Helicobacter ISSN 1523-5378 doi: 10.1111/hel.12163

REVIEW ARTICLE

Treatment of Helicobacter pylori Infection 2014 Anthony O’Connor,* Dino Vaira,† Javier P. Gisbert‡ and Colm O’Morain§ *Leeds Gastroenterology Institute, St. James’s University Hospital, Leeds, UK, †Department of Clinical Medicine, S. Orsola Hospital Bologna, n Sanitaria Princesa (IP) and Centro de University of Bologna, Bologna, Italy, ‡Department of Gastroenterology, Instituto de Investigacio n Biome dica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Hospital Universitario de la Princesa, Madrid, Spain, Investigacio § Department of Gastroenterology, Tallaght Hospital/Trinity College Dublin, Dublin, Ireland

Keywords Peptic ulcer disease, resistance, compliance, first-line, second-line, susceptibility testing. Reprint requests to: Anthony O’Connor, Leeds Gastroenterology Institute, Bexley Wing, St. James’s University Hospital, Leeds, UK. E-mail: Anthony.O’[email protected]

Abstract This review summarizes important studies regarding H.pylori therapy published from April 2013 to April 2014. The main themes that emerge are assessing the efficacy of standard triple therapy, as well as exploring new first-line treatments, predominantly optimized triple therapies and non-bismuth quadruple schemes. Regarding newer non-bismuth quadruple regimens, the compliance and tolerance seem to be similar for sequential and concomitant regimens. Notably, no study yet has demonstrated a clear statistical superiority for either, and a systematic review and meta-analysis may be warranted. Other studies examined the role of levofloxacin and bismuth based therapies in H. pylori eradication. The efficacy of bismuth as a second-line after sequential therapy was particularly noteworthy. Levofloxacin-based therapies also 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 a worry. Individualized therapy, based on factors such as antimicrobial information, resistance data, and CYP2C19 metabolism, may well be the most notable future trend to emerge this year.

Many interesting articles have been published from all parts of the world over the last year assessing many issues around Helicobacter pylori eradication therapy. The main themes that emerge are assessing the efficacy of standard triple therapy, as well as exploring new first-line treatments, mainly optimized triple therapies and non-bismuth quadruple schemes. More studies have focussed on second-line and rescue treatments with novel fluoroquinolones appearing promising in this regard. There was also considerable progress in investigating antibiotic resistance rates with more data emerging from varied parts of the world giving a good global perspective on the problem of resistance. There have also been advances in the use of adjunctive therapies, especially probiotic therapies, which were extensively examined and an exploration of the role of personalized treatments for H. pylori eradication. 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,

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including dyspepsia, peptic ulcer disease, and gastric cancer.

Standard First-Line Therapy Standard triple therapy with a proton-pump inhibitor (PPI), amoxicillin, and clarithromycin remains the most commonly prescribed H. pylori eradication regimen. The evidence from many of the comparison trials with newer therapy formulations would suggest that efficacy of this treatment is in decline, but this is not necessarily a consistent observation. In Japan, over a 10-year time frame, a divergence was seen whereby the eradication rates for triple therapy with clarithromycin did fall significantly over the time period to 65%, but the eradication rate for triple therapy, with metronidazole did not change annually and remained as high as 84% [1]. Another study from Korea showed no decreasing trend in the H. pylori eradication rate over the past 13 years and no difference in the eradication rates depending on

