Helicobacter pylori has been recognized as a major pathogen of humankind for nearly 4 decades. However, despite the impact of treatment of infected individuals and the reduced transmission of infection in communities where socioeconomic living standards have improved, it remains the most common human bacterial pathogen, infecting perhaps half the population of the world.1 As a result, it remains a major cause of morbidity and mortality worldwide.
H. pylori infection invariably causes active chronic gastritis. In most people, this may be clinically silent throughout life, but in a substantial minority, it causes gastroduodenal diseases, most importantly peptic ulcer disease and noncardia gastric cancer and gastric mucosa-associated lymphoid (MALT) lymphoma. It also increases the risk of gastroduodenal ulceration and bleeding in patients taking nonsteroidal antiinflammatory drugs (NSAIDs) and aspirin and is responsible for symptoms in a subset of patients with functional dyspepsia.
H. pylori has been studied intensively. A literature search reveals more than 45,000 publications. A great deal has been learned about the epidemiology of infection, biology, genetics, pathophysiology, disease expression, diagnosis, and treatment. Yet major challenges to our knowledge remain. The precise mode of transmission of infection remains unclear, despite many epidemiological studies that identify risk factors for infection. The determinants of disease expression remain incompletely understood, including many aspects of the host-pathogen interaction. The pathophysiology of this interaction is complex and has been reviewed in detail elsewhere.2,3 The optimal clinical management pathways in different settings remain debated, and refinements in diagnostic modalities continue to be sought. The quest for the most effective, safe, and simple therapy remains the major issue for clinicians, and the problem of antimicrobial resistance to therapy is a major challenge. Optimal surveillance of adverse histologic gastric mucosal changes has not been determined, and the quest for an effective vaccine is ongoing.
There are many reviews and clinical guidelines about H. pylori.4–12 As the field rapidly changes, there is a need for periodic updating and revision of these position papers. Moreover, a major challenge for guidelines is to be relevant across a wide variety of populations with a varying spectrum of diseases and often vastly different resources with which to deal with this. Guidelines not infrequently proffer discordant advice. This is not surprising, as local factors are central to determining the impact and management strategies for H. pylori infection. However, in many places where the impact of H. pylori infection is greatest, there is a lack of high-quality data to determine local best practices. Addressing this knowledge gap is a major challenge. Until that is done, decisions must be based on the best available local evidence, extrapolation from higher quality data from elsewhere and on expert opinion.
The purpose of this update to the WGO guideline is to summarize and update the evidence from a number of the new guidelines that outline best practice and to suggest how these principles may be applied around the world using the “cascades” approach. This approach recognizes the variation in the regional prevalence and impact of infection and the vast differences in health resources available to address the problem necessitating a pragmatic, tailored local approach. The burden of disease wrought by H. pylori falls disproportionally on less well-resourced regions that are less well represented in epidemiological surveys and often not the focus of clinical guidelines.
Key Statement
A major challenge for guidelines is to be relevant across a wide variety of populations with a varying spectrum of diseases and vastly different resources with which to deal with this.
NATURAL HISTORY, TRANSMISSION, AND EPIDEMIOLOGY—GLOBAL ASPECTS
Natural History of Infection
H. pylori infection usually persists for life unless treated with antibiotics or auto eradication occurs when a longstanding infection causes widespread gastric mucosal atrophy and metaplasia with achlorhydria. Transient infection may occur in some infants. Reinfection after treatment in adults is uncommon in both higher and lower prevalence regions. Reinfection may be confused with recrudescence, when the infection is suppressed transiently, below the threshold of detection by tests, but not eradicated by antibiotics. There are variations in the virulence of different H. pylori strains globally. The interplay between host and environmental factors may result in differences in the expression of disease.
Transmission of Infection
Although there are well-described risk factors for infection and plausible hypotheses, the precise mode of transmission is not known definitively. Most infection appears to occur in early childhood, with a minority of cases being acquired by adults. There is strong evidence from epidemiology and genetic studies of person-to-person transmission, particularly within families. Mothers appear to be particularly important in transmission to their young children. Ingestion of the organism seems most plausible through the gastro-oral or oral-oral route. Fecal-oral transmission appears less likely, at least in developed countries. Transmission through water, food, household pets, or flies remains speculative.
Epidemiology
Although half of the world’s population is thought to be infected with H. pylori, there is widespread variation in the prevalence of infection between and within countries (Fig. 1). Furthermore, the prevalence may vary within a single city and between subgroups within a population (Fig. 2).13 For example, there may be wide variations in the prevalence between more affluent urban populations and rural populations.
;)
FIGURE 1: Global prevalence of
Helicobacter pylori. From Hooi et al.
1Prevalence of
Helicobacter pylori among children in Kuala Lumpur, Malaysia. From Goh.
13The quality of prevalence data varies. Many studies are not true prevalence studies but rather audits of clinical subsets. Other studies may not represent a valid cross-section of the populace. Moreover, there is significant variability in the quality of reports. In some regions, diagnostic methods may be less reliable, while some countries are poorly represented as they lack any reliable data at all. For all these reasons, a single figure cannot be taken to summarize and represent the prevalence of infection in an entire country and must be applied with caution. For example, a prevalence study from 1 city from 1 region of a populous multiethnic country with wide variation in socioeconomic standards is unlikely to represent the true prevalence across the entire country and cannot reflect high-risk and low-risk subsets. However, countries and regions can usually be characterized as high, mid, and low prevalence locations.1
The major determinant of the prevalence of infection is socioeconomic status in childhood. Socioeconomic factors reflect levels of hygiene, sanitation, density of living, and educational level.
A strong inverse relationship has been shown consistently. Thus, as expected, the prevalence of infection is generally higher in developing countries and almost ubiquitous in some of the most resource-poor subsets of these populations. Migrants from such regions are recognized as a high-risk group in more developed, low-prevalence countries.
Key Statement
The major determinant of the prevalence of infection is socioeconomic status in childhood.
The prevalence of H. pylori infection increases with age. This is mostly due to the cohort effect, whereby the risk of acquiring infection was greatest during the childhood of those born longer ago compared with more recently, rather than reflecting ongoing adult acquisition. Ethnicity has been described as a risk factor but is most likely closely correlated with socioeconomic status or practices that may increase the risk of transmission rather than having a genetic basis.
A striking observation has been the change in the prevalence of infection over time in some countries. Reports of rapidly falling infection rates, most marked in children and younger adults, are common in developed countries and in countries that have undergone rapid economic development that have led to raised socioeconomic standards. In these countries, the prevalence of infection is now low.
A gradual fall in the prevalence of peptic ulcer disease and noncardia gastric cancer is predicted by this observation as, in general, the prevalence of peptic ulcer disease and gastric cancer reflects the prevalence of H. pylori in a population. Indeed, the prevalence of ulcer disease and gastric cancer has been falling for decades in developed countries. The fall in disease expression lags for many years behind the fall in infection rates. This declining prevalence of infection and disease occurred long before H. pylori was recognized and treatment developed.
As with most endemic infectious diseases, a fall in prevalence has more to do with improvements in population hygiene and sanitation than individual case-by-case treatment, as in most countries, only a minority of infected subjects will ever receive therapy. Notable exceptions are well-resourced high-prevalence countries, such as Japan, where screening and treatment are now done systematically in early adulthood. The prevalence of infection appears stable in countries where standards have not improved or deteriorated and are unlikely to fall substantially until improvements do occur. Peptic ulcer disease remains rampant in many of these countries. The burden of gastric cancer falls disproportionality on these populations also.
Key Statement
As with most endemic infectious diseases, a fall in prevalence has more to do with improvements in population hygiene and sanitation than individual case-by-case treatment, as in most countries, only a minority of infected subjects will ever receive therapy.
