Treatment of Helicobacter pylori Infection 2013

A number of interesting articles have been published over the last year assessing many issues around Helicobacter pylori eradication therapy, including the updated European Consensus Guidelines on H. pylori therapy (Maastricht/Florence Consensus Report) 1. This article addresses the published literature over the last year pertaining to these topics. These focused primarily on assessing the efficacy of standard triple therapy, as well as exploring new first-line treatments, mainly optimized triple therapies and nonbismuth quadruple schemes. There was also progress in investigating antibiotic resistance rates and the rescue therapies required to deal with ensuing treatment failures, especially novel fluoroquinolones. There have also been advances in acid suppression and an evolution in the use of adjuvant therapies, especially probiotic therapies, which were extensively examined. What is without dispute is that the eradication of H. pylori remains a worthwhile goal to alleviate the burden of disease caused by the complications of this infection, including dyspepsia, peptic ulcer disease, and gastric cancer. One particularly interesting paper looked at the role of H. pylori eradication in preventing rebleeding from peptic ulcers and showed virtually no recurrence in patients with complicated ulcers after H. pylori eradication indicating that maintenance antiulcer (antisecretory) therapy is not necessary if eradication is achieved 2.

Triple Therapy

Standard triple therapy with proton-pump inhibitor (PPI), amoxicillin, and clarithromycin remains the most commonly prescribed H. pylori eradication regimen. Two large studies reported sustained cure rates over the last decade between 85 and 90% in Korea 3, 4 and Singapore 5. Of note, a study from Thailand reported 100% cure rates with a 14-day high-dose PPI and long-acting clarithromycin 6. However, several publications from Spain 7, 8, India 9, México 10, Greece 11, and Japan 12 disclosed suboptimal results ranging from 49 to 78%. Duration of therapy was also examined with a study from Kenya suggesting no significant difference between a 7- and 14-day clarithromycin-based triple regimens 13. An interesting study from Israel showed that the addition of a lipid-lowering agent, simvastatin, improved eradication rates. By intention-to-treat (ITT) analysis, eradication rates were 86% for clarithromycin-based triple therapy with simvastatin compared to 69% with placebo 14.

Triple therapy with PPI, amoxicillin, and metronidazole has gained attention lately, on account of increasing clarithromycin resistance. A study of 136 patients in Spain using this triple therapy for 10 days and high-dose esomeprazole gave a cure rate of 82.4% 15. A study from Japan on 110 patients compared clarithromycin to metronidazole as part of a first-line 7-day triple therapy and found superior eradication rates for metronidazole-based therapy, 74.5 vs 96.4%, respectively, by ITT analysis 16. Another study from Japan looking at metronidazole in second-line therapy among patients who had 7 days of metronidazole-based triple therapy revealed eradication rates in excess of 90% 17. These results were not replicated in a study from Tunisia 18, where metronidazole resistance was 60%. Finally, a recent study from Italy 19 reported promising 86% cure rates with a PPI, a macrolide: miocamycin, and tinidazole for 10 days in a setting with previously reported 57% cure rates for standard triple therapy.

Nonbismuth Quadruple Therapies

Sequential therapy remains a hot topic in the H. pylori literature with studies from many parts of the world showing generally superiority over triple therapy, although with variable efficacy results. This modality consists of 5 days of PPI therapy plus amoxicillin, followed by a further 5 days of PPI with two other antibiotics, usually clarithromycin and metronidazole. A high-quality, randomized, multicentre study carried out in Taiwan, where 9% clarithromycin resistance rate is noted, compared a 14-day sequential regimen to a 10-day sequential and 14-day triple therapy (clarithromycin-based) regimens. The eradication rate was 90.7, 87, and 82.3%, respectively 20. Two studies from Italy 21 and Morocco 22 showed eradication rates of 92.5 and 84.5%, respectively. Nonetheless, trials from Iran 23, India 9, Korea 24, 25, and China 26 reported cure rates of only 76.7, 76, 75.9, 82, and 78.3%, respectively. Finally, two systematic reviews on sequential therapy have confirmed the advantage for the sequential regimen over standard triple therapy 27, 28.

