Updates in the Treatment of H. Pylori Infection

Introduction

Helicobacter pylori (H. pylori) is a gram-negative, spiral-shaped bacterium associated with chronic bacterial infections of the stomach. H. pylori is the most frequent cause of gastric inflammatory disorders including chronic gastritis and peptic ulcer disease.¹ It remains as the leading cause of infection-attributable cancers worldwide with a 2018 incidence analysis reporting more than 800,000 cases attributed to the pathogen.²

Given the prevalence of this pathogen and resistance patterns, treatment guidelines were recently updated. The purpose of the article is to review the epidemiology, pathogenesis, diagnosis, and management of H. pylori infection.

Epidemiology

H. pylori is estimated to infect approximately 40% of the world’s population with a wide variation in the prevalence based on geographic region. Although the global prevalence has declined from nearly 60% between 1980 and 1990, over 40% of the global population remains infected. Infection rates are disproportionately distributed based on age, ethnicity, geographic region, and socioeconomic status, with higher prevalence in areas of low and moderate income compared to areas of high income. In North America, infection rates are estimated to be between 30% and 40%, with the highest prevalence in the southern and southeastern regions of the country.^3-5

Most infected individuals will remain asymptomatic without clinically meaningful consequences. However, all infected individuals who do not spontaneously clear the pathogen will develop chronic gastritis, which may lead to a wide range of potentially severe benign and malignant consequences of high morbidity and mortality.⁶

H. pylori infection is generally seen in children and often resolves on its own. However, H. pylori can also affect adults, especially those who travel to areas of higher prevalence. Unlike children, H. pylori infection in adults requires appropriate treatment, as the infection can become chronic if left untreated. The exact mode of transmission of infection remains unclear, though health experts believe the most likely route of transmission is fecal-oral and oral-oral.⁷

Pathogenesis

H. pylori is a highly adapted pathogen with a unique array of features that lead to mobility, evasion of the immune system, and survival, resulting in chronic colonization and transmission.⁸ A unipolar bundle of sheathed flagella allows for high motility and the production of urease—an enzyme that cleaves urea into ammonia and carbon dioxide—permits habitation in the acid environment of the stomach.¹

Both innate and adaptive immune responses occur naturally upon bacterial entry into the gastric mucosa. H. pylori contact with gastric epithelial cells leads to the release of cytokines and chemokines, creating a pro-inflammatory environment. The formation of antibodies to H. pylori through cellular and humoral immune responses has shown to have little benefit in the eradication of the bacteria.¹⁰

The pro-inflammatory environment induced by H. pylori colonization leads to chronic gastritis, which may manifest as asymptomatic in most individuals but over time is thought to be the driving factor in carcinoma development—a progression known as the Correa Cascade (Figure 1).

Diagnosis

Because H. pylori infection is often asymptomatic, particularly in younger individuals, a large percentage of cases go undiagnosed. Among those who develop symptoms, epigastric pain and dyspepsia are the most commonly reported complaints.¹¹ The decision to test and treat H. pylori should be viewed as a singular one, as recommended by the American College of Gastroenterology (ACG).⁴ Table 1 lists the current guideline-recommended indications for testing and treating H. pylori, which includes both symptom-driven testing (eg, dyspepsia) and non-symptom-driven testing (eg, household contact).

There are several diagnostic methods for the detection of H. pylori that are either classified as invasive or non-invasive (Table 2).^1,12

The choice of diagnostic testing method depends on several factors including the need for an upper endoscopy, accessibility of testing, clinical circumstances, and testing sensitivity and specificity.¹² However, general preference should be for non-invasive diagnostic methods as these tests provide both sensitivity and specificity. Non-invasive testing (above) may be used for means of primary diagnosis with the gold standard being the urease breath test (¹³C-urea breath test).

Management

H. pylori is a bacterial infection that warrants treatment in symptomatic individuals or in those individuals at high risk for complications due to chronic colonization (eg, gastric cancer). Treatment regimens are based on a combination of antibiotics and strong acid-suppression. High intragastric pH promotes active replication of H. pylori, thereby making the pathogen more susceptible to antibacterial therapy.^1,4

Emerging clinical guideline updates outline the recommended management for both treatment-naïve and treatment-experienced patients with H. pylori infection. For the purposes of this article, the focus will be on the management of treatment-naïve patients. The optimized bismuth quadruple regimen is currently the preferred first-line treatment for treatment-naïve patients while rifabutin (Mycobutin; Pfizer) triple therapy and potassium-competitive acid blocker dual and triple therapy are alternative regimens. The recommended duration of therapy for all regimens discussed below is 14 days.⁴