THE IMPACT OF H. PYLORI INFECTION AND THE EFFECT OF ERADICATION
H. Pylori and Peptic Ulcer Disease
The recognition that H. pylori was the cause of most duodenal and about two-thirds of gastric ulcers was a seminal, Nobel Prize-winning medical breakthrough.14 In many developed countries with decreasing prevalence of infection and cure of ulcer patients, the proportion of all peptic ulcers due to H. pylori is falling. In less developed countries, where the prevalence of infection remains high and fewer ulcer sufferers receive curative treatment, peptic ulcer disease continues to be a very common and important disease. H. pylori infection has been estimated to confer an individual lifetime risk of peptic ulcer disease of 15% to 20%. Untreated peptic ulcer disease is a chronic relapsing and remitting disease that causes major mortality and morbidity from pain, bleeding, and perforation, as well as economic loss. Eradication of H. pylori heals most active peptic ulcers and prevents further relapse, thus effecting a cure. Eradication of H. pylori with a past history of ulcer disease prevents subsequent relapses.
NSAIDs and aspirin cause most other peptic ulcers. H. pylori and NSAIDs act synergistically to increase the risk of ulcers and bleeding. Eradication of H. pylori reduces this risk before commencing chronic NSAID therapy.
H. pylori and Gastric Cancer and MALT Lymphoma
In susceptible infected hosts, longstanding active chronic gastritis may result in gastric mucosal atrophy with intestinal metaplasia. In the minority, these premalignant mucosal changes progress to dysplasia and clinically silent, early cancer, then advanced gastric cancer. Gastric cancer often presents at an advanced, symptomatic stage and has a generally poor prognosis. H. pylori has been estimated to confer an individual lifetime risk of gastric cancer of 1.5% to 2% in infected individuals. Despite the relatively low individual risk, as the global number of people infected is estimated in the billions, there is a global burden of gastric cancer of over 1 million per year with a high fatality rate (Table 1).15 This burden is not distributed evenly. East Asia- Japan, Korea, and eastern China, has the highest prevalence of the disease. China bears 40% of the world’s gastric cancer. Most, but not all, gastric cancers are H. pylori-related. The risk of progression to gastric cancer varies and is related to host and pathogen factors. Host cofactors include smoking and diet. High salt intake, the consumption of pickled foods, and diets low in antioxidants are dietary cofactors. Host genetic risk factors associated with increased risk include the presence of polymorphisms in genes that determine the expression of IL-1 (proinflammatory cytokines) and pathogen recognition receptors. Genotyping strains of H. pylori reveal differences in virulence factors that promote inflammation that is associated with an increased risk of cancer.
TABLE 1 -
Global Burden of Cancer
| Most common cancers globally |
Most common causes of cancer deaths are cancers of |
| Lung (2.09 million cases) |
Lung (1.76 million deaths) |
| Breast (2.09 million cases) |
Colorectal (862, 000 deaths) |
| Colorectal (1.80 million cases) |
Stomach (783,000 deaths) |
| Prostate (1.28 million cases) |
Liver (782,000 deaths) |
| Skin cancer (nonmelanoma) (1.04 million cases) |
Breast (627,000 deaths) |
| Stomach (1.03 million cases) |
— |
Eradication of H. pylori, before the occurrence of adverse, precancerous histologic changes has been shown to prevent gastric cancer and is the rationale for mass test-and-treat screening programs in young adults in countries with a high burden of disease and sufficient resources to devote to this endeavor. In less well-resourced regions with a high burden of gastric cancer, such a strategy remains aspirational rather than feasible, given cost constraints, logistical difficulties, and competing health care needs.
Eradicating H. pylori after mucosal atrophy and/or intestinal metaplasia are present may reduce but not abolish the risk of gastric cancer.16 In any individual, the residual risk will relate to the extent and severity of the mucosal changes as well as other host risk factors. Endoscopic surveillance of intestinal metaplasia may be appropriate in some settings.
Gastric MALT lymphoma is rare. Most cases are a consequence of H. pylori infection, and the eradication of H. pylori when the lymphoma is at low-grade stage results in regression and cure. Late recurrences after eradication have been reported occasionally.
Key Statement
Eradication of H. pylori before the occurrence of adverse, precancerous histologic changes has been shown to prevent gastric cancer and is the rationale for mass test-and-treat screening programs in young adults in countries with a high burden of disease and sufficient resources to devote to this endeavor.
H. Pylori-Associated Dyspepsia
Most H. pylori gastritis is asymptomatic, but it is commonly associated with upper gut symptoms in the absence of ulcer disease. However, only about a third or less of infected patients with “functional dyspepsia” will have sustained relief of symptoms after eradication therapy. This is because functional dyspepsia is a heterogeneous condition that may be caused by different mechanisms. H. pylori may be causal in some patients with symptoms and be present incidentally in others. However, the proportion of infected patients who improve after eradication therapy is greater than those given empirical acid suppressive therapy. Furthermore, patients may benefit from a reduced lifetime risk of ulcer disease and cancer, especially if treated before adverse histologic changes have developed in the gastric mucosa.
A recently revised classification of gastritis has recognized H. pylori-associated dyspepsia as a distinct entity and incorporated it into ICD 11.11 The classification also highlights the significance of H. pylori gastritis as the precursor lesion that leads to peptic ulcer disease and gastric cancer, irrespective of whether symptoms are present.
H. pylori infection has been associated with a variety of other conditions. In most cases, the association has not been shown to be causal and common conditions will inevitably coexist in some patients. There is modest data linking H. pylori to immune thrombocytopenic purpura and eradication therapy has been tried with variable results.
DIAGNOSIS OF H. PYLORI INFECTION
Who to Test and Treat?
The decision to treat or not to treat H. pylori must be an active one considering individual patients' circumstances and risks. The decision, therefore, to test for H. pylori should only be made with therapeutic intent.
Good Practice Point
The decision to test for H. pylori should only be made with therapeutic intent.
Evidence-based indications for testing for and treating H. pylori are summarized in Table 2.4,17 The applicability of each indication in different regions will depend on the prevalence of infection and disease, resources, competing needs, and individual patient factors. Peptic ulcer disease is the prime indication in most of the world. The clinical benefit and health-economic benefits of short-term curative therapy for a common, chronic, important disease have been amply demonstrated over many years. In resource-poor regions, this indication for therapy should be prioritized.
TABLE 2 -
Indications for
Treatment of
Helicobacter pylori Infection
|
Helicobacter pylori treatment indications |
| Past or present duodenal and/or gastric ulcer, with or without complications |
| Gastric mucosa-associated lymphoid tissue (MALT) lymphoma |
| Gastric mucosal atrophy and or intestinal metaplasia |
| Following resection of early gastric cancer |
| Patients who have first-degree relatives with gastric cancer |
| Patients’ wishes (after full consultation with their physician) |
| Functional dyspepsia |
| To reduce the risk of peptic ulcer and upper gastrointestinal bleeding in nonsteroidal antiinflammatory drug-naive users |
| Before starting long-term aspirin therapy for patients at high risk for ulcers and ulcer-related complications |
| Patients receiving long-term low-dose aspirin therapy and who have a past history of upper gastrointestinal bleeding and perforation |
| Gastroesophageal reflux disease patients requiring long-term proton pump inhibitor |
| As a strategy for gastric cancer prevention in communities with high incidence |
| Unexplained iron-deficiency anemia, or idiopathic thrombocytopenic purpura |
The strength of indication may vary regionally and individually.
Source: Adapted from Fock et al 2009.
4 Adaptations are themselves works protected by copyright. So to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation
HOW TO TEST FOR H. PYLORI
Endoscopic Diagnostic Tests
Diagnostic tests for H. pylori infection may be invasive (endoscopic) or noninvasive (nonendoscopic), (Table 3). Biopsies taken at endoscopy are most commonly for histology and urease testing. Biopsies for culture are less used for diagnosis unless antimicrobial resistance testing is available and required to aid individual clinical decision-making or to determine population resistance rates. The combination of 2 modalities of testing taken from 2 topographical locations within the stomach generally is most effective for diagnosis. In practice, this usually means biopsies taken from the antrum and corpus of the stomach for histology and from the antrum for a urease test. More structured biopsy protocols may be used when there is an additional need for histologic surveillance (such as the OLGA or OLGIM protocols.18 Histology is usually costly and very operator-dependent, and accuracy cannot be assumed unless previously compared with other modalities of testing.
