Current Treatment Options in Gastroenterology DOI 10.1007/s11938-014-0027-6

Stomach (C Howden, Section Editor)

Current Paradigm and Future Directions for Treatment of Helicobacter pylori Infection Jason Ferreira, MD Steven F. Moss, MD*

Address *Division of Gastroenterology, Department of Medicine, Warren Alpert Medical School of Brown University, Rhode Island Hospital, 593 Eddy Street, APC 414, Providence, RI 02903, USA Email: [email protected] Email: [email protected]

* Springer Science+Business Media, LLC 2014

Keywords H. pylori infection I Treatment guidelines I Triple therapy I Quadruple therapy I Concomitant I Sequential I Hybrid I Probiotics I Antibiotic resistance I Vaccine I Culture-guided therapy

Opinion statement Once easily eradicated with triple or quadruple therapy, Helicobacter pylori infection has become increasingly resistant to traditional first-line treatment regimens because of emerging antibiotic resistance coupled with poor patient compliance with completing the treatment course. Given decreasing H. pylori eradication rates, there is considerable interest in evaluating new antibiotic combinations and regimens, the addition of probiotics, and the development of new paradigms such as concomitant, sequential, and hybrid medication dosing strategies. Unfortunately, efforts thus far have not universally improved treatment responses, as promising early results were often not extrapolated to wider populations. This is probably due largely to regional variation in H. pylori resistance patterns. Ideally, the standard of care should be dictated by knowledge of local H. pylori antimicrobial resistance patterns and clinical success rates rather than by empiric extrapolation from the literature. Unfortunately, such knowledge is usually lacking in the USA. The expectation of a first-line regimen is a minimum 80 % eradication rate in the local population. Standard triple therapy with a proton pump inhibitor (PPI), amoxicillin, and clarithromycin may still be effective in some areas; however, in populations with high clarithromycin resistance, quadruple therapy with a metronidazole-based regimen may be a better choice, and concomitant, sequential, or hybrid dosing schedules should also be considered as possible first-line choices. Second- and third-line treatment regimens consist of levofloxacin-based and rifabutin-based therapies, respectively. Further work should be directed at establishing local resistance patterns and eradication rates, developing H. pylori-specific antibiotics, and starting culture-guided treatment programs. Ultimately, the development of an H. pylori vaccine would bypass any issues with antibiotic resistance by preventing the acquisition of infection altogether.

Stomach (C Howden, Section Editor)

Introduction First termed “Campylobacter pyloridis” when identified by Marshall and Warren [1] in 1984 as a causative agent for gastritis and peptic ulceration, H. pylori is a ureaseproducing, spiral-shaped, Gram-negative bacterium. The World Health Organization has classified it as a definite carcinogen since 1994 [2] for its established role in the pathogenesis of gastric cancer and gastric mucosaassociated lymphoid tissue lymphoma. Now, 30 years after its discovery, H. pylori remains the most common bacterial infection in humans, and it is estimated that approximately 50 % of the world’s population is infected [3]. H. pylori tends to be more common in developing countries, and most infections are acquired during childhood. The route of transmission is unclear, but studies have suggested person-to-person transmission via the oral–oral, fecal–oral, or gastro–oral routes as the most likely mechanism [4]. Re-infection in adults following successful eradication is rare and occurs in around 2 % of previously infected persons per year—a rate similar to that of primary adult acquisition of infection [5, 6]. The diagnosis of H. pylori infection can be made using one of several invasive or noninvasive techniques. Endoscopic biopsy of the stomach remains the standard invasive diagnostic platform for H. pylori, as it allows both for identification of the infection and for histologic assessment of the severity of inflammation or the presence of gastric intestinal metaplasia, dysplasia, or neoplasia. Biopsies from both the antrum and the gastric body are recommended and are most often applied in practice; however, the gold standard for gastric biopsy collection, which maximizes sensitivity and specificity, remains the updated Sydney classification, which suggests sampling from five different stomach sites, including 4 cm proximal to the angulus on the lesser curvature, the greater and lesser curvatures of the antrum, 8 cm from the cardia, and the incisura [7]. Although not commonly employed clinically, H. pylori culture in experienced hands is the most specific method for detecting the infection and, although its use is mostly limited to research studies, certain centers also use the test to confirm antibiotic sensitivity in patients after two treatment failures [8]. In addition to histology and culture, rapid urease testing can be performed by placing a tissue biopsy into a urearich medium with a pH indicator. If H. pylori is present, its urease will break down the urea to carbon dioxide and ammonia, which will increase the pH of the medium. False negative results of any of these tests can occur with recent intake of PPIs, bismuth, or antibiotics [9].

