Helicobacter pylori Diagnostics and Treatment: Could a Lack of Universal Consensus Be the Best Consensus?

Helicobacter pylori testing and treatment has become a subject of intense debate and confusion worldwide in recent years, for both laboratory scientists and clinicians. The gastric pathogen H. pylori is believed to infect up to half of the world's population disproportionately, yet it remains a challenging diagnosis for many physicians worldwide. New testing mechanisms have been introduced, but no single universal approach for testing and treating H. pylori has been established to date. In effect, no population on earth has been spared from these chronic infections, but regional differences in prevalence and associated disease severity do exist. Not unexpectedly, there also exist regional approaches in the diagnosis, treatment, and management of these patients. This Q&A borrows the experience of 3 international experts in the field of H. pylori to reflect on the current status of H. pylori management and challenges on 3 separate continents, specifically Australia, Europe, and North America. Several different guidelines exist for the diagnosis/treatment of H. pylori infections. What controversy or challenges do you perceive with current guidelines? Barry Marshall: Guidelines for the treatment of H. pylori infections are aimed toward achieving a cure rate of at least 85%. In the past 10 years, because of gradually increasing resistance to macrolides, the very successful and popular combination treatment using a proton pump inhibitor (PPI),6 clarithromycin, and amoxicillin has declined in effectiveness from greater than an 85% cure rate originally, to the region of 70%–80% in some areas where long-acting macrolides have been used for 10 or more years. This has created research interest in the evaluation of newer and more intensive therapies, often with extra antibiotics added to hopefully eradicate the H. pylori without the emergence of resistant isolates. Over the years, shorter and more-intensive treatments for H. pylori infection have been tried, and these are probably worthy of further investigation. Some of these treatments have high cure rates of H. pylori within 5 days. In most cases, at least 7 days of treatment were required, and the original triple therapy mentioned above was found to be quite successful in the UK and Australia in a 7-day course, with no difference between 10 and 14 days in prospective studies. Therefore, in Australia a 7-day treatment was advocated. In the US, however, there was a difference between 7 and 10 days but no significant difference between 10 and 14 days of therapy. Therefore, in my opinion one would try to achieve the highest cure rate in the greatest number of patients with a duration of treatment that was not excessive but certainly not too short. Ultimately, my choice is to use a 10-day therapy. To avoid the high doses of concurrent antibiotics for long periods of time, clinicians have devised sequential therapies. Two strategies exist here. Strategy 1 is to give some antibacterials for the first half of the treatment and switch to completely different ones in the second half. Sequential therapy consists of a PPI with amoxicillin for the first 5 days and then clarithromycin with metronidazole and a PPI for the next 5 days. This approach has a high cure rate and is relatively cost-effective. Many variations on this plan have evolved, and in my clinic we decided that since amoxicillin gave very few side effects, we would continue the amoxicillin and PPI combination for 10 days and then add extra antibiotics in the last 5 days to that treatment so that during the final 5 days the patient was actually receiving 4 agents at once (i.e., a PPI, amoxicillin, ciprofloxacin (usually), and rifabutin. We observed cure rates of 90% in this type of therapy for patients who previously failed H. pylori eradication. Sequential and complicated therapies in patients for whom recent treatment failed are problematic for physicians, general practitioners, and government health authorities, because they often need to be customized, depending on the previous treatment of the patient, and clearly require careful motivation and compliance by the patient. Therefore, they may best be saved for specialty clinics with experience in treating H. pylori infections. In Australia, this situation is partially resolved by making these “exotic” combinations of antibiotic treatments available from the government health authorities. Nevertheless, the exotic therapies can be used with considerable success, and nearly all H. pylori patients can be successfully cured without too much inconvenience. The controversy with the current guidelines may be related to the pros and cons of different antibiotic combinations in different countries and perhaps to the decision by the managing doctor whether antibiotic sensitivity testing (i.e., endoscopy and biopsy) is required to collect further detailed information on the patient's infection before customized therapy can be initiated. In my opinion, this final issue is probably best left up to the managing physician, depending on the resources available in that clinic. Karen Goodman: The guidelines are based on summaries of published results of clinical trials and other relevant clinical studies and do not adequately account for the substantial variation known to