Management of Helicobacter pylori in 2023: who should be tested, treated, and how

Author

Sander Veldhuyzen van Zanten, MD, FRCPC, MSc, MPH, PhD (biography and disclosures)

Disclosures: No disclosures relevant to this publication. Received peer and non-peer-reviewed funding for clinical studies of Helicobacter infection in the past. Received speaker fees and member of advisory boards for H. pylori related activities. None in the last five years. Mitigating potential bias: Only published trial data is presented. Recommendations are consistent with published Canadian and International guidelines (references 4-7). Recommendations are consistent with current practice patterns.

What gaps I have noticed

Helicobacter pylori (H. pylori) continues to be an important pathogen associated with peptic ulcer disease, dyspepsia, and gastric cancer.

Data that answers these gaps

The epidemiology of H. pylori in Canada is changing.¹ It can now rarely be found in second-generation Canadians, but the prevalence continues to be high in immigrants, children of immigrants, and First Nations Canadians. In an H. pylori positive individual the lifetime risk of developing gastric or duodenal ulcers is 5 to 15% and dyspepsia up to 25%. H. pylori is an important risk factor for development of gastric cancer, but this is rare, occurring in less than 1 in 1,000 infected individuals. Most infections are acquired in childhood, during the first 5–10 years of life.^2,3 In a substantial proportion of individuals, the infection remains dormant and causes no symptoms. Although most H. pylori infections are acquired in childhood, it is not recommended to routinely test family members of H. pylori infected individuals. Among adults, it is very unlikely that H. pylori is transmitted, even when there is close personal contact.

Worldwide and in Canada the guidelines for the treatment of H. pylori infection changed in 2016.^4-7 Details of the medications used, the dosages, and frequencies, are listed in Table 1. Importantly, the recommended duration for most regimens is 14 days.

What I recommend (practice tips)

Who should be tested for Helicobacter and how?

Generally speaking, do not test patients for H. pylori unless you are prepared to treat if they are positive.

Patients who should be tested for H. pylori:

1. Duodenal or gastric ulcer diagnosis (recent or in the past)
2. Dyspepsia (epigastric pain dominant symptoms)
3. First-degree family history of gastric cancer (especially if index case is young)
4. High-risk groups (First Nations, immigrants)

H. pylori can be diagnosed by histology when biopsies are taken during gastroscopy. The urea breath test (UBT) is a very accurate and robust test to diagnose the infection.⁸ More recently, the H. pylori stool antigen test (HpSAT) has been used more frequently.⁹ It is an accurate test but it has a higher proportion of equivocal results than the UBT. Use of serology to detect H. pylori infection is not recommended as it cannot discriminate between a current active infection or an old (treated) infection in the past. Importantly, one has to stop PPIs (proton pump inhibitors) for 14 days prior to performing a urea breath test or HpSAT. The reason is that up to 20% of people while on PPIs may get false negative results due to suppression of the organism by the PPI.¹⁰

Although a large proportion of patients with duodenal or gastric ulcers are H. pylori positive, H. pylori negative ulcers are becoming more common. Therefore, it is recommended to document that a patient is H. pylori positive before initiating treatment. The most common cause of H. pylori negative ulcers are NSAIDs and antiplatelet agents.

Helicobacter treatment recommendations have changed

The conventional triple combination of a PPI, clarithromycin (Cl), and either amoxicillin (A) or metronidazole (Met) is no longer recommended because its success rates have decreased to less than 60%.^11,12 This includes the use of Hp-PAC®, the combination of lansoprazole, amoxicillin, and clarithromycin.

