World trends for H. pylori eradication therapy and gastric cancer prevention strategy by H. pylori test-and-treat

Helicobacter pylori-associated gastritis leads to the development of gastric cancer. Kyoto global consensus report on H. pylori gastritis recommended H. pylori eradication therapy to prevent gastric cancer. To manage H. pylori infection, it is important to choose the appropriate regimen considering regional differences in resistance to clarithromycin and metronidazole. Quinolones and rifabutin-containing regimens are useful as third- and fourth-line rescue therapies.


Introduction
Helicobacter pylori (H. pylori) is one of the main causes of gastric cancer [1,2]. H. pylori leads to gastric oncogenesis through the injection of the oncoprotein CagA into host cells via a type IV secretion system [1]. Kyoto global consensus report on H. pylori gastritis recommended that all individuals with H. pylori infection should receive eradication therapy to prevent gastric cancer [3,4]. In particular, H. pylori test-and-treat should be promoted in regions with high incidence of gastric cancer. Since 2013, H. pylori eradication therapy was approved for all cases of H. pylori gastritis by the national health insurance scheme in Japan, before other countries. From the global scale, a higher incidence of gastric cancer is found in Asia than in Europe and North America [5,6]. In managing effective H. pylori suppression, prevalence of H. pylori infection and incidence of resistance to antimicrobial agents in each region are important factors. In this article, we describe the geographic characteristics of the prevalence of H. pylori infection, gastric cancer, and resistance to antibiotics and discuss the strategy of H. pylori eradication therapy.

Epidemiology of H. pylori infection and gastric cancer incidence
The geographic distribution of the prevalence of H. pylori infection and gastric cancer incidence is shown in Fig. 1. The incidence of gastric cancer is generally in direct proportion to the prevalence of H. pylori infection [6]. However, higher incidences of gastric cancer are found in countries in eastern Asia than in other countries.
Chronic atrophic gastritis, mainly caused by H. pylori infection, is a known precancerous lesion for gastric cancer [7,8]. A cross-sectional comparative study on chronic gastritis between the United Kingdom and Japan showed gastritis in Japan is histologically more severe, present at an earlier age, and more likely to be corpus predominant or pan-gastritis compared with the United Kingdom, whereas there was no significant difference in the prevalence of H. pylori between these countries [9].
Cytotoxin-associated gene A (CagA) is known as a major pathogenetic factor, which is peculiar to H. pylori [10]. To classify the genetic status of CagA, H. pylori CagA is classified into East Asian CagA and Western CagA [11,12]. The East Asian CagA protein possesses stronger SHP-2 binding activity than the Western CagA [13]. The grades of inflammation, activity of gastritis, and atrophy are significantly higher in gastritis patients infected with the East Asian CagA-positive strain than in gastritis patients infected with CagA-negative or Western CagApositive strains [12]. Therefore, the difference of CagA subtypes is the most important factor predicting the risk of gastric cancer.
There has been a progressive and rapid decline in the prevalence of H. pylori infection as well as a fall in the rate of progression of gastric atrophy [14], and a significant decrease in gastric cancer deaths in Japan [15]. These data indicated that a decrease in the prevalence of H. pylori and an increase in the attention to H. pylori might have a direct or indirect link to the reduction of gastric cancer deaths even in regions with high incidence of gastric cancer.

