Abstract
The cure rates of Helicobacter pylori infection by using a combination of a proton pump inhibitor (PPI) and antimicrobial agents are mainly influenced by bacterial susceptibility to antimicrobial agents and the magnitude of acid inhibition during the treatment. Currently used empirical triple therapies do not reliably produce a ≥80% cure rate on an intention-to-treat basis. Therefore, tailored regimens based on relevant microbiological findings and pharmacogenomics are recommended for attaining an acceptable ≥95% cure rate. Recently, virulence factors of H. pylori, such as cagA and vacA, are reported to be major factors determining the cure rates. Individuals infected with strains with cagA-negative and vacA s2 genotypes have significantly increased risk of eradication failure of H. pylori infection. These virulence factors enhance gastric mucosal inflammation and are associated with the development of peptic ulcer and gastric cancer. H. pylori virulence factors induce proinflammatory cytokines, such as interleukin (IL)-1, IL-8, and tumor necrosis factor (TNF)- which influence mucosal inflammation and/or gastric acid secretion. When physicians select an H. pylori eradication regimen with an acceptable cure rate, they might need to consider H. pylori virulence factors, especially cagA and vacA.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Abbreviations
- CYP2C19:
-
cytochrome P450 2C19
- H_2RA:
-
histamine 2-receptor antagonist
- IL:
-
interleukin
- MDR1:
-
multidrug resistance transporter-1
- PPI:
-
proton pump inhibitor
- OipA:
-
outer inflammatory protein
- PAI:
-
pathogenicity island
- TNF:
-
tumor necrosis factor
References
Adamek RJ, Suerbaum S, Pfaffenbach B et al(1998) Primary and acquired Helicobacter pylori resistance to clarithromycin, metronidazole, and amoxicillin-influence on treatment outcome. Am J Gastroenterol 93: 386-89
Al-Ghoul L, Wessler S, Hundertmark T et al(2004) Analysis of the type IV secretion system-dependent cell motility of Helicobacter pylori-infected epithelial cells. Biochem Biophys Res Commun 322: 860-66
Annibale B, Marignani M, Monarca B et al(1999) Reversal of iron deficiency anemia after Helicobacter pylori eradication in patients with asymptomatic gastritis. Ann Intern Med 131: 668-72
Atherton JC, Cao P, Peek RM Jr et al(1995) Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem 270: 17771-7777
Atherton JC, Tham KT, Peek RM Jr et al(1996) Density of Helicobacter pylori infection in vivo as assessed by quantitative culture and histology. J Infect Dis 174: 552-56
Backert S, Selbach M (2008) Role of type IV secretion in Helicobacter pylori pathogenesis. Cell Microbiol 10: 1573-581
Basso D, Zambon CF, Letley DP et al(2008) Clinical relevance of Helicobacter pylori cagA and vacA gene polymorphisms. Gastroenterology 135: 91-9
Bayerdorffer E, Miehlke S, Mannes GA et al(1995) Double-blind trial of omeprazole and amoxicillin to cure Helicobacter pylori infection in patients with duodenal ulcers. Gastroenterology 108: 1412-417
Beales IL, Calam J (1998) Interleukin 1 beta and tumour necrosis factor alpha inhibit acid secretion in cultured rabbit parietal cells by multiple pathways. Gut 42: 227-34
Blaser MJ, Perez-Perez GI, Kleanthous H et al(1995) Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res 55: 2111-115
Boyanova L, Gergova G, Nikolov R et al(2008) Prevalence and evolution of Helicobacter pylori resistance to 6 antibacterial agents over 12 years and correlation between susceptibility testing methods. Diagn Microbiol Infect Dis 60: 409-15
