Maastricht 5 eradication scheme recommendations. Maastricht - IV: modern eradication schemes. I working group: Diagnostics

An article of a review type devoted to one of the leading problems of gastroenterology - the choice of a proton pump inhibitor (PPI) in order to increase the effectiveness of Helicobacter pylori eradication therapy. Based on the analysis of the results of experimental and clinical studies, it was concluded that rabeprazole has a number of distinctive features among other PPIs, which determine the high expediency of its choice for successful eradication therapy. Among them - the maximum effect after the first dose; the dose of rabeprazole is lower compared to the doses of other PPIs (the highest pharmacological activity); rabeprazole more reliably suppresses the secretion of hydrochloric acid, because its destruction in the liver does not depend on the presence of polymorphisms of the cytP450 gene, and the effects of rabeprazole are predictable; rabeprazole is safe for patients taking multiple drugs at the same time; Rabeprazole has a number of pleiotropic effects. A significant argument in favor of prescribing generics has always been their lower cost compared to the cost of the original drug, but they do not always have the proper biological, pharmaceutical and therapeutic equivalence to the original drug. Currently, doctors and their patients are offered Razo®, a generic rabeprazole produced by Dr. Reddy's, which combines the high clinical efficacy of the original drug, safety of use, economic availability and high production culture in accordance with GMP criteria, registered FDA in the "Orange Book" in the category AB.

Keywords: eradication of H. pylori, proton pump inhibitors, rabeprazole, generic, Razo®.

For citation: Kazyulin A.N., Goncharenko A.Yu. Choice of proton pump inhibitor in Helicobacter pylori eradication therapy. Maastricht V // RMJ. 2017. No. 10. pp. 712-717

The choice of proton pump inhibitor in the eradication therapy of Helicobacter pylori infection. Maastricht V
Kazyulin A.N., Goncharenko A.Yu.

Moscow State Medical Dental University named after A.I. Evdokimov

The review is devoted to one of the main problems in gastroenterology - the choice of proton pump inhibitor (PPI) in order to increase the effectiveness of eradication therapy of Helicobacter pylori. Based on the analysis of the results of experimental and clinical studies, it has been concluded that rabeprazole has a number of distinctive features among the other PPIs that determine the high feasibility of its choice for successful eradication therapy. Among them - the maximum effect after the first intake; the dose of rabeprazole is lower in comparison with the doses of other PPIs (the highest pharmacological activity); rabeprazole reliably suppresses the secretion of hydrochloric acid, because its destruction in the liver does not depend on the presence of polymorphisms of the cytP450 gene, and the effects of rabeprazole are predictable; rabeprazole is safe for patients taking several drugs at the same time; rabeprazole has a number of pleiotropic effects. The lower cost of generics compared to the cost of the original drug has always been an important reason for their appointment, but they do not always have the proper biological, pharmaceutical and therapeutic equivalence to the original drug. At present, doctors and their patients are offered the Razo® generic rabeprazole produced by Dr Reddy's®, which combines the high clinical efficacy of the original drug, safety of use, economic accessibility and high production culture in accordance with GMP criteria, registered FDA in the "Orange Book" in the AB category.

key words: H. pylori eradication, proton pump inhibitors, rabeprazole, generic, Razo®.
For quote: Kazyulin A.N., Goncharenko A.Yu. The choice of proton pump inhibitor in the eradication therapy of Helicobacter pylori infection. Maastricht V // RMJ. 2017. No. 10. P. 712–717.

Article devoted to the problem of choosing a proton pump inhibitor

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Sheptulin A.A.

Elena Aleksandrovna Poluektova, doctor, candidate of medical sciences:

– Now the message “Maastricht-IV. Modern eradication schemes”, Arkady Alexandrovich Sheptulin.

Arkady Alexandrovich Sheptulin, professor, doctor of medical sciences:

- Good afternoon, dear colleagues. In order to have a better idea of ​​what the Maastricht-IV Conciliation Conference brought in, let's very briefly, very briefly recall the main provisions of the previous Maastricht-III Consensus.

Consensus "Maastricht-III", first of all, determined the main indications for eradication therapy. You know them well: this is peptic ulcer, this is MALT-lymphoma of the stomach, this is atrophic gastritis, this is a condition after gastric resection for early cancer, these are the closest relatives of patients with gastric cancer and the desire of the patient himself in cases where he has no contraindications for this .

The Maastricht-III Consensus considered three debatable issues related to the relationship of Helicobacter pylorus and diseases such as functional dyspepsia, gastropathy associated with taking non-steroidal anti-inflammatory drugs, and the relationship of Helicobacter pylorus to a wide range of non-gastroenterological diseases.

With regard to functional dyspepsia, a long-standing meta-analysis of a large number of works showed that the effectiveness of eradication in terms of eliminating the symptoms of dyspepsia is low. The NNT is 17: 17 patients we need to treat so that one patient has no complaints. Nevertheless, what Tatyana Lvovna spoke about - the importance of pyloric helicobacter in the development of stomach cancer, and also that pyloric helicobacter is the main risk factor for developing peptic ulcer in countries with high contamination - and we, unfortunately, to such We relate to countries - with functional dyspepsia, it is advisable to determine the infection of pyloric Helicobacter and, if the results are positive, to carry out eradication.

With regard to NSAID-associated gastropathy, it has been established that the risk of developing NSAID gastropathy in H.Pilori-positive patients is higher than in H.Pilori-negative patients, and that eradication reduces the risk of developing ulcers and erosions of the stomach in patients receiving NSAIDs. Before starting NSAIDs, it is advisable to investigate the presence of this infection and, if confirmed, to carry out its eradication. But a very important remark is that only the eradication of pyloric Helicobacter is not enough to prevent the occurrence of NSAID-gastropathy. Therefore, if the patient has additional risk factors for NSAID-gastropathy - advanced age, a history of peptic ulcer disease, concomitant use of corticosteroids or anticoagulants - then in addition to eradication, a cover of proton pump inhibitors is necessarily prescribed.