TABLE 3 -
CASCADES: Diagnostic Tests for
Helicobacter pylori—Relative Availability According to High, Intermediate or Low Levels of Health Care Resources
| Availability of tests related to health care resources |
| Endoscopy-based and nonendoscopic tests |
High resources |
Intermediate resources |
Low resources |
| Endoscopic tests |
| Histology |
Widely |
Usually |
Rarely |
| Commercial urease tests |
Widely |
Widely |
Rarely |
| In-house urease tests |
Widely |
Widely |
Widely |
| Culture |
Many centers |
Major centers |
Rarely |
| PCR: diagnosis/culture |
Major centers |
Rarely |
Rarely |
| Breath tests |
| C14 urea |
Widely |
Usually |
Major centers |
| C13 urea |
Usually |
major centers |
Rarely |
| Stool tests |
| Stool antigen |
Usually |
Usually |
Major centers |
| Stool PCR |
Major centers |
Rarely |
Rarely |
| Serology |
| Venous |
Widely |
Usually |
Usually |
| Finger prick point of-care |
Usually |
Rarely |
Rarely |
| Clinical assessment |
| Symptoms |
Widely |
Widely |
Widely |
In resource-limited regions, reliance on urease tests is common. Most commercial urease tests appear to be accurate to about 95% sensitivity. Although much less expensive than histology, these tests may still incur a significant cost burden on resource-poor regions, especially when the cost is borne by the patient. A commercial test typically costs US$5. In regions where the average daily income for an unskilled worker may be $1 to 2, this may not be affordable. Fortunately, there are very inexpensive generic urease tests that have been available for many years that may be made on-site with a unit cost of about $0.20. These are usually unbuffered tests that give a very rapid result and have sensitivity very similar to commercial tests.19 They are in use in some countries in Africa, Asia, and the Pacific region.
Culturing H. pylori from biopsies requires specific transport conditions, laboratory skills, and equipment. Culture success rates may reach 90% in expert centers but are often lower than that in less expert centers. Subculturing for antimicrobial testing may not always be successful in less expert laboratories also such that results may not always be obtained when required. There are now commercially available real-time PCR tests that allow the detection of H. pylori with high sensitivity and specificity, as well as the mutations causing clarithromycin resistance.20–22 These tests do not require strict preanalytic conditions, and they can be performed in a few hours. The validation and implementation of these rapid, inexpensive kit-based point-of-care antimicrobial resistance tests promise to be a major advance in management. The availability of such tests in regions of high resistance may greatly aid the choice of therapy for individual patients while also facilitating population prevalence surveys.
Good Practice Point
The validation and implementation of rapid, inexpensive kit-based PCR diagnostic and antimicrobial resistance tests promises to be a major advance in management.
The endoscopic diagnosis of duodenal ulcer disease in a higher prevalence, poorly resourced region in a patient not taking NSAIDs has 95% accuracy for predicting the presence of H. pylori. While a biopsy-based test to confirm the infection is desirable, the presence of the duodenal ulcer has a predictive value similar to that of most tests, and so it is reasonable to treat without incurring further costs (unless inexpensive generic urease tests are available).
Noninvasive Diagnostic Tests
When endoscopy is not required or not available, noninvasive tests may be used. Urea breath tests (UBTs) are very useful and have higher diagnostic accuracy than other noninvasive tests to identify H. pylori (in patients without a history of gastrectomy). Somewhat surprisingly, these are not widely available in many countries where H. pylori and peptic ulcer disease are most common. The reasons for this are complex and may include a lack of expertise or resources to setup and operate breath analysis laboratories, the relatively high cost of commercial kit tests or an over-reliance on either empirical therapy or endoscopy. In many cases, valid anxiety about gastric cancer is a major driver of the use of endoscopy (although once symptomatic, gastric cancers are rarely curable). The cost of UBTs varies. In higher-resource countries, costs compare very favorably with endoscopy, although in regions where endoscopy is relatively inexpensive, the cost advantage disappears unless low-cost UBTs are available. The stable isotope C13 UBT test has been validated in detail in multiple locations and is often preferred in well-resourced regions. The C14 UBT uses a very low dose of radioactive isotope and usually has a shorter collection time but has not been as extensively validated. It may be somewhat less accurate. The laboratory setup costs for C13 UBT are higher as a mass spectrometer is required, whereas for C14 UBTs, a less expensive scintillation counter is needed. The real (rather than commercial) unit cost of the C14 isotope is low, so the test could be provided at a very low cost using a central laboratory “hub and spoke” model for service delivery with remotely collected breath samples delivered from throughout a region. Point-of-care commercial kits and analyzers are available. Accuracy varies, and the unit cost of these kits is often high.
Stool antigen testing is another option. These tests appear almost as accurate as UBTs’ but there is frequently less preference by patients and health care and laboratory workers for stool-based tests. Cost is an issue in some locations. Stool-based rapid PCR tests are also available.21 Although these tests face the same acceptance barriers and requiring laboratory equipment and skills, they have the potential to provide rapid diagnosis and antimicrobial resistance testing in a single noninvasive test.
Serological antibody tests are commonly available. While useful as seroepidemiological surveys, these tests often lack the sensitivity and specificity required for individual patient’s decision-making and are generally not very helpful. They need to be validated for specific locations, and the issue of false results due to cross-reactivity is rarely addressed. In a community with moderate H. pylori prevalence, the accuracy of these tests may not exceed 50%.
Testing to Assess Outcome after Eradication Therapy
As eradication success is very variable, outcome assessment is ideally done in all patients, although this may not be feasible universally. Priority should be given to those who remain at the highest risk for harm if the infection is ongoing, such as those treated for complicated ulcer disease (bleeding or perforation).
The biopsy-based test may be used to determine the outcome after eradication therapy when endoscopy is required (eg, to assess gastric ulcer healing and exclude neoplasia or to survey adverse histology). Otherwise, noninvasive tests are preferred. UBTs and stool tests should be done not less than 1 month after the completion of eradication therapy. To minimize false negative results, no antibiotics or bismuth compounds should be taken for at least a month before testing and PPI use should be avoided for at least 1 and preferably 2 weeks. Serology is not useful to assess outcomes as antibody levels often persist for years after therapy. Despite the widespread validation of noninvasive diagnostic tests and in particular breath tests, these are still not available at low cost in many places around the world, and this remains a major unmet clinical need.
Diagnostic Pathways
The choice of diagnostic test depends to a large extent on the clinical context, availability, expertise, and cost. If all modalities for diagnosis are available, the key issue is whether endoscopy is required to investigate symptoms or signs of upper gut disease. In low prevalence, more developed countries, assessment for gastro-esophageal reflux, functional dyspepsia, cardia, and esophageal cancer concerns are common drivers for endoscopy, and it is usual to biopsy the stomach for H. pylori at that time. H. pylori is still an issue in such regions, particularly in higher-risk subgroups, such as older patients and those with lower socioeconomic status or migrants from high-prevalence regions. In these countries, a noninvasive “test-and-treat” strategy using UBTs have been validated in younger patients and is cost-effective, although the use of this strategy may be declining. An empirical trial of PPI therapy is often tried in primary care instead with recourse to endoscopy if symptoms are not relieved. Although popular, this is problematic when symptoms are not typical of gastro-esophageal reflux, and the ideal duration of such a treatment trial is unclear. It may lead to failure to diagnose H. pylori. Although the organism may be incidental to the presentation, treatment in younger adults is associated with significant long-term risk reduction. The cost-effectiveness of management strategies for H. pylori in well-resourced, lower prevalence countries varies with local health care costs.
In higher prevalence countries, there is often a distinct preference by doctor and patient for prompt endoscopy due to the fear of gastric cancer, although, as noted, whether this improves survival when patients present with symptoms is not certain. For individual decision-making, the pretest probability of infection, patient age, the nature of symptoms or signs, and the local prevalence of ulcer disease and gastric cancer must be considered.
Empirical Therapy in Low Resource Regions
Where there is very limited access to endoscopic or noninvasive means of diagnosing H. pylori infection, decision-making must be empirical, based on the clinical setting. Peptic ulcer disease may be strongly suspected on clinical grounds where there is a clear history of periodic upper gut pain and or any past or recent history of upper gut bleeding. In regions where it is known that the prevalence of H. pylori is high and peptic ulcer disease common, it is reasonable to use empirical eradication therapy for the presumptive clinical diagnosis of peptic ulcer disease (Fig. 3). The cohort so treated will include many with peptic ulcer disease, who will gain major benefit. It will also include some who have H. pylori-associated gastritis but no active ulcer. In this group, symptom resolution occurs more frequently than with the use of any other therapy (commonly PPIs), and importantly, successful therapy reduces lifelong risks of peptic ulcer disease and gastric cancer. Treatment of both peptic ulcer disease and gastritis has been shown to be cost-effective also.
