One or two weeks of treatment with Helicobacter Pylori ''standard'' triple therapy in the year 2015?

Helicobacter pylori is a slow-growing, micro-aerophilic, gram-negative micro-organism, usually acquired during childhood. Although the prevalence of H. pylori infection varies depending on age, socioeconomic class, and country, it is one of the most diffuse bacteria with a worldwide distribution. It is well known that H. pylori is involved in the development of several gastroduodenal diseases, including gastritis, peptic ulcer, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Moreover, its potential involvement in the pathogenesis of several extra-gastroduodenal manifestations is under investigation.[1]

According to International Guidelines, multidrug regimens consisting of a proton pump inhibitor (PPI) and two or three antibiotics, among clarithromycin, amoxycillin, and metronidazole, should be used as first choice in treating H. pylori infection.[2] Nevertheless, in different countries, conflicting results on efficacy have been reported using these treatment regimens: A high eradication rate emerged in some studies but not in others where an eradication failure rate, ranging from 20% to 50%, was found.[3] Several alternatives are available and various combinations of traditional drugs have been investigated[4] in order to overcome the increasing H. pylori antibiotic resistance, in particular, to clarithromycin.[5]

In 2002, in a randomized study, we showed that in Turin, Northern Italy, a triple therapy with clarithromycin, amoxycillin, and a PPI for 7 days or for 10 days achieved an eradication rate of 68% or 76%, respectively. Lengthening the treatment conferred no advantages.[6] These values were significantly lower compared with those reported 10 years earlier. In a series of subsequent studies, with both the same and alternative schedules, we did not get better results.[7]

In a recent prospective, randomized, single-blind, controlled study conducted in Shanghai, Wang et al. evaluated the efficacy of the treatment by clarithromycin, amoxycillin, and PPI for 7 or 14 days. H. pylori eradication rates, according to the two regimens, were, in the intention-to-treat (ITT) analysis, 67% for the 14-day regimen versus 56% for the 7 days regimen. These results were statistically significant. The significance decreased in the per-protocol (PP) analysis. In the logistic regression model, duration of treatment resulted in an independent factor correlated with H. pylori eradication, with the rate achieved with the 14 days regimen significantly higher than that achieved with the 7 days regimen in the ITT (P = 0.017) but not in the PP analysis (P = 0.353). Poor compliance or adverse events occurred in 10.4% of the population, with the incidence of dropouts being higher, albeit not significantly, for the 7 days regimen (11.9%) versus the 14 days regimen (9.0%).[8]

The results of this study confirm that the eradication rate achieved by standard clarithromycin-based triple regimen is falling to unacceptable levels worldwide. The loss of significant differences among the two groups in the PP analysis confirms that in clinical practice the period of treatment does not significantly affect the eradication rate. In fact, while with ITT analysis the primary tabulations and summaries of outcome data are by assigned treatment, PP analysis considers only subjects who ended the treatment. Thus, with the former patients who left during either treatment or follow-up (eg, because of side effects) are also included, whereas with the latter only patients who concluded the treatment are considered for statistical analysis. Strangely, lengthening the treatment duration did not influence the compliance or the safety profile.

Recently, Li et al. have published the results of a network meta-analysis evaluating several treatments for H. pylori infection.[9] This methodology rather than comparing trials that evaluated the same treatments, extends the number and type of trials included for clinical decision making. This approach also allows to make indirect comparison across trials and among treatments that have not been tested head to head, as long as the trials are linked by a common treatment arm.[10] Standard triple treatment for 7 days emerged at the bottom of the ranking for both direct and indirect comparison, with an eradication rate of 73%. Lengthening the treatment to 10 or 14 days conferred no significant advantages albeit reaching an eradication rate of 81%. The 7 days concomitant regimen was at the top of the ranking with 94% of eradication rate.[9] However, the validity of the conclusions drawn about this regimen is limited by the scarce number of trials.

In conclusion, the trial by Wang et al. confirms that the 14 days regimen has a disappointing modest superiority with respect to the 7 days regimen of standard therapy for H. pylori eradication,[8] and that firstline treatment regimen should be selected according to area of low (<20%) and high (>20%) clarithromycin resistance.

As final remark, it should be highlighted that in this study patients with gastro-esophageal reflux disease (GERD) were included. According to International Guidelines, H. pylori status has no effect on comparison, severity or treatment efficacy of GERD.[2] However, long-term treatment with PPI could lead to the development of a corpus-predominant gastritis, and in a next step, of atrophic gastritis, accelerated in the presence of H. pylori infection. Since H. pylori eradication prevents the progression to atrophic gastritis, this is the only reason to search for and to treat H. pylori in patients with GERD.