If we take a wide range of non-gastroenterological diseases, then only two nosological forms have been associated with pyloric Helicobacter infection: immune thrombocytopenia - there is a crossover of antibodies to pyloric Helicobacter and antibodies to platelets - and iron deficiency anemia, but in cases where the examination did not reveal other causes of iron deficiency anemia, in particular, bleeding.

As for other diseases, primarily coronary heart disease, there is currently no conclusive evidence for the connection of these diseases with pyloric Helicobacter infection.

The Maastricht-III consensus determined the main provisions in terms of diagnosing H. pylori infection. If the patient does not undergo esophagogastroduodenoscopy, then it is preferable to use a urease breath test, the determination of the pyloric Helicobacter antigen in the feces, or a serological method to diagnose this infection. Most often, we determine the presence of pyloric Helicobacter at the time of gastroduodenoscopy: say, a patient has an ulcer or erosion. Here, a rapid urease test is usually used for diagnosis.

The best way to monitor eradication is to use the urease breath test. If it is impossible to conduct it, examine the antigen of pyloric Helicobacter in feces. Very importantly, current antisecretory therapy reduces the incidence of H. pylori antigen in feces and the rate of positive breath tests.

And it is important that the definition of strains of pyloric Helicobacter - in particular, cagA-strain, vacA-strain and others - does not play any role in deciding on the treatment of patients. If any strain of pyloric Helicobacter pylori is detected, if the patient is included in the list of indications for eradication, it is carried out.

In terms of treatment, the Maastricht-III consensus defined a first-line, second-line, and back-up regimen.

The first-line regimen is a standard triple therapy, Tatyana Lvovna has already spoken about it - it includes proton pump blockers in a double dose. This is Rabeprazole, but earlier we wrote Pariet, because we did not have other drugs. Tatyana Lvovna said that now we already have other analogues of Rabeprazole, and in particular, Ontime - in combination with Clarithromycin and Amoxicillin. This scheme is prescribed if resistance to Clarithromycin in the region does not exceed 20%.

As for the second-line regimen, double-dose proton pump blockers are used here - Tetracycline, Metronidazole and bismuth preparations. It was specifically emphasized that this regimen is also effective in the case of resistant to Metronidazole.

Also, the Maastricht-III consensus found that the effectiveness for a 14-day eradication course is approximately 10% higher on average than a seven-day one.

Finally, if first-line and second-line regimens fail, the clinician has several options for how to proceed. This is to increase the dose of Amoxicillin to three grams per day in combination with even doubled - here not 4 times a day, but four times - let's say, if this is the same Rabeprazole, this is not 40 milligrams, but 80 milligrams per day for 14 days .

It was proposed to replace metronidazole in quadrotherapy regimens with furazolidone, to use in combination with proton pump blockers and amoxicillin antibiotics rifabutin or levofloxacin. The best option for a backup scheme is an individual selection of antibiotics after determining the sensitivity of the inoculated microorganisms.

What is the role of proton pump inhibitors in eradication regimens? First of all, they have an independent anti-helicobacter effect: by reducing the volume of gastric secretion, they increase the concentration of antibiotics in the gastric juice, and, most importantly, create an optimal pH for the action of antibiotics.

Tatyana Lvovna has already spoken about the significance of Rabeprazole. According to the recommendations of the Russian Gastroenterological Association, back in 2000, Rabeprazole was recognized as the most preferable for the treatment of patients with peptic ulcer. What are its advantages: unlike other proton pump inhibitors, it does not interact with the cytochrome P450 system in the liver, and, accordingly, all possible side effects associated with drug interactions are removed. The effect of Rabeprazole develops more quickly and is more pronounced. Rabeprazole is more effective than other proton pump inhibitors in inhibiting the growth of pyloric Helicobacter pylori. And it was shown at one time that a seven-day eradication course with Rabeprazole is more effective than a ten-day eradication course with Omeprazole.

It is shown here that Rabeprazole in all eradication regimens with Metronidazole, Amoxicillin, Clarithromycin has the lowest minimum inhibitory concentration, that is, it is most active against pyloric Helicobacter compared to other proton pump inhibitors.

Here it is shown that the minimum inhibitory concentration of Rabeprazole is 64 times less than that of Omeprazole. In addition, Rabeprazole enhances the production of mucus and mucin, providing protection to the mucous membrane. And here is the slide that Tatyana Lvovna already showed: Ontime is a new form, a new version, a new analogue of Rabeprazole - it is completely similar to Pariet in its pharmacodynamic and pharmacogenetic properties.

What has changed in the years that have passed since the adoption of the Maastricht-III consensus? Firstly, two new eradication schemes have become widespread: sequential therapy and the so-called concomitant. What is the meaning of these schemes? The main challenge is to overcome the rapidly growing resistance to Clarithromycin. The sequential scheme involves two five-day courses: at the beginning with a combination of proton pump inhibitors and Amoxicillin, the second five days are a combination of proton pump inhibitors with Clarithromycin and Metronidazole.

At first, the results of this scheme were perceived by the gastroenterological community with distrust, if only because all the work came from Italy, so there was no confirmation. But by 2011, similar results were obtained in European countries, in the United States of America, so at present this scheme is really considered highly effective.

As for the concomitant eradication regimen, this is a quadruple therapy regimen with an additional antibacterial drug. This is quadruple therapy without bismuth preparations. This is a standard triple therapy, to which another antibacterial drug is added. Most often it is Metronidazole. You can see that the effectiveness of concomitant therapy is also high and reaches 90%.