H. pylori Treatment-Naïve First-Line Regimens

Optimized Bismuth Quadruple (BQT)

Optimized BQT therapy generally consists of a proton pump inhibitor (PPI), bismuth subsalicylate, metronidazole, and tetracycline (preferred over doxycycline). A retrospective single-center analysis in the United States conducted by Alsamman, et al. showed superiority of BQT compared with standard H. pylori triple therapy (consisting of a PPI, clarithromycin, and amoxicillin) with H. pylori eradication rates of 85% vs 75%, respectively.¹³

Notably, eradication rates dropped when duration of therapy was 10 days (77%) and when doxycycline was substituted for tetracycline (67%). While several randomized clinical trials (RCTs) outside of the United States have studied BQT vs triple therapy, inconsistencies in dosing and duration make evaluation of the data difficult.⁴

The BQT regimen is not FDA approved when prescribed as individual components. However, there are currently two FDA approved products which include Pylera(Juvisé Pharmaceuticals) and Helidac (Casper Pharma LLC).^14,15 Pyleraconsists of bismuth subsalicylate, metronidazole, and tetracycline and is FDA approved when combined with omeprazole. However, it is packaged as only a 10-day supply—shorter than the 14-day duration recommended by the ACG.¹⁴

Helidac consists of bismuth subsalicylate, metronidazole, and tetracycline and received initial FDA approval when combined with a histamine-2 receptor antagonist (H2RA) for patients with an associated duodenal ulcer.¹⁵ However, current guidelines do not recommend the use of an H2RA for H. pylori treatment⁴ and therefore an H2RA should be substituted with a PPI. One distinct advantage of the BQT regimen is its lack of amoxicillin and is therefore the preferred regimen in patients with a penicillin allergy.

Rifabutin Triple

Rifabutin triple therapy consists of a combination of rifabutin, amoxicillin, and a PPI. In treatment-naïve patients, rifabutin triple therapy is a suggested regimen partly due to a paucity of data for its use in the first-line setting.⁴

In a meta-analysis conducted by Gingold-Belfer, et al, only 1 RCT compared rifabutin with control in the first-line setting. This trial noted that treatment was more likely to be successful in Asian vs non-Asian patients, and when doses of amoxicillin were greater than or equal to 3000 mg per day, PPI dosing was 80 mg per day or more, or when treatment duration was 14 days.¹⁶

Many of the trials conducted were outside of the United States and current data with rifabutin triple therapy compared to either clarithromycin triple therapy or BQT is lacking. There is currently only 1 FDA approved combination product, Talicia (RedHill Biopharma Inc) which consists of the fixed-dose combination of omeprazole (120 mg per day), rifabutin (150 mg per day), and amoxicillin (3000 mg per day).¹⁷ Therefore, evidence for rifabutin triple therapy in the first-line setting remains limited. However, there are some advantages with rifabutin triple therapy including reported low rifabutin-resistance rates and the lack of concern for macrolide resistance.⁴

Potassium-Competitive Acid Blocker (PCAB) Dual & Triple Therapy

PCAB dual therapy consists of vonoprazan (Voquezna; Phathom Pharmaceuticals Inc) and amoxicillin, compared with vonoprazan triple therapy which consists of vonoprazan, amoxicillin, and clarithromycin (Biaxin; Abbott Laboratories). Vonoprazan is a PCAB that suppresses gastric acid secretion through inhibition of the H+, K+-ATPase enzyme system.¹⁸ This unique mechanism of action has shown more rapid and potent acid suppression when compared to standard doses of PPIs.¹⁹ In addition, unlike PPIs which require doses to be taken at least 30 minutes before a meal, vonoprazan can be taken without regard to meals.

In a RCT conducted by Chey et al, both the vonoprazan dual and triple therapy regimens were compared to standard H. pylori PPI triple therapy (lansoprazole, amoxicillin, and clarithromycin).²⁰ The primary end point was noninferiority in eradication rates in patients with clarithromycin and amoxicillin-resistant strains, and secondary endpoints assessed superiority in eradication rates in both clarithromycin-resistant strains and all patients.²⁰

Both vonoprazan dual and triple therapy met the studies primary endpoint (eradication rates in non-resistant strains: 84.7% for vonoprazan triple, 78.5% for vonoprazan dual, and 78.8% for PPI triple therapy) and secondary end points (eradication rates in clarithromycin-resistant strains and all patients, respectively: 65.8% and 80.8% for vonoprazan triple, 69.6% and 77.2% for vonoprazan dual, and 31.9% and 68.5% for PPI triple therapy).²⁰

