It has been nearly 30 years since Australian scholars Warren and Marshall first reported the successful culture of Helicobacter pylori (H. pylori) and linked its infection to peptic ulcer and chronic gastritis. During this time, several international and national consensus opinions have been developed to promote and standardize the prevention and treatment of H. pylori-related diseases, including the Second Asia-Pacific Consensus, the Second World Gastroenterology Organization Consensus for Developing Countries, the Fourth Maastricht International Consensus, and the North American/European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Consensus. These our third national consensus report on selected issues in H. pylori infection was held in 2007, and a fourth consensus meeting is scheduled for 2012. These new consensuses will be useful for our current clinical work and for the revision of the national consensus. The following is a concise answer to the question “who should be treated, what is the most appropriate method of detection, and what is the most appropriate treatment protocol.
I. Who should be treated
The Maastricht-IV (latest) consensus states that there is strong evidence that eradication of H. pylori reduces the risk of gastric cancer.
H. pylori should be eradicated to prevent gastric cancer in the following cases.
(1) Immediate family members with gastric cancer.
(2) long-term use of acid-suppressing drugs for more than 1 year.
(3) plan to take acid suppressants for more than 1 year.
(4) have environmental factors that put them at high risk of stomach cancer (heavy smoking, working with dust, coal, quartz, cement or quarry workers for a long time).
(5) living in an area with a high incidence of stomach cancer.
(6) Those who are worried about the occurrence of gastric cancer.
The Asia-Pacific Consensus emphasizes that screening and treatment of H. pylori infection in people with high incidence of gastric cancer is an effective strategy to prevent gastric cancer.
The indications for H. pylori eradication in our 2007 Lushan Consensus
Must.
peptic ulcer
Early gastric cancer after surgery
Gastric mucosa-associated lymphoid tissue (MALT) Lymphoma
Chronic gastritis with gastric mucosal atrophy and erosion
Chronic gastritis with indigestion symptoms
Planned long-term use of non-steroidal anti-inflammatory drugs (NSAIDs)
Support.
Family history of gastric cancer
Unexplained iron deficiency anemia
Idiopathic thrombocytopenic purpura (ITP)
Other H. pylori-associated gastric disease (e.g., lymphocytic gastritis, gastric hyperplastic polyps, Ménétrier’s disease)
Personal request for treatment
II. What to test with
The Maastricht-IV (latest) consensus states that fecal H. pylori antigen testing with monoclonal antibodies has been validated with accuracy comparable to that of breath testing. Several consensus statements indicate that serologic testing cannot distinguish between current and previous infections, has low accuracy, and has very limited clinical application, but is suitable for epidemiologic investigations. When endoscopy is not performed, the consensus consensus recommends urea breath test or fecal antigen test.
Third, what treatment plan is most appropriate
This is the focus of the new consensus revision. With the increase in H. pylori resistance, the eradication rate of standard triple therapy, which was previously the first-line regimen, has fallen below or well below 80%; whereas H. pylori infection, as an infectious disease, should have an eradication rate above 90%. The realistic eradication rate is decreasing, but the demand is increasing, and how to solve this contradiction is a challenge for clinicians.
1. Factors affecting the recommended regimen: The main factors are: the high rate of H. pylori resistance, the availability of bismuth (not available in many countries) and furazolidone (not available in developed countries); whether rifabutin is used to eradicate H. pylori (recommended by WGO and Asia-Pacific consensus). High rate of H. pylori resistance (clarithromycin, metronidazole, levofloxacin, moxifloxacin) in China, still availability of bismuth and furazolidone, rifabutin not recommended (second-line anti-TB drug, universal application will lead to an increase in the proportion of drug-resistant strains of M. tuberculosis).
2. Regimen: The Maastricht-III consensus recommends two regimens: the standard triple regimen and the bismuth quadruple regimen, and emphasizes that in areas where the rate of clarithromycin resistance is higher than 15-20%, drug sensitivity testing should be performed before applying the triple regimen containing clarithromycin, or clarithromycin should not be applied. As the eradication rate of the standard triple regimen declined, new regimens have emerged in recent years, including sequential therapy, concomitant therapy, and levofloxacin triple therapy. There are five eradication regimens.
The Maastricht-IV consensus recommends these five regimens.
(1) Standard triple regimen: there are 2 regimens: proton pump inhibitor (PPI) + clarithromycin + amoxicillin and PPI + clarithromycin + metronidazole. Since both regimens include clarithromycin, their application is limited in areas with high rates of clarithromycin resistance. The reported rate of clarithromycin resistance in China is 27%-38%.