The use of regimens with Levofloxacin has become widespread. At the beginning, a daily dose of 500 milligrams was used, at present it is 1000 milligrams. Levofloxacin was prescribed instead of Clarithromycin in standard and sequential therapy regimens. True, the rapidly growing resistance to Levofloxacin immediately turned out to be a serious problem.

So what was the conclusion of the Maastricht IV consensus? You see: 45 experts from 26 countries discussed various issues - indications for eradication, diagnosis and treatment, prevention and screening of cancer. A decision was considered adopted if more than 70% of those present voted for it, and you see three issues that were discussed.

So, with regard to functional dyspepsia. In general, in relation to the testimony, nothing, probably, new in comparison with "Maastricht-III" was positioned. In countries with a high prevalence of H. pylori infection, eradication is indicated for patients with functional dyspepsia. Here I write the diagnosis “chronic gastritis with clinical symptoms” in parentheses, because in our country the majority of doctors, especially general practitioners, still use the clinical diagnosis “chronic gastritis”.

It was reconfirmed that the eradication of Helicobacter pylorus is not a cause of GERD, does not cause an exacerbation of GERD, does not affect the effectiveness of its treatment. However, it has been noted that there is a negative correlation between infection with Helicobacter pylorus, GERD, Barrett's esophagus and the development of esophageal adenocarcinoma.

As for non-gastroenterological diseases, eradication, as we have already said, is carried out in patients with autoimmune idiopathic thrombocytopenia and idiopathic iron deficiency anemia. Eradication may be effective in B12-deficiency anemia, but the level of evidence is still low.

Like the Maastricht-III consensus, Maastricht-IV found that Helicobacter pylorus increases the risk of developing NSAID-gastropathy, so eradication is indicated for patients receiving these drugs for a long time. Eradication can reduce the severity of atrophy in the fundus of the stomach, which is very important in terms of cancer prevention, but does not affect the severity of intestinal metaplasia.

In terms of diagnosis, the two main tests, the urease test and the fecal antigen test, are equivalent in accuracy. As for the serological method, this is the only method whose results are not affected by the contamination of pyloric Helicobacter (I mean the degree), the presence of mucosal atrophy, the use of antisecretory drugs and antibiotics. But it was specifically emphasized that in order to obtain accurate results, it is necessary to determine antibodies only of the immunoglobulin G class.

If the patient is receiving proton pump inhibitors, then they should be stopped two weeks before testing. If proton pump inhibitors cannot be discontinued, then serology should be used. As for the microbiological method, the culture of microorganisms must be obtained from patients with treatment failure for individual selection of drugs.

The new thing that was introduced into diagnostics by the Maastricht-IV regulation is the introduction of molecular methods into clinical practice. For example, a different real-time chain reaction that is used to detect resistance to Clarithromycin.

The Maastricht IV Consensus has reduced the number of eradication regimens currently available. What's left? This is the standard triple regimen (7 or more days), this is the sequential regimen (10 days), this is the bismuth quadruple regimen (also 10 days), this is the concomitant regimen we talked about (10 days) and the only backup regimen with Levofloxacin ( also lasting at least 10 days).

How to apply these schemes? The use of regimens is determined by the rates of resistance to Clarithromycin in a given region. If resistance does not exceed 10%, standard triple therapy can be used as a first-line regimen without prior testing. If Clarithromycin resistance rates range from 10 to 50%, then preliminary testing for sensitivity to this antibiotic is necessary.

What do we see in the countries of Western Europe? The same sensitivity in Austria and Hungary shows that the two countries were once one country. But at the same time, we are seeing very low levels of sustainability in, say, Ireland and Germany.

As for our country, you see: various studies conducted in St. Petersburg, Smolensk, Nizhny Novgorod and Novosibirsk showed that resistance to Clarithromycin in our country is less than 10%. This means that we are following the recommendations for regions with low Clarithromycin resistance. In this case, the standard triple therapy remains the first-line regimen. Bismuth sequential therapy or quadruple therapy can be used. As a second-line regimen, a quadruple therapy regimen with bismuth preparations or triple therapy with Levofloxacin. And the third-line scheme is based on individual determination of sensitivity to antibiotics.

It was again confirmed that doubling the dose of proton pump inhibitors can increase its effectiveness by about 5%. For the first time, it was officially stated that the use of probiotics as adjuvant therapy along with antibiotics in eradication regimens can increase efficacy. We used to widely prescribe probiotics, in particular Enterol, but mainly to reduce the risk of side effects, intestinal disorders. But it turned out that it is possible to increase the effectiveness of eradication in this way.

Efficiency monitoring, as before, should be carried out 4 weeks after eradication, using a urease breath test or fecal antigen determination.

As for the relationship between pyloric Helicobacter and stomach cancer, Tatyana Lvovna spoke about this in great detail, that eradication prevents the development of stomach cancer and its recurrence after surgical treatment. But the best results are achieved when eradication is carried out before severe atrophy and intestinal metaplasia.

Tatyana Lvovna has already spoken about the recommendations of the Russian Gastroenterological Association, made on the basis of Maastricht-IV, taking into account the specifics of our country. Given that resistance to Clarithromycin in Russia does not exceed 10%, the standard triple therapy remains the first-line regimen. There are measures that can improve its effectiveness: this is an increase in the dose of proton pump inhibitors, an increase in the duration of treatment and the addition of bismuth preparations, in particular tripotassium dicitrate.

As a variant of the first-line eradication scheme, classical four-component therapy can be used. This regimen can also be used as a second-line therapy regimen in case of failure of standard triple therapy. And triple therapy with Levofloxacin can be prescribed after an unsuccessful attempt at eradication with a regimen of standard triple therapy and quadruple therapy with bismuth tripotassium dicitrate.

