A Malaysian consensus report on the diagnosis and treatment of Helicobacter pylori infection

Abstract

Helicobacter pylori is one of the most common chronic bacterial infections in humans and responsible for 90% of duodenal ulcers and 70–90% of gastric ulcers. Despite this, many misconceptions regarding the appropriate diagnostic method and treatment strategies still exist in the Malaysian clinical practice. Under the initiative of the steering committee, an expert panel consisting of nine key opinion leaders in the field of gastroenterology convened to develop a set of consensus statements that are relevant to the Malaysian healthcare practice. The panel members reviewed the current evidence on the management of H. pylori infection, focusing on the best practices that are relevant to the Malaysian population based on clinical experience and published clinical evidence. Using the modified Delphi method, the panel achieved consensus in three areas of H. pylori infection management: indications for testing, diagnosis, and treatment. The panel proposed a set of 19 consensus statements, which were synthesized via two rounds of blinded voting and group discussions. The recommendations provided are relevant to the Malaysian population and can be used as a guide by physicians across various healthcare settings to facilitate appropriate diagnostic testing and treatment of H. pylori infection.

The recommended first‐line therapy for H. pylori infection is a 2‐week standard triple therapy (STT) consisting of a proton pump inhibitor (PPI), clarithromycin, and amoxicillin. For patients with penicillin allergy, a PPI‐clarithromycin‐metronidazole combination therapy is the preferred first‐line treatment. For patients who have failed the 2‐week STT, the recommended rescue therapy is a 2‐week high‐dose dual therapy.

Introduction

Helicobacter pylori is one of the most common chronic bacterial infections in humans, affecting approximately 90% of patients with duodenal ulcers and about 80% of patients with gastric ulcers. ¹ , ² It is a Gram‐negative, flagellated, spiral bacteria commonly acquired through direct contact with an infected person or contaminated surface via the fecal–oral, oral–oral, and gastro–oral routes. ³ Since its discovery in 1982, the causes, pathogenesis, and treatment of peptic ulcer disease (PUD) have been rewritten and deemed as one of the most significant medical advances of the 20th century. ⁴ , ⁵ , ⁶

H. pylori infection presents a high healthcare burden. A study from the United States estimated the annual healthcare cost associated with gastroduodenal ulcers at approximately USD777 million in 2015. ⁷ Despite the availability of global guidelines on the management of H. pylori infection, clinical gaps still exist in Malaysia, particularly in the diagnosis and treatment of H. pylori infection. Although H. pylori is a well‐known pathogen, many misconceptions regarding the proper diagnosis and treatment of the infection still exist among medical practitioners and even gastroenterologists in Malaysia, leading to common mistakes made in routine clinical practice. Therefore, it is essential to develop a set of expert recommendations to guide physicians on the appropriate diagnostic testing and treatment strategies tailored to the local clinical practice.

Methods

Consensus development process

The steering committee of this consensus development comprised of Khean‐Lee Goh, Yeong Yeh Lee, Raja Affendi, and Alex HR Leow. Two areas were discussed: the diagnosis and treatment of H. pylori infection. An expert panel consisting of nine key opinion leaders in the field of gastroenterology were chosen from public, private, and university hospitals in Malaysia. The scope of the panel was to develop a set of consensus statements focusing on the diagnosis and treatment of H. pylori infection that are relevant to the Malaysian healthcare practice. A series of expert panel meetings were held online from June 2022 to July 2022.

The modified Delphi method was used in the development of this set of consensus statements. ⁸ The steering committee drafted the preliminary statements and further refined the statements after discussion with the expert panel. These preliminary statements along with their supporting evidence were circulated to all panel members for two rounds of voting. In the first round of voting, the panel members were tasked to convey their respective position on the drafted consensus statements anonymously through an electronic system. Each panel member was asked to rate the quality of the evidence, the strength of the recommendation, and their level of agreement. Panel members were allowed to propose minor amendments to the statements to ensure that they represent the actual clinical practice setting in Malaysia, and to comment on the supporting evidence provided. The steering committee perused the comments and revised the statements and supporting evidence accordingly.

The revised statements were then re‐circulated electronically for a final round of voting. The consensus agreement and voting results are presented. Panel members were asked to indicate one of the following levels of agreement: “Strongly agree”, “agree with minor reservation,” “agree with major reservation,” “disagree with minor reservation,” “disagree with major reservation,” and “strongly disagree.” For votes other than “strongly agree” or “agree with minor reservation,” panel members provided the reasons for their reservations or disagreement. A consensus was defined as a combined “strongly agree” and “agree with minor reservation” acceptance rate of ≥80.0%. Strength of recommendations and quality of evidence were evaluated based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system (Table 1). ⁹ For the statements where no recommendations were made, the grade of recommendation was deemed “not applicable.” The consensus statements derived and their respective levels of agreement are summarized in Table 2.

