How can the current strategies for Helicobacter pylori eradication therapy be improved ?

This article was originally presented at a conference entitled "Helicobacter pylori: Basic Mechanisms to Clinical Cure 2002", sponsored by Axcan Pharma, November 10-14, 2002, Maui, Hawaii Gastroenterology Unit, City Hospital National Health Service Trust, Birmingham, United Kingdom Correspondence: Dr P Moayyedi, Gastroenterology Unit, City Hospital National Health Service Trust, Dudley Road, Winson Green, Birmingham B18 7QH, United Kingdom. Telephone 44-0-121-5075924, fax 44-0-121-5075925, e-mail p.moayyedi@bham.ac.uk AC Ford, P Moayyedi. How can the current strategies for Helicobacter pylori eradication therapy be improved? Can J Gastroenterol 2003;17(Suppl B):36A-40A.

E radication therapy for Helicobacter pylori infection has become an important weapon in the clinician's armoury against dyspepsia.The European Helicobacter pylori Study Group (EHPSG) suggests that H pylori eradication is strongly recommended for patients with peptic ulcer disease, mucosa-associated lymphoid tissue (MALT) lymphoma, atrophic gastritis, postgastric cancer resection, patients with a first-degree relative with gastric cancer and as part of a test and treat strategy (1).The Maastricht 2-2000 consensus also suggested H pylori eradication is advisable for patients with nonulcer dyspepsia, long term acid suppression and before nonsteroidal anti-inflammatory drug therapy (1).With such a variety of indications, it is important to optimize current strategies to eradicate H pylori infection.
Trials indicate that clarithromycin-based proton pump inhibitor (PPI) triple therapies are the most effective regimens for the treatment of H pylori infection (2,3).A systematic review (4) reported that ranitidine bismuth citrate triple therapy regimens are as effective as their PPI counterparts in eradicating H pylori, but because PPI-based triple therapies are more widely used they are the focus of the present review.The aims of the present paper are to address the optimum doses of the drugs used in PPI-based clarithromycin triple therapies to reach conclusions as to the optimal regimens.Strategies that could improve on these therapies using existing antibiotics will also be explored.

OPTIMUM DOSE AND DURATION OF PPI IN CLARITHROMYCIN-BASED THERAPY Optimum dose of PPI
The dose of PPI required in amoxycillin dual therapy is important, with increasing acid suppression leading to greater efficacy (5).A review and meta-analysis of the literature was performed to evaluate whether the dose of PPI was also important in clarithromycin-
In three RCTs (17)(18)(19), 378 patients were evaluated with single versus double standard dose PPI in clarithromycin and metronidazole (PCM) regimens.There was no statistically significant difference between single versus double dose PPI therapy in PCM regimens (RRR 2%; 95% CI -7% to 10%) (Figure 2).The number of patients evaluated in PCM trials was less than in PAC trials and, therefore, the power of this meta-analysis is limited.Nevertheless, the available data suggest that single dose PPI therapy is sufficient for PCM triple therapy.

Optimum PPI
A meta-analysis of 10 RCTs performed in 2001 (20), evaluating a total of 1348 patients, showed that there was no significant difference between omeprazole and lansoprazole-containing triple therapies of seven days or more.
However, five RCTs (16,(21)(22)(23)(24) evaluating 934 patients were found that compared the equivalent doses of rabeprazole and omeprazole in PAC regimens.Meta-analysis of these trials suggests that rabeprazole is superior to omeprazole (RRR 8%, 95% CI 2% to 14%; NNT 16, 95% CI 9 to 65) (Figure 3).With regard to the use of rabeprazole in PCM regimens, there was only one trial comparing it to an omeprazole-containing regimen, and that trial showed no significant difference between the two regimens (22).There was insufficient evidence to allow any comparison between pantoprazole and the other PPIs to be made.

Optimum dose of clarithromycin
The question of the optimum dose of clarithromycin has already been the subject of a systematic review published in 1999 (25).At that time, there were four trials, evaluating a total of 385 patients, comparing clarithromycin 250 mg with clarithromycin 500 mg in a PAC regimen.Meta-analysis suggested that the higher dose of clarithromycin was optimal (RRR 11%, 95% CI 3% to 18%; NNT 11, 95% CI7 to 42) (20).There were also four trials, evaluating a total of 642 patients, comparing 250 mg with 500 mg of clarithromycin in a PCM regimen.Doubling the dose of clarithromycin had no statistically significant effect on eradication rates (RRR 2%; 95% CI -4% to 7%) (20) and a dose of 250 mg has, therefore, been recommended (1).
Since this review, another RCT was identified ( 26) that shows a benefit in favour of 250 mg of clarithromycin in a PAC regimen.If this trial is included in the meta-analysis, the results become more heterogeneous and the overall effect of increasing the dose of clarithromycin in a PAC regimen is not statistically significant.It is difficult to explain why a lower dose of clarithromycin would be superior in eradicating H pylori infection, and the balance of evidence still suggests that the higher dose of clarithromycin should be recommended when included in PAC regimens.