Recommended treatments (summarized in Table 1 below):

1. The new recommended first-line therapy is called concomitant or ClAMet (using the initials of clarithromycin (Cl), amoxicillin (A), and metronidazole (Met)) given for 14 days.^4-7 Its efficacy is 80–85%.
2. The best second-line therapy is bismuth-based quadruple therapy (PPI, bismuth, metronidazole, and tetracycline) given for 14 days. The higher dose of metronidazole 500 mg is the author’s preference as there is evidence that it can better overcome partial resistance to metronidazole.¹³ This is a robust treatment that can also be used as first line. The downside of bismuth-based quadruple therapy (Bi-Quad) is that it is a complex regimen consisting of up to 24 pills a day. Some of the medications need to be taken twice and others four times a day. Bi-Quad also has more side effects than concomitant therapy.
3. The third-line therapy is the combination of a PPI, amoxicillin, and levofloxacin (PPI-AL) given for 14 days. The author uses the higher dose of levofloxacin 500 mg bid. Sometimes PPI-AL is given as second line instead of Bi-Quad because it is an easier regimen to take, but it is less well tested. PPI-AL should not be used as first-line therapy because the background rate of levofloxacin resistance is high in Canada, up to 15%.¹⁴ This high rate is likely explained by the high use of fluoroquinolones for other indications.
4. There is a fourth-line therapy consisting of a PPI with amoxicillin and rifabutin (Rif). In Canada, its efficacy is 62% when given as rescue therapy.¹⁵ This is the only therapy for which the duration is 10 days instead of 14 days. However, family physicians may want to consider referring patients to a GI specialist should the three first-choice therapies have failed. Use of rifabutin often needs special authorization. In the USA, a combination tablet of omeprazole, amoxicillin, and rifabutin (Talicia), has been available since 2019. It has been tested as a first-line therapy and the success rate of 10-day therapy was 84%.¹⁶ The tablet is not available in Canada and the decision to move the PPI-amoxicillin-rifabutin combination to first line requires more studies.

If the above-listed four therapies are given in sequence to individuals who failed higher order therapies (i.e., start with concomitant, followed by B-Quad, etc.) the cumulative success rate is 96–97%.^{17, 18} The first choice of therapy in patients with a true penicillin allergy is Bi-Quad. If that fails, the second line of therapy is triple therapy with PPI, Clarithromycin, and Metronidazole (PPI-CM) given for 14 days.⁴

One thing to note, although there are pharmacologic differences among the different PPIs, resulting in differences in acid suppression¹⁹, for day-to-day practice PPIs, when given in standard doses, are generally considered equal when treating common conditions such as Gastro Esophageal Reflux Disease (GERD) or peptic ulcer disease (PUD). For treatment of H. pylori, there is some evidence that using the more potent PPIs, such as esomeprazole or rabeprazole, slightly higher success rates are achieved compared to pantoprazole.²⁰

What patients need to know about the treatments

It is important that patients get a clear explanation about these treatments, preferably with a handout. Examples of handouts the author uses about the importance of H. pylori infection and the different treatments are available in the patient handouts section below. Prescribing anti-Helicobacter therapy is difficult to do well over the phone. It is helpful for patients to prescribe these treatments in a blister pack, as the regimens are complex. That way patients are not confused about which medications have to be taken and when. Patients should be told that compliance is very important as cure rates drop significantly if treatments are not taken for the full duration. See handouts for patients.

Is it necessary to test whether the treatment was successful?

It is generally recommended to test whether treatment was successful. In primary care, UBT or the stool antigen test are used for this. Importantly, one has to wait at least 4 weeks after the treatment was finished before re-testing is done to avoid getting false negative results. Once again, it is important that PPI therapy, if there is an ongoing need for it after the antibiotics are finished, is held for 14 days prior to the repeat testing for Helicobacter.¹⁰ Patients can be managed during those 14 days with standard doses of antacids if they have symptoms while off the PPI. If the patient is negative after appropriate testing for cure was done, it is very unlikely such a patient will get re-infected later in life. In adults, most patients who are thought to have a re-infection, in fact, have a false negative test result in the past. They usually have recrudescence of their original H. pylori strain.²¹