occur across populations with respect to geography and/or socioeconomic status. The guidelines may be relevant more or less to the locations represented by the experts who developed them, but they are often adhered to by policy makers elsewhere when local guidelines are lacking. This is a problem because the variations across populations are more complex than just dividing the world into developed and developing countries, or East and West. A better, though not perfect, way to divide the world with respect to this variation is to separate populations with high and low H. pylori prevalence. For example, my work in the Canadian Arctic and that of colleagues in Alaska show that high-prevalence populations located within developed countries have H. pylori infection management and control issues similar to those encountered in the developing world. However, there will remain differences in the cost-effectiveness of specific clinical approaches owing to other differences, including bacterial strain susceptibility to therapy, the ability of individuals to adhere to complex therapies, other host factors that influence treatment effectiveness, rates of peptic ulcer disease and gastric cancer in the absence of treatment, costs of preventive measures, and costs of treating disease in the absence of preventive measures. A systematic review of clinical trials showed inadequate performance of therapies recommended in many authoritative guidelines (triple therapies that include clarithromycin), even in the locations targeted by the recommendations. As a result, the review authors encouraged clinicians to ignore irrelevant guidelines and use what works locally, which highlights a gap in the evidence given that trial-based evidence to identify what works locally is not available for most locations. In Canada, guidelines generated by the Canadian Helicobacter Study Group in the past decade have influenced practice across the country. New physicians have been educated according to these guidelines, and provincial and territorial healthcare systems have based H. pylori management policies on them. The motivation for the Canadian North H. pylori (CANHelp) Working Group, which I formed with colleagues to begin community-based H. pylori research projects in the Northwest Territories in 2007, was the widespread perception among healthcare providers and affected-community members that the current H. pylori management practices based on Canadian guidelines were not effective at managing an infection that increases the risk of gastric cancer (which is known to occur at higher rates in indigenous Arctic communities). Our current research, now taking place in communities in the Yukon and Northwest Territories, aims to generate local evidence that healthcare policy makers can use for more effective management of H. pylori infection and associated disease. The initial identification of the high prevalence of H. pylori infection in an indigenous Arctic population came from researchers with the CDC Arctic Investigations Program in Alaska. Since then, similar findings have been reported for Greenland, Canada, and Siberia. Investigators working in these areas are currently linked through the Circumpolar H. pylori Working Group, in which I represent Canada. Motivated by Brian MacMahon of the Alaska Health Department, this group has drafted recommendations for H. pylori management in high-prevalence populations, which we hope to publish. Guidelines issued by the CDC unit in Alaska to educate physicians trained in the mainland US and practicing medicine in Alaska native communities differ from Canadian and other Western guidelines, in that a test-and-treat approach is not recommended for patients presenting with dyspepsia. This is due to the high prevalence of H. pylori among Alaska natives (around 80%), the poor effectiveness of treatment, and relatively high reinfection rates. Even within this circumpolar group, we have noted some internal regional variation in the prevalence of H. pylori, antibiotic susceptibility, and reinfection rates. For this reason, we have attempted to make the recommendations robust to variation from place to place and to the availability of local information. Serology is widely used in the US to diagnose H. pylori despite practice guidelines and many medical insurance companies discouraging its use. Why has serological testing remained a standard testing method, and what role does it play in the diagnosis of H. pylori infections? Barry Marshall: Serologic testing for H. pylori is sensitive but not as specific as other “direct” diagnostic tests, such as breath tests and biopsy tests. Serology measures IgG antibody in the blood, so it detects the presence or a history of H. pylori infection. Often, low concentrations of IgG remain for many years after the eradication of H. pylori, and when H. pylori has been treated in the past year or two, moderate concentrations of IgG may persist for many months. This is useful information, because in the patient being investigated for the first time for H. pylori and who has not had recent antibiotic treatments specifically for H. pylori, a positive serologic test indicates a probable H. pylori infection, and the physician may choose to proceed with treatment on the basis of that test alone. Once the patient has been treated on one occasion for H. pylori, a positive serologic test