So, once again summing up that the first-line regimen in our country is standard triple therapy and quadruple therapy with bismuth preparations, the second-line regimen is quadruple therapy with bismuth preparations and triple therapy with Levofloxacin, and the third-line regimen is selected individually, taking into account the results of determining antibiotic resistance.

Thus, to summarize, we can say that the main indications for the eradication of Helicobacter pyloric infection remain the same. The choice of eradication scheme depends on the level of resistance of Helicobacter pylori strains to Clarithromycin. The main eradication regimens at present are the standard triple regimen, the quadruple therapy regimen with bismuth tripotassium dicitrate. As for sequential and concomitant therapy, you noticed that we do not yet recommend them in our Russian recommendations, since we do not have experience of the effectiveness of this regimen in our country. When we get the first results, then we will discuss the place of these schemes.

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STRATEGY TEST TREATMENT

  1. A test-treat strategy can be used for unexplored dyspepsia in populations with a high prevalence (>20%). This approach is based on a local risk/benefit ratio and is not applicable to patients with anxiety symptoms, older individuals with an increased risk of cancer (1a, A).
  2. The main non-invasive tests used for the test-treatment strategy are the urease breath test and the determination of monoclonal antigens in feces. Some validated serological tests can also be used (2a, B).

Acidity and functional dyspepsia

  1. Helicobacter pylori eradication produces long-term relief of dyspepsia in 1 in 12 patients with Helicobacter pylori infection and functional dyspepsia and is superior to other treatments (1a, A).
  2. Helicobacter pylori infection can increase or decrease secretion depending on the extent of inflammation in the stomach (2b, B).

Helicobacter pylori and gastroesophageal reflux disease

  1. Helicobacter pylori infection does not affect the severity, frequency of symptoms, or efficacy of therapy in gastroesophageal reflux disease. Eradication of Helicobacter pylori does not exacerbate gastroesophageal reflux disease and does not affect the effectiveness of treatment (1a, A).
  2. Epidemiological studies demonstrate an inverse relationship between the prevalence of Helicobacter pylori on the one hand, the severity of gastroesophageal reflux disease and the incidence of adenocarcinoma of the esophagus, on the other (2a, B).

Helicobacter pylori, aspirin and non-steroidal anti-inflammatory drugs

  1. Helicobacter pylori is associated with an increased risk of complicated and uncomplicated gastroduodenal ulcers in patients taking non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin (2a, B).

Helicobacter pylori eradication reduces the risk of complicated and uncomplicated gastroduodenal ulcers associated with NSAIDs and low-dose aspirin (1b, A).

  1. Helicobacter pylori eradication is useful before starting NSAID therapy. Eradication is mandatory for a history of peptic ulcer disease (1b, A).

One eradication of Helicobacter pylori does not reduce the incidence of gastroduodenal ulcers in patients already receiving long-term NSAIDs. In this case, continued treatment with proton pump inhibitors (PPIs) and eradication of Helicobacter pylori is required (1b, A).

  1. Testing for Helicobacter pylori should be performed in patients with a history of gastroduodenal ulcer who are taking aspirin. The long-term incidence of bleeding ulcers is low in patients who have received eradication, even in the absence of gastroprotective treatment (2b, B).

Helicobacter pylori and proton pump inhibitors

10a. Long-term treatment with PPIs in patients with Helicobacter pylori is associated with the development of gastritis predominantly in the body of the stomach. The process of loss of specialized glands is accelerated, leading to atrophic gastritis (1c, A).

10b. Eradication of Helicobacter pylori in patients receiving long-term PPI leads to a cure for gastritis and prevents the progression of atrophic gastritis. However, there is no evidence that the risk is reduced (1b, A).

Provisions on intestinal metaplasia

11a. Evidence is accumulating that post-Helicobacter pylori eradication improves corpus function. However, the extent to which this is related to the regression of atrophic gastritis remains unclear (2a, B).

11b. There is no evidence that eradication of Helicobacter pylori leads to regression of intestinal metaplasia (2a, B).

Helicobacter pylori and MALT lymphoma

  1. Helicobacter pylori eradication is the first line treatment for low-grade borderline lymphoma (1b, A).

Regulations on extragastric diseases

  1. There is evidence of an etiological role for Helicobacter pylori in unexplained iron deficiency, idiopathic thrombocytopenia, and vitamin B12 deficiency. In these situations, it is necessary to identify and treat Helicobacter pylori (for iron deficiency anemia - 1a, A, for idiopathic thrombocytopenia - 1b, A, for vitamin B12 deficiency - 3b, B).

Available evidence does not reveal a clear causal relationship between Helicobacter pylori and other extragastric diseases, including cardiovascular and neurological.

  1. It has been proven that Helicobacter pylori does not have a protective effect against bronchial asthma and atopy, obesity and related diseases, and that the eradication of Helicobacter pylori causes or worsens these diseases.
  2. In patients with Helicobacter pylori, eradication of Helicobacter pylori improves the bioavailability of thyroxine and L-dopa (2b, B).

TREATMENT OF HELICOBACTER PYLORI INFECTION

Diagnostic non-invasive tests

  1. The diagnostic accuracy of detecting Helicobacter pylori antigens in feces, validated by a monoclonal laboratory test, is equal to the urease breath test (1a, A).
  2. Not all serological tests are equal. Due to the variable accuracy of various commercial assays, only validated IgG serological assays should be used (1b, B).
  3. Validated serological tests can be used for recent use of antimicrobials and antisecretory drugs, for bleeding ulcers, atrophy, and gastric cancer (1b, B).
  4. In patients treated with PPIs:

1) if possible, PPIs should be discontinued 2 weeks before testing with culture, rapid urease test, urease breath test, or fecal Helicobacter pylori antigen testing (1b, A).