Brandt S, Kwok T, Hartig R et al(2005) NF-kappaB activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein. Proc Natl Acad Sci USA 102: 9300-305
Broutet N, Marais A, Lamouliatte H et al(2001) cagA status and eradication treatment outcome of anti-Helicobacter pylori triple therapies in patients with nonulcer dyspepsia. J Clin Microbiol 39: 1319-322
Broutet N, Tchamgoue S, Pereira E et al(2003) Risk factors for failure of Helicobacter pylori therapy-results of an individual data analysis of 2751 patients. Aliment Pharmacol Ther 17: 99-09
Calvet X, Garcia N, Lopez T et al(2000) A meta-analysis of short versus long therapy with a proton pump inhibitor, clarithromycin and either metronidazole or amoxycillin for treating Helicobacter pylori infection. Aliment Pharmacol Ther 14: 603-09
Cammarota G, Cianci R, Cannizzaro O et al(2000) Efficacy of two one-week rabeprazole/levofloxacin-based triple therapies for Helicobacter pylori infection. Aliment Pharmacol Ther 14: 1339-343
Censini S, Lange C, Xiang Z et al(1996) cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Natl Acad Sci USA 93: 14648-4653
Chaudhuri S, Chowdhury A, Datta S et al(2003) Anti-Helicobacter pylori therapy in India: differences in eradication efficiency associated with particular alleles of vacuolating cytotoxin (vacA) gene. J Gastroenterol Hepatol 18: 190-95
Cover TL, Tummuru MK, Cao P et al(1994) Divergence of genetic sequences for the vacuolating cytotoxin among Helicobacter pylori strains. J Biol Chem 269: 10566-0573
De Francesco V, Faleo D, Panella C et al(2002) Sequential eradicating therapy: a treatment that does not discriminate Helicobacter pylori strains in patients with nonulcer dyspepsia?. Am J Gastroenterol 97: 2686-687
De Francesco V, Zullo A, Margiotta M (2004) Sequential treatment for Helicobacter pylori does not share the risk factors of triple therapy failure. Aliment Pharmacol Ther 19: 407-14
Dossumbekova A, Prinz C, Mages J (2006) Helicobacter pylori HopH (OipA) and bacterial pathogenicity: genetic and functional genomic analysis of hopH gene polymorphisms. J Infect Dis 194: 1346-355
Elviss NC, Owen RJ, Breathnach A et al(2005) Helicobacter pylori antibiotic-resistance patterns and risk factors in adult dyspeptic patients from ethnically diverse populations in central and south London during 2000. J Med Microbiol 54: 567-74
Elviss NC, Owen RJ, Xerry J et al(2004) Helicobacter pylori antibiotic resistance patterns and genotypes in adult dyspeptic patients from a regional population in North Wales. J Antimicrob Chemother 54: 435-40
Emilia G, Longo G, Luppi M et al(2001) Helicobacter pylori eradication can induce platelet recovery in idiopathic thrombocytopenic purpura. Blood 97: 812-14
Fischer W, Puls J, Buhrdorf R et al(2001) Systematic mutagenesis of the Helicobacter pylori cag pathogenicity island: essential genes for CagA translocation in host cells and induction of interleukin-8. Mol Microbiol 42: 1337-348
Furuta T, El-Omar EM, Xiao F et al(2002) Interleukin 1beta polymorphisms increase risk of hypochlorhydria and atrophic gastritis and reduce risk of duodenal ulcer recurrence in Japan. Gastroenterology 123: 92-05
Furuta T, Shirai N, Kodaira M et al(2007) Pharmacogenomics-based tailored versus standard therapeutic regimen for eradication of H. pylori. Clin Pharmacol Ther 81: 521-28
Furuta T, Shirai N, Takashima M et al(2001) Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin. Clin Pharmacol Ther 69: 158-68