FIGURE 3: CASCADES: Treatment pathways for upper gut symptoms in high H. pylori prevalence regions with low health care resources. Treating H. pylori in the context of possible ulcer disease dominates the clinical pathway as the clinical and health-economic benefits likely exceed that of other strategies.
With empirical symptom-based eradication therapy, there will be a subgroup treated who are not infected and may have other diagnoses. This group will not be benefited from eradication therapy, and there are costs involved and the unnecessary use of antibiotics, but the likelihood of major harm is low, and the overall benefit to the treated group justifies this approach. Indeed, the Asia-Pacific Consensus Group on H. pylori specifically endorsed such an approach in regions where H. pylori and peptic ulcer disease are common and access to investigations is either economically or geographically unavailable to many. Empirical use of PPI therapy is likely to be less beneficial than the initial treatment. Such an approach should be supported by programs to educate health care workers to recognize symptoms more likely to be due to ulcer disease and to apply this strategy selectively. In these resource-poor regions, treating all upper gut symptoms with such an approach is harder to justify.
NSAID use is widespread, and NSAID-related peptic ulcer disease is common and may coexist with H. pylori infection. In an empirical setting of suspected ulcer disease, when NSAIDs (including aspirin) are being used, it is reasonable to both treat H. pylori and address the NSAID risk by ceasing these agents where possible and treating with PPIs for some weeks after completion of eradication therapy.
Good Practice Point
In resource-poor, high-prevalence regions where no diagnostic testing is available, a history suggesting chronic ulcer disease—periodic upper gut pain and or past or present melaena, infers a high likelihood of H. pylori ulcer disease and justifies empirical eradication therapy, especially in patients with no history or NSAID or aspirin use.
TREATMENT OF H. PYLORI INFECTION
There are a vast number of studies addressing issues of therapies and numerous expert guidelines recommending choices of therapy. However, much of the literature and advice derives from well-resourced countries, with relatively little coming from poorly resourced countries that bear the major burden of H. pylori-caused diseases. Principles for antibiotic therapy that apply universally have been established. However, there are key issues that must be addressed locally to determine the best local practice, as antimicrobial resistance patterns and, therefore, eradication rates vary regionally 23,24, and other local issues such as drug cost and availability influence choice of therapy.
The key principles that guide the choice of eradication therapy are outlined in Table 4.
TABLE 4 -
The key Principles that Guide the Choice of
Helicobacter pylori Eradication Therapy
| Key principles Helicobacter pylori eradication therapy choice |
| 1. Randomized controlled treatment trials and meta-analyses provide the highest level of evidence but are not available for many regions. Local audits of treatment outcomes are useful |
| 2. Treatment recommendations based on resistance patterns and outcome data from 1 region may not be applicable elsewhere due to variations in resistance rates and other factors |
| 3. Generating high-quality local data and monitoring antibiotic resistance and treatment outcomes are priorities |
| 4. Ad hoc, unproven therapies should be avoided |
| 5. The main determinant of eradication success is pretreatment antibiotic resistance |
| 6. Primary resistance to clarithromycin, metronidazole, and levofloxacin varies widely regionally |
| 7. Major determinates of primary resistance appear to be the magnitude and duration of community usage of these antibiotics as monotherapy for other indications |
| 8. Prior personal exposure of a patient to these drugs is likely to result in resistance and increases the chance of treatment failure |
| 9. Primary clarithromycin resistance (CR) has been reported to have increased in many countries over relatively few years while remaining stable in other countries |
| 10. Primary or secondary resistance to amoxicillin and tetracycline are so rare as not to affect treatment choices |
| 11. As much treatment is given presumptively or after noninvasive H. pylori testing, the choice of therapy will be based on knowledge of likely antimicrobial resistance patterns locally |
| 12. When endoscopy is done, culture is not often done routinely before first-line therapy in most places, but this will vary with skills, resources, and local knowledge of resistance rates and outcomes. Ideally, culture should be used to monitor local resistance trends over time also |
| 13. The availability of rapid, inexpensive point-of-care PCR antimicrobial resistance testing may change individual treatment choices and facilitate surveillance of trends in resistance |
| 14. Secondary resistance after treatment failure is very common for clarithromycin, metronidazole and perhaps levofloxacin |
| 15. Repeating the same therapy has a low likelihood of success and should be avoided |
| 16. The choice of the second line and subsequent therapies, if needed, should follow a logical decision path that involves using the most effective drugs first, avoiding repeating the same therapy, and evidenced-based choices of subsequent therapies |
| 17. Culture has a very limited role in determining the choice of salvage therapies |
| 18. Dose and duration of therapy will influence outcomes |
| 19. Treatment should be preceded by informed consent that outlines the potential risks and benefits of therapy |
| 20. Compliance is a major modifiable determinant of eradication success and should be supported with clear verbal and written information |
| 21. Smoking has an adverse effect on eradication success |
| 22. Nonmodifiable risk factors for treatment failure may include CYP 219 polymorphisms and virulence factors of the organism |
| 23. The role and value of potassium-competitive acid blockers such as vonoprazan is still evolving. These drugs are not affected by CYP2C19 polymorphisms and result in more uniform and potent inhibition of gastric acid secretion |
| 24. Costs may be minimized by using high-quality generic drugs, especially in resource-poor regions |
| 25. The drugs required should be on essential drug lists and be widely available |
These key principles must be adapted regionally according to available resources.
TRANSLATING TREATMENT PRINCIPLES INTO THERAPEUTIC CHOICES
Choice of First-Line Eradication Therapy
Application of these principles of therapy will ensure the best outcomes possible. In well-resourced regions, treatment may be based on high-quality trials and audit and culture data; in resource-poor regions, reliance on knowledge of the community or personal antibiotic usage and any local audit of outcomes will influence the use of therapies recommended in guidelines from elsewhere.4–12
PPI, Amoxicillin, Clarithromycin Triple Therapy
In many parts of the world, triple therapy, comprising a proton pump inhibitor with amoxicillin and clarithromycin (PPI-AC), remains the most commonly used first-line therapy. This combination was the first very widely recommended therapy and superseded less effective triple therapies. It has been very well evaluated over the years. The major determinant of eradication success with this combination is pretreatment clarithromycin resistance (CR). The prevalence of antibiotic resistance, particularly CR, varies widely around the world (Table 5). Where clarithromycin has and is used commonly as monotherapy for other infections, CR is often high and increasing. There are views that this therapy should be abandoned where primary CR rates are known to be 15% to 20% or greater because of the impact this has on eradication rates. A somewhat arbitrary minimum eradication rate of 80% on an intention-to-treat basis is often quoted as a benchmark for acceptable therapy. This is a common eradication rate for PPI-AC in real-world studies where CR rates are moderate or low (ie, below 15% to 20%). Unacceptably lower eradication results may occur in countries where CR prevalence is higher.