Given that none of the current H. pylori therapies are 100% successful it is my practice to always test whether cure has been received after each treatment. I generally give a patient three or four rounds of treatment if needed but I should state that I have a special interest in H. pylori. What to do with patients who fail more than four therapies should be decided on a case-by-case basis. This may in part depend on the indication for treatment. An option is to refer the patient for antibiotic resistance testing for which a gastroscopy is required. Knowledge of the resistance pattern on the strain may guide further therapy. However, testing of H. pylori strains is not widely available in Canada and data on resistance are scarce. The data show that resistance to clarithromycin and metronidazole and also levofloxacin is high. Resistance to amoxicillin and tetracycline is rare.^{4,14, 22-24}

Another management option is the decision not to treat Hp any further, but possibly observe these patients long-term. Long-term follow-up especially is a consideration, if there is a family history of gastric cancer or if more severe gastric metaplasia was present on histology.^25,26

Peptic ulcer disease

There are a few important recommendations in the management of patients diagnosed with acute peptic ulcer disease (duodenal or gastric ulcers), and especially bleeding ones, for example during a hospitalization. If they turn out to be H. pylori positive it is important to continue PPI therapy after the 14-day anti-Helicobacter treatment, for at least 8–16 weeks, to ensure adequate healing of the ulcer. Importantly, in such patients, the PPI should not be stopped until there is proof that the H. pylori infection has been successfully cured. The reason for this is that should treatment have failed to cure H. pylori, these patients are at risk of getting recurrent ulceration (with possible bleeding) if PPI maintenance therapy is not given.²⁷ A decision whether or not to continue PPI longer term should only be taken once cure of H. pylori has been established.

There is evidence that anti-Helicobacter therapy is effective in the treatment of H. pylori positive gastric or duodenal ulcers. However, a proportion of such patients will require long-term PPI therapy because of ongoing symptoms even though H. pylori was cured. Another reason for ongoing acid-suppressive therapy may be that some of these patients, especially older ones (> 65–70 years) require, for example, anticoagulation and/or antiplatelet agents for management of cardiovascular risk factors. Given that they, therefore, have an ongoing risk of developing (bleeding) ulcers it is reasonable to maintain such patients on a once-a-day PPI for ulcer prophylaxis.

The role of Helicobacter in dyspepsia and GERD

There is definite evidence that a test and treat strategy for H. pylori is efficacious in patients who present with dyspepsia symptoms in primary care.²⁸ Dyspepsia is defined as epigastric pain or discomfort which may be accompanied by other upper GI symptoms, such as burning sensation or excessive burping. Compared to no-antibiotic treatment, more patients will have permanent resolution of their dyspepsia symptoms following cure of the H. pylori infection. However, clinical trial data, including studies from Canada, have shown that more than 50% of dyspepsia patients will have ongoing dyspepsia symptoms, often requiring acid suppressive therapy, after successful cure of the infection.²⁸

Another important comment on the management of dyspepsia is that there is good evidence that PPIs work in epigastric pain dominant dyspepsia (ulcer-like dyspepsia), and in those who have concomitant symptoms of heartburn (reflux-like dyspepsia). However, PPIs are generally not effective in so-called dysmotility-like dyspepsia where upper abdominal bloating rather than epigastric pain or discomfort is the dominant symptom.²⁹ In this subgroup of patients, PPIs do not provide benefits. In such patients overlap with possible IBS or other diagnoses needs to be further explored.

In Canada nowadays, gastroesophageal reflux disease (GERD) is more common than dyspepsia. The diagnosis of GERD can be made based on the presence of dominant symptoms of heartburn and/or regurgitation.³⁰ Importantly the clinical course of GERD (frequency of symptoms, need for acid suppressive therapy) will not be altered by successful cure of a coexisting H. pylori infection.³¹ It is important to tell patients about this as most of them will require ongoing maintenance therapy with PPI for control of their GERD symptoms even though H. pylori has been cured. For this reason, it is not recommended to routinely test for H. pylori at the time GERD is diagnosed in patients. This is in contrast to the patient who has dyspepsia, defined by epigastric pain or discomfort as the dominant symptom rather than heartburn, where a test for Helicobacter is recommended.³⁰