Nonbismuth quadruple therapy, also termed “concomitant,” has been proposed as an alternative to the sequential therapy that is less confusing for the patient and more likely to facilitate compliance with therapy. It involves using concurrently all three antibiotics with PPI usually for a period of 10–14 days. A study from Spain showed that this performs very well in patients with clarithromycin-resistant strains, with eradication rates close to 90% 29. Another study from Thailand reported cure rates of 96% with a 10-day concomitant therapy 30. During this year, three trials have compared triple and concomitant therapy in Greece 11, Korea 4, and Japan 12, all of them showing an advantage of concomitant therapy (90.5 vs 73.8%, 91.4 vs 86.1%, and 94.9 vs 68.3%, respectively). Finally, two studies compared nonbismuth sequential and concomitant therapies in terms of efficacy and found comparable eradication rates with a trend toward better outcomes for concomitant therapy, with the eradication rates being 75.6 vs 80.8% and 80.0 vs 88.1%, respectively 31, 32. An updated review on concomitant therapy, involving 2070 patients from 19 studies, confirmed a mean 88% cure rate, clearly superior to triple therapy, and with a safe profile 33.

A therapeutic innovation, so-called “hybrid,” represents a combination of sequential and concomitant therapy. It consists of a standard 14-day sequential regimen but with the amoxicillin continued for the entire period, turning out to be a “concomitant” therapy for the last 7 days. In a study from Iran, hybrid therapy showed significantly superior results over sequential therapy (89.5 vs 76.7%) 23. A study from the Nobel laureate group in Australia looked at a novel concomitant therapy with PPI, amoxicillin, rifabutin, and ciprofloxacin and obtained eradication rates of 95.2%; in cases of penicillin allergy, the amoxicillin was substituted by bismuth with no significant decrease in eradication (94.2%) 34.

Bismuth-Based Therapy

Bismuth-based therapy has also been studied this year. Regarding first-line therapies, a pilot study showed an eradication rate of 97.1% (per-protocol) for a 14-day bismuth-based quadruple classical therapy in Hispanic patients in the US 35. Cure rates declined significantly when the duration of the therapy was 10 days or less. Another study from Turkey showed 81% cure rate on ITT analysis for a 14-day bismuth modified sequential therapy 36. Ecabet sodium is another antiulcer drug that has been proposed as an alternative to bismuth. A study from an area of China with high levels of antibiotic resistance showed roughly equivalent eradication rates of 68.4 and 68.0% (ITT) for ecabet and bismuth-based therapy, respectively 37. In the setting of second-line therapy, a Korean study showed eradication rates of 83.5% for 1 week and 87.7% for 2 week courses of bismuth-based therapy 38. Another study from Taiwan showed good outcomes for H. pylori eradication with bismuth-based therapy using levofloxacin (78.9%) and metronidazole (79.7%) 39. When used with furazolidone, a bismuth-based second-line therapy in Iran revealed an eradication rate of 80.6% 40.

Studies Including Fluoroquinolones

Levofloxacin can be a useful agent for H. pylori eradication across a number of settings; first or second-line, and as part of a triple, sequential, or concomitant regimen. As a triple first-line regimen, it has shown cure rates of 85.5 and 78.1% with a 7-day duration in China 26 and India 41, whereas using 10 days of duration led to 82.8% eradication rates in Spain 42. These two studies did not find significant differences between triple standard and triple levofloxacin-based therapies 26, 42. A 10-day levofloxacin-based sequential therapy achieved 82.8% cure rates 26, whereas an Italian study showed that a 5-day concomitant regimen was equally efficacious as a 10-day sequential regimen with eradication rate of 92.2 vs 93.3%, with the shorter concomitant regimen being considerably cheaper 43. In the second-line setting, a study of levofloxacin triple therapy from Spain showed reasonable eradication rates of 73.8% that remained stable over a period of 5 years 44. Very similar results were obtained from a study in Taiwan where a 78.1% eradication rate was obtained with a week of levofloxacin-based triple therapy compared with 75% for tetracycline treatment 45. A Chinese study suggested that very good eradication rates could be obtained from longer (14 day) durations of levofloxacin-based triple therapy (86.3%). However, levofloxacin resistance was high in this cohort (32%), and cure rates were notably higher for the levofloxacin-susceptible group compared to the resistant one (92 vs 33%) 46. Finally, a meta-analysis showed levofloxacin-based triple therapy to be superior to quadruple therapy for second-line eradication, with cure rates of 76.5% compared to 67.4% in Italy 47.