Table 1.

Categorization of quality of evidence, strength of recommendations, ⁹ and consensus agreement

Level/grade	Description
Quality of evidence
High	Further research is very unlikely to change our confidence in the estimate of effect
Moderate	Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low	Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low	Any estimate of effect is very uncertain
Strength of recommendations
Strong	When the desirable effects of an intervention clearly outweigh the undesirable effects, or clearly do not
Weak	When the trade‐offs are less certain—either because of low quality evidence or because evidence suggests that desirable and undesirable effects are closely balanced
Agreement for consensus †
1. Strongly agree 2. Agree with minor reservation 3. Agree with major reservation 4. Disagree with minor reservation 5. Disagree with major reservation 6. Strongly disagree

^† Consensus level was defined as ≥80.0% of the sum of the votes of “strongly agree” plus “agree with minor reservation”.

Table 2.

Summary and strength of consensus statements: Consensus agreement was achieved for all statements

Consensus statements	Strength
Section 1: Indications for testing
1. Patients with current or past gastric or duodenal ulcers should be tested for H. pylori infection	Strongly agree (100%), high‐quality evidence
2. Patients with uninvestigated dyspepsia should be tested for Helicobacter pylori infection	Strongly agree (88.90%); agree with minor reservation (11.10%), high‐quality evidence
3. Patients with gastric MALT lymphoma should be tested for H. pylori infection	Strongly agree (100%), high‐quality evidence
4. Individuals with family history of gastric cancer should be tested for H. pylori infection	Strongly agree (100%); high‐quality evidence
Section 2: Diagnosis
5. Patients undergoing gastroscopy should have biopsies taken for a RUT for the diagnosis of H. pylori	Strongly agree (88.89%); agree with minor reservation (11.11%); high‐quality evidence
6. Histological examination gives an accurate diagnosis of H. pylori infection	Strongly agree (66.67%); agree with minor reservation (33.33%), high‐quality evidence
7. Among noninvasive diagnostic tests, UBT gives a very accurate diagnosis	Strongly agree (100%), high‐quality evidence
8. Serological tests have limited diagnostic accuracy	Strongly agree (88.89%); agree with minor reservation (11.11%), high‐quality evidence
9. Apart from serology, all diagnostic tests must be performed when the patient is not taking antibiotics or PPIs for at least 2–4 weeks	Strongly agree (88.89%); agree with minor reservation (11.11%), high‐quality evidence
10. Patients with GIT bleeding frequently gives rise to a false‐negative biopsy test for H. pylori	Strongly agree (77.78%); agree with minor reservation (22.22%), high‐quality evidence
11. Serology cannot be used for testing for successful eradication	Strongly agree (100%), high‐quality evidence
12. Testing for eradication success should be carried out using UBT	Strongly agree (100%), high‐quality evidence
Section 3: Treatment
13. H. pylori infection should be treated when tested for and a positive result obtained	Strongly agree (100%), high‐quality evidence
14. The recommended first‐line therapy for H. pylori is a 2‐week STT consisting of a PPI, clarithromycin, and amoxicillin	Strongly agree (88.89%); agree with minor reservation (11.11%), high‐quality evidence
15. An alternative first‐line therapy is HDDT consisting of a PPI and amoxicillin for 2 weeks	Strongly agree (88.89%); agree with minor reservation (11.11%), moderate‐quality evidence
16. Treatment failures should not be re‐treated with the same first‐line regimen	Strongly agree (100%), high‐quality evidence
17. For patients who have failed STT for 2 weeks, the recommended rescue therapy is HDDT for 2 weeks	Strongly agree (66.67%); agree with minor reservation (22.22%); agree with major reservation 11.11%), moderate‐quality evidence
18. Testing for antibiotic susceptibility in treatment failures is recommended but not mandatory	Strongly agree (66.67%); agree with minor reservation (22.22%); agree with major reservation (11.11%), moderate‐quality evidence
19. Promising eradication regimen includes PCAB triple therapy or high‐dose PCAB dual therapy for 2 weeks	Strongly agree (88.89%); agree with minor reservation (11.11%), moderate‐quality evidence

GIT, gastrointestinal; HDDT, high‐dose dual therapy; MALT, mucosa‐associated lymphoid tissue; PCAB, potassium‐competitive acid blocker; PPI, proton pump inhibitor; RUT, rapid urease test; STT, standard triple therapy; UBT, urea breath test.