The incidence of gastric cancer has been decreasing for decades in Canada but it is still more common than esophageal cancer. ³² Apart from smoking, presence of H. pylori is the only other main modifiable risk factor for gastric cancer. It is recommended that all 1^st degree relatives of gastric cancer patients are tested and, if positive, treated for Helicobacter, especially if the index case occurred at a younger age.^25,32 The risk of gastric cancer is much higher in First Nations people compared to the average Canadian population^33,34,35 and the high prevalence of H. pylori is likely a partial explanation for this. The prevalence of H. pylori is also high in immigrants from certain areas, such as Southeast Asia and Central and South America. In those patients, one should have a low threshold to test for H. pylori infection. In general, in children, who have a 1^st degree relative with gastric cancer, the recommendation is to wait with testing and treatment until after they have gone through puberty.

Table 1. The most commonly used treatments for H. pylori infection

• Proton Pump Inhibitor=PPI. Options: Omeprazole 20mg, Pantoprazole 40 mg, Lansoprazole 30 mg, Rabeprazole 20mg, Esomeprazole 40mg, Dexlansoprazole 60mg
• Cl=Clarithromycin
• M= Metronidazole
• A= Amoxicillin
• B= Bismuth subsalicylate
• T= Tetracycline
• L=Levofloxacin

Handouts for patients

1. Helicobacter infection of the stomach
2. Concomitant Therapy (CLAMET)
3. Bismuth-based Quadruple Therapy (Bi-Quad)
4. PPI-Amoxicillin-Levofloxacin Therapy (P-AL)
5. Rifabutin-based Triple Therapy (P-A-Rif)

(Download all)