2) If this is not possible, a validated IgG serological test can be performed (2b, B). Endoscopic strategy

  1. 1) It is important to determine culture and standard antimicrobial susceptibility in regions or populations with high clarithromycin resistance before initiating first-line therapy if a standard clarithromycin-containing regimen is being used.

Culture and standard antimicrobial susceptibility testing should be performed in all regions before second-line therapy, for another reason, or when second-line therapy has failed (5, D).

2) If standard susceptibility testing is not possible, a molecular test can be used to detect H. pylori and resistance to clarithromycin and/or fluoroquinolone on gastric biopsy (1b, A).

  1. 1) If H. pylori is isolated from gastric biopsies, the susceptibility test should include metronidazole (1b, A).

2) If susceptibility to clarithromycin is determined by molecular testing, additional culture determination of resistance to metronidazole is not justified (5, D).

  1. Triple therapy with PPIs and clarithromycin should be discontinued without prior clarithromycin susceptibility testing if clarithromycin resistance in the region is greater than 15–20% (5, D).
  2. In regions with low levels of clarithromycin resistance, clarithromycin regimens are recommended as first-line empiric therapy. An alternative is the appointment of quadruple therapy with a bismuth preparation (1a, A).
  3. Prescribing a high dose of PPI (twice daily) improves the efficacy of triple therapy (1b, A).
  4. An increase in the duration of triple therapy with PPI and clarithromycin from 7 to 10-14 days increases the eradication success rate by 5% (1a, A).
  5. The effectiveness of the schemes "PPI + clarithromycin + metronidazole" and "PPI + clarithromycin + amoxicillin" is the same (1a, A).
  6. Several pro- and prebiotics show promising results as adjunctive therapies to reduce side effects (5, d).
  7. PPI-clarithromycin-containing regimens should not be tailored to the characteristics of the patient, other than the dose (5, d).

Second line therapy

  1. 1) After a failed PPI plus clarithromycin regimen, bismuth quadruple therapy or levofloxacin triple therapy is recommended (1a, A).

Third line therapy

Areas with high levels of clarithromycin resistance, first-line therapy

  1. In regions with high levels of clarithromycin resistance, bismuth quadruple therapy is recommended as first-line empiric therapy. If this regimen cannot be implemented, sequential therapy or quadruple therapy without bismuth is recommended (1a, A).

Regions with high levels of clarithromycin resistance, second- to third-line therapy

  1. 1) Triple therapy with levofloxacin is recommended after failure of bismuth quadruple therapy in areas with high clarithromycin resistance (5, d).

2) The growing level of resistance to levofloxacin should be taken into account (2b, B).

  1. After failure of second-line therapy, treatment should be based on antibiotic susceptibility testing whenever possible (4, A).

When to penicillin

  1. In penicillin-allergic patients in areas of low clarithromycin resistance, PPI + clarithromycin + metronidazole may be given as first-line therapy.

Bismuth quadruple therapy is preferred in regions with high clarithromycin resistance (2c, B).

THERAPY CONTROL

  1. The urease breath test and laboratory-validated monoclonal test for Helicobacter pylori antigens in stool are recommended as non-invasive tests to assess the success of eradication therapy. Serology is not used (1a, A).
  2. To determine successful eradication of H. pylori, the interval after completion of therapy should be at least 4 weeks (2b, B).
    1. 1) In uncomplicated duodenal ulcer after treatment with Helicobacter pylori, continued PPI treatment is not recommended (1a, A).

2) For gastric ulcer and complicated duodenal ulcer, continued PPI is recommended (1b, A).

  1. Eradication therapy for bleeding ulcers should begin as soon as oral feeding is resumed (1b, A).

PREVENTION OF CANCER AND OTHER COMPLICATIONS

  1. Helicobacter pylori infection is the most persistent risk factor for stomach cancer. Elimination of Helicobacter pylori is the most promising strategy for reducing the incidence of gastric cancer (1a, A).
  2. There is strong evidence that Helicobacter pylori infection has a direct mutagenic effect in animal models and cell lines (C).
  3. Bacterial virulence factors influence the risk of gastric cancer, but there are no specific markers of bacterial virulence that can be recommended for clinical practice (1a, A).
  4. Host genetic factors influence the risk of gastric cancer, but there are no specific markers for genetic testing that can be recommended for clinical practice at present (1b, A).
  5. The influence of environmental factors is inferior to the influence of Helicobacter pylori infection on the risk of gastric cancer (1a, A).
  6. Histopathological changes at the morphological level indicate that:

1) stomach cancer rarely develops in the absence of chronic gastritis;

2) the prevalence and severity of gastritis, together with atrophy, are associated with the development of cancer (2b, A).

  1. Mechanisms at the functional level indicate that:

1) atrophic gastritis of the body of the stomach causes hypochlorhydria;

2) hypochlorhydria promotes the growth of non-Helicobacter pylori organisms that are capable of producing metabolites with carcinogenic potential (2c, A).