Other quinolones have also been proposed as first-line eradication therapies. A study from Italy disclosed that the addition of bismuth to a 10-day triple moxifloxacin-based therapy significantly increased eradication rates (92 vs 77%) 48. Similarly, a Chinese group showed that adding furazolidone to a triple levofloxacin-based therapy resulted in higher eradication rates (86 vs 67%) 49. A study from Taiwan showed that a newer quinolone, gemifloxacin, has superior antimicrobial activity to levofloxacin in vitro, with the potential ability to overcome quinolone resistance 50.

Second-Line Therapy

As outlined in previous paragraphs, the uses of quinolone-based, bismuth-based, and quadruple therapies are all acceptable options for second-line therapy. It is not advisable to repeat the first line of treatment and whichever second line is chosen ought to have at least one different constituent antibiotic. Choice of second-line therapy is therefore contingent on what has been used as first line. The current Maastrich-IV guidelines suggest that after failure of a PPI-clarithromycin-containing treatment, either a bismuth-containing quadruple therapy or levofloxacin-containing triple therapy is recommended as second-line treatment 1.

Rescue Therapy

Current European Guidelines suggest that third-line therapy be based on antimicrobial susceptibility testing after obtaining biopsy specimens for culture 1. In this regard, three interesting studies from China 51, Taiwan 52, and Italy 53 have shown promising results through this strategy. In the first study, four different bismuth-based quadruple therapies combining amoxicillin, tetracycline, furazolidone, or metronidazole achieved cure rates >90% in patients with one or more previous therapy failure, even with metronidazole resistance 51. In the Taiwanese study, individualized regimens according to resistance as defined by PCR genotyping led to eradication rates of 78.9% (15/19), 92.2% (47/51), and 71.4% in patients who received clarithromycin-, levofloxacin- and tetracycline-based sequential therapies, respectively 52. In Italy, a culture-based rescue antibiotic strategy showed eradication rates for levofloxacin triple therapy of 90% and rifabutin triple therapy of 88.6% 53. By contrast, one recent study suggested that 99.5% eradication can be achieved by the adoption of an empiric third-line regimen 54.

As a third-line regimen, levofloxacin plus rifaximin was seen to be successful in 65% of cases with standard triple therapy and bismuth-based quadruple therapy prior failure in China 55. A study from Korea showed better eradication for rifabutin-based triple therapy than levofloxacin-based therapy (71.4 vs 57.1%) 56. In Italy, 67.2% of patients obtained eradication from a third-line levofloxacin regimen 57 and 65% with a ciprofloxacin-based third-line triple therapy with PPI and metronidazole 58. Two studies from Japan have reported promising results with a new generation quinolone -sitafloxacin- as a third-line regimen. In a pilot study, triple sitafloxacin-based therapy achieved 75% cure rates 59, whereas a multicenter trial reported that a triple regimen with sitafloxacin was more effective than levofloxacin, with eradication rates of 70 vs 43.1% 60.

One study from Japan suggested that a 14-day high-dose PPI and amoxicillin dual therapy were an effective option (63%), especially for patients with low pretreatment urea breath test titers indicating a small load of H. pylori 61. Two studies from Italy 62 and Spain 63, this latter being the largest series reported to date involving 100 patients, have reported a 50% eradication rate for rifabutin as a fourth-line agent.

Antimicrobial Resistance

Interesting work was carried out on H. pylori resistance this year in diverse parts of the world. A large-scale multicentre European study revealed resistance rates of 17.5% for clarithromycin, 14.1% for levofloxacin and 34.9% for metronidazole, with a significant association found between outpatient antibiotic use and the proportion of antibiotic resistance 64. Resistance to amoxicillin, tetracycline, and rifabutin was close to nil. In Asia, resistance rates are even higher, as evidenced by studies published from China and Korea. In China, resistance rates to clarithromycin, metronidazole, levofloxacin, amoxicillin, gentamicin, and furazolidone were 21.5, 95.4, 20.6, 0.1, 0.1, and 0.1%, respectively, with more than 25% of patients having resistance to more than one antibiotic 65. In Korea, the primary resistance rate for amoxicillin was 14.9%, clarithromycin resistance occurred in 23.7%, and levofloxacin resistance was 28.1%, all of which had significantly increased since 2003 66. In Africa, a study from Senegal showed no resistance to amoxicillin or tetracycline, very low resistance to clarithromycin (1%), but considerable metronidazole resistance (85%) 67.