Consensus statements

Section 1: Indications for testing

Consensus question: Who should be tested for H. pylori infection?

 

Statement 1: Patients with current or past gastric or duodenal ulcers should be tested for H. pylori infection

Strength of recommendation: Strong

Evidence level: High

Consensus agreement: 100% (Strongly agree—100%)

H. pylori infection has been established as one of the key factors in the pathogenesis of PUD, as its eradication resulted in the permanent cure of PUD. ⁷ A systematic review of 52 clinical trials concluded that effective H. pylori eradication resulted in ulcer healing and prevention of recurrence, as well as its associated complications such as bleeding and perforation. ⁵ Successful H. pylori eradication resulted in the reduction of the yearly relapse rate of 80.0% for duodenal ulcer and of 60.0% for gastric ulcer to <5.0%. ⁵ Therefore, it is recommended that patients who currently have peptic ulcers—either gastric or duodenal—and those who have had them in the past should be tested for H. pylori infection so that they may receive the appropriate eradication therapy.

Statement 2: Patients with uninvestigated dyspepsia should be tested for H. pylori infection

Strength of recommendation: Strong.

Evidence level: High.

Consensus agreement: 100% (Strongly agree—88.90%; Agree with minor reservation—11.10%)

Dyspepsia is defined as predominant epigastric pain lasting at least 1 month, which can be accompanied by other upper gastrointestinal symptoms such as epigastric fullness, nausea, vomiting, or heartburn. ¹⁰ A meta‐analysis reported that uninvestigated dyspepsia affects 21.0% of the global population. ¹¹ According to the Rome III definition, H. pylori is one of the causes of dyspepsia in the absence of peptic ulcer. ¹² Successful eradication of H. pylori will significantly reduce the long‐term risk of developing either peptic ulcer or gastric cancer. ¹³ Therefore, the American College of Gastroenterology, the Canadian Association of Gastroenterology, and the Kyoto and Maastricht guidelines on dyspepsia unanimously have recommended the “test and treat” approach for patients with dyspepsia. ¹⁰ , ¹⁴ , ¹⁵ , ¹⁶

A study conducted by Mahadeva et al. investigating the cost effectiveness, safety, and patient satisfaction of the H. pylori “test and treat” strategy with prompt endoscopy in young Malaysian adults with uninvestigated dyspepsia showed that the prevalence of H. pylori ranged from 30.0% to 35.3%. The authors suggested that the H. pylori “test and treat” approach in this group of patients would be effective in treating dyspeptics with underlying PUD. ¹⁷

Statement 3: Patients with gastric mucosa‐associated lymphoid tissue (MALT) lymphoma should be tested for H. pylori infection

Strength of recommendation: Strong

Evidence level: High

Consensus agreement: 100% (Strongly agree—100%)

The accumulation of organized lymphoid tissue, which is a precursor to primary gastric lymphoma, has been shown to be etiologically associated with H. pylori infection. ¹⁸ H. pylori infection has been observed in approximately 90.0% of gastric MALT lymphoma cases, and in vitro studies have shown that tumor cells proliferate through T‐cell stimulation in the presence of H. pylori. ¹⁹

From a multicenter cohort follow‐up study in patients with gastric low‐grade MALT lymphoma (N = 420), H. pylori eradication resulted in complete remission in 77.0% of patients. ²⁰ Long‐term follow‐up of the cohort showed that disease relapse was seen in only 3.1% (10/323) of patients who responded to H. pylori eradication, while progressive disease was seen in 27.0% (27/97) of non‐responders during the follow‐up periods ranging from 3.0 to 14.6 years (median 6.04 years). ²¹

Clinical studies have shown that H. pylori eradication therapy leads to tumor regression and complete remission in 50.0%–90.0% cases; therefore, it is recommended that all patients with gastric MALT lymphoma be tested for H. pylori. ¹⁸ , ²⁰ , ²¹

Statement 4: Individuals with a family history of gastric cancer should be tested for H. pylori infection

Strength of recommendation: Strong

Evidence level: High

Consensus agreement: 100% (Strongly agree—100%)

First‐degree relatives of patients with gastric cancer have a 2‐ to 10‐fold increased risk of developing gastric cancer. ²² , ²³ A study by El‐Omar et al. has shown that relatives of patients with gastric cancer will have an increased prevalence of precancerous gastric abnormalities if they are infected with H. pylori. ²³ The authors also found that eradication of the infection led to resolution of gastric inflammation in all subjects and resolution of hypochlorhydria and atrophy in 50.0% of subjects. ²³ In a single‐center, double‐blinded, placebo‐controlled trial (N = 3100), subjects with H. pylori infection and who were first‐degree relatives of patients with gastric cancer had a reduced risk of gastric cancer if they received eradication therapy. ²⁴

Therefore, first‐degree relatives of patients with gastric cancer are potential candidates of the H. pylori “test and treat” approach, which has been shown to be more cost effective compared with prompt endoscopy. ²⁵

Section 2: Diagnosis

Consensus question: What are the best tests for the diagnosis of H. pylori?

