Background: After the approval of health insurance coverage of eradication therapy for Helicobacter pylori-positive peptic ulcer disease (PUD) in 2000, comprehensive coverage for H. pylori infection itself was implemented in 2013. Methods: We did a literature search using PubMed database on the management of H. pylori infection including indications, regimens, outcomes of current eradication therapies, trends of antibiotic resistance rates and proposed third-line rescue therapy in Japan. We also collected data on changes of eradication rates in our hospital by searching electronic medical records. Results: After implementation of insurance coverage of eradication therapy for PUD, dramatic reduction of the number patients with PUD as well as spending on ulcer drug was documented. According to the current regulation, proton pump inhibitor (PPI)-based triple therapy with 2 antibiotics, amoxicillin (AMPC) plus clarithromycin, for 7 days is approved as the first-line therapy. After failure of the first-line therapy, PPI plus AMPC and metronidazole is authorized as the second line, which maintains an excellent eradication rate of over 90% in Japan. When these two therapies fail, a sitafloxacin-based therapy seems to be most promising among many rescue regimens. Conclusion: Comprehensive public health insurance coverage of H. pylori infection will promote eradication in Japanese people infected with H. pylori, whose risk of developing gastric cancer has been shown to be high. It also provides us a unique opportunity to study whether the broader indications can accelerate the reduction of gastric cancer in Japan in the same way we witnessed the reduction of PUD.

Keywords:
Helicobacter pylori, Eradication therapy, Antibiotic resistance, Gastric cancer, Peptic ulcer
1.
Fujisawa T, Kumagai T, Akamatsu T, Kiyosawa K, Matunaga Yl: Changes in seroepidemiological pattern of Helicobacter pylori and hepatitis A virus over the last 20 years in Japan. Am J Gastroenterol 1999;94:2094-2099.
2.
Nakajima S, Nishiyama Y, Yamaoka M, Yasuoka T, Cho E: Changes in the prevalence of Helicobacter pylori infection and gastrointestinal diseases in the past 17 years. J Gastroenterol Hepatol 2010;25(suppl 1):S99-S110.
3.
Asaka M, Kato M, Sugiyama T, Satoh K, Kuwayama H, Fukuda Y, Fujioka T, Takemoto T, Kimura K, Shimoyama T, Simizu K, Kobayashi S; Japan Helicobacter pylori Eradication Study Group: Follow-up survey of a large-scale multicenter, double-blind study of triple therapy with lansoprazole, amoxicillin, and clarithromycin for eradication of Helicobacter pylori in Japanese peptic ulcer patients. J Gastroenterol 2003;38:339-347.
4.
Miwa H, Sakaki N, Sugano K, Sekine H, Higuchi K, Uemura N, Kato M, Murakami K, Kato C, Shiotani A, Ohkusa T, Takagi A, Aoyama N, Haruma K, Okazaki K, Kusugami K, Suzuki M, Joh T, Azuma T, Yanaka A, Suzuki H, Hashimoto H, Kawai T, Sugiyama T: Recurrent peptic ulcers in patients following successful Helicobacter pylori eradication: a multicenter study of 4940 patients. Helicobacter 2004;9:9-16.
5.
Uemura N, Mukai T, Okamoto S, Yamaguchi S, Mashiba H, Taniyama K, Sasaki N, Haruma K, Sumii K, Kajiyama G: Effect of Helicobacter pylori eradication on subsequent development of cancer after endoscopic resection of early gastric cancer. Cancer Epidemiol Biomarkers Prev 1997;6:639-642.
6.
Fukase K, Kato M, Kikuchi S, Inoue K, Uemura N, Okamoto S, Terao S, Amagai K, Hayashi S, Aska M; Japan Gast Study Group: Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomized controlled trial. Lancet 2008;372:392-397.
7.