Epidemiology of resistance to antimicrobial agents in H. pylori
Considering effective treatment of H. pylori eradication, it is important to have a deep understanding of the epidemiology of resistance to antimicrobial agents.
Resistance to amoxicillin is either null or less than 1% [16], and no significant changes in resistance were observed [17]. Therefore, amoxicillin is, and will be, a key drug in the treatment of H. pylori. On the contrary, we reported unsuccessful eradication treatment increased resistance even to amoxicillin [18]; thus, rescue therapy should be also determined considering amoxicillin resistance.
The geographic distribution of resistance to clarithromycin and metronidazole is shown in Fig. 2 [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]. Interestingly, there is only a limited relationship between geographic factors and resistance to clarithromycin and metronidazole. Among the countries in eastern Asia, high resistance to clarithromycin and low resistance to metronidazole are found in Japan; low resistance to clarithromycin and high resistance to metronidazole are found in Korea; and high resistance to both clarithromycin and metronidazole is found in China. In northern Europe, there is generally a low resistance to clarithromycin. In some countries, such as Italy, China, Vietnam, and Mexico, high resistance to both clarithromycin and metronidazole is reported. A significant increase in resistance to clarithromycin and metronidazole was noted over the last year [35,36], suggesting that acquisition of resistance is related to high consumption rates of these antibiotics.
The prevalence of primary resistance to quinolones has been reported to range from 2 to 22% [28]. The prevalence of quinolone resistance is reported to be relatively higher in Japan, Korea, and Italy (15-22%), and to be very low in China and Egypt (approximately 2%).
The prevalence of primary resistance to rifabutin, if rifamycins have not been used, is very low [37][38][39].   [40] clarithromycin resistance, bismuth-containing quadruple therapy is recommended as a first-line treatment. In regions with high clarithromycin resistance but low to intermediate metronidazole resistance, non-bismuth quadruple concomitant therapy (PPI, amoxicillin, clarithromycin and metronidazole) can be an alternative treatment [40,42]. In areas of high dual clarithromycin and metronidazole resistance, bismuth-containing quadruple therapy is the recommended first-line treatment. Ten-day bismuth quadruple therapy is more effective than 10-days standard triple therapy as first-line therapy for patients with H. pylori-induced chronic gastritis in China (86.1 vs 58.4%, ITT analysis) [43].
After failure of the first-line treatment (triple or nonbismuth quadruple) and second-line treatment (quinolonecontaining therapy), the bismuth-based quadruple therapy is recommended. Rescue therapy with bismuth-containing quadruple therapy in patients achieved 83% of successful eradications in France [44]. After failure of first-line treatment with bismuth quadruple and second-line treatment, it is recommended to use a quinolone-based triple or quadruple therapy [40]. In regions with high clarithromycin resistance but low to intermediate metronidazole resistance, triple therapy (amoxicillin, metronidazole, and PPI) is also effective when metronidazole was not used as a first-line regimen [45,46].
Reports of third-and fourth-line treatment are described in Tables 1, 2, 3. Quinolone-based therapy is one of the most used third-line regimens. Levofloxacin have been widely used as H. pylori rescue therapy [47][48][49][50][51]. However, the effectiveness of levofloxacin-based therapies against gyrA mutation positive strains is insufficient; the eradication rates are approximately 40% [52,53]. Sitafloxacincontaining treatment achieved up to 70% of successful eradications for gyrA mutation positive strains [54][55][56][57]. A randomized study revealed that the eradication rate of sitafloxacin-based triple regimens was better than that of levofloxacin-based triple regimens [49]. Therefore, sitafloxacin is currently the most useful fluoroquinolone, if available. However, resistance to quinolones is acquired easily, and some strains develop strong resistance via acquisition of double mutations in gyrA [58,59].
On the contrary, rifabutin-containing therapy has been reported as a third-line treatment [48,[60][61][62][63][64]. Because the resistance to rifabutin is rare, rifabutin-containing therapy can overcome H. pylori strains with resistance to multiple antibiotics. However, there is a concern about side effects, such as leukopenia and thrombocytopenia, and occurrence of multi-resistant strains of Mycobacterium tuberculosis; thus, application of rifabutin-containing therapy should be chosen very carefully [65]. Regarding duration of rifabutincontaining therapy, 10-day or longer regimens were better than 7-day regimens [63,65]. We reported 83.3% achieved successful eradication with 10-day rifabutin-containing regimens and 94.1% with 14-day regimens [63]. Regarding PPI dosage, rifabutin therapies with high dose PPI achieved more effective eradication than normal PPI dosing [66]. Bismuth had an additional effect on rifabutin-containing regimen [64]. On the contrary, high-dose PPI and amoxicillin dual therapy is a useful option as an alternative third-line treatment regimen [49,50,60,67]. We previously reported eradication rate of 63.0% with rabeprazole (10 mg qid) and amoxicillin (500 mg qid) for 14 days [67]. The eradication rates are not better than those of quinolone-or rifabutincontaining therapy; however, fewer concerns about some complications and acquisition of new drug resistance is an advantage for high-dose PPI and amoxicillin dual therapy.
Vonoprazan, a first-in-class potassium-competitive acid blocker that has a strong gastric acid secretion inhibitory effect, is spotlighted. Vonoprazan, amoxicillin, and clarithromycin triple regimen clearly improved the efficacy for eradicating clarithromycin-resistant strains when compared to the standard lansoprazole, amoxicillin, and clarithromycin triple regimen (82.0 vs. 40.0%) [41]. The reports of vonoprazan-containing regimens are limited to only the triple regimens [68]; therefore, other regimens including vonoprazan, such as bismuth-quadruple therapy or concomitant therapy, are expected.   [69]. Meta-analysis also showed that the occurrence of metachronous gastric cancer after endoscopic resection of early gastric cancer is significantly lower in the H. pylori eradication group compared with the control non-eradicated group, and that the odds ratio for the incidence of metachronous gastric cancer in the eradication group was 0.42 [70]. Systematic review and meta-analysis of randomized controlled trials, of which six individual randomized controlled trials were included, also revealed that eradication therapy reduced the risk of primary gastric cancer in healthy asymptomatic infected individuals compared with control individuals, and that the relative risk was 0.66 [71]. Take et al. showed that eradication of H. pylori reduced the risk of developing gastric cancer in patients with peptic ulcer diseases; however, the risk is higher in the patients with severe atrophic gastritis than those with mild or moderate atrophic gastritis [72]. These data suggested that ''the earlier, the better'' in H. pylori eradication prevents gastric cancer.

Conclusions
H. pylori-associated gastritis leads to the development of gastric cancer. H. pylori should be eradicated in patients at a younger age, possibly after adolescence at the earliest, to prevent gastric cancer. However, even after endoscopic resection of early gastric cancer, H. pylori eradication reduces the incidence of metachronous gastric cancer. The incidence of gastric cancer is generally in direct proportion to the prevalence of H. pylori infection, even in eastern Asia where the prevalence of gastric cancer is relatively high. There are regional differences in resistance to clarithromycin, metronidazole, and quinolones. Resistance to amoxicillin and rifabutin is generally rare. To manage H. pylori infection, it is important to choose the appropriate regimen considering regional differences in resistance to clarithromycin and metronidazole. Quinolones or rifabutin-containing regimen are useful as third-or fourth-line rescue therapies.

Compliance with ethical standards
Conflict of interest During the last 2 years, H.S. received scholarship funds for the research from Daiichi-Sankyo Co., Otsuka Pharmaceutical Co. Ltd., and Tsumura Co., and received service honoraria from Astellas Pharma Inc, AstraZeneca K.K., Daiichi-Sankyo Co., Otsuka Pharmaceutical Co. Ltd., Mylan EPD Co., Takeda Pharmaceutical Co., Ltd., and Zeria Pharmaceutical Co. Ltd.
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