 

Statement 5: Patients undergoing gastroscopy should have biopsies taken for a rapid urease test (RUT) for the diagnosis of H. pylori

Strength of recommendation: Strong

Evidence level: High

Consensus agreement: 100% (Strongly agree—88.89%; Agree with minor reservation—11.11%)

RUT is an easy‐to‐use, quick, and inexpensive test that indirectly shows the presence of H. pylori by detecting urease in the gastric mucosa. ²⁶ It is the most commonly used test for the diagnosis of H. pylori infection in routine upper endoscopy practice. ²⁶ , ²⁷ , ²⁸ It is especially helpful in cases where the physician would like to initiate a treatment regimen promptly. ²⁶ The expert panel opined that two biopsies taken from both the antrum and from normal‐appearing corpus can provide the best result for RUT.

A study conducted by Goh et al. on endoscopic biopsies (N = 274) showed that RUT had high sensitivity (96.6%), high specificity (99.2%), high positive predictive value (99.3%), and high negative predictive value (96.2%). ²⁸

In a study comparing the accuracy and reaction time of the CLO test (Ballard Medical Products, Draper, Utah, USA) and the Pronto Dry test (Medical Instruments Corporation, Solothurn, Switzerland), both were highly accurate for the diagnosis of H. pylori infection and were completely concordant with sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of 98.1%, 100%, 100%, 98.1%, and 99.0%, respectively. ²⁶

Statement 6: Histological examination gives an accurate diagnosis of H. pylori infection

Strength of recommendation: Not applicable

Evidence level: High

Consensus agreement: 100% (Strongly agree—66.67%; Agree with minor reservation—33.33%)

Histology plays a significant role in the detection of H. pylori and offers more information about the degree of inflammation and associated pathology, such as atrophic gastritis, intestinal metaplasia, and gastric cancer. ²⁹

Among the various diagnostic tests available for H. pylori detection, histological examination of gastric biopsy is considered the most accurate. ²⁷ , ³⁰ In a study comparing the performance of established diagnostic tests, histology demonstrated the highest sensitivity (99.3%), followed by RUT (96.6%), Gram stain (92.5%), and culture (80.8%). ²⁸ To guarantee maximum diagnostic yield, it is recommended to obtain at least two biopsy specimens from both the antrum and the corpus. ³¹

Owing to some of its limitations, such as incurring additional costs, having a longer turnaround time, and requiring well‐trained personnel to conduct, histological examination is usually reserved for patients who tested negative using the RUT or when histology is required to rule out malignancy. ²⁷ , ²⁹

Statement 7: Among noninvasive diagnostic tests, the urea breath test (UBT) gives a very accurate diagnosis

Strength of recommendation: Not applicable

Evidence level: High

Consensus agreement: 100% (Strongly agree—100%)

Noninvasive diagnostic tests comprise serology; detection of labeled metabolic products of urea hydrolysis in the breath, urine, or, blood; and the detection of antigen in the stool. ³² It does not require an endoscopy, making them more affordable and convenient compared with invasive methods. Because of this, noninvasive diagnostic techniques are preferred in cases where additional information via endoscopy is not required. ³³

Of the myriads of noninvasive diagnostic tests, UBT is useful for diagnosing current H. pylori infection and can be used for follow‐up after treatment. It can be easily performed when repeated tests are required. ³⁴ The expert panel opined that a multiple‐point UBT assessment is preferred over a single‐point test in clinical practice. UBT has been shown to be one of the most accurate methods for assessing the H. pylori status. ³⁴ , ³⁵ , ³⁶ In a study investigating the efficacy of the ¹⁴C UBT, the test showed a sensitivity and specificity of 100.0%. ¹⁴C UBT could clearly distinguish between H. pylori‐positive and ‐negative samples. ³⁴

Statement 8: Serological tests have limited diagnostic accuracy

Strength of recommendation: Not applicable

Evidence level: High

Consensus agreement: 100% (Strongly agree—88.89%; Agree with minor reservation—11.11%)