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duration of therapy when standard triple therapy with metronidazole is used, although some decrease was noted in the rate of eradication when clarithromycin was prescribed [2]. It is unclear whether intention-totreat (ITT) or per-protocol (PP) eradication rates were used in this study. A Cochrane systematic review was conducted this year on what the optimum duration of therapy is for H. pylori eradication treatment [3]. This review looked at 75 eligible studies and concluded that increasing the duration of PPI-based triple therapy increases H. pylori eradication rates and that for therapy with PPI, clarithromycin, and amoxicillin, which remains the most commonly used combination, prolonging treatment duration from 7 to 10 or from 10 to 14 days is associated with a significantly higher eradication rate, with the optimal duration of therapy being of at least 14 days. The eradication rate reported, as first-line therapy, for PPI, amoxicillin, and clarithromycin lasting 14 days was 83.5%; for PPI, clarithromycin, and metronidazole lasting 14 days, the rate was 68.6%; and for PPI, amoxicillin, and metronidazole, it was 82%. This was confirmed by another study from Canada that found 14 days of therapy to be clearly superior to 7 days (83 vs 64%, respectively) [4]. It is clear that multiple factors influence treatment success, and one study from Korea this year set out to address these various factors [5]. They found that age ≥50 years, female gender, BMI 55%. In Morocco, two randomized studies were performed comparing sequential to standard therapy. In both, sequential therapy performed impressively against

standard triple, with ITT eradication rates of 65.9% in the standard triple therapy group and 82.8 in the sequential therapy group in one, and 94.2% for sequential and 70% for metronidazole-based triple therapy and 78% for clarithromycin-based triple in the other [20,21]. Another two randomized, prospective studies carried out in India also showed significantly better eradication rates for sequential therapy [22,23]. One study on patients with all causes of dyspepsia showed an advantage for sequential therapy with an ITT eradication rate of 88.2 vs 79.1% for triple [22]. A second study looking at patients with documented peptic ulcer disease also found sequential therapy superior although the raw ITT eradication rates were less impressive (76.0 vs 61.9%) [23]. Three meta-analyses examining the efficacy of sequential versus standard triple therapy in Asia were also published this year, all of which favored sequential therapy. One included all studies with Asian adults and reported a pooled RR of 1.1 for eradication with sequential therapy over standard triple with an NNT of 14 [24]. In a second metaanalysis limited to nine studies conducted in Asia, the odds ratio (OR) for eradication of H. pylori with sequential therapy over standard triple was 1.8 [25]. A further meta-analysis of Korean studies only also favored of sequential therapy with an OR of 1.8 [26]. Concomitant therapy was evaluated in one article published this year from an area of high antibiotic resistance and found to have an ITT eradication rate in first-line therapy of 91.5 and 60.6% as second therapy [27]. Again, however, this does not seem to be able to overcome the hurdle of dual resistance with multivariate analysis, showing that dual resistance was the only independent significant predictor of treatment failure, although 55% of dual resistant strains were eradicated [27]. Hybrid therapy is an attempt to combine the principle of the induction phase of sequential therapy as a

Table 1 Head-to-head studies comparing various formulations of four-drug non-bismuth-based therapy Eradication for hybrid (%)

Eradication for sequential (%)

Eradication for concomitant (%)

Statistically significant differences?

343 338 164 420

90 n/a n/a 89.5 82.7

n/a 81 14 days 75.6 76.7 90

No No No Yes No

270

80

91.1

91.7 87 80.8 n/a 5 days 78.1 14 days 86.3 85.5

Author

Country

Study design

N

Molina-Infante et al. [28] McNicholl et al. [29] Lim et al. [30] Sardarian et al. [31] De Francesco et al. [32]

Spain Spain Korea Iran Italy

RCT RCT Randomized, pilot RCT Randomized

Zullo et al. [33]

Italy

Randomized, pilot

No

RCT, randomized controlled trial. Eradications are on intention-to-treat analysis.

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© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 38–45

O’Connor et al.

means of overcoming resistance with the benefits of the four drugs of the concomitant therapy. It involves using PPI and amoxicillin for 14 days, while clarithromycin and metronidazole or an equivalent is added for the final 7 days. In a large Spanish study this year, it gave results equivalent to concomitant therapy with ITT eradication rates of 90% for hybrid compared with 91.7% for concomitant [28]. However, significantly more patients were compliant with hybrid therapy (98.8%) than concomitant therapy (95.2%). Conceivably, there may also be a cost-benefit by reducing the number of drugs required. This was just one of six head-to-head randomized studies that compared the various forms of non-bismuth four-drug therapy [28– 33]. These are summarized in Table 1. In only one case was a statistically significant difference observed, favoring hybrid over sequential therapy [31]. The largest effect in favor of concomitant therapy was noted in the largest study, a Spanish trial, and in a multivariate analysis undertaken as part of this: Concomitant treatment showed an OR of 1.5 toward better eradication rate which was of borderline significance [29].