Key Statement
The major determinant of eradication success with PPI-AC is pretreatment clarithromycin resistance
TABLE 5 -
Pooled Prevalence of Primary and Secondary Antibiotic Resistance, Stratified by World Health Organization Region
| WHO region |
Pooled prevalence of antibiotic resistance, % (95% CI) |
| Africa region |
Clarithromycin |
Metronidazole |
Levofloxacin |
Cla+Met |
Amoxicillin |
Tetracycline |
| Overall |
15 (0-30) |
91 (87-94) |
14 (12-28) |
— |
38 (32-45) |
13 (9-17) |
| Americas region |
Clarithromycin*
|
Metronidazole |
Levofloxacin |
Cla+Met |
Amoxicillin |
Tetracycline |
| Primary |
10 (4-16) |
23 (2-44) |
15 (5-16) |
– |
10 (2-19) |
– |
| Secondary |
18 (13-23) |
30 (19-41) |
22 (3-42) |
– |
7 (1-13) |
– |
| Not specified†
|
– |
– |
– |
3(0-13)‡
|
– |
4 (1-11) ‡
|
| Overall |
14 (9-19) |
27 (14-39) |
14 (12-28) |
3 (0-13)‡
|
8 (3-13) |
4 (1-11)‡
|
| Eastern Mediterranean region |
Clarithromycin |
Metronidazole |
Levofloxacin |
Cla+Met |
Amoxicillin |
Tetracycline |
| Primary |
33 (23-44) |
56 (46-66) |
19 (10-29) |
19 (0-39) |
14 (8-20) |
10 (4-15) |
| Secondary |
17 (10-27) |
65 (54-74)‡
|
30 (14-46) |
11 (6-20) |
10 (5-18)‡
|
17 (8-26) |
| Not specified†
|
25 (17-32) |
67 (61-72) |
– |
8 (4-11) |
15 (8-22) |
– |
| Overall |
29 (23-25) |
61 (55-67) |
23 (14-32) |
14 (5-23) |
14 (10-18) |
10 (8-13) |
| European region |
Clarithromycin*
|
Metronidazole*
|
Levofloxacin*
|
Cla+Met*
|
Amoxicillin |
Tetracycline |
| Primary |
18 (16-20) |
32 (27-36) |
11 (9-13) |
1 (0-2) |
0 (0-0) |
0 (0-0) |
| Secondary |
48 (38-57) |
48 (38-58) |
19 (14-24) |
18 (16-20) |
0 (0-0) |
0 (0-1) |
| Not specified†
|
33 (26-39) |
47 (35-39) |
14 (10-18) |
7 (0-13) |
1 (0-2) |
1 (0-2) |
| Overall |
32 (25-31) |
38 (33-42) |
14 (12-16) |
15 (12-18) |
0 (0-0) |
0 (0-0) |
| Southeast Asia region |
Clarithromycin |
Metronidazole*
|
Levofloxacin*
|
Cla+Met |
Amoxicillin |
Tetracycline |
| Primary |
10 (5-16) |
51 (26-76) |
30 (14-46) |
– |
2 (0-5) |
0 (0-1) |
| Secondary |
15 (8-27)‡
|
44 (32-58)‡
|
24 (15-37) |
– |
– |
– |
| Not specified†
|
25 (0-55) |
80 (57-100) |
5 (3-11) |
6 (1-10) |
28 (0-62) |
1 (1-2) |
| Overall |
17 (6-28) |
59 (40-78) |
25 (13-28) |
6 (1-10) |
12 (6-17) |
0 (0-12) |
| Western Pacific region |
Clarithromycin*
|
Metronidazole*
|
Levofloxacin |
Cla+Met*
|
Amoxicillin |
Tetracycline*
|
| Primary |
34 (30-38) |
47 (37-57) |
22 (17-28) |
8 (6-10) |
1 (1-1) |
2 (1-2) |
| Secondary |
67 (54-80) |
62 (50-71) |
30 (20-39) |
13 (8-18 |
1 (1-2) |
0 (0-1) |
| Not specified†
|
25 (21-29) |
69 (64-74) |
19 (17-21) |
14 (11-18) |
1 (1-2) |
10 (7-14) |
| Overall |
34 (30-38) |
55 (51-59) |
24 (21-26) |
11 (9-13) |
1 (1-1) |
2 (1-2) |
Cla+Met, combined resistance to clarithromycin and metronidazole.
*P-value for subgroup comparison <0.05.
†Not specified: the study did not report the type of resistance.
‡Only 1 study contributed to analysis.
The optimal duration of therapy is contentious. Recent calls for universal 14-day PPI-AC therapy usually originate from regions of higher CR. Initial studies were mostly for 7 days, although that duration may have been influenced by the registration trial design. Proponents of the longer duration of therapy point to somewhat higher eradication rates in systematic reviews. However, there are other considerations that influence the duration of therapy, particularly in resource-poor countries. Adding a second week of therapy may increase eradication rates, typically by about 10%. This means the number of patients needed to treat with an extra week of therapy to achieve 1 more treatment success is 10. The price of this higher eradication rate, if achieved, includes a doubling of the cost of treatment, which is a major issue in resource-poor regions. (Note that the cost of a week of triple therapy in very resource-poor regions may be as much as weekly earnings for the lowest paid). The risk of adverse effects increases considerably with protracted antibiotics also, as does the likelihood of noncompliance. An alternative is to give shorter therapy where compliance is likely to be greater and adverse effects and costs fewer, with the understanding that 10% more patients may need a second-line salvage therapy. Overall antibiotic use will be much lower with the second strategy as long as first-line eradication rates are at least moderately high. In some well-resourced countries, longer therapy is usually recommended, but there needs to be more modelling in resource-poor regions of shorter courses. It must also be noted that acceptable eradication rates with 1-week PPI-AC therapy have been reported from several countries, and the incremental benefit of a longer course has not been studied. The optimal dosing for the PPI (standard or high dose) and clarithromycin (250 or 500 mg twice daily) has not been determined in most locations. In high CR regions, neither 1 nor 2 weeks of this therapy may give acceptable eradication rates. In such places, the choice for first-line therapy varies.
The role and value of potassium-competitive acid blockers (PCABs), such as vonoprazan, in place of PPIs in any eradication therapy, is evolving. These drugs are not affected by CYP2C19 polymorphisms and result in more uniform and potent inhibition of gastric acid secretion.25 There have been favorable reports from Japan and some other Asian countries that await confirmation to determine the role and applicability of PCABs in eradication therapy elsewhere.
Bismuth-based Quadruple Therapies
The other core choice for first-line therapy, especially in regions of high primary CR, remains bismuth-based quadruple therapy. The best-studied regimen involves a PPI, bismuth, tetracycline, and metronidazole (PPI-BTM). This treatment has stood the test of time because it results in reliable and acceptable eradication rates irrespective of primary MR, as the addition of a PPI to BTM appears to overcome MR. Good results have been achieved with 7-day therapy, although there are proponents of longer (10 to 14 d) treatments. The major drawbacks of this therapy are the clumsy dosing regimen (as it is usually dosed 4 times daily) and the common but usually mild adverse effects that may impair adherence. Reduced access to bismuth and tetracycline may limit use in some places. However, where these drugs are not readily available or not registered, it is often feasible to import generic drugs at low cost, with the permission of the relevant authorities.
A quadruple therapy substituting amoxicillin for tetracycline (PPI-BAM) has been long reported but less used but may provide acceptable outcomes.
More recently, converting standard PPI-AC triple therapy to a quadruple therapy by the addition of bismuth (B+PPI-AC) has been reported with favorable results from some locations.26 The value of this in overcoming CR is yet to be fully determined and merits detailed evaluation.
Nonbismuth-Based Quadruple Therapies
There are advocates for nonbismuth quadruple therapies, usually meaning the addition of metronidazole to PPI-AC triple therapy (PPI-ACM). This may increase eradication rates if metronidazole resistance (MR) rates are low or moderate but it is unlikely to be very helpful in the many regions of the world where primary MR and/or CR are high. Moreover, treatment failures will often be found to have dual resistance. Such concomitant therapy has been studied in well-resourced countries but rarely in poorly resourced countries. Sequential or hybrid regiments are less well-studied, appear not to offer superior eradication, are clumsy to prescribe, and pose particular challenges with adherence and, as a result, are not recommended.
Where metronidazole sensitivity is known from testing, PPI-AM may be used first line with reasonable outcomes. It is also suitable in locations where the population MR is known to be low.
Levofloxacin Triple Therapy
Levofloxacin triple therapy (PPI, amoxicillin and levofloxacin, PPI-AL for 10 to 14 d) has been used in first-line therapy when levofloxacin resistance (LR) is known or presumed to be low, but this combination has not been studied extensively in this role with most reports relating to second-line therapy. Reports of high levofloxacin resistance rates in some countries will limit the usefulness of this therapy in these locations. The treatment is generally well tolerated. There have been recent concerns about the risks of fluoroquinolone use. With levofloxacin, this relates to the rare risk of tendinitis or myositis. The precise prevalence of this adverse effect is not well documented, but it appears more common in the elderly and those with inflammatory arthritis or renal impairment and is best avoided in those high-risk subgroups if alternatives exist. A higher dose of levofloxacin and possibly a high-dose PPI may be associated with superior eradication success. A related quinolone, moxifloxacin has also been used. It has been less studied and has a broader spectrum of activity, so it is generally not preferred over levofloxacin.