Serological tests are cheap and convenient, but they vary greatly in accuracy. ³⁷ One of the limitations associated with the use of serology is that no single H. pylori antigen is recognized by sera from all subjects, and thus antigen reagent preparations should contain multiple strains of H. pylori. ³⁸ Besides that, it is difficult to define a cut‐off value that distinguishes between positive and negative subjects. ³ , ³⁷ Different cut‐off values are recommended in children, as they seem to mount a different antibody response to H. pylori infection as compared to adults. ³⁹ Among individuals aged >50 years, serology results tend to be more inconsistent. ⁴⁰ H. pylori strains vary antigenically between countries, and therefore any serological tests will need to be locally validated before they are used clinically. ³⁷

Statement 9: Apart from serology, all diagnostic tests must only be performed when the patient is not taking antibiotics or proton pump inhibitors (PPIs) for at least 2–4 weeks

Strength of recommendation: Strong

Evidence level: High

Consensus agreement: 100% (Strongly agree—88.89%; Agree with minor reservation—11.11%)

The accuracy of diagnostic tests such as culture, histology, RUT, UBT, and stool antigen tests is highly dependent on the intragastric bacterial load. ²⁷ , ⁴¹ Treatments such as antimicrobials (e.g., antibiotics or bismuth) or PPIs that reduce H. pylori load, such that the infection is undetectable, may lead to false‐negative results. ²⁶ , ²⁷ , ⁴¹

As it takes time for the residual bacteria to recover and repopulate the stomach, it is recommended that diagnostic tests or post‐treatment testing be delayed by at least 2 weeks if the patient was taking PPIs ²⁶ , ⁴² and at least by 4 weeks if the patient was on antibiotics to ensure that the results are reliable. ³⁷ , ⁴¹ , ⁴² , ⁴³ On the other hand, serological tests are unaffected by the use of antibiotics or proton pump inhibitors (PPIs); however, it cannot be used in post‐treatment testing, as the antibody levels can persist in the serum for a long time after successful eradication. ⁴⁴

Statement 10: Gastrointestinal (GIT) bleeding frequently gives rise to a false‐negative biopsy test for H. pylori

Strength of recommendation: Not applicable

Evidence level: High

Consensus agreement: 100% (Strongly agree—77.78%; Agree with minor reservation—22.22%)

GIT bleeding is associated with significant morbidity and mortality, with PUD being the most frequent cause. ³² , ⁴⁵ Studies have reported a lower prevalence of H. pylori infection among patients with GIT bleeding, but it has been noted that these studies may have used invasive methods of diagnosis to assess the H. pylori status. ⁴⁶

A systematic review and a meta‐analysis of the diagnostic accuracy of various tests that aimed to detect H. pylori infection in patients with bleeding PUD concluded that invasive (biopsy‐based) methods, such as RUT, histology, and culture, have low sensitivity in patients with this complication and give rise to false‐negative results. ⁴⁵ It has been hypothesized that the presence of albumin in the blood leads to decreased sensitivity of RUT. ⁴⁷

As fasting is necessary in patients with acute GIT bleeding, UBT may not always be feasible, as patients are required to drink a urea‐containing solution (and sometimes a citric acid solution). Furthermore, hospitalized patients with GIT bleeding are frequently treated with PPIs, which may result in false‐negative UBT results. However, low‐dose, capsulated ¹³C UBT has been shown to accurately diagnose H. pylori infection and it is useful in patients with GIT bleeding since only a small sip of water is required to facilitate the digestion of the capsule. ⁴⁵

Serology is the only diagnostic test that is unaffected by the local changes in the stomach such as acute bleeding or low bacterial load. As such, its use is recommended in this group of patients, as well as to confirm the results of other diagnostic methods. ⁴⁸ , ⁴⁹ However, owing to the emergent situation during a GIT bleed, it may not be a practical test. Furthermore, results are not immediately available.

Statement 11: Serology cannot be used for testing for successful eradication

Strength of recommendation: Strong

Evidence level: High

Consensus agreement: 100% (Strongly agree—100%)

Even though antibody titres may decrease after successful H. pylori eradication, the decline is variable and serum antibodies can persist for a long period. ³⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁵¹ Qualitative tests can remain positive for up to 3 years, and quantitative tests do not show a significant decline in antibody levels for 6–12 months after successful treatment. ⁴⁸ Therefore, serological tests cannot be considered reliable or clinically useful since antibody titres may never fall low enough to be considered “negative.” ³³ , ⁴¹ Owing to this reason and other limitations associated with serological testing as highlighted in Statement 8, serology should not be used to test for eradication success.

