Introduction
Helicobacter pylori (H. pylori) eradication in patients with peptic ulcers can reduce the recurrence of infection and increase wound healing. H. pylori eradication is recommended for treatment of all peptic ulcers according to the 1994 National Institutes of Health (NIH) Agreement [1 ,2 ,3]. To eradicate H. pylori infection, group therapy (triple therapy) including the use of a hydrogen pump inhibitor, usually omeprazole, and a combination of two antibiotics (amoxicillin and clarithromycin, or amoxicillin and metronidazole), is used, but drug resistance and the side effects of antibiotics make the treatment process difficult. In general, antibiotics disrupt the human gastrointestinal microflora. Moreover, there are limitations for the use of triple therapy, due to patients’ sensitivity to antibiotics or causing liver and kidney dysfunction [4].
The recurrence of H. pylori infection has increased in the last 10 years, and it is still a public health problem in the world. Its recurrence after eradication has an upward trend over time and is different based on region, gender, and eradication methods [5]. The recurrence is significantly lower in developed countries than in developing countries [3]. In a review study, one-year H. pylori re-infection was reported 0-41.5% or more [6]. Treatment of H. pylori infection can improve peptic ulcer and gastric lymphoma and prevent gastric cancer, but its recurrence can eliminate these effects [7, 8]. The first step in designing an appropriate recurrence prevention strategy is to obtain information about the recurrence rate in the study area. Considering that no study has been condcuted to evaluate the recurrence rate of H. pylori after 5 years, the present study was performed to evaluate the H. pylori re-infection, 3 and 5 years after eradication.
Methods
This cross-sectional study was conducted in 2017 in Guilan province of Iran. A total of 169 patients were enrolled 3 to 5 years after eradication treatment. The H pylori infection was determined by an endoscopy procedure (combination of rapid urease test with histology or histology alone). The successful H. pylori eradication was confirmed by a Urea Breath Test (UBT) 8 weeks after the end of H. pylori eradication therapy. Inclusion criteria were: no use of Proton pump inhibitors (PPIs) in the last two weeks and not taking antibiotics and bismuth in the last four weeks. Second UBT was performed for all subjects 3-5 years after the end of therapy using carbon-14 UBT. Before the second UBT, the patients’ characteristics including age, gender, occupation, education, smoking, alcohol consumption, type of consumed water, and place of residence (urban or rural) were surveyed using a standardized questionnaire by interview. From patients’ medical records, following information were obtained: type of medication regimen, the initial diagnostic method to confirm the presence of H. pylori, and secondary diagnostic method to confirm eradication after treatment. 
Results
The mean age of participants was about 44.9±11.2 years (ranged 17-74 years). Their other demographic characteristics are presented in Table 1.




In terms of the medication regimen, 94.7% of patients received a four-drug regimen including bismuth, pantoprazole, clarithromycin, and amoxicillin (BPCA). The results of UBT showed that only one participant had a recurrence 5 years after the end of treatment who was a 63-year old woman, with high school diploma, employee, tap water consumer, urban dweller, non-smoker, non-alcoholic drinker, and with BPCA regimen
Discussion
In our study, the recurrence of H. pylori infection 5 years after eradication was positive in only one patient, and the recurrence rate was 0.6%. The annual recurrence rate of H. pylori infection is 0-30% worldwide [9]. The recurrence rate of H. pylori after eradication is very different in Iran with no specific pattern (from 0.5% to more than 25%) [10, 11].
According to our study, the recurrence rate of H. pylori infection is very low. In comparison with developed countries, the level of eradication in Iran is optimal, although the results are debatable. In this study, a variety of 2-, 3-, and 4-drug regimens with low sample sizes were used. It is recommended the larger community be examined by comparing different treatment regimens. Moreover, it is recommended to assess the recurrence rate of H. pylori infection at the intervals of 5 to 10 years.

Ethical Considerations
Compliance with ethical guidelines
This study was approved by the Ethics Committee of Guilan University of Medical Sciences. (Code: IR.GUMS.REC.1394.496). Written informed consent was obtained from the participants. They were free to leave the study at any time. 

Funding
This study was funded by Guilan University of Medical Sciences. 

Authors' contributions
All authors equally contributed to preparing this article.

Conflict of interest
The authors declared no conflict of interest.

Acknowledgements
The authors would like to thank the personnel of Gastrointestinal and Liver Diseases Research Center, Razi University Hospital, and all participants for their cooperation.