Furuta T, Shirai N, Takashima M. et al(2002) Effect of genotypic differences in interleukin-1 beta on gastric acid secretion in Japanese patients infected with Helicobacter pylori. Am J Med 112: 141-43
Furuta T, Shirai N, Xiao F et al(2004) Polymorphism of interleukin-1beta affects the eradication rates of Helicobacter pylori by triple therapy. Clin Gastroenterol Hepatol 2: 22-0
Gasbarrini A, Franceschi F, Tartaglione R et al(1998) Regression of autoimmune thrombocytopenia after eradication of Helicobacter pylori. Lancet 352: 878
Gatta L, Zullo A, Perna F et al(2005) A 10-day levofloxacin-based triple therapy in patients who have failed two eradication courses. Aliment Pharmacol Ther 22: 45-9
Gisbert JP, Morena F (2006) Systematic review and meta-analysis: levofloxacin-based rescue regimens after Helicobacter pylori treatment failure. Aliment Pharmacol Ther 23: 35-4
Godoy AP, Ribeiro ML, Benvengo YH et al(2003) Analysis of antimicrobial susceptibility and virulence factors in Helicobacter pylori clinical isolates. BMC Gastroenterol 3: 20
Graham DY, Lu H, Yamaoka Y (2007) A report card to grade Helicobacter pylori therapy. Helicobacter 12: 275-78
Graham DY, Lu H, Yamaoka Y (2008) Therapy for Helicobacter pylori infection can be improved: sequential therapy and beyond. Drugs 68: 725-36
Graham DY, Shiotani A (2008) New concepts of resistance in the treatment of Helicobacter pylori infections. Nat Clin Pract Gastroenterol Hepatol 5: 321-31
Grayson ML, Eliopoulos GM, Ferraro MJ et al(1989) Effect of varying pH on the susceptibility of Campylobacter pylori to antimicrobial agents. Eur J Clin Microbiol Infect Dis 8: 888-89
Greenberg PD, Cello JP (1999) Lack of effect of treatment for Helicobacter pylori on symptoms of nonulcer dyspepsia. Arch Intern Med 159: 2283-288
Hopkins RJ, Girardi LS, Turney EA (1996) Relationship between Helicobacter pylori eradication and reduced duodenal and gastric ulcer recurrence: a review. Gastroenterology 110: 1244-252
Hunt RH (1993) pH and Hp-gastric acid secretion and Helicobacter pylori: implications for ulcer healing and eradication of the organism. Am J Gastroenterol 88: 481-83
Hussein NR, Mohammadi M, Talebkhan Y et al(2008) Differences in virulence markers between Helicobacter pylori strains from Iraq and those from Iran: potential importance of regional differences in H. pylori-associated disease. J Clin Microbiol 46: 1774-779
Ishida Y, Goto Y, Kondo T et al(2006) Eradication rate of Helicobacter pylori according to genotypes of CYP2C19, IL-1B, and TNF-A. Int J Med Sci 3: 135-40
Ishizaki T, Horai Y (1999) Review article: cytochrome P450 and the metabolism of proton pump inhibitors -emphasis on rabeprazole. Aliment Pharmacol Ther 13(suppl 3): 27-6
Isomoto H, Inoue K, Furusu H et al(2003) High-dose rabeprazole-amoxicillin versus rabeprazole-amoxicillin-metronidazole as second-line treatment after failure of the Japanese standard regimen for Helicobacter pylori infection. Aliment Pharmacol Ther 18: 101-07
Kamada T, Haruma K, Komoto K et al(1999) Effect of smoking and histological gastritis severity on the rate of H. pylori eradication with omeprazole, amoxicillin, and clarithromycin. Helicobacter 4: 204-10
Kawakami E, Machado RS, Ogata SK et al(2006) Furazolidone-based triple therapy for H. pylori gastritis in children. World J Gastroenterol 12: 5544-549
Kondo S, Shinomura Y, Kanayama S et al(1994) Interleukin-1 beta inhibits gastric histamine secretion and synthesis in the rat. Am J Physiol 267: G966-71