Statement 12: Testing for eradication success should be carried out using the UBT

Strength of recommendation: Strong

Evidence level: High

Consensus agreement: 100% (Strongly agree—100%)

Noninvasive tests should be used to confirm H. pylori eradication except in cases where repeat endoscopy is indicated (e.g., patients with gastric ulcer). ⁵² UBT is a convenient and robust test that shows the presence or absence of a current infection with high accuracy. ³² , ³³ , ³⁵ , ⁵² When it is used 4 weeks after eradication therapy, UBT shows equivalent or even better accuracy as compared with biopsy‐based tests. ³⁷ Therefore, it is the preferred method to assess the success of H. pylori eradication. ³⁴

Section 3: Treatment

Consensus question: Who should be treated for H. pylori infection?

 

Statement 13: H. pylori infection should be treated when tested for and a positive result obtained

Strength of recommendation: Strong

Evidence level: High

Consensus agreement: 100% (Strongly agree—100%)

H. pylori infection is a disease of the gastric mucosa that can cause progressive gastric atrophy and impaired acid secretion. ²² , ⁵³ , ⁵⁴ The bacterium is a major gastric carcinogen that causes unrelenting, lifelong inflammation, producing genotoxic molecules such as reactive oxygen and reactive nitrogen intermediates and resulting in both oxidative damage and nitrosation of DNA bases. ²² H. pylori infection is transmittable, with the infection mainly clustering in families with children. ⁵⁴ Patients with PUD can experience pain, have reduced quality of life, and an increased risk of mortality and suffer the risk of ulcer complications, such as GIT bleeding. PUD also incurs a significant amount of economic burden due to the cost of drugs, doctor visits, tests, and lost time from work. ⁵⁴ Although no convincing evidence exists to suggest that eradicating H. pylori improves the symptoms of non­ulcer dyspepsia, testing for the infection should still become part of the routine investigation of dyspeptic patients, as treatment can prevent significant burden of disease and mortality. ⁵⁵ , ⁵⁶

Statement 14: The recommended first‐line therapy for H. pylori infection is a 2‐week standard triple therapy (STT) consisting of a PPI, clarithromycin, and amoxicillin

Strength of recommendation: Strong.

Evidence level: High

Consensus agreement: 100% (Strongly agree—88.89%; Agree with minor reservation—11.11%)

In the late 1990s, the 1‐week STT comprising a PPI, amoxicillin, and clarithromycin was widely adopted as a the first‐line eradication therapy for H. pylori infection throughout the globe, as it was found to be highly efficacious, well tolerated, and associated with high patient compliance. ⁵⁷ , ⁵⁸ , ⁵⁹ , ⁶⁰ The regimen was recommended for the eradication of H. pylori infection in Asia and Malaysia in 1998. ⁵⁷ , ⁶¹ , ⁶²

Leow et al. investigated the efficacy of a 14‐day STT regimen (rabeprazole 20 mg BD, amoxicillin 1 g BD, and clarithromycin 500 mg BD) versus that of the same 1‐week STT regimen with an added bismuth compound. The intention‐to‐treat analysis showed that adding bismuth to the 7‐day STT did not result in an increased eradication rate. However, extending the STT to 14 days resulted in significantly higher eradication rate (88.6%) compared with 7‐day STT (79.3%). ⁵⁸

In an earlier study, Qua et al. demonstrated the low intention‐to‐treat eradication rate of the 1‐week STT regimen (71.2%) ⁵⁷ even though resistance rates to clarithromycin across several studies have been consistently low. Based on a systematic review by Yuan et al., extending the treatment duration of a PPI‐based triple therapy to 14 days has been shown to achieve higher eradications rates. ⁶³ Collectively, results from the studies by Leow et al. and Yuan et al. show that the 2‐week STT regimen offers consistently high eradication rates.

Resistance rates towards clarithromycin are low in Malaysia ⁶⁴ ; recent findings from two single‐center studies in Malaysia have shown that the primary resistance rate to clarithromycin was approximately 12%–15%. ⁶⁵ , ⁶⁶ However, we have to be cognizant that the resistance patterns to antibiotics, may be changing. Owing to the increasing use of antibiotics, a growing body of evidence has reported a rapid increase in clarithromycin‐resistant H. pylori strains throughout the world, resulting in lower rates of H. pylori eradication. ⁶⁷ , ⁶⁸ , ⁶⁹ Results from meta‐analyses and systematic reviews have shown that the majority of clarithromycin‐based triple therapy failed to reach an intention‐to‐treat eradication rate of 80.0%. ⁷⁰ There is also evidence showing that resisance to clarithromycin, fluoroquinolone, and multiple other drugs is emerging in our region. ⁶⁵ , ⁶⁶ , ⁷¹ , ⁷²

Therefore, continued monitoring of the antimicrobial resistance of key antibiotics, especially clarithromycin, is important. Like with the management of all other infectious diseases, experts have recommended that susceptibility testing for H. pylori should be carried out before treatment, at least for clarithromycin. Empirical therapy should only be used if proven to be highly effective locally. ⁷³