  1. Helicobacter pylori eradication abolishes the inflammatory response and slows down and may stop the progression of atrophy. In some cases, atrophy may decrease (1a, A).
  2. There is strong evidence that eradication of Helicobacter pylori reduces the risk of gastric cancer (1c, A).
  3. The risk of gastric cancer can be more effectively reduced by eradication therapy before the development of precancerous conditions (1a, A).
  4. Helicobacter pylori eradication for gastric cancer prevention is cost-effective in certain high-risk populations (3, B).
  5. Helicobacter pylori eradication brings additional clinical and economic benefits in addition to the prevention of gastric cancer (1a-4 for various diseases).
  6. The Helicobacter pylori screening-treatment strategy should be used in groups at significant risk for gastric cancer (2c, A).
  7. Validated serological tests for Helicobacter pylori and markers of atrophy (eg, pepsinogens) are the best available tests to identify individuals at high risk for gastric cancer (1a, B).
  8. Risk stratification of patients with premalignant gastric conditions is useful and can be based on the severity and extent of the injury (2b, B).
  9. Helicobacter pylori eradication for the prevention of stomach cancer can be used in the following cases:
  • first-degree relatives of family members with stomach cancer;
  • patients with previous gastric cancer who underwent endoscopic treatment or subtotal;
  • patients with severe paraangastritis, gastritis predominantly of the body of the stomach, severe atrophy;
  • patients with chronic gastritis and low acidity for more than 1 year;
  • patients with pronounced environmental risk factors for gastric cancer (heavy smoking, high exposure to dust, coal, quartz, cement and / or work in a quarry);
  • Helicobacter pylori-positive patient with fear of gastric cancer (1a-4).
  1. Helicobacter pylori eradication to prevent gastric cancer should be considered in high-risk populations (1c, A).
  2. Factors to consider when developing prevention strategies should include:
  • the incidence of gastric cancer in this population;
  • the likelihood of a change in the incidence of cancer if the intervention is not carried out;
  • availability of conditions in primary health care and other logistics;
  • the likelihood of adherence to a given population;
  • availability of resources;
  • the possibility of re-testing and treatment in case of ineffective eradication (A).
  1. The combination of antibiotics is selected according to local resistance patterns (2b, B).
  2. Vaccination may be the best choice to eliminate Helicobacter pylori infection in a population. Serious efforts are needed to develop a vaccine (4, A).

21: (a) High-risk precancerous conditions require endoscopic follow-up.

(b) Prospective studies are needed to evaluate the optimal control interval (2c, A).

The article was prepared and edited by: surgeon

A.G. Evdokimova, L.V. Zhukolenko, G.S. Slobodkina, A.V. Tomova
MGMSU them. A.I. Evdokimova, Moscow
City Clinical Hospital No. 52, Moscow

The article discusses the European guidelines for the eradication of H. pylori. The expansion of indications for eradication therapy, the growth of resistance to the antibiotics used, as well as the increase in doses of proton pump inhibitors are emphasized.
Key words: peptic ulcer, eradication, recommendations.

Current treatment of Helicobacter-associated disorders (according to the IV Maastricht Consensus, 2010)

A.G.Evdokimova, L.V.Zhukolenko, G.S.Slobodkina, A.V.Tomova
A.I.Evdokimov MSMSU, Moscow
City Hospital №52, Moscow

The article discusses current guidelines on the eradication of H. pylori. Paper spotlights widening of indications for the eradication, increase in bacterial resistance level to antibiotics, and increasing of proton pump inhibitors doses.
Keywords: peptic ulcer, eradication, guidelines.

About the author:
Evdokimova Anna Grigorievna – Doctor of Medical Sciences, Professor, Department of Therapy No. 1 of the Faculty of Postgraduate Education of the Moscow State University of Medicine and Dentistry named after I.I. A.I. Evdokimova

In 1983, Australian researchers B. Marshall and R. Warren independently isolated a microorganism from a biopsy specimen of a patient with chronic antral gastritis, subsequently named Helicobacter pylori (H. pylori). This discovery marked the beginning of a new branch of development of gastroenterology, forced the world medical community to revise a number of provisions on the pathology of the gastroduodenal zone and single out a group of Helicobacter-associated diseases. According to modern concepts, H.pylori is an important link in the etiopathogenetic development of chronic gastritis type B, peptic ulcer of the stomach and duodenum, MALT-lymphoma and non-cardiac gastric cancer. In order to study the pathogenesis of H.pylori-associated diseases, the European Helicobacter pylori Study Group (EHSG) was established in 1987, under the patronage of which conciliation conferences were held, with the participation of leading experts in this field of research, clinical data were summarized and discussed, recommendations for the diagnosis and treatment of H. pylori were made.
The first recommendations were developed in the city of Maastricht in 1996, in connection with which they got their name - "The First Maastricht Consensus". As new data on H. pylori are obtained, every five years, a revision of the document regulating the tactics and strategy for managing patients suffering from Helicobacter-associated diseases is carried out. By tradition, all conciliation meetings, regardless of their location, began to bear the name of the Maastricht Consensus. Under the auspices of the EHSG, conferences were held and recommendations Maastricht-II (2000) and Maastricht-III (2005) were developed. The last revision of the recommendations took place in 2010 in the city of Florence (Maastricht IV). The full text of the recommendations was published in February 2012 in the journal Gut, in English. The translation of the recommendations into Russian (in full) can be found in the additional issue of the Bulletin of the Practical Doctor.
The IV conciliation conference was attended by 44 experts from 24 countries. The working group considered three sets of tasks associated with H. pylori infection:
clinical scenarios and indications for the treatment of H. pylori infection;
diagnostic tests and treatment of infection;
prevention of stomach cancer and other complications.
Recommendations are based on modern and reliable data (according to the developed classes and levels of evidence-based medicine, formulated at consensus conferences).