Sasazuki S, Inoue M, Iwasaki M, Otani T, Yamamoto S, Ikeda S, Hanaoka T, Tsugane S; the Japan Public Health Center Study Group: Effect of Helicobacter pylori infection combined with CagA and pepsinogen status on gastric cancer development among Japanese men and women: a nested case-control study. Cancer Epidemiol Biomarkers Prev 2006;15:1341-1347.
8.
Asaka M, Kato M, Takahashi S, Fukuda Y, Sugiyama T, Ota H, Uemura N, Murakami K, Satoh K, Sugano K: Guidelines for the management of Helicobacter pylori infection in Japan: 2009 revised edition. Helicobacter 2010;15:1-20.
9.
Asaka M, Sugiyama T, Kato M, Satoh K, Kuwayama H, Fukuda Y, Fujioka T, Takemoto T, Kimura K, Shimoyama T, Simizu K, Kobayashi S: A multicenter, double-blind study on triple therapy with lansoprazole, amoxicillin and clarithromycin for eradication of Helicobacter pylori in Japanese peptic ulcer patients. Helicobacter 2001;6:254-261.
10.
Kuwayama H, Luk G, Yoshida S, Nakamura T, Kubo M, Uemura N, Harasawa s, Kaise M, Sanuki E, Haruma K, Inoue M, Shimatani T, Mieno H, Kamanishi M, Watanabe H, Nakashima M, Nakazawa S: Efficacy of a low-dose omeprazole-based triple-therapy regimen for Helicobacter pylori eradication independent of cytochrome P450 genotype: The Japanese MACH Study. Clin Drug Investig 2005;25:293-305.
11.
Higuchi K, Maekawa t, Nakagawa K, Chouno S, Hayakumo T, Tomono N, Orino A, Tanimura H, Asahina K, Matsuura N, Endo M, Hirano M, Sakamoto C, Inomoto T, Arakawa T: Efficacy and safety of Helicobacter pylori eradication therapy with omeprazole, amoxicillin and high- and low-dose clarithromycin in Japanese patients: a randomized, double-blind, multicenter study. Clin Drug Investig 2006;26:403-414.
12.
Kuwayama H, Asaka M, Sugiyama T, Fukuda Y, Aoyama N, Hirai Y, Fujioka T; Japan Rabeprazole Study Group: Rabeprazole-based eradication therapy for Helicobacter pylori: a large-scale study in Japan. Aliment Pharmacol Ther 2007;25:1105-1113.
13.
Higashida A, Mamori S, Kuwada T, Mitsuoka T, Taki M, Suga Y, Senda E, Ashida C, Yamada H: Effectiveness of esomeprazole-based triple therapy of H. pylori in young patients in Japan. Scand J Gastroenterol 2013;48:121-122.
14.
Malfertheiner P, Megraud F, O'Morain CA, Atherton J, Axon AT, Bazzoli F, Gensinii GF, Gisbert JP, Graham DY, Rokkas T, El-Omar EM, Kuipers EJ; European Helicobacter Study Group: Management of Helicobacter pylori infection - the Maastricht IV/Florence consensus report. Gut 2012;61:646-664.
15.
Asaka M, Satoh K, Sugano K, Sugiyama T, Takahashi S, Fukuda Y, Ota H, Murakami K, Kimura K, Shimoyama T: Guidelines in the management of Helicobacter pylori infection in Japan. Helicobacter 2001;6:177-86.
16.
Research Group for Assessment and Adaptation of Guideline for Gastric Ulcer: Evidence-based guideline for gastric ulcer treatment (in Japanese). Tokyo, Jiho KK, 2003.
17.
Wotherspoon AC, Doglioni C, Diss TC, Pan L, de Boni M, Isaacson PG: Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 1993;342:575-577.
18.
Sugiyama T, Asaka M, Nakamura T, Nakamura S, Yonezumi S, Seto M: API2-MALT1 chimeric transcript is a predictive marker for the responsiveness of Helicobacter pylori eradication treatment in low-grade gastric MALT lymphoma. Gastroenterology 2001;120:1884-1885.