Kudo T, Nurgalieva ZZ, Conner ME et al(2004) Correlation between Helicobacter pylori OipA protein expression and oipA gene switch status. J Clin Microbiol 42: 2279-281
Kurzawski M, Gawronska-Szklarz B, Wrzesniewska J et al(2006) Effect of CYP2C19*17 gene variant on Helicobacter pylori eradication in peptic ulcer patients. Eur J Clin Pharmacol 62: 77-80
Letley DP, Atherton JC (2000) Natural diversity in the N terminus of the mature vacuolating cytotoxin of Helicobacter pylori determines cytotoxin activity. J Bacteriol 182: 3278-280
Loivukene K, Kolk H, Maaroos HI et al(2000) Metronidazole and clarithromycin susceptibility and the subtypes of vacA of Helicobacter pylori isolates in Estonia. Scand J Infect Dis 32: 59-2
Lopez-Brea M, Martinez MJ, Domingo D et al(1999) Metronidazole resistance and virulence factors in Helicobacter pylori as markers for treatment failure in a paediatric population. FEMS Immunol Med Microbiol 24: 183-88
Maeda S, Yoshida H, Ikenoue T et al(1999) Structure of cag pathogenicity island in Japanese Helicobacter pylori isolates. Gut 44: 336-41
Megraud F (1998) Epidemiology and mechanism of antibiotic resistance in Helicobacter pylori. Gastroenterology 115: 1278-282
Megraud F, Lamouliatte H (2003) Review article: the treatment of refractory Helicobacter pylori infection. Aliment Pharmacol Ther 17: 1333-343
Miyachi H, Miki I, Aoyama N et al(2006) Primary levofloxacin resistance and gyrA/B mutations among Helicobacter pylori in Japan. Helicobacter 11: 243-49
Moshkowitz M, Konikoff FM, Peled Y et al(1995) High Helicobacter pylori numbers are associated with low eradication rate after triple therapy. Gut 36: 845-47
Murakami K, Sato R, Okimoto T et al(2003) 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 17: 119-23
Nagahara A, Miwa H, Kawabe M et al(2004) Second-line treatment for Helicobacter pylori infection in Japan: proton pump inhibitor-based amoxicillin and metronidazole regimen. J Gastroenterol 39: 1051-055
Padol S, Yuan Y, Thabane M et al(2006) The effect of CYP2C19 polymorphisms on H. pylori eradication rate in dual and triple first-line PPI therapies: a meta-analysis. Am J Gastroenterol 101: 1467-475
Perri F, Clemente R, Festa V et al(1998) Relationship between the results of pre-treatment urea breath test and efficacy of eradication of Helicobacter pylori infection. Ital J Gastroenterol Hepatol 30: 146-50
Peterson WL (1997) The role of antisecretory drugs in the treatment of Helicobacter pylori infection. Aliment Pharmacol Ther 11(suppl 1): 21-5
Queiroz DM, Dani R, Silva LD et al(2002) Factors associated with treatment failure of Helicobacter pylori infection in a developing country. J Clin Gastroenterol 35: 315-20
Rhead JL, Letley DP, Mohammadi M et al(2007) A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer. Gastroenterology 133: 926-36
Rudi J, Reuther S, Sieg A et al(2002) Relevance of underlying disease and bacterial vacA and cagA status on the efficacy of Helicobacter pylori eradication. Digestion 65: 11-5
Russo F, Berloco P, Cuomo R et al(2003) Helicobacter pylori strains and histologically-related lesions affect the outcome of triple eradication therapy: a study from southern Italy. Aliment Pharmacol Ther 17: 421-28
Saad RJ, Schoenfeld P, Kim HM et al(2006) Levofloxacin-based triple therapy versus bismuth-based quadruple therapy for persistent Helicobacter pylori infection: a meta-analysis. Am J Gastroenterol 101: 488-96