References

1. Veldhuyzen van Zanten SJ, Pollak PT, Best LM, Bezanson GS, Marrie T. Increasing prevalence of Helicobacter pylori infection with age: continuous risk of infection in adults rather than cohort effect. J Infect Dis. 1994;169(2):434-437. doi:10.1093/infdis/169.2.434 (Request with CPSBC or view with UBC)
2. Hooi JKY, Lai WY, Ng WK, et al. Global prevalence of Helicobacter pylori infection: systematic review and meta-analysis. Gastroenterology. 2017;153(2):420-429. doi:10.1053/j.gastro.2017.04.022 (View)
3. Malaty HM, El-Kasabany A, Graham DY, et al. Age at acquisition of Helicobacter pylori infection: a follow-up study from infancy to adulthood. Lancet. 2002;359(9310):931-935. doi:10.1016/S0140-6736(02)08025-X (View with CPSBC or UBC)
4. Fallone CA, Chiba N, van Zanten SJO, et al. The Toronto consensus for the treatment of Helicobacter pylori infection in adults. Gastroenterology. 2016;151(1):51-69.e14 (Request with CPSBC or view with UBC)
5. Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG clinical guideline: treatment of Helicobacter pylori Infection [published correction appears in Am J Gastroenterol. 2018 Jul;113(7):1102]. Am J Gastroenterol. 2017;112(2):212-239. doi:10.1038/ajg.2016.563 (View with CPSBC or UBC)
6. Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection—the Maastricht V/Florence consensus report. Gut. 2017;66(1):6-3. (View)
7. Malfertheiner P, Megraud F, Rokkas T, et al. Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report. Gut. 2022;gutjnl-2022. doi:10.1136/gutjnl-2022-327745 (View)
8. Chiba N, van Zanten SJO. 13C-Urea breath tests are the non-invasive method of choice for Helicobacter pylori detection. Can J Gastroenterol. 1999;13(8):681-683. doi:10.1155/1999/683452 (Request with CPSBC or view with UBC)
9. Best LM, Takwoingi Y, Siddique S, et al. Non-invasive diagnostic tests for Helicobacter pylori infection. Cochrane Database Syst Rev. 2018;3(3):CD012080. doi:10.1002/14651858.CD012080.pub2 (View)
10. Graham DY, Opekun AR, Hammoud F, et al. Studies regarding the mechanism of false negative urea breath tests with proton pump inhibitors. Am J Gastroenterol. 2003;98(5):1005-1009. doi:10.1111/j.1572-0241.2003.07426 (View with CPSBC or UBC)
11. Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut. 2010;59(8):1143-1153. doi:10.1136/gut.2009.192757 (Request with CPSBC or view with UBC)
12. Rodgers C, van Zanten SV. A meta-analysis of the success rate of Helicobacter pylori therapy in Canada. Can J Gastroenterol. 2007;21(5):295-300. doi:10.1155/2007/419784 (View)
13. Dore MP, Lu H, Graham DY. Role of bismuth in improving Helicobacter pylori eradication with triple therapy. Gut. 2016;65(6):870-878. doi:10.1136/gutjnl-2015-310084 (Request with CPSBC or view with UBC)
14. Best L, Cooper-Lesins G, Haldane D, Veldhuyzen van Zanten SJO. Helicobacter pylori antibiotic resistance in Canadian populations (abstr S1293). Gastroenterology. 2004;126:S1293. A-189 (View, pg 46)
15. van Zanten SV, Desai S, Best L, et al. Rescue therapy using a rifabutin-based regimen is effective for cure of Helicobacter pylori infection. Can J Gastroenterol. 2010;24(5):303-306. doi:10.1155/2010/637908 (View)
16. Graham DY, Canaan Y, Maher J, Wiener G, Hulten KG, Kalfus IN. Rifabutin-Based Triple Therapy (RHB-105) for Helicobacter pylori eradication: a double-blind, randomized, controlled trial. Ann Intern Med. 2020;172(12):795-802. doi:10.7326/M19-3734 (Request with CPSBC or view with UBC)
17. Buttenschoen J, D’Souza P, Veldhuyzen van Zanten S. Cumulative results of Helicobacter pylori therapy using sequential therapy, bismuth quadruple therapy, levofloxacin-based triple therapy, and other regimens. Can J Gastroenterol Hepatol. 2016;30(Suppl A):A-229. doi: 10.1155/2016/4792898 (View)
18. Krahn T, van Zanten S. A142 Trends in Helicobacter pylori treatment and cure in Edmonton: 2015-2020. J Can Assoc Gastroenterol. 2021;4:129-131 (View)
19. Graham DY, Tansel A. Interchangeable Use of proton pump inhibitors based on relative potency. Clin Gastroenterol Hepatol. 2018;16(6):800-808.e7. doi:10.1016/j.cgh.2017.09.033 (View)
20. Fernández-Salazar L, Campillo A, Rodrigo L, et al. Effectiveness and safety of high-dose dual therapy: results of the European registry on the management of Helicobacter pylori infection (Hp-EuReg). J Clin Med. 2022;11(12):3544. Published 2022 Jun 20. doi:10.3390/jcm11123544 (View)