②Bismuth quadruple regimen: The classic bismuth quadruple regimen consists of bismuth + PPI + tetracycline + metronidazole, and the WGO consensus indicates that both antibiotics are also available as clarithromycin + amoxicillin. In fact the Maastricht-III consensus on bismuth quadruple regimen also does not emphasize the limitation of tetracycline and metronidazole. Other antibiotics such as furazolidone and levofloxacin have also been used in bismuth quadruple regimens. There are now foreign preparations that place bismuth, tetracycline, and metronidazole in the same capsule for ease of administration. The eradication rate of this preparation plus PPI in a 10-d quadruple regimen (classical quadruple) was 93% by protocol (PP) analysis and 80% by intention-to-treat (ITT) analysis in a large multicenter European study, while the standard triple regimen as a control had eradication rates of only 70% and 55% for 7 d [9]. A national study [10] also showed that the classical quadruple regimen had 10-d eradication rates of 89.4% (ITT) and 91.6% (PP), while the standard triple regimen as a control had 7-d eradication rates of 63.5% (ITT) and 65.1% (PP). The standard triple regimen with bismuth improved the efficacy by about 10-14%. 2 weeks of PPI + amoxicillin + furazolidone + bismuth improved the efficacy by 15-20% compared with the control group without bismuth.
(iii) Sequential therapy: The classic regimen consists of two 5-d regimens: PPI + amoxicillin for the first 5 d and PPI + clarithromycin + metronidazole for the second 5 d. The Maastricht-IV consensus recommends sequential therapy as the first-line option, but the Asia-Pacific consensus does not consider the current data in Asia sufficient to recommend sequential therapy. Sequential therapy is recommended. In our multicenter, large sample study, the eradication rate of classical sequential therapy PP analysis was 75.2%, while the eradication rate of classical sequential therapy PP analysis was 75.2%.
In our multicenter, large sample study, the classical sequential therapy PP analysis showed an eradication rate of 75.2% compared to the standard triplet regimen as a control with a 10-d eradication rate of 75.1% (P=0.528), and sequential therapy did not show an advantage.
(iv) Concomitant therapy: The combination of the three antibiotics and the PPI in the sequential regimen (in no particular order) is known as concomitant therapy, and thus the latter is the counterpart of the former regimen. In fact, concomitant therapy predates sequential therapy, although in earlier years it was called PPI plus 3 antibiotics or quadruple therapy without bismuth. A meta-analysis showed that the eradication rate of concomitant therapy was essentially the same as that of sequential therapy [15] and higher than that of the standard triple regimen [16], for which information is lacking in our country.
⑤ Levofloxacin triple regimen: the original intention of this regimen was to replace the highly resistant clarithromycin with levofloxacin to improve the eradication rate. Our multicenter, large sample study [17] showed that the eradication rate of levofloxacin triple regimen for 7 d as initial treatment for PP analysis (83.0%, 122/147) was comparable to standard triple therapy (PPI + clarithromycin + amoxicillin) for 7 d (78.2%, 111/142), with less than optimal efficacy.
3. The question of first- and second-line regimens: what is the basis for dividing first- and second-line regimens? The usual reasons for retaining as second-line application are the high cost of the regimen or the high adverse effects. The Maastricht-III consensus recommends PPI + amoxicillin + metronidazole or PPI + tetracycline + metronidazole for second-line regimens without bismuth. (See Figure 1 for Maastricht-IV consensus recommendations.) The second-line regimen in areas of high clarithromycin resistance is levofloxacin triplet, which also appears to be unused in first-line therapy. If the choice of second-line regimen was primarily
If the choice of second-line regimen is based mainly on “not used”, then we have more options because there are many combinations of antibiotics. If we do not stick to first- and second-line regimens, we should more accurately refer to initial therapy and remedial therapy. There are currently only six antibiotics used to eradicate H. pylori. Amoxicillin, furazolidone, and tetracycline have low resistance rates (<5%) and are relatively resistant to treatment failure, whereas clarithromycin, metronidazole, and levofloxacin have high or very high resistance rates and are susceptible to resistance after treatment failure. Theoretically, the combination of two low resistance antibiotics has the best efficacy, the combination of one highly resistant and one low resistance has the second best efficacy, and the combination of two highly resistant antibiotics has the lowest efficacy. When choosing antibiotics for initial and remedial treatment, the issue of bacterial resistance should be fully considered. At present, the supply of tetracycline and furazolidone in China is very little, and after the application of easily resistant antibiotics in the initial treatment, it is not advisable to apply them again, if coupled with the patient's penicillin allergy, then there will be no drug available for remedial treatment.