19.
Guideline committee of Japanese Society of Helicobacter Research: Guideline in the management of Helicobacter pylori infection in Japan: 2003 revision (in Japanese). Jap J Helicobacter Res 2003;4(suppl):2-16.
20.
Ohkusa T, Takashimizu I, Fujiki K, Suzuki S, Shimoi K, Horiuchi T, Sakurazawa T, Aniake K, Ishii K, Kumagai J, Tanizawa T: Disappearance of hyperplastic polyps in the stomach after eradication of Helicobacter pylori. A randomized, clinical trial. Ann Intern Med 1998;129:712-715.
21.
Suzuki T, Matsushima M, Masui A, Watanabe K, Takagi A, Ogawa Y, Shirai T, Mine T: Effect of Helicobacter pylori eradication in patients with chronic idiopathic thrombocytopenic purpura - a randomized controlled trial. Am J Gastroenterol 2005;100:1265-1270.
22.
Sasaki M, Ogasawara N, Utsumi K, Kawamura N, Kamiya T, Kataoka H, Tanida S, Mizoshita T, Kaugai K, Joh T: Changes in 12-year first-line eradication rate of Helicobacter pylori based on triple therapy with proton pump inhibitor, amoxicillin and clarithromycin. J Clin Biochem Nutr 2010;47:53-58.
23.
Kato M, Yamaoka Y, Kim JJ, Reddy R, Asaka M, Kashima K, Osato MS, El-Zaatari AK, Groham DY, Kwon DH: Regional differences in metronidazole resistance and increasing clarithromycin resistance among Helicobacter pylori isolates from Japan. Antimicrob Agents Chemother 2000;44:2214-2216.
24.
Kobayashi I, Murakami K, Kato M, Kato S, Azuma T, Takahashi S, Uemura N, Katsuyama T, Fukuda Y, Haruma K, Nasu M, Fujioka T: Changing antimicrobial susceptibility epidemiology of Helicobacter pylori strains in Japan between 2002 and 2005. J Clin Microbiol 2007;45:4006-4010.
25.
Murakami K, Sato R, Okimoto T, Nasu M, Fujioka T, Kodama M, Kagawa J: Efficacy of triple therapy comprising rabeprazole, amoxicillin and metronidazole for second-line Helicobacter pylori eradication in Japan, and the influence of metronidazole resistance. Aliment Pharmacol Ther 2003;17:119-122.
26.
Isomoto H, Inoue K, Furusu H, Enjoji A, Fujimoto C, Yamakawa M, Hirakata Y, Omagari K, Mizuta Y, Murase K, Shimada S, Murata I, Kohno S: High-dose rabeprazole-amoxicillin versus rabeprazole-amoxcicillin-metronidazole as second-line treatment after failure of the Japanese standard regimen for Helicobacter pylori infection. Aliment Pharmacol Ther 2003;18:101-107.
27.
Shimoyama T, Fukuda S, Mikami T, Fukushi M, Munakata A: Efficacy of metronidazole for the treatment of clarithromycin-resistant Helicobacter pylori infection in a Japanese population. J Gastroenterol 2004;39:927-930.
28.
Nagahara A, Miwa H, Kawabe M, Kurosawa A, Asaoka D, Hojo M, Iijima K, Terai T, Ohkusa T, Miyazaki A, Sato N: Second-line treatment for Helicobacter pylori infection in Japan: proton pump inhibitor-based amoxicillin and metronidazole regimen. J Gastroenterol 2004;39:1051-1055.
29.
Shirai N, Sugimoto M, Kodaira C, Nishino M, Ikuma M, Kajimura M, Ohashi K, Ishizaki T, Hishida A, Furuta T: Dual therapy with high doses of rabeprazole and amoxicillin versus triple therapy with rabeprazole, amoxicillin, and metronidazole as a rescue regimen for Helicobacter pylori infection after the standard triple therapy. Eur J Clin Phamacol 2007;63:743-749.