21. Xia HX, Windle HJ, Marshall DG, Smyth CJ, Keane CT, O’Morain CA. Recrudescence of Helicobacter pylori after apparently successful eradication: novel application of randomly amplified polymorphic DNA fingerprinting. Gut. 1995;37(1):30-34. doi:10.1136/gut.37.1.30 (View)
22. Best LM, Haldane DJ, Bezanson GS, Veldhuyzen van Zanten SJ. Helicobacter pylori: primary susceptibility to clarithromycin in vitro in Nova Scotia. Can J Gastroenterol. 1997;11(4):298-300. doi:10.1155/1997/159637. (Request with CPSBC or view with UBC)
23. Fallone CA. Epidemiology of the antibiotic resistance of Helicobacter pylori in Canada. Can J Gastroenterol. 2000;14(10):879-882. doi:10.1155/2000/562159 (Request with CPSBC or view with UBC)
24. Morse AL, Goodman KJ, Munday R, et al. A randomized controlled trial comparing sequential with triple therapy for Helicobacter pylori in an Aboriginal community in the Canadian North [published correction appears in Can J Gastroenterol. 2014 Mar;28(3):167]. Can J Gastroenterol. 2013;27(12):701-706. doi:10.1155/2013/143047 (View)
25. Choi IJ, Kim CG, Lee JY, et al. Family History of gastric cancer and Helicobacter pylori treatment. N Engl J Med. 2020;382(5):427-436. doi:10.1056/NEJMoa1909666 (Request with CPSBC or view with UBC)
26. Gupta S, Li D, El Serag HB, et al. AGA Clinical Practice Guidelines on Management of Gastric Intestinal Metaplasia. Gastroenterology. 2020;158(3):693-702. doi:10.1053/j.gastro.2019.12.003 (View)
27. Chan FK, Chung SC, Suen BY, et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med. 2001;344(13):967-973. doi:10.1056/NEJM200103293441304 (View)
28. Chiba N, Van Zanten SJ, Sinclair P, Ferguson RA, Escobedo S, Grace E. Treating Helicobacter pylori infection in primary care patients with uninvestigated dyspepsia: the Canadian adult dyspepsia empiric treatment-Helicobacter pylori positive (CADET-Hp) randomised controlled trial. BMJ. 2002;324(7344):1012-1016. doi:10.1136/bmj.324.7344.1012 (View)
29. Moayyedi P, Delaney BC, Vakil N, Forman D, Talley NJ. The efficacy of proton pump inhibitors in nonulcer dyspepsia: a systematic review and economic analysis. Gastroenterology. 2004;127(5):1329-1337. doi:10.1053/j.gastro.2004.08.026 (Request with CPSBC or view with UBC)
30. Veldhuyzen van Zanten SJ, Flook N, Chiba N, et al. An evidence-based approach to the management of uninvestigated dyspepsia in the era of Helicobacter pylori. Canadian Dyspepsia Working Group. CMAJ. 2000;162(12 Suppl):S3-S23 (View)
31. Moayyedi P, Bardhan C, Young L, Dixon MF, Brown L, Axon AT. Helicobacter pylori eradication does not exacerbate reflux symptoms in gastroesophageal reflux disease. Gastroenterology. 2001;121(5):1120-1126. doi:10.1053/gast.2001.29332 (Request with CPSBC or view with UBC)
32. Canadian Cancer Statistics Advisory Committee in collaboration with the Canadian Cancer Society, Statistics Canada and the Public Health Agency of Canada. Canadian Cancer Statistics 2021. Toronto, ON: Canadian Cancer Society; 2021. Accessed July 31, 2023 (View)
33. Goodman KJ, Jacobson K, Veldhuyzen van Zanten S. Helicobacter pylori infection in Canadian and related Arctic Aboriginal populations. Can J Gastroenterol. 2008;22(3):289-295. doi:10.1155/2008/258610 (View)
34. Cheung J, Goodman K, Munday R, et al. Helicobacter pylori infection in Canada’s Arctic: searching for the solutions. Can J Gastroenterol. 2008;22(11):912-916. doi:10.1155/2008/614538 (View)
35. Colquhoun A, Hannah H, Corriveau A, et al. Gastric Cancer in Northern Canadian Populations: A focus on cardia and non-cardia subsites. Cancers (Basel). 2019;11(4):534. Published 2019 Apr 15. doi:10.3390/cancers11040534 (View)

PathwaysBC Resources

Helicobacter pylori associated duodenal/gastric ulcer: adult patient treatment recommendations. Bugs & Drugs. Accessed July 19, 2023. https://pathwaysbc.ca/ci/1886

Patient handouts for tests, emailable via PathwaysBC:

1. Patient instructions: Helicobacter pylori stool antigen test. LifeLabs. Accessed July 19, 2023. https://pathwaysbc.ca/ci/5953
2. Patient instructions: Helicobacter pylori urea breath test. LifeLabs. Accessed July 19, 2023. https://pathwaysbc.ca/ci/1977

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Management of Helicobacter pylori in 2023 who should be tested, treated, and how

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