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Nowadays no one can doubt the importance of Helicobacter pylori infection in the development of gastritis, gastroduodenal ulcer disease and gastric cancer. The most solid argument supporting the causal role of this micro-organism in peptic ulcer disease is the evidence that eradicating it is associated with a dramatic decrease in the rate of ulcer relapses.1 Consequently, a definitive cure could be on the point to be brought about – and not just a temporary scarring – of gastroduodenal ulcer disease by eradicating H. pylori. Being able at last to change the natural course of peptic ulcer disease is one of the most significant advances in gastroenterology in recent decades. On the other hand, H. pylori infection has been shown to be closely related with gastric adenocarcinoma and with low-grade gastric mucosa associated lymphoid tissue (MALT) lymphoma. Furthermore, regression of MALT lymphoma has been demonstrated following H. pylori eradication.2
Given that a recurrence of infection with H. pylori seems to be a practically essential requisite for an ulcer relapse to occur subsequently, and that reappearance of the micro-organism explains some of the MALT lymphoma recurrences, the study of the incidence of the organism's recurrence represents an extremely important issue. The availability of therapies with optimal eradication rates would be of little value if the infection is again identified in a relatively short period, with the consequent risk for recurring ulcer or lymphoma.
Both the overall incidence of H. pylori recurrence and its chronologic aspects – the exact moment when it appears – have scarcely been studied. The influence of different variables is neither known on this recurrence; yet these are precisely the factors that are important in differentiating between true reinfection (i.e. when the patient is infected with a new strain of H. pylori) and recrudescence (when the pre-treatment strain of H. pylori becomes detectable again).3
Therefore, the aim of our study was not only to evaluate the incidence of recurrence of H. pylori infection in a 5-year follow-up study of 1000 patients, but also to assess the different variables that could influence it; among these variables, the most noteworthy are the following: (i) chronology of recurrences (do recurrences appear at a constant rate over the time?); (ii) age at reinfection (does age affect recurrences?); (iii) waiting time to define eradication of H. pylori after antibiotic treatment finalizes (is 4 weeks enough?); (iv) diagnostic methods to check for H. pylori eradication (is 13C-urea breath test sufficient?); and (v) efficacy of eradication regimen (does the efficacy of therapy influence further recurrences?). The response to the aforementioned questions will help to clarify the progression of post-therapy H. pylori infection and this will clarify our questions as to the true benefit of H. pylori eradication therapy.
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- Patients and methods
- Conflict of interest
In this study, we have evaluated the incidence of recurrence of H. pylori infection in 1000 patients in a 5-year follow-up study. This is, to our knowledge, the largest study up to now evaluating recurrence of H. pylori infection.3 Although other authors have previously included a higher number of patients in their studies, we have followed up a large number of subjects for several years – e.g. more than 200 patients were followed up to 5 years – resulting in the remarkably high (total) follow-up of 2744 patient-years.
A total of 71 recurrences were observed in our study, giving a yearly recurrence rate of 2.6%. This value is similar to that reported in most developed countries, but lower than in developing ones.3 The socioeconomic level of the country in question might be a predictor of reinfection risk. A recently performed systematic review calculated a mean annual reinfection rate of 3.4% and 8.7%, respectively in developed and developing countries.3 Therefore, the ‘cured once, cured forever’ statement5 may not hold true for H. pylori-infected patients living in developing countries. Nevertheless, although the overall reinfection rate is considerably higher in developing than in developed countries, several discrepancies show that reinfection is not consistently higher in areas of high H. pylori prevalence than in areas of low prevalence.6
Cumulative recurrence rates were 5.3% at 1 year, 6.8% at 2 years, 7% at 3 years, 7.6% at 4 years and 9.3% at 5 years (Figure 1), which indicates that the probability of recurrence is higher during the first year. Other authors have also observed that the risk of being reinfected with H. pylori seems to be mainly limited to a few months or 1 year after being given eradication treatment, as the incidence of delayed reinfection is substantially lower.7 If all H. pylori recurrences were true reinfections, one would expect these recurrences to appear at a constant rate over time, and this is not the case. In fact, some studies have evaluated the patients who had remained H. pylori negative 12 months after eradication and have shown that the recurrence rates are relatively low.8–12 Beyond the first year, the rates come close to the rate of natural acquisition of H. pylori infection in adulthood.13 These observations suggest that most of the recurrences detected during the first months after treatment are actually late recrudescences. Several studies using molecular fingerprinting techniques (polymerase chain reaction) favour this hypothesis, as they confirm that the identified micro-organisms (before and after therapy) are usually genetically identical.3, 13
The impossibility of detecting infection 1–2 months after completing therapy could be explained by several hypotheses: (i) lower bacterial density after antibiotic administration;8 (ii) persistence of micro-organisms in areas with gastric metaplasia in the duodenum,14 in inter- or intra-cellular regions;15 (iii) transitory modification of its morphology from spiral to coccoid by the H. pylori;16 and (iv) the micro-organism might lodge in reservoirs outside the gastrointestinal system, such as saliva or dental plaque.17
Mean age of our reinfected patients at 1 year was lower than that of patients without recurrence, and age correlated with H. pylori recurrence in the multivariate analysis. Thus, the recurrence rate at 1 year in patients <52 years was 7.1%, and only 3.9% when patients were ≥52 years. Furthermore, differences were observed when Kaplan–Meier curves were compared depending on age. Some observations suggest that both primary infection and reinfection with H. pylori is acquired mainly in childhood and only rarely at an adult age.18–21 This hypothesis is supported by the results of the study by Rowland et al.22 which found that risk of reinfection amongst children under 5 years old was 26 times higher than that amongst older individuals. Likewise, some studies have observed that the average age of reinfected patients is lower than that of patients who remain H. pylori negative,23–26 although other studies performed in children could not confirm that the risk of reinfection depends on age.27 The reason for this relationship between lower age and H. pylori recurrence is unknown, nor is it known whether it is due to differences in the distribution of other risk factors among age groups.
