Future of Helicobacter pylori and its feasibility

KEYWORDS:

• Triple therapy
• Kyoto consensus meeting
• treatment guideline
• vonoprazan and vaccine

The microaerophilic bacterium Helicobacter pylori (H. pylori) is highly adapted to survive in the gastric mucosa of humans where it can persist for several decades [1]. Unfortunately, H. pylori infection is quite common as approximately 50% of the world population is infected with this pathogen. The recognition of H. pylori as the cause of severe gastroduodenal disorders was a massive change not only in the gastroenterology, but also in general medicine [2,3]. After the discovery of the H. pylori by Marshall and Warren, thousands of researchers have conducted investigations to find the exact association of this bacterium with those digestive diseases [4]. Host genetic factors, environmental conditions, and bacterial virulence determinants act together to initiate chronic gastritis, which may result in severe gastroduodenal disorders [3]. Even today the exact mechanisms involved in the pathogenesis of H. pylori are the focus of many laboratories worldwide [3]. The aim of this editorial is to stimulate the discussion on how H. pylori infections can best be treated. Initially, complete eradication of the bacterium was considered as the ideal goal for clinicians and scientists [5,6]. The many published guidelines on the management of this infection are clear evidence of this but in spite of these the worldwide prevalence of the bacterium is still not quickly declining [5,7,8]. In the Western world H. pylori may be slowly disappearing, but this is mostly due to improved housing conditions, lifestyle, and hygiene. These ‘non-treatment’ factors have effectively reduced the infection risks, resulting in the so-called birth cohort effect in the Western world [9]. However, we believe this strong decrease may come to a halt as higher numbers of small children go to creches, daycare, and preschools [10]. Exposure to less hygienic child conditions results in more and more youngsters are infected with difficult to treat (multi) drug resistant H. pylori [11]. While the treatment guidelines in themselves are effective on a per patient basis, we are still far from an ideal form of management of this infection on a national/global scale. The problem with H. pylori eradication treatment is: 1) they are often based on worldwide guidelines (i.e. not including local resistance data) and 2) they are rarely incorporate microbiological susceptibility data of the infecting strains. This because physicians want to quickly cure their patients and culture from biopsies is not only difficult, but also due to the slow growth of H. pylori resistance determination often takes 2 weeks [3]. Hence, solid local microbiological resistance data often lack resulting in empirical choice of antibiotics based on international guidelines.