Saruc M, Goksel G, Ozkaya S et al(2001) The effect of CagA status on response to Helicobacter pylori eradication therapy in Western Turkey. Braz J Med Biol Res 34: 1435-439
Scholte GH, van Doorn LJ, Cats A et al(2002) Genotyping of Helicobacter pylori in paraffin-embedded gastric biopsy specimens: relation to histological parameters and effects on therapy. Am J Gastroenterol 97: 1687-695
Sharara AI, Chaar HF, Aoun E et al(2006) Efficacy and safety of rabeprazole, amoxicillin, and gatifloxacin after treatment failure of initial Helicobacter pylori eradication. Helicobacter 11: 231-36
Sheu BS, Yang HB, Su IJ et al(1996) Bacterial density of Helicobacter pylori predicts the success of triple therapy in bleeding duodenal ulcer. Gastrointest Endosc 44: 683-88
Shimoyama T, Fukuda S, Mikami T et al(2004) Efficacy of metronidazole for the treatment of clarithromycin-resistant Helicobacter pylori infection in a Japanese population. J Gastroenterol 39: 927-30
Sugimoto M, Furuta T, Shirai N et al(2006) Influences of proinflammatory and anti-inflammatory cytokine polymorphisms on eradication rates of clarithromycin-sensitive strains of Helicobacter pylori by triple therapy. Clin Pharmacol Ther 80: 41-0
Sugimoto M, Furuta T, Shirai N et al(2004) Different dosage regimens of rabeprazole for nocturnal gastric acid inhibition in relation to cytochrome P450 2C19 genotype status. Clin Pharmacol Ther 76: 290-01
Sugimoto M, Furuta T, Shirai N et al(2007) Evidence that the degree and duration of acid suppression are related to Helicobacter pylori eradication by triple therapy. Helicobacter 12: 317-23
Sugimoto M, Furuta T, Shirai N et al(2007) Treatment strategy to eradicate Helicobacter pylori infection: impact of pharmacogenomics-based acid inhibition regimen and alternative antibiotics. Expert Opin Pharmacother 8: 2701-717
Sugimoto M, Furuta T, Shirai N et al(2005) Comparison of an increased dosage regimen of rabeprazole versus a concomitant dosage regimen of famotidine with rabeprazole for nocturnal gastric acid inhibition in relation to cytochrome P450 2C19 genotypes. Clin Pharmacol Ther 77: 302-11
Sugimoto M, Kajimura M, Shirai N et al(2006) Outcome of radiotherapy for gastric mucosa-associated lymphoid tissue lymphoma refractory to Helicobacter pylori eradication therapy. Intern Med 45: 405-09
Suzuki T, Matsuo K, Sawaki A et al(2006) Systematic review and meta-analysis: importance of CagA status for successful eradication of Helicobacter pylori infection. Aliment Pharmacol Ther 24: 273-80
Takashima M, Furuta T, Hanai H et al(2001) Effects of Helicobacter pylori infection on gastric acid secretion and serum gastrin levels in Mongolian gerbils. Gut 48: 765-73
Take S, Mizuno M, Ishiki K et al(2005) The effect of eradicating helicobacter pylori on the development of gastric cancer in patients with peptic ulcer disease. Am J Gastroenterol 100: 1037-042
Treiber G, Wittig J, Ammon S et al(2002) Clinical outcome and influencing factors of a new short-term quadruple therapy for Helicobacter pylori eradication: a randomized controlled trial (MACLOR study). Arch Intern Med 162: 153-60
Uemura N, Mukai T, Okamoto S et al(1997) Effect of Helicobacter pylori eradication on subsequent development of cancer after endoscopic resection of early gastric cancer. Cancer Epidemiol Biomarkers Prev 6: 639-42
Uemura N, Okamoto S, Yamamoto S et al(2001) Helicobacter pylori infection and the evelopment of gastric cancer. N Engl J Med 345: 784-89