An important consideration when choosing a treatment regimen for eradication of H. pylori is antibiotic resistance. Clarithromycin and levofloxacin resistance rates continue to rise, particularly in the United States. A meta-analysis conducted by Ho et al, found resistance rates for clarithromycin to be 31.5% and 37.6% for levofloxacin.²¹ Of note, resistance rates for metronidazole were found to be 42.1%, but were considerably lower for amoxicillin (2.6%), tetracycline (0.87%), rifabutin (0.17%).

As such, current guidelines do not recommend empiric treatment with clarithromycin or levofloxacin-containing regimens in treatment-naïve patients. Rather, their use should be reserved for treatment-experienced patients and when antibiotic susceptibility is confirmed.⁴

Post-Treatment Eradication Testing

Patients who receive treatment for H. pylori should undergo testing to confirm eradication of the pathogen. It is necessary to test patients for cure due to the consequences of persistent H. pylori, which includes peptic ulcer disease, gastric Mucosa-Associated Lymphoid Tissue (MALT) lymphoma, and gastric adenocarcinoma. The same testing methods utilized for initial diagnosis are utilized to confirm eradication, apart from serological antibody testing, as antibody levels can remain positive for months to years after eradication of H. pylori.⁴

Like diagnostic testing, non-invasive methods are preferred when testing for cure, when clinically appropriate, with both the ¹³C-urea breath and fecal antigen being highly accurate methods to confirm eradication. It is prudent to consider both timing of post-treatment testing and cessation of therapies utilized in the treatment of H. pylori. A minimum of 4 weeks should have elapsed from the completion of H. pylori treatment before performing a urea breath or fecal antigen test.⁴

Additionally, as PPIs may result in false-negative urea breath and fecal antigen tests, these should be withheld at least 2 weeks prior, while antibiotics and bismuth salts should be avoided for at least 4 weeks prior to testing.^4,22 Limited data with PCABs suggests reduced accuracy of the urea breath test and therefore, similar consideration as PPIs should be taken.²³

Conclusion

H. pylori is the most common bacterial infection worldwide and remains the leading cause of infection-related cancers. Although most infected individuals remain asymptomatic, those that are not able to spontaneously clear the pathogen will develop chronic gastritis which may potentially lead to more severe clinical consequences including peptic ulcer disease and gastric cancers.

Treatment regimens for H. pylori consist of a combination of potent acid-suppression and antibacterial therapy. The optimized bismuth quadruple therapy is currently the preferred first-line treatment regimen for treatment-naïve patients, including those with a penicillin allergy. Other recommended regimens include rifabutin triple therapy and potassium-competitive acid blocker dual and triple therapy (see Table 3 for summary of recommendations). Optimal treatment duration for all first-line regimens is 14 days. Following completion of treatment, it is necessary to confirm eradication of the pathogen due to the potential for severe clinical sequela of persistent infection.

Adherence to guideline-recommended regimens and appropriate posttreatment testing are essential to reduce the risk of persistent infection and its associated complications. As therapeutic options continue to evolve, ensuring successful eradication remains the cornerstone of preventing long-term disease progression.

REFERENCES

1. Malfertheiner P, Camargo, M.C., El-Omar, E. et al. Helicobacter pylori Infection. Nat Rev Dis Primers; 2023 9(19). doi:10.1038/s41572-023-00431-8

2. de Martel C, Georges D, Bray F, et al. Global Burden of Cancer Attributable to Infections in 2018: a worldwide incidence analysis. Lancet Glob Health. 2020; 8: e180-190. doi:10.1016/S2214-109X(19)30488-7

3. Hooi J, Lai W, Ng W, et al. Global Prevalence of Helicobacter pylori Infection: systematic review and meta-analysis. Gastroenterology. 2017; 153:420-429. doi:10.1053/j.gastro.2017.04.022

4. Li Y, Choi H, Leung K, et al. Global Prevalence of Helicobacter pylori Infection Between 1980 and 2022: a systematic review and meta-analysis. The Lancet Gastroenterology & Hepatology. 2023; 8(6): 553-564. doi:10.1016/S2468-1253(23)00070-5

5. Jalaly J, Couturier M, Burnham CA, et al. Multicenter Evaluation of Helicobacter pylori IgG Antibody Seroprevalence Among Patients Seeking Clinical Care in the US. J Appl Lab Med. 2018; 2(6): 904-913. doi: 10.1373/jalm.2017.025569