4. The relationship between duration of therapy and efficacy: The Asia-Pacific consensus states that extending the duration of the standard triplet regimen from 7 d to 14 d has a limited effect on improving efficacy. the Maastricht-IV consensus states that extending the duration from 7 d to 10 d or 14 d increases the eradication rate by 5%. In fact, an earlier meta-analysis of the relationship between duration and efficacy showed an increase in eradication rates of approximately 12% at 14 d compared to 7 d [18]. However, a subsequent meta-analysis showed no difference in eradication rates not only at 10 d compared to 7 d, but also at 14 d compared to 7 d. A study of standard triple therapy (PPI + clarithromycin + amoxicillin) combined with bismuth at 7 d versus 14 d showed that 2 weeks
eradication rate was approximately 14% higher than 1 week (ITT analysis 93.7% vs. 80.0%); the difference in eradication rate between 1 and 2 weeks for clarithromycin-sensitive strains of infection was minimal, but for clarithromycin-resistant strains of infection, the eradication rate was significantly higher for the 2-week course than for 1 week [20]. This result suggests that the extended course of bismuth quadruple therapy can improve the efficacy and overcome clarithromycin resistance to some extent, thus solving the problem of applying clarithromycin in areas with a high rate of clarithromycin resistance. A review by leading international experts in H. pylori research confirmed the significance of the findings. The results of other studies also suggest that the improved efficacy of extended courses of bismuth quadruple therapy appears to be significant compared to extended courses of standard triple therapy.
Based on the above evidence, it is necessary to discuss the possibility of applying the five regimens recommended by the Maastricht-IV consensus in China, taking into account our national situation.
① Standard triplet regimen: should be eliminated or at least not suitable for use in most areas of China. Rationale: The rate of clarithromycin resistance in China far exceeds the 15%-20% threshold; the eradication rate is lower or far lower than 80%, and the role of prolonging the course of treatment is limited; the eradication rate of quadruple therapy regimen is higher.
② Sequential therapy: should not be used. Reason: No advantage shown in our multicenter, large sample study; more reliable efficacy of bismuth quadruple therapy.
(③) Concomitant therapy: should not be used. Reason: Bismuth may be more appropriate to replace an antibiotic (to reduce adverse effects and have more leeway in choosing antibiotics for remedial treatment); lack of information from our country.
④ Levofloxacin triple therapy: should not be used. Reason: The rate of levofloxacin resistance in China has approached or exceeded that of clarithromycin; the eradication rate of clinical application is not satisfactory; the combination of bismuth quadruple therapy may improve the efficacy.
⑤ Bismuth quadruple therapy: Until a new regimen is available, it should be the main or only regimen to eradicate H. pylori in China. Reasons: Bismuth is available in China, and the advantages of bismuth in H. pylori eradication should be fully utilized (Maastricht-IV consensus emphasizes that sequential therapy or concomitant therapy should be used when bismuth is not available); the eradication rate is higher compared with the above four regimens; bismuth is inexpensive and has a higher safety profile. The results of meta-analysis showed that the only significantly different adverse effect of bismuth quadruple therapy for 1~2 weeks compared with the regimen without bismuth was the black color of stool.
6, the significance of drug sensitivity test: there are two main roles, the first is to monitor the rate of drug resistance of H. pylori in various regions, and the second is to guide individual treatment. Maastricht-IV consensus suggests that drug sensitivity testing should be performed after two treatment failures or when endoscopy is performed for other reasons after one treatment failure, and this consensus has the lowest level of evidence and recommendation (expert opinion). The Asia-Pacific consensus meeting did not reach consensus on the issue of drug sensitivity testing (no statement) and only mentioned at the end of the consensus report: “…… However, in most cases antibiotic drug sensitivity testing does not influence the choice of second or third line.” The WGO consensus includes drug sensitivity testing as good practice point, but the consensus goes on to mention that the use of endoscopy is impractical in most developing countries. The inability to perform drug sensitivity testing with no endoscopy demonstrates the contradictory views in their consensus. Clinical studies comparing the use of drug sensitivity test results to guide individual therapy versus expert empirical therapy are lacking. In addition, there are certain problems with the drug sensitivity test itself, such as accessibility, reliability, and inconsistent results in vivo and ex vivo.
Other factors affecting eradication rates: ①Smoking: The Asia-Pacific consensus states that smoking decreases the eradication rate of H. pylori. CYP2C19 gene polymorphism: This gene is involved in PPI metabolism, and there are polymorphisms (which can be tested), in which fast metabolizing individuals taking PPI have weaker acid suppression effect, which will reduce the eradication rate of H. pylori by PPI-based triple therapy. The Asia Pacific Consensus states that it is more practical to select high efficacy or increase the dose of PPI than to test for CYP2C19 typing in order to overcome the CYP2C19 polymorphism in remedial therapy. (3) Whether supplementation with probiotics and prebiotics can improve the eradication rate of H. pylori: The Maastricht-IV consensus did not answer this question positively, but only indicated that supplementation with certain probiotics and prebiotics can reduce the adverse effects of eradication therapy.