References

1. Sachs G, Scott DR. Helicobacter pylori: Eradication or preservation. F1000 Medicine Reports. 2012; 4:7. [DOI:10.3410/M4-7] [PMCID]
2. Lee YC, Chiang TH, Chou CK, Tu YK, Liao WC, Wu MS, et al. Association between Helicobacter pylori eradication and gastric cancer incidence: A systematic review and meta-analysis. Gastroenterology. 2016; 150(5):1113-24.e5. [DOI:10.1053/j.gastro.2016.01.028] [PMID]
3. Raymond J, Thiberge JM, Dauga C. Diagnosis of Helicobacter pylori recurrence: Relapse or reinfection? Usefulness of molecular tools. Scandinavian Journal of Gastroenterology. 2016; 51(6):672-8. [PMID]
4. Selgrad M, Malfertheiner P. Treatment of Helicobacter pylori. Current Opinion in Gastroenterology. 2011; 27(6):565-70. [DOI:10.1097/MOG.0b013e32834bb818] [PMID]
5. Zhao H, Yan P, Zhang N, Feng L, Chu X, Cui G, et al. The recurrence rate of Helicobacter pylori in recent 10 years: A systematic review and meta-analysis. Helicobacter. 2021; 26(6):e12852. [DOI:10.1111/hel.12852]
6. Niv Y. H pylori recurrence after successful eradication. World Journal of Gastroenterology. 2008; 14(10):1477-8. [DOI:10.3748/wjg.14.1477] [PMID] [PMCID]
7. Gunaid AA, Hassan NA, Murray-Lyon IM. Recurrence of Helicobacter pylori infection 1 year after successful treatment: Prospective cohort study in the Republic of Yemen. European Journal of Gastroenterology & Hepatology. 2004; 16(12):1309-14. [DOI:10.1097/00042737-200412000-00012] [PMID]
8. Gürel S, Beşişk F, Demir K, Mungan Z, Kaymakoğlu S, Boztaş G, et al. After the eradication of Helicobacter pylori infection, relapse is a serious problem in Turkey. Journal of Clinical Gastroenterology. 1999; 28(3):241-4. [DOI:10.1097/00004836-199904000-00011] [PMID]
9. Mansour-Ghanaei F, Taefeh N, Joukar F, Besharati S, Naghipour M, Nassiri R. Recurrence of Helicobacter pylori infection 1 year after successful eradication: A prospective study in Northern Iran. Medical Science Monitor. 2010; 16(3):CR144-8. [PMID]
10. Najafi M, Sobhani M, Khodadad A, Farahmand F, Motamed F. Reinfection rate after successful Helicobacter pylori eradication in children. Iranian Journal of Pediatrics. 2010; 20(1):58-62. [PMID]
11. Tirgar Fakheri H, Eshqi F. [The recurrence rate of helicobacter pylori infection 2 years after eradication (Persian)]. Journal of Mazandaran University of Medical Sciences. 2007; 17(58):72-8. http://jmums.mazums.ac.ir/article-1-215-en.html
12. Zendehdel N, Nasseri-Moghaddam S, Malekzadeh R, Massarrat S, Sotoudeh M, Siavoshi F. Helicobacter pylori reinfection rate 3 years after successful eradication. Journal of Gastroenterology and Hepatology. 2005; 20(3):401-4. [DOI:10.1111/j.1440-1746.2005.03561.x] [PMID]
13. Xue Y, Zhou LY, Lu HP, Liu JZ. Recurrence of Helicobacter pylori infection: Incidence and influential factors. Chinese Medical Journal. 2019; 132(7):765-71. [DOI:10.1097/CM9.0000000000000146] [PMID] [PMCID]
14. Xia HX, Talley NJ, Keane CT, O’Morain CA. Recurrence of Helicobacter pylori infection after successful eradication: Nature and possible causes. Digestive Diseases and Sciences. 1997; 42(9):1821-34. [DOI:10.1023/A:1018827322470] [PMID]
15. Mansour-Ghanaei F, Sanaei O, Joukar F. Clinical validation of an office-based 14C-UBT (Heliprobe) for H. Pylori diagnosis in Iranian dyspeptic patients. Gastroenterology Research and Practice. 2011; 2011:930941. [PMID] [PMCID]
16. Fakheri H, Merat S, Hosseini V, Malekzadeh R. Low-dose furazolidone in triple and quadruple regimens for Helicobacter pylori eradication. Alimentary Pharmacology & Therapeutics. 2004; 19(1):89-93. [DOI:10.1046/j.1365-2036.2003.01822.x] [PMID]
17. Fakheri H, Saberi Firoozi M, Bari Z. Eradication of Helicobacter pylori in Iran: A review. Middle East Journal of Digestive Diseases. 2018; 10(1):5-17. [DOI:10.15171/mejdd.2017.84] [PMID] [PMCID]
18. Fakheri H, Malekzadeh R, Merat S, Khatibian M, Fazel A, Alizadeh BZ, et al. Clarithromycin vs. Furazolidone in quadruple therapy regimens for the treatment of Helicobacter pylori in a population with a high metronidazole resistance rate. Alimentary Pharmacology & Therapeutics. 2001; 15(3):411-6. [DOI:10.1046/j.1365-2036.2001.00931.x] [PMID]
19. Hu Y, Wan JH, Li XY, Zhu Y, Graham DY, Lu NH. Systematic review with meta-analysis: The global recurrence rate of Helicobacter pylori. Alimentary Pharmacology & Therapeutics. 2017; 46(9):773-9. [DOI:10.1111/apt.14319] [PMID]
20. Gisbert JP. The recurrence of Helicobacter pylori infection: Incidence and variables influencing it. A critical review. American Journal of Gastroenterology. 2005; 100(9):2083-99. [DOI:10.1111/j.1572-0241.2005.50043.x] [PMID]
21. O’Connor A, Furuta T, Gisbert JP, O’Morain C. Review-treatment of Helicobacter pylori infection 2020. Helicobacter. 2020; 25 (Suppl 1):e12743. [DOI:10.1111/hel.12743] [PMID]
22. Bell G, Powell K. Helicobacter pylori reinfection after apparent eradication-the Ipswich experience. Scandinavian Journal of Gastroenterology. 1996; 215:96-104. [PMID]
23. Gisbert JP, Pajares JM, García-Valriberas R, Abraira V, Boixeda D, García-Grávalos R, et al. Recurrence of Helicobacter pylori infection after eradication: Incidence and variables influencing it. Scandinavian Journal of Gastroenterology. 1998; 33(11):1144-51. [PMID]