Clinical scenarios and indications for the treatment of H. pylori infection
Indications for the diagnosis and treatment of H. pylori infection (Maastricht-III and Maastricht-IV) included such pathological conditions as:
dyspepsia of unspecified etiology (unexplored dyspepsia);
functional dyspepsia (FD);
gastroesophageal reflux disease (GERD);
NSAID gastropathy;
extragastrointestinal diseases associated with Helicobacter pylori infection.
Consensus (III and IV) distinguished the concepts of examined and unexamined dyspepsia. For undiagnosed dyspepsia, a test and treat strategy was recommended - diagnose and treat in areas with a high prevalence of H. pylori infection (above 20%), in young patients without the presence of so-called “anxiety” symptoms. This strategy involves the use of non-invasive tests to detect H. pylori infection: a urease breath test or a stool test for the presence of antigens using monoclonal antibodies. The clinical effect is achieved at a minimum cost (endoscopic examination is excluded), without psychological and physiological discomfort for the patient.
In FD, eradication therapy is recognized as the optimal and effective method of treatment and is recommended for all infected patients. H. pylori eradication was found to produce complete and lasting relief of FD symptoms in 1 in 12 patients, with an advantage over other treatments. It was emphasized that infection with H. pylori can cause both an increase and a decrease in the level of acidity of gastric juice, depending on the nature of the inflammatory process of the mucous membrane.
Regarding the tactics of treating patients with H. pylori-associated GERD, the recommendations remained almost the same. H. pylori infection does not significantly affect the severity of the course, the recurrence of symptoms and the effectiveness of treatment.
The new consensus document noted a negative relationship between the prevalence of H. pylori and the severity of GERD, as well as the incidence of Barrett's esophagus and adenocarcinoma of the esophagus.
In the materials of the III Maastricht Agreement there are indications of a synergistic damaging effect of H. pylori and non-steroidal anti-inflammatory drugs (NSAIDs) on the gastric mucosa. The IV Maastricht Agreement recommends that all patients requiring long-term use of NSAIDs, selective cyclooxygenase-2 inhibitors or acetylsalicylic acid should be diagnosed and treated for H. pylori infection. In addition, the need for long-term use of proton pump inhibitors (PPIs) in this category of patients along with anti-Helicobacter therapy was emphasized.
The issue of the effect of anti-Helicobacter therapy on atrophy and intestinal metaplasia of the mucosa was discussed. A meta-analysis of 12 studies involving 2658 patients showed that eradication of H. pylori in atrophy significantly improves the condition of the mucous membrane of the body, but not the antrum, and does not affect intestinal metaplasia.
Eradication therapy is the first-line therapy for low-grade gastric lymphoma (MALT-lymphoma). In the early stages of the development of MALT-lymphoma (I-II stage), anti-Helicobacter therapy in 60-80% leads to a cure. In the presence of translocation, this type of treatment is not effective, and additional alternative methods are required.
With regard to extragastrointestinal diseases, there is evidence of a connection between Helicobacter pylori infection and the development of iron deficiency anemia of unspecified etiology (in 40% of cases), idiopathic thrombocytopenic purpura (in 50% of cases) and vitamin B12 deficiency.
Available data do not allow us to state that there is a clear relationship between other diseases, including diseases of the cardiovascular system and neurological diseases. The relationship between H.pylori and a number of neurological diseases was revealed: stroke, Alzheimer's disease, Parkinson's disease. However, the data obtained are insufficient to establish a clear causal relationship or interaction with treatment.
A negative relationship has been demonstrated between H. pylori infection and the spread of certain diseases such as asthma, obesity and allergies in childhood.
It has been established that in some patients infected with H. pylori, eradication increases the bioavailability of drugs, in particular, thyroxine and L-dopa.