Levofloxacin and Other Fluoroquinolones The role of fluoroquinolones as first-, second-, and third-line therapies has also been examined in depth this year. Two meta-analyses were published on the use of levofloxacin as first-line therapy. Both found levofloxacin-based therapy to be roughly equivalent in efficacy to standard triple therapy. The first analysis of seven trials found a crude eradication rate of 79% for levofloxacin-based therapy versus 81.4% for standard triple without any significant difference between the two regimens (risk ratio 0.97; 95% CI; 0.93, 1.02) [34]. The second, larger meta-analysis of nine trials had broadly similar findings with 80.2% eradication rate for levofloxacin-based therapy versus 77.4% for standard triple [35]. However, this group performed subgroup analysis and identified that the standard triple regimen was statistically superior to a 7-day levofloxacin-based scheme in Asia, but levofloxacin-based triple therapy was superior in European countries. A further small study from Venezuela, where clarithromycin resistance is high, reported 67% eradication with clarithromycin-based therapy for 10 days compared with 95% for levofloxacin-based triple therapy [36]. As a second-line therapy, levofloxacin has been shown in the past to have considerable merit. In a trial on treatment failures post-non-bismuth-based sequential or concomitant therapy, levofloxacin-based triple therapy for 10 days led to a 74% eradication rate with

© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 38–45

Treatment of H. pylori Infection 2014

only 6% reporting side effects, which were all mild [37]. Another study suggested that when used as triple therapy in second line, 14 days of therapy were more effective than 10, with ITT eradication rates of 86 and 68%, respectively, found in patients who had failed standard first-line triple therapy [38]. A further study, from Turkey, looked at the utility of levofloxacin as a second-line therapy when given in a sequential or concomitant regime [39]. This study found ITT cure rates of 82.2% for levofloxacin sequential therapy as secondline and 90.6% for a levofloxacin concomitant regimen. In a Korean second-line study, levofloxacin-based triple therapy was less effective than quadruple therapy when both were given over 7 days, 67.9 vs 84.2% [40]. As a third-line agent, the newer fluoroquinolone agent sitafloxacin, which has lower minimum inhibitory concentration for H. pylori, was seen to be effective in a study from Japan [41]. In this study, patients who had failed to achieve eradication after both clarithromycin and metronidazole-based triple therapy were given sitafloxacin along with PPI and either amoxicillin or metronidazole for one and 2 weeks, and in all four regimens were found to achieve ITT eradication rates of 84.1% for 1 week and 88.9% for 2 weeks with amoxicillin, and of 90.9% for 1 week and 87.2% for 2 weeks with metronidazole.

Bismuth-Based Therapies Bismuth, like the fluoroquinolones, is a versatile antiH. pylori agent that appears to have benefits as a firstline and rescue therapy. In one large study from China, patients were randomized to receive sequential or bismuth-based quadruple therapy with a crossover design built-in for treatment failures [42]. As first-line agents, similar ITT eradication rates were found: 89.4% for sequential and 92.7% for bismuth-based therapy. One hundred percent success was noted for both treatments in the crossover arms for treatment failures, giving an impressive cumulative eradication rate of 100% for two lines of therapy. Interestingly, the overall incidence of adverse events was significantly higher in the bismuthbased arm (16.7 vs 8.1%). Two other studies were published from Turkey looking at bismuth as a first-line agent. The first found an eradication rate of 90.7% when bismuth was used with PPI, amoxicillin, and clarithromycin [43]. The second study looked at the use of ranitidine bismuth citrate as an alternative to PPI and found it to be as effective, but in this case, eradication rates were poor in both arms (65.1% for ranitidine bismuth citrate users and 63.6% for PPI users) [44]. Two further studies looked at the role of bismuth in secondline therapy. A large study from China on 424 patients

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Treatment of H. pylori Infection 2014

O’Connor et al.

