This multi-centre randomised trial of three regimens for eradicating H. pylori involved a large sample of adults recruited from the general populations of seven Latin American sites. The prevalence of H. pylori infection among screened participants was high, and nearly all individuals who tested UBT-positive were randomised into the trial. Participants tended to adhere closely to the protocol by returning for their follow-up UBT and taking their prescribed tablets. There was little difference among the three treatment arms in adherence and serious side effects. Our principal outcome measure, the probability of H. pylori eradication, was higher for 14-day standard triple therapy than for both four-drug regimens, and these results did not vary significantly by age, sex, study site, or history of chronic dyspeptic symptoms.
presents a major global health challenge that probably can best be addressed through practical, inexpensive, and population-based interventions in the resource-limited countries where it is most prevalent. From this perspective our trial’s size, technical simplicity, broad geographic coverage within Latin America, community-based population, use of locally-sourced generic drugs, and statistically robust findings across important subgroups reflect the realities of a region where H. pylori
-associated diseases are especially burdensome. The trial results are important in that they contradict those of meta-analyses that indicated that four-drug regimens (triple therapy plus a nitroimidazole) given concomitantly or sequentially were clearly superior to triple therapy,14–16
and they suggest that findings based primarily on data from Europe and other high-income regions may not be readily generalizable to lower-income countries.
We observed probabilities of H. pylori
eradication of less than 80% with five-day concomitant and ten-day sequential regimens by the intention-to-treat analysis, whereas meta-analyses had reported probabilities greater than 90% for both.14–16
A more recent trial from Taiwan comparing-day regimens of concomitant versus sequential four-drug therapies also reported that both regimens were more than 90% successful.20
The estimated effectiveness of our three-drug regimen (82%) in the intention-to-treat analysis was only modestly greater than found in the meta-analyses (77%–79%). Thus, the divergence between our findings and those of the meta-analyses largely represents the substantially worse performance of the four-drug regimens.
Geographic variations in the pattern of H. pylori
resistance to antibiotics might account for some of these discrepancies in results. In clinical series from several of the countries where our trial was conducted, clarithromycin resistance in H. pylori
isolates has been reported to be less prevalent than in Europe, and metronidazole resistance substantially more prevalent (as high as 80%).21–24
Clarithromycin resistance strongly diminishes the effectiveness of triple therapy, so a better outcome with triple therapy would be expected if the prevalence of resistance in our trial population actually was low. 13,21,25
A high prevalence of resistance to metronidazole in our study population is a plausible, but less certain, explanation for the worse-than-expected success of the four-drug regimens.25
Results according to antibiotic resistance are available from only two trials of sequential therapy versus triple therapy, and the combined data showed that sequential therapy was successful in 96% (68 of 71) of patients with metronidazole-resistant organisms compared to 78% (46 of 59) for triple therapy.16,26
There are no comparable data from trials of concomitant versus triple therapy. The presence of organisms resistant to both antibiotics would likely cause treatment to fail for all three studied regimens, but there are only scant data on this topic from Latin America.
We employed a 14-day regimen of triple therapy, whereas prior trials of the four-drug regimens generally compared them to seven or ten days of triple therapy. In one meta-analysis 14-day triple therapy regimens were slightly, but statistically significantly, superior to those of seven days or ten days; thus, longer duration conceivably enhanced the performance of triple therapy in our trial.27
Success with the four-drug regimens perhaps would also improve with greater duration;13,20,28
however, this would increase their cost.
We drew our participants from the general population of adults in the community, whilst prior trials studied patients with gastrointestinal symptoms.14–16
The success of H. pylori
treatment with triple therapy or sequential therapy has not been shown to be affected by a diagnosis of peptic ulcer disease or dyspepsia, and the superiority of triple therapy over the four-drug regimens in our trial did not vary significantly according to history of chronic dyspeptic symptoms.14
Although our trial was not blinded, the outcome measure (UBT) was objectively determined and seems unlikely to be biased. We used locally-available generic sources of drugs, but the differences in treatment response among centres cannot be easily attributed to variable drug quality, since some of the greatest differences were seen between Nicaragua and Honduras, centres that obtained their drugs from the same source.
For individuals with H. pylori
infection in much of Latin America, 14 days of triple therapy is probably the preferred empiric treatment. Nevertheless, the 87% eradication success in participants who adhered to the regimen is suboptimal in the clinical setting, and its effectiveness may decrease over time as clarithromycin resistance increases. Better H. pylori
treatment regimens for Latin American populations conceivably could be designed based on local antibiotic resistance data. However, the relatively small number of published reports on antibiotic resistance in this region generally pertain to H. pylori
isolates obtained from symptomatic patients undergoing endoscopy in urban, academic centres, and thus their results might not be applicable to broader populations.21
Lacking representative data on resistance, and given the daunting technical and financial challenges of obtaining these data, treatment guidelines for Latin America and other regions with limited resources may have to rely primarily on the results of large, simple clinical trials of empiric therapies in the specific populations to which the guidelines would apply. These data could be supplemented by subsequent monitoring of effectiveness in practice over time and by the results of antibiotic resistance testing in selected patients, where feasible.
We designed our study as a preliminary step towards implementing programs of gastric cancer prevention in Latin America. H. pylori
-associated gastric cancer results from a decades-long progression from normal mucosa to invasive cancer.3,29
The most promising preventive approach appears to be eradication of H. pylori
before cancer develops, and a number of randomised clinical trials have evaluated this strategy. The results show that eradicating H. pylori
slows or reverses progression of pre-malignant histological lesions, but no trial has been large enough to show a definitive cancer-preventive effect.30,31
Nevertheless, analyses have indicated that H. pylori
eradication programs would be cost-effective over the long term if they prevented only 10% of gastric cancer deaths; over the short term they would reduce costs of care for peptic ulcers and dyspepsia symptoms.32–34
Eradication programs are potentially even more cost-effective in regions such as Latin America, where the burden of H. pylori
-associated diseases is greater.
Our trial experience suggests that population-wide clinical trials or public health programs of H. pylori
eradication are feasible in Latin America. UBT-positive individuals readily agreed to be randomised to antibiotic treatment, and all three regimens of generic drugs resulted in probabilities of eradication comparable to those obtained in prior prevention programs.31
The 14-day triple-drug regimen had superior results, but the lower cost of the shorter-duration regimens may make them acceptable for use in preventive programs where resources are particularly scarce. Other considerations, including risks of recrudescence and re-infection following eradication, will also be important considerations.
Panel: Research in context
Consensus groups that represent both global and Latin American perspectives have designated triple-drug regimens of a proton pump inhibitor plus amoxicillin and clarithromycin taken for 7–14 days as a standard approach for eradicating H. pylori
However, the effectiveness of these regimens appears to have diminished to unacceptably low levels over time, and recent meta-analyses of clinical trials from Europe and Asia indicate that four-drug regimens that add metronidazole or tinidazole to triple therapy achieve superior results.12–16
A Medline search revealed no reports of relevant trials from Latin America, an area where H. pylori
-associated diseases are common and where wide-scale eradication programs may be indicated.
Our findings show that in the Latin American populations we studied, in contrast to many European and some Asian populations, 14-day standard triple therapy is more effective than five-day concomitant or ten-day sequential four-drug regimens that include metronidazole for eradicating H. pylori. One thus cannot safely assume that the observed effectiveness of H. pylori eradication regimens in one area will apply equally well elsewhere.