Helicobacter pylori recurrence at 1 year in patients previously treated with low efficacy therapies was 11.3%, and only 4.7% when therapies used were of high efficacy. In our study, we classified as low efficacy therapies those combining omeprazole–amoxicillin (32% eradication rate) or omeprazole–amoxicillin–metronidazole (56% eradication rate). Although some authors have achieved relatively encouraging results with this last triple regimen, mean eradication rate of only approximately 70% was calculated in a systematic review.28 Therapy regimen correlated with H. pylori recurrence in the multivariate analysis, and differences were observed when Kaplan–Meier curves were compared depending on type of therapy. Therefore, the lower the efficacy of an antibiotic therapy, the greater the likelihood that recurrence will occur, again suggesting that in these cases temporary ‘clearance’ has been achieved rather than true eradication.3 However, other data are in contrast with the concept that unsuccessful treatment regimens are associated to a high recurrence rate. Thus, some authors have shown that infection relapse does not differ between patients treated with dual treatments (with low efficacy) or triple regimens (highly effective),29 and others have reported very low reinfection rates even when treatments with a very low H. pylori eradication efficacy have been prescribed.30 Nevertheless, a different interpretation can be given for this relationship:31 the negative predictive value of a diagnostic method will be low when the prevalence of infection is high (as occurs after low efficacy eradication therapies) and, consequently, false negative results will be more frequent as the therapeutic efficacy lowers. Therefore, recurrences would not be influenced by the therapy per se, but would just reflect the inadequate negative predictive value of diagnostic methods when they are used after ineffective therapy. Nevertheless, whatever the interpretation, the clinical relevance of this observation on the prognosis of the patient is similar.
The optimum time for confirming success of eradication therapy is a matter of debate. In 1992, the American Food and Drug Administration recommended that this time should oscillate between 10 and 14 weeks.32 In addition, some authors have suggested postponing the confirmation of eradication until several months after therapy.11, 33–37 However, waiting time to define eradication of H. pylori after antibiotic treatment finalizes (4 vs. 8 weeks) did not correlate with recurrence of the infection in our study. Furthermore, several other studies suggest that a 4-week time span is enough to confirm eradication,1, 38 and this convention is generally accepted by the scientific community.7, 39 In summary, although the current functional definition for eradication (4-week rule) is arbitrary, post-therapy eradication can be safely confirmed at that time with 13C-urea breath test in clinical practice.
The number and characteristics of the diagnostic methods for confirming eradication also seem to affect future recurrence of H. pylori infection.34, 35 Obviously, less sensitive techniques (with more false-negative results) will favour the misinterpretation of the ‘eradication’ concept. For example, the rapid urease test is not reliable for confirming H. pylori eradication if it is the only diagnostic test used.40, 41 On the other hand, diagnostic methods capable of making an overall evaluation of the gastric mucosa (as the urea breath test) are especially appropriate for confirming eradication, in contrast to diagnostic tests based on gastric biopsy specimens, which, at least in theory, can be associated with sample errors. Results of the present study, where the number and characteristics of diagnostic methods to confirm H. pylori eradication (breath test vs. both breath test plus histology) did not correlate with incidence of recurrences, indicate that 13C-urea breath test is sufficient to safely confirm H. pylori eradication success, probably due to the remarkable accuracy of this method for the confirmation of H. pylori eradication.42
Finally, a clinically relevant question is whether it is necessary to perform routine controls (for example with annually 13C-urea breath test) in patients with H. pylori eradication success, to detect recurrence of the infection. As the incidence of reinfection is relatively low, at least in industrialized countries as ours, it seems unnecessary to perform periodic controls after eradication success. However, in patients with bleeding peptic ulcers and with MALT lymphoma, where the clinical relevance of reinfection is especially evident – as in both cases reappearance of the disease after reinfection has been reported – control for recurrence of H. pylori may be suggested.3