to 50% and 40%, respectively.⁶

Eradication strategies have shifted in recent years because of AMR. For example, the 2007 American College of Gastroenterology (ACG) guidelines on H pylori treatment recommended 14 days of clarithromycin-based triple therapy, including a proton pump inhibitor and either amoxicillin or metronidazole, as a first-line treatment approach. However, ACG guidelines published in 2017 recommended against this regimen in regions where the rate of clarithromycin-resistant H pylori infections in patients with previous macrolide exposure is greater than 15%.^7,6

For these patients, bismuth-based and non-bismuth-based quadruple therapies were the recommended first-line regimens in the 2017 guidelines.⁶ By 2022, however, researchers reviewing various international guidelines and treatment comparisons concluded, “[N]onbismuth quadruple therapies for 10-14 days and vonoprazan-based triple therapy for 7 days are the currently recommended H pylori treatment regimens,” with eradication rates of approximately 90% even in settings with a high prevalence of antimicrobial-resistant strains. ⁸

The use of multiple antibiotics in these regimens, as with previously recommended regimens, carries the risk of contributing to AMR as well as gut microbiota dysbiosis.⁸

Cumulative study results indicate probiotic supplementation may improve gut dysbiosis associated with antibiotic use in H pylori infection, although findings have been mixed and of low quality overall thus far. Further research is needed to elucidate this point as well as the effect of probiotics on H pylori eradication, adverse effects, and treatment adherence, as some findings have shown more favorable outcomes in each of these areas with adjuvant probiotic therapy.^6,9

For further insight into the evolving approach to H pylori eradication, we spoke with Steven Moss, MD, Professor of Medicine in the Division of Gastroenterology at Brown University in Providence, Rhode Island, and co-author of the 2017 ACG guidelines on H pylori treatment; and Waseem Ahmad, MD, Assistant Professor in the Division of Gastroenterology at the University of California, San Francisco, School of Medicine.

What is the role of H pylori eradication in gastric cancer? Are there special considerations regarding H pylori screening or treatment in patients with a high risk for gastric cancer?

Dr Moss:Clinical studies have demonstrated that eradication of H pylori can prevent about 50% of all gastric cancers. Screening programs have been established in some countries in Southeast Asia that have a very high prevalence of H pylori and gastric cancer, such as China, Japan, and Korea. Trials of H pylori screening and treatment are in process in some other countries to establish whether they should be implemented across populations. In the United States we do not have any screening programs or trials, but these are being considered, especially in populations at high risk, such as immigrant populations from high-prevalence countries.

There is now high-quality evidence that first-degree relatives of patients with gastric cancer should be screened for H pylori and treated if testing positive for infection.⁴

Dr Ahmad: Gastric cancer is among the most prevalent types of cancer worldwide, and it is a leading cause of cancer-related mortality.³ The most common type of gastric cancer is non-cardia gastric adenocarcinoma (NCGA), with chronic H pylori infection being the strongest risk factor of developing this condition. If H pylori infection is not eradicated, patients can transition from having H pylori gastritis to atrophic gastritis to intestinal metaplasia to dysplasia to NCGA. Once individuals have established intestinal metaplasia, there is increased risk for progressing to NCGA such that periodic endoscopic surveillance should be advised.

Certain demographics have increased risk for H pylori infection, such as individuals who are Hispanic, non-Hispanic Black, and Asian American. Patients from these populations, especially Asian Americans, may benefit from endoscopic screening for gastric cancer and subsequent surveillance if intestinal metaplasia is identified.¹⁰ Non-invasive diagnostics compared with endoscopic evaluation for H pylori in these populations would not offer a cost-effective advantage in preventing gastric malignancy at this time.

Are there any recent or emerging developments that may improve treatment for H pylori infection?

Dr Moss:Rifabutin-based triple therapy was approved by the US Food and Drug Administration (FDA) several years ago and can be used in first- or second-line therapy.¹¹ Triple and dual first-line therapies with vonoprazan replacing PPIs were approved by the FDA in 2022 and are expected to be launched in the US shortly.^12,13 Both these new treatments offer alternatives to bismuth quadruple therapy, which has been the standard first-line therapy for several years, but which patients find difficult to tolerate.

Editor’s note: These treatments include vonoprazan and amoxicillin in dual therapy or vonoprazan with amoxicillin plus clarithromycin in triple therapy. In nonresistant strains, eradication rates were 78.5% with dual vonoprazan therapy and 84.7% with triple vonoprazan therapy compared with 78.8% with lansoprazole triple therapy; in clarithromycin-resistant strains, eradication rates were 69.6% and 65.8% compared with 31.9%, respectively.¹²

Dr Ahmad: The dilemma that clinicians currently face when treating H pylori is that, historically, treatment regimens rely on clarithromycin, penicillin, and/or levofloxacin, all of which are used in other infectious conditions. As antibiotic resistance to these medications have increased and susceptibility testing has not been streamlined or easy to perform, alternative treatment regimens are needed.

Fortunately, having the 2 new treatment regimens involving vonoprazan, one of which does not use clarithromycin, may help with H pylori eradicationand decrease the risk for complications related to H pylori.

How are clinicians addressing the issue of antibiotic resistance in the context of H pylori treatment?

Dr Moss:Antibiotic resistance is the main barrier to successful H pylori eradication. High rates of resistance to clarithromycin and levofloxacin in the US have been reported. This is the reason why clarithromycin-based triple therapy should no longer be used as a treatment for H pylori infection unless it is proven that the H pylori strain is sensitive to clarithromycin. Similar logic applies to the use of levofloxacin in triple regimens. Unfortunately, most clinicians are unaware of the rates of resistance to these antibiotics in their communities.

Dr Ahmad: Unfortunately, there are currently no established protocols to assess for individual resistance to select antibiotics. To minimize treatment failure, clinicians should review with patients their prior medical and pharmacy records for certain antibiotic exposures.¹⁴ We do know there are areas where antibiotic resistance is more prevalent and that individuals from where H pylori is endemic are at increased risk for treatment failure. In these cases, clinicians may consider pursuing quadruple therapy as a more favorable option than standard triple therapy.

What are the top remaining needs in terms of research and clinician education regarding H pylori treatment?

Dr Moss:We need to make resistance testing more available, develop programs to report and distribute information about H pylori antibiotic resistance, conduct comparative trials of the newer H pylori treatments against the older H pylori standard of bismuth quadruple therapy, and educate clinicians that clarithromycin or levofloxacin-based triple therapies are no longer recommended because of high resistance rates.

Clinicians should also be educated about the need to perform a test of cure after the end of H pylori therapy to make sure the treatment worked. Without this, many patients will be at risk for the adverse clinical outcomes of action, such as gastric cancer and peptic ulcers.

Dr Ahmad: H pylori continues to have a significant clinical and economic impact worldwide. With the rising rates of H pylori treatment failure, ongoing research and implementation of protocols that promote initial H pylori eradication are critical. Research at the local or population level assessing for antibiotic resistance patterns and treatment success of select regimens may help guide appropriate initial and refractory H pylori treatment.¹⁴

From a practical standpoint, clinicians should ensure that patients are adherent to treatment regimens, that eradication is confirmed following treatment, and that allergies to certain antibiotics—namely penicillin—are scrutinized, as all of these factors will have short- and long-term consequences on successful treatment.