There are a number of other less well-studied treatments that nonetheless have been recommended in various reviews. Furazolidone, for example, has been used in locations where CR and LR are high, but quality data attesting to its value are meager compared with established therapies, and its precise role remains to be defined.
When antimicrobial resistance by culture or rapid PCR testing is used, tailored therapy may be prescribed to individual patients. This is likely to have the most value in regions of higher primary CR, to allow avoidance of clarithromycin use in first-line therapy. Validation and acceptance of stool-based PCR testing offer the prospect of extending this benefit to primary care and in circumstances where endoscopy is not required or accessible.
An overview summary of first-line treatment regimens and their composition is shown in Tables 6 and 7.
TABLE 6 -
Overview of First Line Eradication Therapies
| Therapy |
Application |
Success |
Dose and Duration |
| PPI-AC |
Widespread, where primary CR is low |
Major determinant is primary CR |
7-14 d Standard or high-dose PPI |
| PPI-BTM PPI-BAM |
Widespread where available Useful when high primary CR Reduced access may limit use in some places |
Reliable and acceptable eradication rates, irrespective of primary MR Adherence may be challenging |
7-14 d Standard or high-dose PPI Metronidazole >1500 md/day preferable |
| B+PPI-AC |
Less data. May help when CR high |
Early data encouraging |
Usually 14 d |
| PPI-ACM |
Limited in high CR and MR regions |
May increase eradication if low MR |
Varies |
| PPI-AL |
May be used first line when LR is low especially if CR high but most reports are for second-line therapy |
Effective when LR low |
For 10 to 14 d. Standard or high-dose PPI |
| PPI-AM |
In low MR regions or when known sensitivity |
Low if MR high |
7 to 14 d Standard or high-dose PPI |
| PPI-AR |
Usually used third or fourth line it at all |
Moderate. Risk of neutropaenia an issue |
Varies |
| PPI-A |
Usually used third or fourth line if at all |
Moderate |
Both in higher dose and longer duration |
| Other |
If local evidence of efficacy but usually little data |
Usually low |
Varies |
A indicates amoxicillin; B, bismuth; C, clarithromycin; L, levofloxacin; M, metronidazole; PPI, proton pump inhibitor; R, rifabutin.
TABLE 7 -
Typical Composition, Doses and Duration of Triple Therapies and Quadruple Therapy Combinations
| Triple Therapies |
1 |
2 |
3 |
| All twice daily for 7-14 d |
PPI |
amoxicillin 1 g |
clarithromycin 500 mg |
|
PPI |
metronidazole 400 mg |
clarithromycin 500 mg |
|
PPI |
amoxicillin 1 g |
metronidazole 400 mg |
| All twice daily for 10 to 14 d |
PPI |
amoxicillin 1 g |
levofloxacin 500 mg |
| All twice daily for 7 to 10 d |
PPI |
amoxicillin 1 g |
rifabutin 150 mg |
| Quadruple therapies |
1 |
2 |
3 |
4 |
| For 7 to 14 d |
PPI twice daily |
bismuth 120 mg 4 times daily |
metronidazole 400 to 500 mg three times daily |
tetracycline 500 mg 4 times daily |
|
(amoxicillin 500 to 1000 mg 3 times daily, has been substituted for tetracycline) |
| all twice daily for 7 to 14 d |
bismuth 240 mg |
PPI |
amoxicillin 1 g |
clarithromycin 500 mg |
Published dosing and duration vary, see text.
Choice of Second and Subsequent Eradication Therapies
Second line or salvage therapies after first-line eradication failure have been well-studied in some locations, but data is completely lacking in many resource-poor regions.4–12
Bismuth-based Quadruple Therapy and Levofloxacin Triple Therapy
The most commonly studied and used second-line therapies include standard bismuth-based quadruple therapy for 7 to 14 days and levofloxacin triple therapy for 10 to 14 days, as described above. Both have been shown to achieve eradication rates above 80%. The choice between these 2 depends on whether or not there is knowledge of local primary levofloxacin resistance rates, availability, experience, adherence, and cost. A longer duration of therapy (ie, 14 d) is often recommended but issues addressing local outcomes, costs and adherence are needed. When these treatments fail, the other therapy is the usual third choice. In experienced centers, overall eradication rates with judiciously chosen therapies after first-line failure, should approach 98% after up to 3 treatments.
Other Salvage Therapies
Other salvage therapies that have been used include a rifabutin-based triple. It is generally less effective, and the risk of significant neutropenia may be as high as 1%, which tends to limit its use. It is usually avoided in regions with high tuberculosis prevalence. High-dose dual PPI with amoxicillin therapy (PPI-A) has been used with some success. Non bismuth quadruple therapies are generally ineffective as salvage therapies due to secondary CR and MR. Where metronidazole sensitivity is known after testing, PPI-AM may be used second line with reasonable outcomes, but it is generally not used second line empirically. Furazolidone has been used and recommended as a component of therapy in some regions. There are few high-quality eradication studies that include this drug and a dearth of randomized trials. Concern about its safety and use has led to it becoming unavailable in the United States and the European Union.
Where appropriate treatment pathways have been followed, and therapy has failed, ad hoc therapies at the whim of the prescriber should be avoided, and ongoing infection accepted unless subspecialty expertise or a clinical trial is available. In some patients, such as those with relapsing ulcer disease, eradication failure may result in the requirement for maintenance antisecretory therapy.
Treatment Choices for Penicillin Allergic Patients
For patients who are penicillin allergic, metronidazole may be substituted for amoxicillin and combined with a PPI and clarithromycin. However, primary MR reduces the efficacy of this. Bismuth quadruple therapy is a very good alternative (PPI-BTM). If both these therapies fail, there are limited further options. In patients who have a remote, uncertain, or unlikely history of penicillin allergy and where resources are available, formal assessment for type 1 penicillin allergy may be done. This involves the measurement of penicillin antibodies followed by skin prick testing and, if negative, a supervised oral challenge. When done in lower-risk patients, up to 80% of such patients have been shown not to be allergic to penicillin, and they may be treated safely with amoxicillin-containing therapies as required (usually PPI-AL or PPI-AC if clarithromycin was not used initially). Such a strategy has been shown to allow successful eradication therapy in most patients. Where there is a clear history of a type 1 reaction previously, allergy is assumed, and testing is not indicated.
Treatment Pathways
In summary, in well-resourced regions where local rates of CR and MR (and sometimes LR) are known, evidenced-based treatment choices in regions of lower CR are usually PPI-AC first line with PPI-BTM or PPI-AL therapies second and third line in either order. In higher CR regions, PPI-BTM may be used. B+PPI-AC or PPI-AL may be alternative first-line therapies. Second-line choices depend on what was used first: PPI-BTM or PPI-AL may be used if not used previously.
In resource-poor regions where community CR and MR have not been defined or are known to be high, the choice of therapy is based on empirical audits of outcomes, an individual patient’s prior personal history of antibiotic exposure as monotherapy, known levels of community use of such drugs, availability, and cost (Table 8). PPI-AC is still widely chosen with PPI-BTM or PPI-AL, or even nonbismuth quadruple therapies as alternative first line or salvage therapies. However, where it is known that first-line therapy results with clarithromycin results in poor outcomes, 1 of the other therapies described may be preferred. Data defining rates of levofloxacin resistance are sorely needed, as LR appears to be common in many regions, and the quality of some published data are uncertain. PPI-BTM quadruple therapy therefore is likely to be a good first and subsequent choice as it avoids the issue of poor outcomes due to resistance, but use is sometimes limited by availability, compliance, and adverse effects. Whatever therapeutic pathway is chosen, it is crucial not to repeat the same therapy as this is a very low-value strategy after first-line failure due to secondary antibiotic resistance. Eradication success for PPI-AC, for example, may be 80% or more first line but as low as 8% when that treatment is repeated after first-line failure. Most of this is attributable to secondary CR. Unfortunately, in some places, this practice is still widespread but should be discouraged. Lastly, patient access to inexpensive generic medications and medical education remain significant challenges to be overcome in many regions.