Acid Inhibition

A pilot study on the H2 receptor antagonist latifudine showed that it can achieve similar eradication rates to regimes based on PPIs at a significantly reduced cost 68. Although twice daily dosing of PPI is the standard of care for H. pylori eradication, one study from Taiwan looked at single dose esomeprazole vs pantoprazole and found superior eradication rates for the former 69. A high-quality meta-analysis showed higher eradication rates for both esomeprazole (82.3%) and rabeprazole (80.5%) than for first-generation PPIs (76.2–77.6%) 70.

Probiotics

The use of probiotics as adjuvant therapies in H. pylori eradication in recent years has been a topic of considerable interest. This last year has been especially prolific, albeit with notable divergent results. The most promising probiotic appears to be Lactobacillus species, and the most significant studies focused on the use of this agent. One Chinese study showed significantly improved eradication rates when twice daily L. acidophilus was used alongside standard triple therapy (81.6 vs 61.5%) 71. A randomized double-blinded, placebo-controlled trial in Iranian children disclosed a positive effect of a mixture probiotic, mainly Lactobacillus sp. added to PPI, amoxicillin, and furazolidone on eradication rates (90 vs 69%) 72. An Italian study found L. reuteri supplementation to improve both eradication rates and side-effect profile when used as part of a second-line levofloxacin-based regimen 73. Nonetheless, two recent studies from Iran 74, 75, involving standard triple and bismuth therapy and other three studies from Italy 76-78 dealing with triple and sequential therapy (two of them in children 74, 76), could not show eradication benefit from probiotic use, albeit it usually reduced antibiotic-related adverse events (especially diarrhea and nausea), thus improving compliance. A double-blind, placebo-controlled trial from Brazil could not show either increased efficacy nor decreased side effects after the addition of a probiotic to a triple therapy containing lansoprazole, tetracycline, and furazolidone 79. A study looked at the effect of probiotic treatment alone, independent of antibiotics, and showed that L. johnsonii MH 68 and L. salivarius subsp. salicinius AP-32 effectively suppressed H. pylori viability, and decreased the level of gastritis 80. A meta-analysis of 10 clinical trials was carried out on this hot topic in the past year and obtained by ITT analysis a pooled odds ratio of 2.066 in favor of the probiotics supplementation group vs the group without probiotics. In addition, a pooled odds ratio of 0.305 was calculated for the incidence of total side effects in the probiotics supplementation group. This suggests beneficial effects of probiotics both on efficacy and tolerance 81.

Recurrence

A recurrence risk for H. pylori infection of 11.5% was observed in a multicentre Latin American study. Recurrence was significantly associated with study site, nonadherence to initial therapy and children in the household 82. This is a considerably higher recurrence rate than the previously documented.

Conclusions

There have been many and diverse studies pertaining to H. pylori eradication treatment in the published literature over the last 12 months, often with conflicting outcomes. Cure rates for standard triple therapy remain acceptable in quite a few settings nowadays, with evolving novel triple therapies being added to our armamentarium. Regarding newer nonbismuth quadruple regimens, there is a trend of superiority emerging for the concomitant therapy over the sequential regimen, although this may imply greater financial costs and probably higher ecological impact. Further research is warranted with the hybrid therapy, that is, combining sequential and concomitant therapy. Bismuth remains a viable option, particularly in second-line treatment, where available. Levofloxacin-based therapies appear to be useful and versatile as part of different antibiotic combinations and in first-, second-, and third-line therapies. The emerging problem of quinolone resistance remains worrying, but there is some hope that newer generation quinolones may partially overcome this issue, especially sitafloxacin, moxifloxacin, or gemifloxacin. Some promising works have been reported for rescue therapy using individualized therapies upon antimicrobial resistance information. Probiotic therapy, especially with Lactobacillus sp., appears to have a clear effect in terms of reducing side effects and probably improving compliance, but insufficient data exists as of yet to conclude that their use improves eradication rates. In some geographical areas, recurrence of H. pylori infection is more common than had previously been thought and this, coupled with the poor rates of compliance to testing to ensure eradication has been achieved, is a cause of concern.