Noninvasively, H. pylori can be diagnosed via serology, urea breath testing, and stool antigen assays. Serologic testing is based on an enzyme immunoassay that detects immunoglobulin (IgG), but the performance characteristics of serology are suboptimal and, because serology may remain positive after successful H. pylori eradication, it is no longer recommended for clinical practice [10]. Urea breath testing relies on the urease activity of H. pylori to break down orally administered 13 C- or 14C-labeled urea into labeled CO2 and ammonia. The labeled CO2 is then measured in exhaled breath. Stool antigen testing uses an enzyme immunoassay to detect the presence of H. pylori in a stool sample. In patients with ulcers, or in those with persistent symptoms, the urea breath test or the stool antigen test can be used to determine whether H. pylori has been successfully eradicated, by performing the test at least 4 weeks after the patient completes treatment, without the need for endoscopy. Either of these tests can produce false negative results if patients are taking PPIs, antibiotics, or bismuth preparations around the time of the assay. It is recommended that PPIs be discontinued for at least 2 weeks before these tests are performed. Regardless of the diagnostic method that is used, once H. pylori has been detected, eradication therapy is recommended to relieve the burden caused by resulting dyspepsia and peptic ulcer disease, and to reduce the risk of gastric cancer development. Unfortunately, the treatment of H. pylori infection can be difficult and frustrating for both the clinician and the patient, as optimal universal guidelines have yet to be defined and treatment requires a complicated regimen exploiting the synergistic effect of at least two antibiotics and an antisecretory agent. By raising the gastric pH, PPIs increase the bactericidal effect of antibiotics against H. pylori. However, because of complex dosing regimens, leading to poor patient compliance and increasing antibiotic resistance, which has reduced eradication rates to unacceptable levels (G80 %) among different H. pylori strains, the treatment of this infection remains a moving target. H. pylori resistance to metronidazole, clarithromycin, or fluoroquinolones has become relatively common worldwide, with rates exceeding 20 % for each agent in many populations, although amoxicillin resistance fortunately remains relatively rare despite its widespread use. This review presents the most recent data behind different treatment regimens and proposes a logical generalized approach to H. pylori therapy, as well as possible future directions of treatment.

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Treatment First-line regimens Triple therapy Standard triple therapy consisting of a PPI, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily for 7–14 days remains the standard of care in areas with known clarithromycin resistance rates of under 20 % [11••]. For example, recent studies from Korea have reported eradication rates of about 86 % with 7–14 days of triple therapy [12, 13], and eradication rates in Singapore with 7 days of triple therapy were 90.2 % in 2005 and 88.7 % in 2010 [14]. In addition, a Turkish group recently showed an 84.2 % eradication rate with 14 days of triple therapy [15]. However, this success is not universal, as several other groups have reported much less favorable eradication rates. Recent eradication rates with standard triple therapy were 73.2 % in Japan (7 days) [16], 73.8 % in Greece (10 days) [17], 66.4 % in China (10 days) [18], and 65.9 % in Morocco (7 days) [19]. These low eradication rates with triple therapy have been attributed to increasing clarithromycin resistance and underscore the importance of knowing regional H. pylori resistance patterns before choosing a first-line regimen. Interestingly, a recent randomized, controlled trial in Israel [20] has shown that adding simvastatin to 7 days of triple therapy improves eradication rates to 86 % from 69 % and may be a way to continue to use triple therapy despite increasing clarithromycin resistance. The mechanism of this higher eradication rate is unknown and awaits independent confirmation. It may be a direct antiinflammatory or antimicrobial effect, but it might also be related to the known drug interaction between simvastatin and clarithromycin, which would theoretically increase blood levels of clarithromycin. Either way, further studies should explore the addition of a statin to triple therapy as a way of increasing response rates in areas where eradication rates are suboptimal with triple therapy alone. Additional measures that have been looked at to improve the rates of response to triple therapy include increasing the length of therapy, altering PPI dosing, and adding probiotics to the treatment regimen. In terms of the optimal length of triple therapy, a recent Cochrane review [21•] suggested that 14 days is superior to 7 days, with the data indicating a significantly increased cure rate with 10 days of therapy compared with 7 days (79.9 % versus 75.7 %), and an increased eradication rate with 14 days of therapy versus 10 days (84.4 % versus 78.5 %). However, at least one recent study refuted the difference in eradication rates with different lengths of therapy, reporting no significant difference between 7- and 14-day treatment courses [22]. Another frequently researched topic is optimizing PPI choice and dosing to maximize triple-therapy eradication rates. Several studies have confirmed that use of a high-dose PPI (more than 20 mg twice daily) with triple therapy confers better eradication rates than standard daily doses of the PPI. One meta-analysis [23] compared cure rates with 7-day triple therapy and calculated an 82 % cure rate in the high-dose PPI group, compared with74 % in the standard-dose group. As to which PPI to choose, some recent evidence in the form of a metaanalysis [24•] has suggested better response rates with esomeprazole and