van der Hulst RW, van der Ende A, Dekker FW et al(1997) Effect of Helicobacter pylori eradication on gastritis in relation to cagA: a prospective 1-year follow-up study. Gastroenterology 113: 25-0
van der Hulst RW, Weel JF, Verheul SB et al(1996) Treatment of Helicobacter pylori infection with low or high dose omeprazole combined with amoxycillin and the effect of early retreatment. Aliment Pharmacol Ther 10: 165-71
van Doorn LJ, Schneeberger PM, Nouhan N et al(2000) Importance of Helicobacter pylori cagA and vacA status for the efficacy of antibiotic treatment. Gut 46: 321-26
Wang M, Furuta T, Takashima M et al(1999) Relation between interleukin-1beta messenger RNA in gastric fundic mucosa and gastric juice pH in patients infected with Helicobacter pylori. J Gastroenterol 34(suppl 11): 10-7
Wermeille J, Cunningham M, Dederding JP et al(2002) Failure of Helicobacter pylori eradication: is poor compliance the main cause?. Gastroenterol Clin Biol 26: 216-19
Wolfe MM, Nompleggi DJ (1992) Cytokine inhibition of gastric acid secretion-a little goes a long way. Gastroenterology 102: 2177-178
Wong BC, Lam SK, Wong WM et al(2004) Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 291: 187-94
Wotherspoon AC, Doglioni C, de Boni M et al(1994) Antibiotic treatment for low-grade gastric MALT lymphoma. Lancet 343: 1503
Xia HH, Talley NJ, Blum AL et al(2003) Clinical and pathological implications of IgG antibody responses to Helicobacter pylori and its virulence factors in non-ulcer dyspepsia. Aliment Pharmacol Ther 17: 935-43
Yamaoka Y, Kikuchi S, el-Zimaity HM et al(2002) Importance of Helicobacter pylori oipA in clinical presentation, gastric inflammation, and mucosal interleukin 8 production. Gastroenterology 123: 414-24
Yamaoka Y, Kita M, Kodama T et al(2002) Helicobacter pylori infection in mice: Role of outer membrane proteins in colonization and inflammation. Gastroenterology 123: 1992-004
Yamaoka Y, Kita M, Kodama T et al(1996) Helicobacter pylori cagA gene and expression of cytokine messenger RNA in gastric mucosa. Gastroenterology 110: 1744-752
Yamaoka Y, Kodama T, Gutierrez O et al(1999) Relationship between Helicobacter pylori iceA, cagA, and vacA status and clinical outcome: studies in four different countries. J Clin Microbiol 37: 2274-279
Yamaoka Y, Kudo T, Lu H et al(2004) Role of interferon-stimulated responsive element-like element in interleukin-8 promoter in Helicobacter pylori infection. Gastroenterology 126: 1030-043
Yamaoka Y, Kwon DH, Graham DY (2000) A M(r) 34,000 proinflammatory outer membrane protein (oipA) of Helicobacter pylori. Proc Natl Acad Sci USA 97: 7533-538
Yamaoka Y, Ojo O, Fujimoto S et al(2006) Helicobacter pylori outer membrane proteins and gastroduodenal disease. Gut 55: 775-81
Yamaoka Y, Orito E, Mizokami M et al(2002) Helicobacter pylori in North and South America before Columbus. FEBS Lett 517: 180-84
Zanten SJ, Bradette M, Farley A et al(1999) The DU-MACH study: eradication of Helicobacter pylori and ulcer healing in patients with acute duodenal ulcer using omeprazole based triple therapy. Aliment Pharmacol Ther 13: 289-95
Zhao JJ, Wang JB, Yang L et al(2007) Influence of Helicobacter pylori genotype on triple eradication therapy. J Gastroenterol Hepatol 22: 2251-255
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Sugimoto, M., Yamaoka, Y. Virulence factor genotypes of Helicobacter pylori affect cure rates of eradication therapy. Arch. Immunol. Ther. Exp. 57, 45–56 (2009). https://doi.org/10.1007/s00005-009-0007-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00005-009-0007-z