Elsevier

The Lancet

Volume 378, Issue 9790, 6–12 August 2011, Pages 507-514
The Lancet

Articles
14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trial

https://doi.org/10.1016/S0140-6736(11)60825-8Get rights and content

Summary

Background

Evidence from Europe, Asia, and North America suggests that standard three-drug regimens of a proton-pump inhibitor plus amoxicillin and clarithromycin are significantly less effective for eradication of Helicobacter pylori infection than are 5-day concomitant and 10-day sequential four-drug regimens that include a nitroimidazole. These four-drug regimens also entail fewer antibiotic doses than do three-drug regimens and thus could be suitable for eradication programmes in low-resource settings. Few studies in Latin America have been done, where the burden of H pylori-associated diseases is high. We therefore did a randomised trial in Latin America comparing the effectiveness of four-drug regimens given concomitantly or sequentially with that of a standard 14-day regimen of triple therapy.

Methods

Between September, 2009, and June, 2010, we did a randomised trial of empiric 14-day triple, 5-day concomitant, and 10-day sequential therapies for H pylori in seven Latin American sites: Chile, Colombia, Costa Rica, Honduras, Nicaragua, and Mexico (two sites). Participants aged 21–65 years who tested positive for H pylori by a urea breath test were randomly assigned by a central computer using a dynamic balancing procedure to: 14 days of lansoprazole, amoxicillin, and clarithromycin (standard therapy); 5 days of lansoprazole, amoxicillin, clarithromycin, and metronidazole (concomitant therapy); or 5 days of lansoprazole and amoxicillin followed by 5 days of lansoprazole, clarithromycin, and metronidazole (sequential therapy). Eradication was assessed by urea breath test 6–8 weeks after randomisation. The trial was not masked. Our primary outcome was probablity of H pylori eradication. Our analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, registration number NCT01061437.

Findings

1463 participants aged 21–65 years were randomly allocated a treatment: 488 were treated with 14-day standard therapy, 489 with 5-day concomitant therapy, and 486 with 10-day sequential therapy. The probability of eradication with standard therapy was 82·2% (401 of 488), which was 8·6% higher (95% adjusted CI 2·6–14·5) than with concomitant therapy (73·6% [360 of 489]) and 5·6% higher (–0·04% to 11·6) than with sequential therapy (76·5% [372 of 486]). Neither four-drug regimen was significantly better than standard triple therapy in any of the seven sites.

Interpretation

Standard 14-day triple-drug therapy is preferable to 5-day concomitant or 10-day sequential four-drug regimens as empiric therapy for H pylori infection in diverse Latin American populations.

Funding

Bill & Melinda Gates Foundation, US National Institutes of Health.

Introduction

Helicobacter pylori infects most of the world's adult population and is the principal cause of gastric cancer, accounting for an estimated 60% of all cases.1, 2, 3 Gastric cancer is second only to lung cancer as a cause of cancer death worldwide, and almost all of the nearly 1 million cases and 0·75 million deaths each year occur in east Asia and Latin America.4 Although gastric cancer death rates have fallen in recent decades, the number of deaths has actually increased as a consequence of ageing populations, and gastric cancer is projected to rank among the ten leading global causes of death by 2030.5, 6 H pylori is also the main cause of peptic ulcer disease, which accounts for the loss of about 4·6 million disability-adjusted life-years every year worldwide, with most of the burden borne by populations in low-income and middle-income countries.7 Population-wide eradication programmes seem to offer the most direct approach to reducing the enormous human and economic consequences of H pylori infection; however, none has been implemented to date.8

Large programmes for H pylori eradication require a practical and inexpensive antibiotic regimen that is effective in the specific locale where it will be used. Standard antibiotic regimens for H pylori usually entail a proton-pump inhibitor, amoxicillin, and clarithromycin, taken together over 7–14 days.9, 10, 11 However, the effectiveness of these triple-therapy regimens seems to have diminished over time, largely as a result of emerging resistance of the organism to clarithromycin.12, 13 Recent meta-analyses have shown that regimens that add a nitroimidazole (metronidazole or tinidazole) to triple therapy and are given either sequentially for 10 days or concomitantly for 5 days are significantly more successful at eradication of H pylori infection than are triple-therapy regimens.14, 15, 16 These regimens also require fewer doses of antibiotics and thus might be more affordable in low-resource settings. Almost all the evidence supporting these four-drug regimens comes from Europe and Asia; few data are available from Latin America, a region with some of the world's highest rates of gastric cancer mortality.17 We therefore undertook a randomised trial in Latin America comparing the effectiveness of four-drug regimens given concomitantly or sequentially with that of a standard 14-day regimen of triple therapy. The trial also provided insights into the feasibility of community-based programmes of H pylori eradication.

Section snippets

Study design and patients

The trial (SWOG S0701) was a randomised trial of empiric 14-day triple, 5-day concomitant, and 10-day sequential therapies for H pylori infection in seven Latin American sites: Chile (Santiago), Colombia (Túquerres), Costa Rica (Guanacaste), Honduras (Santa Rosa de Copán), Mexico (Ciudad Obregón and Tapachula), and Nicaragua (León). Between September, 2009, and June, 2010, study research staff recruited potential participants from the general population of adult men and women aged 21–65 years

Results

1859 potentially-eligible adults agreed to participate in the study and completed the screening interview and intake questionnaire, but seven withdrew before the urea breath test (figure). The test was positive for 1471 (79%) of 1852 tested participants. Eight patients with a positive test were not randomly assigned because they opted not to be treated, could not be randomly assigned within 2 weeks of their urea breath test, or had a disqualifying factor (eg, pregnancy). Six participants with a

Discussion

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. The prevalence of H pylori infection in screened participants was high, and nearly all individuals who had a positive urea breath test were randomly assigned into the trial. Participants tended to adhere closely to the protocol by

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