who had failed a variety of first-line agents looked at the efficacy of bismuth when given as a quadruple therapy along with lansoprazole as PPI and either tetracycline or amoxicillin with metronidazole or furazolidone [45]. This study showed ITT eradication rates of 87.9–95.2% for all combinations with the best outcome being for lansoprazole, bismuth, amoxicillin, and furazolidone. Side effects were frequent and occurred in 33.6% of subjects but significantly more frequently in those taking metronidazole. A smaller study from Taiwan limited to those who had failed sequential therapy again, showed impressive second-line outcomes for bismuth in this cohort, with 23 of 24 (95.8%) achieving eradication [46]. As a third-line agent, bismuth also may be useful. In one multicenter study from Spain published recently, an eradication rate of 65% was observed for third-line bismuth-based quadruple therapy when standard therapy with clarithromycin and levofloxacin had failed [47].

Probiotics Studies on the role of probiotics as an adjunct to H. pylori eradication treatment have again been somewhat equivocal this year. The most frequently studied agents have been Lactobacillus sp. strains. In one study where 70 na€ıve patients were treated, Lactobacillus reuteri increased eradication rate by 8.6% and reduced the reported side effects when compared with placebo-supplemented triple therapy [48]. A meta-analysis of nine studies on probiotic use as an adjunct to triple therapy found that when specific Lactobacillus strains were used, eradication rates raised significantly by 17%, but when multistrain probiotics were used, eradication rates enhanced by only 2.8% [49]. This also was reflected in two other trials from Iran and Brazil where multistrain probiotics as adjunct therapy failed to show a benefit

for eradication [50,51]. Another study examined the role of L. reuteri without antibiotic therapy, finding a cure rate of 13.6% (3/22) when it was used with PPI [52]. Bifidobacterium infantis has also been proposed as having anti-H. pylori activity, and in a study this year from Asia, it was observed that adding it to standard triple therapy increased the cure rate from 68.9% to 83%, and when pretreatment with 2 weeks of B. infantis was given as well, the success rate of eradication increased to 90.5% [53].

Resistance There were many studies on H. pylori resistance levels in the last year. These studies on resistance over the last year are summarized in Table 2 [54–62]. One of the most significant of these was a systematic review of studies on resistance in Latin American countries [54]. This found that antibiotic resistance rates varied significantly by drug and by country, but not by year of sample collection [54]. This was corroborated by a Brazilian study [56]. However, it was in contrast to other studies from outside the Latin America region that showed rising resistance rates to certain antibiotics over time, especially with regard to levofloxacin resistance [55,57– 60]. Regarding secondary resistance, a large German study of over 5000 strains found this to be also a major problem, especially with reference to fluoroquinolones. In this study, from 2006 onward, a steady annual increase was noted in the level of levofloxacin/ciprofloxacin, and triple resistance (quinolone, clarithromycin, and metronidazole) was noted, peaking in 2011 with 29.1% for fluoroquinolone resistance and 18.6% for triple resistance. Patients who had undergone previous unsuccessful eradication attempts were far more likely to be both quinolone resistant and triple resistant than those who had not [63].

Table 2 Primary antibiotic resistance rates to Helicobacter pylori infection

Author

Region

Amoxycillin (%)

Clarithromycin (%)

Metronidazole (%)

Rifabutin (%)

Furazolidone (%)

Tetracycline (%)

Fluoroquinolone (%)

Camargo et al. [54] Hsiang et al. [55] Suzuki et al. [56] An et al. [57] Vekens et al. [58] Selgrad et al. [59] O’Connor et al. [60] Su et al. [61] Lee et al. [62]

Latin America New Zealand Brazil Korea Belgium Germany Ireland China Korea

4 NR NR 2.1 0.8 0 NR 0.1 14.9

12 16.4 2.4 16.0 13.3 7.5 NR 21.5 23.7

53 49.3 NR 56.3 26.1 32.5 NR 95.4 NR

NR NR NR NR NR

Treatment of Helicobacter pylori infection 2014.

This review summarizes important studies regarding H.pylori therapy published from April 2013 to April 2014. The main themes that emerge are assessing...
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