30.
Murakami K, Okimoto T, Kodama M, Sato R, Watanabe K, Fujioka T: Evaluation of three different proton pump inhibitors with amoxicillin and metronidazole in retreatment for Helicobacter pylori infection. J Clin Gastroenterol 2008;42:139-142.
31.
Fujioka T, Aoyama N, Sakai K, Miwa Y, Kudo M, Kawashima J, Matubara Y, Miwa J, Yakabi K: A large-scale nationwide multicenter prospective observational study of triple therapy using rabeprazole, amoxicillin, and clarithromycin for Helicobacter pylori eradication in Japan. J Gastroenterol 2012;47:276-283.
32.
Matsuzaki J, Suzuki H, Nishizawa T, Hirata K, Tsugawa H, Saito Y, Okada S, Fukuhara S, Hibi T: Efficacy of sitafloxacin-based rescue therapy for Helicobacter pylori after failure of first- and second-line therapies. Antimicrob Agents Chem 2012;56:1643-1645.
33.
Hirata Y, Ohmae T, Yanai A, Sakitani K, Hayakawa Y, Yoshida S, Sugimoto T, Mistuno Y, Akanuma M, Yamaji Y, Ogura K, Maeda S, Koike K: Sitafloxacin resistance in Helicobacter pylori isolates and sitafloxacin-based triple therapy as a third-line regimen in Japan. Int J Antimicorb Agents 2012;39:352-355.
34.
Murakami K, Furuta T, Ando T, Nakajima T, Inui Y, Oshima T, Tomita T, Mabe K, Sasaki M, Suganuma T, Nomura H, Satoh K, Hori S, Inoue S, Tomokane T, Kudo M, Amagai K, Iwamoto J, Miwa J, Kodama M, Okimoto T, Kato M, Asaka M; the Japan Gast Study Group: Multi-center randomized controlled study to establish the standard third-line regimen for Helicobacter pylori eradication in Japan. J Gastroenterol 2013;48:1128-1135.
35.
Sone Y, Kumada T, Toyoda H, Yokoyama M, Kato M, Asaka M: Eradicating Helicobacter pylori in peptic ulcer diseases reduces medical costs in the community. Helicobacter 2006;13:346-351.
36.
Take S, Mizuno M, Ishiki K, Nagahara Y, Yoshida T, Yokota K, Oguma K, Okada H, Siratori Y: The effect of eradicating Helicobacter pylori on the development of gastric cancer in patients with peptic ulcer disease. Am J Gastroenterol 2005;100:1037-1042.
37.
Takenaka R, Okada H, Kato J, Makidono C, Hori S, Kawahara Y, Miyoshi M, Yumoto E, Imagawa A, Toyokawa T, Sakabuchi K, Shiratori Y: Helicobacter pylori eradication reduced the incidence of gastric cancer, especially of the intestinal type. Aliment Pharmacol Ther 2007;25:805-812.
38.
Ogura K, Hirata Y, Yanai A, Shibata W, Ohmae T, Mitsuno Y, Maeda S, Watabe H, Yamaji Y, Okamoto M, Yoshida H, Kawabe T, Omata M: The effect of Helicobacter pylori eradication on reducing the incidence of gastric cancer. J Clin Gastroenterol 2008;42:279-283.
39.
Yanaoka K, Oka M, Ohata H, Yoshimura N, Deguchi H, Mukoubayashi C, Enomoto S, Inoue I, Iguchi M, Maekita T, Ueda K, Utsunomiya H, Tamai H, Fujishiro M, Iwane M, Takeshita T, Mohara O, Ichinose M: Eradication of Helicobacter pylori prevents cancer development in subjects with mild gastric atrophy identified by serum pepsinogen levels. Int J Cancer 2009;125:2697-2703.
40.