6. Chey W, Howden C, Moss S, et al. ACG Clinical Guideline: treatment of Helicobacter pylori infection. The American Journal of Gastroenterology. 2024; 119(9): 1730-1753. doi:10.14309/ajg.0000000000002968

7. Kayali S, Manfredi M, Gaiani F, et al. Helicobacter pylori, Transmission Routes and Recurrence of Infection: state of the art. Acta Biomed. 2018; 89(8-S): 72-76. doi:10.23750/abm.v89i8-S.7947

8. Suerbaum S, Michetti P. Helicobacter pylori Infection. N Engl J Med. 2002; 347: 1175-1186. doi: 10.1056/NEJMra020542

9. Zhang X, Arnold I.C., Muller A. Mechanisms of Persistence, Innate Immune Activation and Immunomodulation by the Gastric Pathogen Helicobacter pylori. Curr Opin Microbiol. 2020; 54: 1-10. doi:10.1016/j.mib.2020.01.003

10. Arshad U, Sarkar S, Talesh A, et al. A Lack of Role for Antibodies in Regulating Helicobacter pylori Colonization and Associated Gastritis. Helicobacter. 2020; 25(2): e12681. doi: 10.1111/hel.12681

11. Sobala, G. M. et al. Acute Helicobacter pylori Infection: clinical features, local and systemic immune response, gastric mucosal histology, and gastric juice ascorbic acid concentrations. Gut. 1991; 32:1415–1418. doi:10.1136/gut.32.11.1415

12. Bordin D, Voynovan I, Andreev D, et al. Current Helicobacter pylori Diagnostics. Diagnostics (Basel). 2021; 11(8): 1458. doi:10.3390/diagnostics11081458

13. Alsamman M, Vecchio E, Shawwa K, et al. Retrospective Analysis Confirms Tetracycline Quadruple as Best Helicobacter pylori Regimen in the USA. Dig Dis Sci. 2019; 64(10): 2893-2898. doi:10.1007/s10620-019-05694-4

14. PYLERA. Prescribing information. Laboratoires Juvisé Pharmaceuticals; 2025. Accessed September 30, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/050786s029lbl.pdf

15. HELIDAC. Prescribing Information. Casper Pharma LLC; 2025. Accessed September 30, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/050719s026lbl.pdf

16. Gingold-Belfer R, Niv Y, Levi Z, et al. Rifabutin Triple Therapy for First-line and Rescue Treatment of Helicobacter pylori Infection: a systematic review and meta-analysis. Journal of Gastroenterology and Hepatology .2021; 36(6): 1392-1402. doi: 10.1111/jgh.15294.

17. Talicia. Prescribing information. RedHill Biopharma Ltd.; 2024. Accessed September 30, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213004s014lbl.pdf

18. Voquezna (vonoprazan). Package insert. Phathom Pharmaceuticals, Inc. 2022

19. Laine L, Sharma P, Mulford D, et al. Pharmacodynamics and Pharmacokinetics of the Potassium-Competitive Acid Blocker Vonoprazan and the Proton Pump Inhibitor Lansoprazole in US Subjects. Am J Gastroenterol. 2022; 117(7): 1158-1161. doi:10.14309/ajg.0000000000001735

20. Chey W, Megraud F, Laine L, et al. Vonoprazan Triple and Dual Therapy for Helicobacter pylori Infection in the United States and Europe: randomized clinical trial. Gastroenterology. 2022; 163(3): 608-619. doi: 10.1053/j.gastro.2022.05.055

21. Ho J, Navarro M, Sawyer K, et al. Helicobacter pylori Antibiotic Resistance in the United States Between 2011 and 2021: a systematic review and meta-analysis. Am J Gastroenterol. 2022; 117(8): 1221-1230. doi: 10.14309/ajg.0000000000001828

22. Kodama M, Murakami K, Okimoto T, et al. Influence of Proton Pump Inhibitor Treatment on Helicobacter pylori Stool Antigen Test. World J Gastroenterol. 2012; 18(1): 44-48. doi:10.3748/wjg.v18.i1.44

23. Takimoto M, Tomita T, Yamasaki T, et al. Effect of Vonoprazan, a Potassium-Competitive Acid Blocker, on the 13C-Urea Breath Test in Helicobacter pylori-Positive Patients. Dig Dis Sci. 2017; 62: 739-745. doi.org:10.1007/s10620-016-4439-0