For patients with penicillin allergy, a PPI–clarithromycin–metronidazole combination therapy is the preferred first‐line treatment. Bismuth quadruple therapy, comprising a PPI, bismuth, tetracycline, and metronidazole, also is as an effective alternative first‐line therapy, especially in areas with high clarithromycin resistance ¹⁴ , ¹⁵ ; however, bismuth compounds are not easily available in Malaysia and they have not been tested in our population. Nevertheless, most patients presenting with a history of penicillin allergy do not have true immune‐mediated reactions; therefore, patients who fail first‐line therapy should be considered for allergy testing so that amoxicillin‐containing salvage regimens can be safely prescribed once true allergy is ruled out. ¹⁵

Statement 15: An alternative first‐line therapy is a 2‐week high‐dose dual therapy (HDDT) consisting of a PPI and amoxicillin

Strength of recommendation: Strong

Evidence level: Moderate

Consensus agreement: 100% (Strongly agree—88.89%; Agree with minor reservation—11.11%)

Clarithromycin resistance rates is steadily increasing in Malaysia and this poses a significant threat to the treatment of H. pylori infection. An alternative first‐line therapy in place of clarithromycin is needed. ⁷¹ , ⁷⁴

In the HDDT regimen, PPIs are given in multiple doses, and this has been shown to achieve potent acid suppression and sustained levels of high intragastric pH, even during night‐time. ⁷⁵ Increasing intragastric pH to ≥6 also increases the sensitivity of H. pylori to amoxicillin. ⁷⁶ Additionally, amoxicillin is also given in multiple doses, which ensures a stable level of amoxicillin above the minimum inhibitory concentration. ⁷⁶

In Taiwan, a large‐scale, multi‐hospital trial that compared the efficacy of a HDDT with that of standard therapies revealed in the intention‐to‐treat analysis that H. pylori was eradicated in 95.3% of patients in the HDDT group. This rate was significantly higher compared with the sequential therapy group and the STT group. ⁷⁷ A study by Leow et al. confirmed that HDDT resulted in a high eradication rate (92.8%) comparable to that of the 2‐week STT regimen (86.2%) among Malaysian patients on intention‐to‐treat analysis. ⁷⁴ The treatment algorithm for the eradication of H. pylori infection is summarized in Figure 1.

Figure 1.

Proposed algorithm for the selection of Helicobacter pylori eradication regimen. HDDT, high‐dose dual therapy; PPI, proton pump inhibitor; STT, standard triple therapy; UBT, urea breath test.

 

Statement 16: Treatment failures should not be re‐treated with the same first‐line regimen

Strength of recommendation: Strong

Evidence level: High

Consensus agreement: 100% (Strongly agree—100%)

Failure to achieve eradication is usually attributed to poor patient compliance, resistant strains of H. pylori, low intragastric pH, or a high bacterial load. Because of these factors, the minimum inhibitory concentration and/or the sufficient time required to kill the bacteria was not attained. ⁷⁸

Although clarithromycin is highly efficacious against H. pylori, resistant strains emerge in the case of first‐line therapy failure. ⁷⁸ In a retrospective comparative study, patients who had received the same regimen after failure of first‐line STT with clarithromycin exhibited an eradication rate of only 52.9%, whereas patients who were administered STT with metronidazole achieved an eradication rate of 81.3% by intention‐to‐treat analysis. The study further verifies that antibiotics, especially clarithromycin, should not be consecutively administered as second‐line treatment. ⁷⁹

Statement 17: For patients who have failed the 2‐week STT, the recommended rescue therapy is a 2‐week HDDT

Strength of recommendation: Strong

Evidence level: Moderate

Consensus agreement: 88.89% (Strongly agree—66.67%; Agree with minor reservation—22.22%; Agree with major reservation 11.11%)

HDDT overcomes the issue of clarithromycin resistance, as there is no known cases of H. pylori resistance to amoxicillin in Malaysia to date. ⁶⁴ , ⁷⁴ As elucidated in Statement 15, HDDT has been shown to be highly efficacious, achieving an eradication rate of 92.8% when used locally in the treatment of H. pylori infection. ⁷⁴

Goh et al. found that when HDDT was used as rescue therapy in patients with previous treatment failure, the eradication rate was 89.2% in the intention‐to‐treat analysis. ⁸⁰ Meta‐analyses that aimed to assess the efficacy and tolerability of HDDT as rescue therapy for H. pylori eradication showed that HDDT was comparable to other recommended rescue regimens with fewer side effects. ⁸¹ , ⁸²

A 3‐year, single‐center, prospective, open‐labeled study found that PPI–amoxicillin–levofloxacin triple therapy can be used as rescue therapy in the case of treatment failures. ⁸³ However, the authors caution the rapid emergence of levofloxacin resistance and recommend to reserve its use for second‐line rescue therapy. ⁸³

Other rescue therapies such as bismuth quadruple therapy, ⁸⁴ sequential regimen followed by levofloxacin‐based triple regimen, ⁸⁵ and reverse hybrid therapy ⁸⁶ have shown promising results but they have not been tested in the Malaysian setting and may require further validation. Furthermore, these treatment regimens are complex and are difficult for patients to adhere to.