TABLE 8 -
CASCADES:
Treatment Considerations Where Local Resistance Rates are Not Well Defined, Individual Patient Testing is not Available and Low Resources
| First-line Therapies |
| PPI-AC |
In regions where clarithromycin resistance rate is thought to be low or moderate (<20%) |
If prior clarithromycin use in monotherapy or combination, assume resistance and avoid in first-line therapy |
|
|
7-day minimum duration, likely higher eradication success with 10 to 14 d (consider costs) |
|
|
Use quality generic drugs to minimize costs |
|
|
Encourage compliance with full course |
| Quadruple therapy |
In regions where clarithromycin resistance rates are likely >20% |
Avoid PPI-AC first line |
|
|
Quadruple therapy overcomes MR. Unaffected by CR |
|
|
May be more difficult to take and ‘nuisance’ adverse effects are common |
|
|
Encourage compliance with full course Generic drugs may be less expensive than triple therapy |
| PPI-AC or Quadruple therapies |
In regions with unknown clarithromycin resistance rates |
Avoid clarithromycin if past personal patient exposure |
|
|
PPI-AC otherwise a reasonable choice |
|
|
Quadruple therapy also a good option |
| Second-line therapies |
| Quadruple therapy Levofloxacin triple therapy |
After the failure of clarithromycin-containing regimen |
Avoid repeating the same treatment |
|
|
Avoid using clarithromycin again as secondary resistance will be high and eradication success very low |
|
|
Levofloxacin triple therapy is a good option if no prior personal exposure and resistance is thought to be low or moderate |
|
Clarithromycin or Levofloxacin triple therapy |
After the failure of quadruple therapy |
Check compliance |
|
|
Levofloxacin is preferred if likely high CR region or past personal exposure. |
A indicates amoxicillin; C, clarithromycin; CR, clarithromycin resistance; MR, metronidazole resistance; PPI, proton pump inhibitor.
An appropriate pathway for choosing therapy is outlined in Figure 4.
FIGURE 4: Treatment pathways for
H. pylori. CR indicates Clarithromycin resistant; CS, Clarithromycin sensitive; P/PPI, proton pump inhibitor, B, bismuth, M: metronidazole; MR: metronidazole resistance; R: Rifabutin; T: tetracyclin; C: clarithromycin; A: amoxicillin; L: levofloxacin; PBMT: Bismuth quadruple therapy; PMC: Clarithromycin-based PPI triple therapy with metronidazole; PAMC: Concomitant nonbismuth quadruple therapy; PAC: Clarithromycin-based PPI triple therapy with amoxicillin; PAL: Levofloxacin-based therapy; HDDT: High-dose dual therapy; PAR: Rifabutin containing triple therapy.
$=Given the increasing levofloxacin resistance in certain areas, susceptibility testing, if available, is recommended before using PAL. SOURCE: Fallone et al 2019.
27 The Role of Culture
Surveying H. pylori resistance patterns to define population prevalence and changes in prevalence will guide treatment choices. In some well-resourced regions it is possible to tailor therapy based on individual antimicrobial sensitivity testing of endoscopic biopsies before treatment. This is not the norm in clinical practice, however, and in any case, culture and subculture for resistance testing may fail in less expert laboratories. Moreover, much treatment is given in primary care, where noninvasive testing and treating is conducted. After treatment failure, antibiotic sensitivity testing from cultured biopsies is unlikely to have a major role in clinical decision-making. If clarithromycin has been used and failed, secondary CR is so common as to make testing for it unhelpful, and a different therapy should be chosen. Defining MR is occasionally useful if PPI-AM might be an option, but it does not influence the choice of PPI-BTM as that therapy is unaffected by MR. Levofloxacin is used empirically in most regions where the prevalence of LR is known to be low. Furthermore, in vitro sensitivity of H. pylori to other antibiotics does not infer therapeutic success and ad hoc regimens should not be designed in this way.
If point of-care inexpensive biopsy (or stool-based) molecular techniques (PCR) for rapid determination of resistance become widely available, these may change practice by having a major impact on treatment selection. There is the possibility that such tests could replace urease tests by confirming the presence of infection and by providing rapid antimicrobial resistance data to guide individualized therapy at a cost only a little greater than current commercial urease tests. Stool-based tests would enable treatment tailored to antimicrobial sensitivity to be conducted in primary care without the need for endoscopy.
Compliance
Whatever therapy is prescribed, every effort must be made to maximize compliance. This entails the prescriber spending time with a patient to explain the importance of taking all of the therapy and not interrupting treatment. This is particularly important in regions where regulations governing antibiotic use may be lax or not enforced, and antibiotics may be obtained over the counter from pharmacies. Patients may buy drugs in small quantities for a day or 2 with a risk of nonpersistence if symptoms are not immediately relieved or if any adverse effects occur. Clearly, the whole course of therapy should be prescribed and dispensed at the onset. Nuisance adverse effects, such as transient taste disturbance that is common with clarithromycin and metronidazole, should be anticipated and explained so that their occurrence does not cause cessation of therapy. The use of printed material for dosing support and information has been found to be useful. As cigarette smoking is a known adverse predictor of outcome, smoking cessation before and during therapy may improve outcomes, although this is not well-studied. Smoking cessation also aids in ulcer healing. A role for probiotics in reducing adverse effects (and possibly improving outcomes) has been asserted, but this needs more and higher quality evidence.
Good Practice Point
Patients should always be advised that successful eradication depends on compliance with the treatment. Time should be taken to counsel the patient, explaining how to take the multidrug therapy and anticipating adverse side effects. The need to complete the treatment should be emphasized. Written or pictorial information may aid compliance also.
After Treatment
Ideally, outcome assessment should be done in all treated patients, although in practice, this is not available in many places. Where endoscopy was done initially and gastric atrophy and or intestinal metaplasia was identified, a decision must be made regarding endoscopic mucosal surveillance.28 This may benefit individual patients, but an overall reduction in gastric cancer mortality is yet to be demonstrated clearly. When focal high-grade gastric mucosal dysplasia is found, these areas may be removed endoscopically, while more advanced neoplasia requires surgery. Dysplasia may be detected using enhanced imaging or by mapping biopsy specimens without discrete endoscopically visible lesions. These patients require endoscopic reassessment, preferably with image-enhanced and magnifying endoscopy, within 6 months for high-grade dysplasia and 12 months for low-grade dysplasia.
As atrophy and intestinal metaplasia are common, endoscopic surveillance will consume a lot of endoscopy resources and have an opportunity cost against other health care needs. Therefore, generally, only higher-risk individuals are usually offered surveillance. High risk usually means the presence of more extensive gastric mucosal changes (involving antrum and corpus) and or a family history of gastric cancer. The ideal strategy remains to be determined. Accurate endoscopic detection and characterization of mucosal changes require specific training, modern endoscopes, and skilled pathologists.
REGIONAL VIEWS FOR BEST PRACTICE ERADICATION THERAPY BASED ON LOCAL DATA AND RESOURCES
Australia
Australia has had low clarithromycin (6% to 8%) and high metronidazole (45% to 50%) resistance rates reported. Levofloxacin data are sparse but primary resistance seems very low, with the possible exception of rates in migrants from high resistance regions. As a result, standard triple therapy with PPI, amoxicillin, and clarithromycin remains the recommended first-line therapy, unless and until evidence of rising clarithromycin resistance emerges. Reported 7-day eradication rates are 80% to 87%. Fourteen-day therapy has not been studied formally. Salvage therapies include levofloxacin triple therapy for 10 days (eradication rate 80% to 90%) and standard dose quadruple therapy (PPI, bismuth, tetracycline, and metronidazole) for 7 to 14 days with similar outcomes. Levofloxacin, tetracycline, and bismuth are not registered locally, so are not often used in first-line therapy. These drugs must be obtained through a special access scheme from abroad or by compounding pharmacies when required for salvage treatments. Rifabutin triple therapy has been used less commonly (76% eradication). Concomitant therapies have not been studied locally.
Pacific Islands
Local resistance data is lacking at present, and there are few systematic data determining the outcome of therapy. Therefore, the choice of therapy is usually extrapolated from international guidelines and determined by drug availability. Clarithromycin triple therapy is commonly chosen with PPI and amoxicillin or metronidazole, despite clinical suspicion of high MR affecting the efficacy of the latter. Cost, availability, local expertise, and adherence to therapy are all barriers to effective treatment. There are no audited salvage therapy data. Ad hoc therapies and repeat clarithromycin therapy after first-line failure are discouraged.