is of very little use, since it is likely a false positive. Because of the popularity of treating H. pylori and because of the many strong antibiotics in common use, in Western countries there are many patients who still have the antibody but in whom H. pylori has been eradicated either accidentally or deliberately. These patients make up about 15% of those with positive serology. Therefore, at the very least in serologically positive patients, a confirmatory noninvasive test such as the breath test or even a stool test may be performed in patients before the treatment is commenced. Recognize that about 15% of serologic test results are false positives, and in countries where H. pylori prevalence is rather low (such as Australia, where it is 20%), at least one-third of treated patients will not actually have H. pylori, if serology alone is used for diagnosis. Follow-up tests should always include a test for actual H. pylori infection, such as the urea breath test (UBT) or the stool antigen test (SAT) or, if endoscopy is being contemplated, biopsy tests of the gastric mucosa. Francis Mégraud: H. pylori serology is an indirect method of detection and, as any serology, can lead to a false negative in cases of weak immunological response at the extreme ages of life or in cases of immunodeficiency. Furthermore, false-positive results can be seen if cross-reacting antigens are present or, taking into account the half-life of immunoglobulins, if a recent eradication occurred. A large number of kits with various accuracies are on the market. It may also be that antigenicity varies among strains from different ethnic groups. Furthermore, studies testing the accuracy of serological tests were performed in comparison to reference tests, sometimes with suboptimal performances (e.g., the lack of specificity of serology observed was, in fact, due to the lack of sensitivity of the reference method). And, when systematic reviews were performed, all of the studies were mixed without taking into account the type of kit and the reference used, leading to a poor outcome. Serology has the important advantage of being a noninvasive method that is easy to perform. In recent years, more and more patients are taking over-the-counter PPIs when they suffer from dyspepsia and seek medical attention only if the symptoms persist. PPIs do not eradicate H. pylori but lead to an important decrease in the bacterial load, which greatly decreases the sensitivity of the direct methods of H. pylori detection, leaving serology as the only valid method. As highlighted in recent guidelines, serology still plays an important role for the pretreatment diagnosis of H. pylori infection and not for follow-up after treatment, because the antibodies persist for months or even years after eradicating the bacteria. There are also other specific situations where serology is of interest, e.g., in the case of atrophy, mucosa-associated lymphoid tissue lymphoma, or gastric carcinoma, when the bacteria are reduced to below the threshold of detection by the other methods. However, given the variability in serological kits as recently published, it is imperative to use those with the best accuracy. Karen Goodman: Not all medical insurance companies discourage the use of serology. For example, in the Yukon Territory serology is the only covered H. pylori–testing method, and I believe this to be true in some Canadian provinces. Until recently, other methods were not widely available. In many areas, the SAT is not generally available to healthcare practitioners. In Alberta and the Northwest Territories, all healthcare providers must use the same laboratory to process the UBT, and they do not consider the test valid for children 5 years of age and under, although there is no doubt that it is more valid than serology for diagnosing H. pylori in this age group. I would consider the lack of availability of other methods to be a major driver for the continued use of serology, as well as the much lower cost of serology relative to other methods. There is also greater infrastructure in typical clinical care settings (and research settings) for collection of blood samples and use of serological assays relative to the infrastructure required for collection of stool samples or for the infrastructure required for the collection and, especially, the analysis of breath samples. All of this combined makes serology more convenient than other methods for most clinical care settings. In addition, many H. pylori experts believe that serology is an adequate testing method for older children and adults who have not been treated recently to eliminate H. pylori infection. This belief likely stems from early H. pylori studies, many of which showed a high correlation between seropositivity and indicators of active infection. These were generally studies of adults, most of whom would have been infected for decades, in an era when H. pylori infection had not been widely targeted for treatment. It is my impression that recent studies show more evidence of substantial of who are for H. pylori but negative on indicators of active infection, but I not that this has been in published systematic have similar performance for the and have specific populations in which one method the these tests be used Francis Mégraud: has become a reference method for H. pylori It has the advantage of not being