At the recent, Kyoto global consensus meeting, a unique proposal with respect to the management of H. pylori infections was made and this proposal is the main focus of this editorial [12]. In order to achieve worldwide eradication, the newly proposed guideline defined all H. pylori–colonized persons are candidates to receive an appropriate (empirical) treatment consisting of two antibiotics combined with vonoprazan fumarate (Takecab) as acid blocker.. While one can easily argue that a global eradication of H. pylori by simple antibiotic combination therapy is not a feasible target, Japan has since then launched a program for mass-eradication of this bacterium. The program that primarily targets persons that are at increased risk to develop gastric cancer may diminish the cancer rate, but due to development of antibiotic resistance it may be less effective than estimated. Even when effective, the effect on cancer rates will only be visible in a couple of years. Nevertheless, China and Taiwan also recently started similar programs. To fight the low efficacy rate of antibiotic only therapies, the use of a novel potassium-competitive acid blocker called ‘’Vonoprazan’’ was simultaneously launched in Japan [13]. While studies showed that the use of vonoprazan fumarate increases the efficacy of current anti-H. pylori combination therapy this drug is to our knowledge not commercially available outside Japan.This surely limits the implementation of the antibiotic-based therapy as proposed at the Kyoto consensus. The main advantage of vonoprazan-based triple therapy over traditional PPI-based triple therapy is that activity of the first is less affected by the low gastric pH resulting in higher cure rates [14]. Current evidence suggests that vonoprazan can maintain a high gastric pH, thereby helping to eradicate H. pylori. Due to the acceptable eradication rates in clinical trials performed in recent years, vonoprazan-based triple therapy is highly recommended for H. pylori–colonized patients and persons who are at risk to develop gastric cancer [15,16]. Thus, wide-spread application of vonoprazan in clinical setting for mass-eradication of H. pylori may be an inevitable part of therapeutic regimens in the near future. But one has to realize that vonoprazan is not a wonder drug, and as with other anti-H. pylori triple therapy the effectivity of the combination treatment is predominantly depended on the antibiotic susceptibility of the infecting strain, and a more convenient/effective PPI is not going to change this fact. In spite of the long list of antibiotics, and combinations of antibiotics and supplementary therapeutics, most therapies will become less effective as H. pylori seems able to rapidly develop antibiotic resistance to most of them. This rapid resistance development is largely due to the fact that H. pylori does not require the acquisition of novel genes in order to become resistant as all know resistance is based on mutations in genes already present in its genome [17]. This high resistance has resulted in there not being any reliable nationwide empiric regimen left for a given population [18]. While antibiotic resistance rates are increasing no novel antibiotic are becoming available to fight the resistant bacteria due to the reduced enthusiasm by pharmaceutical companies to invest on new drugs against H. pylori. Therefore, it is to be expected that the Kyoto guideline that once more depends on the eradication of the H. pylori with antibiotics is bound to fail. Given that significant resistance rapidly emerged to all antibiotics used in any previous eradication guideline, it is our opinion that the Kyoto guidelines had better suggested to work on, for example, vaccination as an alternative method of nationwide management of this bacterium [19,20]. The implementation of antibiotics combined with preventive and therapeutic vaccination programs is, in our minds, the only feasible key toward successfully protecting against the severe gastrointestinal disorders associated with H. pylori infection. Unfortunately, vaccination is currently not commercially available, and to our knowledge not many investigators are working on this alternative route. The primary concept of H. pylori vaccination was presented after successful experiments in animal models which reported that protection against other helicobacters could be achieved by antigen-based immunization applied at the mucosal level. Unfortunately, in humans vaccinated individuals did develop an immune response but in spite of this they failed to completely prevent (prophylactic vaccines) or eradicate (therapeutic vaccines) the bacterial colonization. In part this failure could have been predicted as H. pylori is highly variable and unlike most bacteria a change of the serotype does not require a complete exchange of gene clusters but (similar to H. pylori antibiotic resistance) is depending on simple mutations (phase variation) in existing genes [19]. Thus, while neither prophylactic or therapeutic vaccines can prevent or eradicate H. pylori colonization they do reduce the load of the bacterium at the colonized sites [22,23]. This reduced colonization was initially not stressed enough but it may well be enough to delay the development of gastric cancer for a few decades. Unfortunately, most researchers were trying to develop therapeutic vaccines in order to provide a rapid solution for management of H. pylori infections [24,25]. But if one considers the potential effects of achieved bacterial load reduction on long term cancer prevention the limited studies on this subject are promising [26]. In high-risk patients, physicians and patients want more direct effects. For this, one could postulate to first use a vaccine (in order to obtain a bacterial load reduction) followed a few weeks later by a regular antibiotic treatment. This may not only provide enhanced eradication rates, but also as a welcome side effect of the lowered bacterial load also reduce the development of antibiotic resistance. To summarize in our minds simply introducing a new antibiotic-based regime is not going to solve the situation. While vonoprazan is a good enhancement of current antibiotics-based strategies, it is currently only available in Japan and even if it was available worldwide it does not offer a true alternative therapeutic strategy. Unfortunately, safe and reliable vaccines providing protection against H. pylori infection are currently not commercially available at all. Hence, we feel that the key for the future management of this infection should be in promoting research into therapeutic and prophylactic alternatives as only a combination of eradication strategies can provide a solution for the future management of this infection.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

The manuscript was not funded.