Diagnostic tests and treatment of H. pylori infection
Within the framework of recent consensuses, the issue of concepts and criteria for the primary diagnosis of H. pylori infection was considered. Priority was given to non-invasive methods, primarily the urea breath test and the analysis of feces for the presence of antigens using monoclonal antibodies, and their virtual equivalence was emphasized. In some cases (antibiotics, PPIs, gastrointestinal bleeding, atrophy of the gastric mucosa, stomach cancer) associated with a decrease in bacterial load, it is possible to use serological methods for determining H. pylori. The IV Maastricht Agreement emphasizes the great variability of antigens used in commercial serological test systems and recommends only standardized tests for the detection of Ig-G antibodies.
The use of PPIs can cause false positive results for all diagnostic methods (with the exception of serological methods). In connection with the above, it is recommended to stop taking PPIs two weeks before culture studies. If it is impossible to cancel the drugs, priority is given to serological tests with the determination of Ig-G antibodies.
Maastricht-III (2005) recommended the use of a combination as first-line anti-Helicobacter therapy:
PPI at standard dose;
(omeprazole 20 mg, lansoprazole 30 mg, rabeprazole 20 mg, or esomeprazole 20 mg);
clarithromycin (CLR) 500 mg;
amoxicillin (AMC) 1000 mg or metronidazole (MTR) 500 mg
All drugs were prescribed 2 times a day, lasting at least 10–14 days.
As a second-line therapy (quadrotherapy):
bismuth tripotassium dicitrate (BCM) 120 mg 4 times a day;
tetracycline (TTP) 500 mg 4 times a day;
metronidazole (MTR) 500 mg 3 times a day;
PPI at standard dose.
In some cases, the use of quadruple therapy as first-line therapy was allowed.
In the IV Maastricht Consensus, various approaches to prescribing therapy are proposed, depending on the resistance of the microorganism to clarithromycin (CLR). These recommendations are based on data from more than a hundred meta-analyses of the effectiveness of various anti-Helicobacter therapy regimens conducted from 1992 to 2010. . With resistance to CLR, the effectiveness of the standard three-component eradication scheme (including CLR) is significantly reduced and is no more than 10-30%. In the absence of an effect on primary therapy, when choosing a second line of therapy during endoscopy, a standard determination of sensitivity to antibiotics is necessary, which is associated with a high probability of resistance to antibacterial drugs. In the absence of a response to second-line therapy, antibiotic susceptibility testing is performed in all cases. A culture method for identifying H. pylori susceptibility to CLR is recommended in regions where the frequency of resistance of H. pylori strains exceeds 15–20%. At the same time, it was noted that if it is not possible to perform a cultural study of sensitivity, it is advisable to use molecular methods for determining sensitivity directly in biopsy specimens to determine resistance to CLR, as well as to fluoroquinolone antibiotics.
Thus, the IV Maastricht Consensus somewhat expanded the indications for determining the sensitivity of H. pylori to antibacterial drugs:
Before prescribing standard triple therapy in regions with high resistance to CLR (above 15–20%).
Before prescribing second-line therapy during endoscopy in all regions.
If second-line therapy fails.
In accordance with the new recommendations, the choice of an anti-Helicobacter therapy regimen is dictated by the level of HP resistance to antibacterial drugs in a given region.
I. If resistance to CLR does not exceed 15-20%, then standard triple therapy can be used as first-line therapy:
IPP + KLR + AMK or IPP + KLR + MTP or
standard quadruple therapy with bismuth preparation: PPI+MTR+TTR+VSM.
Currently, schemes with AMK and MTP are considered equivalent. Dosages of drugs remain the same. An innovation of the IV Maastricht Agreement is the introduction of regulated treatment regimens for patients with allergies to penicillin drugs. In such cases, the scheme with AUA is excluded, triple therapy with levofloxacin is possible: PPI + CLR + levofloxacin.
As a second-line therapy, standard quadruple therapy with a bismuth preparation is used (PPI + MTR + TTR + VSM). In case of inefficiency, an individual selection of the drug is carried out based on the sensitivity of H. pylori to antibacterial drugs - third-line therapy (table).
II. In regions with high resistance to CLR, only bismuth therapy - quadruple therapy (PPI + MTR + STR + VSM) is recommended as first-line therapy. In countries where this drug is not available (France), sequential eradication therapy should be considered as an alternative therapy:
PPI+AMK 5 days, then PPI+CLR+MTR 5 days or
bismuth-free quadruple therapy: PPI+CLR+AMA+MTR.
Sequential anti-Helicobacter therapy has not been discussed in previous consensuses, but a series of successful studies in recent years has made it possible to include it in the latest recommendations. Consistent prescription of antibacterial drugs - overcoming the resistance of H. pylori to CLR and reducing side effects from the use of antibacterial drugs.
Triple therapy with levofloxacin is recommended as second-line therapy: PPI + levofloxacin + AUA.
If there is no effect, to continue treatment, it is necessary to determine the sensitivity of H. pylori to antibacterial drugs (see table). Consensus materials emphasize the rapid growth of levofloxacin-resistant strains of H. pylori.
A 2010 consensus showed that prolongation of triple therapy from day 7 to day 10–14 increased the eradication rate by an average of 5%, and not by 12% as previously thought.
To evaluate the effectiveness of anti-Helicobacter therapy, standard non-invasive tests are used (breath test with urea and analysis of feces for the presence of antigens using monoclonal antibodies), serological methods are not recommended. The result of eradication is determined at least 4 weeks after the end of treatment.
It has been argued that the administration of high doses of PPIs (twice a day) increases the effectiveness of triple therapy by 8%.
It was noted that the inclusion of certain types of probiotics and prebiotics in standard triple therapy significantly reduces the incidence of side effects from the use of antibacterial drugs, but this issue requires further study.
For the first time, the expert council of the latest consensus clearly regulated the indications and duration of acid-suppressive therapy. In uncomplicated duodenal ulcers, the use of PPIs after eradication is not recommended. On the contrary, with gastric ulcer and complicated course of duodenal ulcer, continued treatment with PPI is indicated. In the case of ulcerative bleeding, eradication therapy is recommended to begin immediately after the resumption of oral nutrition, to reduce the frequency of rebleeding.

Prevention of stomach cancer and other complications
The prevalence of gastric cancer in the population and high mortality (about one million people per year) in the outcome of the disease.
According to some researchers, infection with H. pylori increases the risk of developing stomach cancer by about six times. At the moment, the pathogenetic relationship between gastric cancer and H. pylori is the subject of numerous studies in the field of genetics, morphology and pathophysiology. According to the Maastricht Consensus III, pathogenic carcinogens include bacterial virulence factors, aggravated family history, autoimmune pathology, nutritional factors, and socioeconomic factors. Maastricht IV expanded these provisions. To date, there is evidence of a direct mutagenic effect of H. pylori in cell lines and animal models. However, a specific genetic marker recommended for use in clinical practice has not yet been found.
One of the topical issues is the possibility of preventing and inhibiting paroneoplastic processes in the gastric mucosa (atrophy and intestinal metaplasia) by anti-Helicobacter pylori therapy. A recent meta-analysis showed that atrophy can regress, but only in the body of the stomach. Intestinal metaplasia is an irreversible process.
The latest consensus highlights when eradication should be performed to prevent the development of gastric cancer:
diagnosis of gastric cancer in relatives, the first degree of kinship;
patients with a history of gastric neoplasm who underwent endoscopic examination or subtotal resection of the stomach;
patients suffering from high-risk gastritis;
patients with chronic suppression of gastric acid production (more than a year);
patients with external risk factors for stomach cancer (smoking, exposure to dust, coal, quartz);
H.pylori-positive patients who fear the development of stomach cancer
The statement about the need to develop a vaccine is accepted, since vaccination may be the best way to eliminate H. pylori infection in the population.

Conclusion
Thus, the history of the European recommendations for the diagnosis and treatment of H. pylori infection has more than 15 years. The last period was marked by a number of significant additions:
Attention is drawn to the expansion of indications for eradication therapy.
The growth of resistance to CLR dictates the need for rational use of drugs, the need to improve and integrate new regimens. Use as first line quadruple therapy and sequential therapy. New treatment regimens with levofloxacin have been introduced for patients allergic to penicillin drugs, and a treatment option is being considered for regions where bismuth drugs are not available. The use of drugs with a low level of resistance to H. pylori: bismuth drugs, TTR, AMK.
The use of high dose PPIs in first-line triple therapy protocols is recommended.
Significantly strengthened the position of supporters of the prevention of gastric cancer through eradication therapy.

Literature
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