on the of the breath to or on to or the A SAT using a antibody and an in to an method, has an accuracy to the The use of one or the other of these tests in fact, more linked to and In many patients are to give and a breath The situation may be different for who may have into a it is easy for the to a stool for In patients, the situation is different due to the sensitivity of SAT may be In the tests may be used at the extreme ages of Karen Goodman: The variation in of these tests across populations that we should not they are measures of H. pylori infection in the It is likely that there are when H. pylori through the without the a situation that a a positive SAT and a negative there is evidence that H. pylori the may not a situation that a a positive with a negative It is not that there is some between these tests, because one (UBT) detects the in its typical and the other (SAT) detects the when it is leaving the the must be for the to be but this is not required for the SAT to be positive. factors must be when which of these tests to use. Some experts believe the SAT is more for and children and it for this age group. In my research, I have found that stool samples are much to collect in the field than breath and so I have always the in settings. that method has its and some experts using more than one or the same one test or combination of tests is it is best to results according to what the test actually measures (e.g., by may or may not be H. pylori in the H. pylori antigens in may or may not be from bacteria and may or may not have the Barry Marshall: The is because it measures the in the gastric and the difference between a negative test to and positive tests high for is so that a is found between negative and positive patients. The SAT should also give a negative or positive result, but the test measures the from the Therefore, there is a less between the antigen in a negative patient a positive patient. Therefore, the SAT on a that has been decided from large of patients but may a little from patient to patient for Therefore, it is not that when have been the accuracy of the is with high and the accuracy of the SAT is in the of For the most the tests are but in my experience adults the breath there may be a or taking a breath test or in a the SAT can be In and of course, are to collect and so may be the diagnostic There is about H. pylori, antibiotics in therapies (e.g., macrolides, What is this there any Francis Mégraud: The about resistance of H. pylori to some antibiotics is for macrolides and but not for H. pylori is resistance by and not by of These are to occur and then be for when the bacteria are to the The population of H. pylori in a may have some bacteria. this population is to a the will be and the resistant ones will be for and as a population of resistant The same is true for being the antibiotic of choice H. pylori in this group, but the is The of resistant is even with than with macrolides, because the is In both cases, it is that the resistant has a different to the In other if it is to the to this resistant can when the is not there it is also that the in other on the which will the of the as for In the of resistant because macrolides or are as the only antibiotic for or infections, and the in the gastric is the best to for resistant The situation with to metronidazole is there is a lack of in testing this in even in the same This may be due to the of the to the metronidazole in a that is not there is a lack of clinical correlation between the observed and the clinical outcome. often and despite the high H. pylori eradication This can be by the with the other antibiotic and by the high in the when the treatment is For these testing for metronidazole resistance is not recommended Two have been The first is to use the antibiotics It has been that the triple therapy after 5 days of many the first treatment greatly decreases the bacterial load, including resistant the second treatment to be The second is to use a combination of not by the resistance the therapy. have that a and metronidazole given for 10 days with a PPI to a high eradication even if the strain to be metronidazole resistant in Barry Marshall: Because of the widespread use of antibiotics such as macrolides, and for the eradication of H. pylori, we do a in resistance of H. pylori to these however, H. pylori always remains to amoxicillin, and Once these are there are treatments that can be used to eradicate H. pylori infections that have failed previous therapies. The of is that the 4 antibacterials mentioned above can be in different often with a PPI, to H. Therefore, one or more of the antibiotics that resistance due to can be used in to the therapy to up the H. treatments such as PPI, and metronidazole are effective and useful for who are to the of extra such as ciprofloxacin and to a therapy of PPI and amoxicillin results in very high cure rates with therapies. is probably by widespread use of antibiotics in the in doses that are not H. but that the large population of gastric H. pylori to a There are so that most patients those to still have the of 3 or 4 different treatments with cure rates of there is for although this should be with and careful with the recommended and guidelines of therapy. pump inhibitor Canadian North H. pylori stool antigen test urea breath

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