Statement 18: Testing for antibiotic susceptibility in treatment failures is recommended but not mandatory

Strength of recommendation: Strong

Evidence level: Moderate

Consensus agreement: 88.89% (Strongly agree—66.67%; Agree with minor reservation—22.22%; Agree with major reservation 11.11%)

Antibiotic susceptibility is vital to the success of H. pylori eradication, and therefore nowadays routine susceptibility testing is recommended before treatment initiation. ⁸⁷ However, the use of culture and when to use it have been a subject of debate because H. pylori culture is not always accessible on a routine basis and requires the use of endoscopy. ⁸⁸ Furthermore, the success of culture is low even in specialized laboratories. ⁶⁶ Some studies have suggested that antibiotic susceptibility should be tested only after failure of the second treatment attempt or when resistance is suspected. ⁸⁹ , ⁹⁰

Molecular techniques for detecting resistance to antibiotics offer an attractive alternative to conventional susceptibility testing, as they are more robust and they do not require stringent transport or laboratory requirements for the primary culture of the bacterium. ⁶⁶ , ⁷¹ , ⁷² A molecular approach involving a stool polymerase chain reaction test is a noninvasive, quick, and convenient way to detect H. pylori antimicrobial resistance. ⁸⁷ However, the use of molecular techniques is limited by their lack of accessibility, as only very few laboratories provide them as a clinical service in Malaysia.

Statement 19: Promising eradication regimens include a 2‐week potassium‐competitive acid blocker (PCAB) triple therapy or a 2‐week high‐dose PCAB dual therapy

Strength of recommendation: Not applicable

Evidence level: Moderate

Consensus agreement: 100% (Strongly agree—88.89%; Agree with minor reservation—11.11%)

PCAB is a new class of gastric acid suppressing agents that have been proven to be efficacious for the eradication of H. pylori infection. In a randomized, double‐blinded, multicenter, parallel‐group study, the PCAB vonoprazan 20 mg was found to be non‐inferior to lansoprazole 30 mg as part of first‐line triple therapy with amoxicillin 750 mg and clarithromycin 200 or 400 mg (eradication rate: 92.6%) and as part of second‐line triple therapy with amoxicillin 750 mg and metronidazole 250 mg (eradication rate: 98.0%) in H. pylori‐positive patients with a history of gastric or duodenal ulcer. ⁹¹

A randomized, open‐label, two‐period, cross‐over study evaluating the acid‐inhibitory effects of PCAB (vonoprazan 20 mg) and two PPIs (esomeprazole 20 mg and rabeprazole 10 mg) found that the acid‐inhibitory effect of vonoprazan was significantly greater than that of esomeprazole or rabeprazole. ⁹²

In a prospective, randomized, open‐label comparative study, Khoo et al. found that PCAB triple therapy with vonoprazan, amoxicillin, and clarithromycin for 1 week showed comparable efficacy to PCAB triple therapy for 2 weeks and PCAB dual therapy with high‐dose amoxicillin for 2 weeks and was well tolerated. ⁹³

In a randomized, controlled trial of treatment‐naïve patients with H. pylori infection, an eradication rate of 87.4% for H. pylori was achieved using 1‐week vonoprazan‐based triple therapy. ⁹⁴ A phase III clinical trial conducted among patients in the United States and Europe who had H. pylori infection showed that vonoprazan triple therapy (vonoprazan 20 mg, amoxicillin 1 g, and clarithromycin 500 mg) and vonoprazan dual therapy (vonoprazan 20 mg BD and amoxicillin 1 g TDS) for 2 weeks were efficient in eradicating H. pylori infection with an eradication rate of 84.7% and 78.5%, respectively. ⁹⁵

Conclusion

The 19 evidence‐based consensus statements developed by the expert panel focused on the appropriate diagnosis and treatment strategies for the eradication H. pylori infection. The recommendations provided are relevant to the Malaysian population and can be used as a guide by physicians across various healthcare settings to facilitate appropriate diagnostic testing and treatment of H. pylori infection.