Figure 3) Randomized controlled trials of rabeprazole versus omeprazole in proton pump inhibitor with clarithromycin and amoxycillin regimens. df Degrees of freedom
trials giving greater variability than larger trials (Figure 5).The finding that there is no difference in efficacy between optimal PAC and PCM regimens is unexpected, because three metaanalyses have suggested that PCM is approximately 20% less effective against metronidazole-resistant strains of H pylori (45)(46)(47).It is unlikely that all trials had a low prevalence of resistant strains and the number of patients evaluated gives the power to detect even small differences in efficacy between the two regimens (RRR 0%; 95% CI -3% to 3%).Furthermore, there was no significant heterogeneity between the trials, yet many were from different countries with a different prevalence of H pylori metronidazole resistance.Again, the number of patients evaluated gives excessive power for detecting heterogeneity between studies and it is surprising that none was found.These data suggest that PCM may be more effective than PAC in metronidazole-sensitive H pylori strains and that the impact of metronidazole resistance may not be as marked as observational studies suggest.

STRATEGIES TO IMPROVE EXISTING REGIMENS Optimum duration of treatment
The most obvious strategy to improve the efficacy of clarithromycin-based PPI triple therapy is to increase the length of therapy.Indeed, American guidelines recommend 10 days of therapy, while European guidelines suggest that seven days is sufficient {1,48}.Shortening the duration of triple therapy to less than seven days has been shown to have a deleterious effect on eradication rates (23,48).

New approaches using existing antibiotics
A recent trial performed in Italy (61) compared a novel 10-day eradication regimen, in the form of five days of rabeprazole 20 mg and amoxycillin 1 g twice daily followed by five days of rabeprazole 20 mg, clarithromycin 500 mg and tinidazole 500 mg twice daily, with a standard seven-day PAC regimen in 1099 H pylori-positive patients.H pylori was eradicated in 378 of 399 patients (95%) allocated to the 10-day therapy compared with 301 of 397 patients (76%) given seven days of PAC.This is an interesting finding, but the regimen also needs to be compared with a standard PCM regimen and further trials are needed to ensure that these results can be replicated in other centres.

Ford and Moayyedi
Can J Gastroenterol Vol

CONCLUSIONS
The optimum H pylori eradication regimen is still the subject of intensive research, with the results of many RCTs being published each year.The Cochrane collaboration ( 62) is conducting a systematic review that will hopefully give definitive answers as to the most effective therapy.This publication is eagerly awaited but until then a picture appears to be emerging.PAC and PCM are equally effective but the latter requires a lower dose of PPI and clarithromycin.PCM is, therefore, less expensive than PAC and is the most cost effective option.However, the EHPSG guidelines prefer the combination of PAC to be used as first-line treatment (1).The reason for this is that if PAC fails, the second-line treatment of quadruple therapy with PPI, bismuth, metronidazole and tetracycline involves treatment of the patient antibiotics that they have not previously received.The overall success rate for this strategy could theoretically be as high as 98% (63), whereas if PCM fails as first-line treatment the second-line approach would be PPI and amoxycillin dual therapy, giving an overall theoretical eradication rate of 95% (20).
There can be no generic recommendation for an eradication regimen that should be applied to all cases of H pylori infection.Each clinical situation should be considered separately and, using the information available, the best decision for the treatment of that patient should be made.In a 'test and treat' strategy for the management of dyspepsia and when H pylori eradication is being used to treat nonulcer dyspepsia, PCM should be used.This is because the gains from H pylori eradication are relatively small (64) and, therefore, the cheapest strategy will be the most cost effective (20).In other cases such as peptic ulcer disease and MALT lymphoma, where the evidence suggests that eradication carries a more definite advantage, PAC should be used, and may be more effective if the duration of therapy is 14 days and the possibility that rabeprazole may be more effective in this regimen deserves further consideration.

Improving current strategies for H pylori eradication
Can J Gastroenterol Vol 17 Suppl B June 2003 39B

Figure 7 )
Figure 7) Randomized controlled trials comparing 14-with seven-day proton pump inhibitor triple therapy.df Degrees of freedom 17 Suppl B June 2003 38B