Maehata Y, Nakamura S, Fujisawa K, Esaki M, Moriyama T, Asano K, Fuyuno Y, Yamaguchi K, Egashira I, Kim H, Kanda M, Hirahashi M, Matsumoto T: Long-term effect of Helicobacter pylori eradication on the development of metachronous gastric cancer after endoscopic resection of early gastric cancer. Gastrointest Endosc 2012;75:39-46.
41.
Nakamura S, Sugiyama T, Matsumoto T, Iijima K, Ono S, Tajika M, Tari A, Kitadai Y, Matsumoto H, Nagaya T, Kamoshida T, Watanabe N, Chiba T, Origasa H, Asaka M; JAPAN GAST Study Group: Long-term clinical outcome of gastric MALT lymphoma after eradication of Helicobacter pylori: a multicenter cohort follow-up study of 420 patients in Japan. Gut 2012;51:507-513.
42.
Miki K: Gastric cancer screening by combined assay for serum anti-Helicobacter pylori IgG antibody and serum pepsinogen levels - ‘ABC method'. Proc Jpn Acad SerB Phys Biol Sci 2011;87:405-411.
43.
Malfertheiner P, Sipponen P, Naumann M, Moayyedi P, Megraud F, Xiao SD, Sugano K, Nyren O; the Lejondal H. pylori-Gastric Cancer Task Force: Helicobacter pylori eradication has the potential to prevent gastric cancer: a state-of the-art critique. Am J Gastroenterol 2005;100:2100-2115.
44.
Fock KM, Talley N, Moayyedi P, Hunt R, Azuma T, Sugano K, Xiao SD, Lam SK, Goh KL, Chiba T, Uemura N, Kim JG, Kim N, Ang TL, Mahachai V, Mitchell H, Rani AA, Liou JM, Vilaichone RK, Sollano J; Asia-Pacific Consensus Conference: Asia-Pacific consensus guidelines on gastric cancer prevention J Gastroenterol Hepatol 2008;23:351-365.
45.
Take S, Mizuno M, Ishiki K, Inada T, Okuno T, Yoshida t, Yokota K, Oguma K, Kita M, Okada H, Yamamoto K: Reinfection rate of Helicobacter pylori after eradication treatment: a long-term prospective study in Japan. J Gastroenterol 2012;47:641-646.
46.
Kato S, Matsukura N, Tsukada K, Matsuda N, Mizoshita T, Tsukamoto T, Tatematsu M, Sugisaki Y, Tajiri T: Helicobacter pylori infection-negative gastric cancer in Japanese hospital patients: incidence and pathological characteristics. Cancer Sci 2007;98:790-794.
47.
Kamangar F, Dawsey SM, Blaser MJ, Perez-Perez GI, Pietinen P, Newschaffer CJ, Abnet CC, Albanes D, Virtamo J, Taylor PR: Opposing risks of gastric cardia and noncardia gastric adenocarcinomas associated with Helicobacter pylori seropositivity. J Natl Cancer Inst 2006;98:1445-1452.
48.
Hansen S, Vollset SE, Darakhshan MH, Fyte V, Melby KK, Aase S, Jellum E, McColl KE: Two distinct aetiologies of cardia cancer, evidence from premorbid serological markers of gastric atrophy and Helicobacter pylori status. Gut 2007;56:918-925.
49.
Sjorund M, Wreiber K, Andersson DI, Blaser MJ, Engstrand L: Long-term persistence of resistant Enterococcus species after antibiotics to eradicate Helicobacter pylori. Ann Intern Med 2003;139:483-487.
50.
Jerenberg C, Lofmark S, Edlund C, Jansson JK: Long-term ecological impacts of antibiotic administration on the human intestinal microbiota. ISME J 2007;1:56-66.
51.
Sugano K: Prevention of gastric cancer: urgent need to implement Helicobacter pylori eradication therapy as a primary preventive measure in Japan. J Gastroenterol 2007;42(suppl):1-2.
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2014
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