Southeast Asia
There is good evidence that amoxicillin and tetracycline resistance is low and stable (<5%), but MR is generally high (30% to 100%). CR has been increasing but varies significantly across Southeast Asian countries (ranging from 2% to 43%). For most regimens, 14-day duration should be used unless there is local evidence to prove reliable eradication rates with a shorter duration. Ideally, first-line regimens should be considered based on local antibiotic resistance rates due to the wide range of antibiotic resistance across countries. PPI-BTM has been reported consistently to have >90% successful rate. Second-line regimens should contain antibiotics not used previously or those for which resistance is unlikely to develop, such as amoxicillin or tetracycline. PPI-BTM should be considered if it is not yet used. Rifabutin should not be considered in regions with a high prevalence of M. tuberculosis. Eradication failure after the second attempt should be considered for antibiotic susceptibility tests.
Eurasia
On the basis of a pilot study, the prevalence of H. pylori seropositivity among healthy adults in Armenia is 41.5%, increasing with age (13.6% in the age group of 18 to 25 y and 83.3% to over 65 y). The rate of resistance to clarithromycin in 2018 was as low as 3.6% and to 12.8% for fluoroquinolones. However, new research is warranted, especially during the COVID-19 pandemic when there has been an unprecedented increase in the number of prescriptions for macrolides and respiratory fluoroquinolones by primary care providers in the country. Tetracycline is only available in 100 mg tablets, making the conventional quadruple regimen highly inconvenient. Adapted from Maastricht guidelines, local recommendations propose 14-day clarithromycin triple therapy as first-line treatment and a modified bismuth quadruple therapy (PPI, bismuth, amoxicillin, and metronidazole) as alternative first-line therapy. Second-line options include triple or quadruple treatment with levofloxacin. None of the eradication regimens has been studied locally for efficacy.
Western Europe
CR is most relevant for the selection of first-line therapy. This varies among and within European countries. Therefore, monitoring antibiotic resistance remains essential at the population level. Recent European registry data from >30.000 patients in 27 countries 29 reported pretreatment resistance rates of the following: clarithromycin 23%, metronidazole 32%, and dual resistance 13%. There is a dichotomy, with lower CR in central and northern Europe; in Germany, primary CR is still below the cut-off of 15%. Triple therapy with amoxicillin and clarithromycin for 14 days in such conditions remains effective and is commonly used first line. Where primary CR >15%, bismuth quadruple treatments for 10 (or 14 d if components of this regimen are administered individually) is recommended first line. Concomitant therapy, which includes 3 antibiotics instead of 2 used in bismuth-based quadruple, is unpopular in most countries. Metronidazole in PPI triple therapies has been mostly abandoned and reserved for individual cases (ie, amoxicillin allergy or proven susceptibility to metronidazole).
Increasing resistance to levofloxacin has excluded this antibiotic as a component in any first-line regimen. Its use is becoming increasingly worrisome even if used second line. Rifabutin is effective in the third line and recommended after repeated treatment failure as a component of a rescue regimen.
European recommendations put emphasis on testing (13C-UBT) for assessing individual treatment response. Resistance testing of the commonly used antibiotics is encouraged after treatment failures.
Southern Europe
Rising antibiotic resistance is the main issue. Pretreatment antibiotic susceptibility for clarithromycin should be determined before first-line treatment, but this is not feasible for most patients currently. Therefore, the choice of therapy is based on the local prevalence of CR. However, this information is lacking in most regions of Italy; a high prevalence, (30%), has been reported in some central and southern regions. A 10-day or 14-day bismuth-based quadruple therapy or nonbismuth concomitant quadruple therapy is recommended first-line where CR is >15% or unknown. The efficacy of these 2 regimens is not affected by CR or MR, and bismuth-based quadruple therapy performs well when there is dual resistance. Thus, bismuth quadruple therapy may be considered the best choice for empirical first-line treatment in Italy.
Standard triple therapy, PPI plus clarithromycin and amoxicillin or metronidazole/tinidazole is effective in clarithromycin-sensitive strains, but fails when there is CR. A 14-day standard triple therapy should be used first-line only in areas with a known low prevalence of CR (<15%), in patients without previous use of macrolide, or where this regimen has been proven to achieve high eradication rates.
Sequential therapy, with PPI plus amoxicillin for 5 to 7 days followed by PPI plus metronidazole and clarithromycin for 5 to 7 days, is a regimen designed to overcome the issue of clarithromycin resistance. However, data on the efficacy of this regimen are contradictory. Recent guidelines have discouraged the use of it, despite some reports from Italy of eradication rates around 90%, even with CR. Second-line treatments include levofloxacin-containing triple therapy and bismuth quadruple therapy. Probiotic supplementation could be used with the aim of reducing antibiotic-related adverse events.
North America
North America has variable clarithromycin resistance (17% to 32% in different studies) and high metronidazole (44%) resistance. Amoxicillin resistance was 6% in a recent study and rifabutin resistance was 0%. US guidelines recommend that for first-line treatment, clarithromycin triple therapy should be confined to patients with no previous history of macrolide exposure who reside in areas where clarithromycin resistance among H. pylori isolates is known to be low. Some suburban and rural areas of the country meet these criteria. First-line treatment with bismuth quadruple therapy or concomitant therapy consisting of a PPI, clarithromycin, amoxicillin, and metronidazole is recommended as first-line therapy in most areas. A combination of rifabutin, amoxicillin and omeprazole has been approved for H pylori treatment in the United States. Its role in initial therapy remains to be determined.
South and Central America
Studies on clarithromycin resistance in South and Central America remain sparse, with some rates already exceeding 20%. The highest prevalences are described in Mexico, Colombia, Argentina, and Brazil. The indiscriminate use of azithromycin (a low-cost drug) may select macrolide-resistant mutants and aggravate CR rates. Low resistance rates for amoxicillin have been documented, but some studies show a high percentage in Brazil. If this trend is confirmed, it would be an alarming situation due to the central role of these antibiotic therapies.
The classic triple regimen with PPI, amoxicillin and clarithromycin for 7 to 14 days remains the most widely used regimen, followed by bismuth quadruple therapy as alternative or second line therapy and levofloxacin-based therapy as salvage option. Reported resistance to levofloxacin is scarce, but high levels were found in Peru. The associated use of metronidazole is common for first-line quadruple therapy, but the reported prevalence of resistance is above 50% in Central America, Mexico, and in some countries of South America such as Brazil and Colombia.
Recurrence rates are above 3% to 5% per annum, with geographic variability have been reported; data are lacking from many regions. Medication cost, societal guidelines adherence by physicians, lack of UBT in many regions, unavailability of bismuth salts, furazolidone, and rifabutin in some countries, and absence of high-quality local studies to validate anti-H. pylori regimens constitute barriers to be overcome. Most health systems of the region still run suboptimally on these issues.
Africa
H. pylori and its complications are highly prevalent across Africa. In some regions, the population prevalence of infection is over 80%, and in such areas, empiric treatment for H. pylori infection is a reasonable clinical strategy in patients with uncomplicated dyspepsia. Stool H. pylori antigen testing is perhaps the most commonly available diagnostic test for active infection, but there are caveats regarding its use, as documented elsewhere in this guideline. Treatment of H. pylori infection can be problematic in Africa. Metronidazole resistance appears to be very common throughout the continent, and clarithromycin resistance is a major problem in North Africa and parts of West and East Africa. Some of these data are relatively old and likely understate the current magnitude of antibiotic resistance in the region. Although clarithromycin-based triple therapy is the standard treatment option in many African settings, clinicians should assess the success of this regimen in their local context, if only by testing for persistent infection one month after completion of therapy. Quadruple therapy may be considered as an alternative first-line treatment option. Bismuth is not available in many African countries, and in these settings, nonbismuth quadruple therapy can be used, including a high-dose PPI, high-dose amoxicillin, and 2 additional antibiotics such as tetracycline, a quinolone, rifampicin, or nitazoxanide; there is some concern that widespread rifampicin usage might hasten the emergence of MDR TB in African contexts.