Stomach (C Howden, Section Editor) rabeprazole (82.3 % and 80.5 %, respectively) when compared with omeprazole, lansoprazole, or pantoprazole (76.2–77.6 %). In addition to examining the optimal length of triple-therapy regimens and PPI dosing to maximize cure rates, the use of probiotics as an adjuvant to improve H. pylori eradication has drawn considerable interest. Many recent studies have examined this topic, with inconsistent results—probably because of the variety of formulations and species of probiotics of different qualities that are available. One study looking at the effect of probiotic treatment alone on H. pylori in isolation demonstrated that Lactobacillus salivarius ssp. salicinius AP32 and Lactobacillus johnsonii MH-68 were effective in decreasing the severity of gastritis and H. pylori viability, indicating that probiotics themselves may have direct effects against H. pylori [25]. Further studies looking into Lactobacillus species in combination with triple therapy have also shown promise. An Italian study [26] found that Lactobacillus reuteri improved eradication rates and reduced the side effects of H. pylori treatment, while a Chinese group [27] demonstrated a significant enhancement in cure rates (81.6 % versus 61.5 %) with twice daily Lactobacillus acidophilus supplementation alongside traditional triple therapy. A randomized, double-blinded, placebo-controlled study [28] of Iranian children showed superior eradication rates (90 % versus 69 %) when a mixed probiotic of predominantly Lactobacillus species was used in combination with H. pylori treatment. Unfortunately, other recent studies from Italy [29] and Iran [30] failed to show improved eradication rates with adjuvant probiotic treatment, although they did show fewer antibiotic-induced side effects, particularly nausea and diarrhea, and therefore better compliance with therapy when probiotics were added to the regimen. Given all of the varying results, a recent meta-analysis [31•] of ten clinical trials was conducted to better assess the effect of adjuvant probiotic therapy with a preparation containing both Lactobacillus and Bifidobacterium species in addition to H. pylori treatment. This analysis concluded that adjuvant probiotics improved outcomes, with significantly higher eradication rates (odds ratio 2.07) and a significantly decreased total incidence of side effects (odds ratio 0.305). Overall, although further study is needed to clarify which species, formulations, and dosing of probiotics are most effective, there appears to be a reduction in side effects and, potentially, an improvement in eradication rates with adjuvant probiotics. Another modification to triple therapy that has been examined recently is the substitution of metronidazole for clarithromycin in areas with high clarithromycin resistance. Recent studies of metronidazole-based triple therapy in Spain [32] and Japan [33] showed a cure rate of 82.4 % with 10 days of therapy in the Spanish population and a superior eradication rate of 96.4 % (versus 74.5 % with clarithromycin-based triple therapy) with 7 days of therapy in the Japanese population. Interestingly, these improved cure rates with metronidazole-based triple therapy did not hold up in populations known to have high metronidazole resistance, such as in Tunisia [34].

Quadruple therapy As an alternative to triple therapy, quadruple therapy serves as a first-line regimen in many parts of the world where clarithromycin resistance is greater than 20 %. Both bismuth-based and non–bismuth-based quadruple regimens

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have been studied. Standard bismuth-based quadruple therapy consists of a PPI, bismuth subsalicylate 525 mg four times daily, metronidazole 250 mg four times daily, and tetracycline 500 mg four times daily. Recent data from a Chinese study [35] suggested that standard bismuth–based quadruple therapy still remains effective in some populations, with 92.7 % eradication rates being quoted. However, several other studies, including a recent meta-analysis [36] of 12 randomized, controlled trials, have suggested lower eradication rates of 77.6 %. One of the major recent issues with prescribing standard bismuthbased quadruple therapy has been the lack of availability of tetracycline, which has led some clinicians to substitute it with doxycycline 100 mg twice daily, although there is little evidence to support this switch. One Chinese study [37], which looked at using 10 days of doxycycline in addition to esomeprazole, bismuth, and amoxicillin versus standard quadruple therapy for patients who had failed first-line triple therapy, found eradication rates of 72.5 % with doxycycline-based therapy versus 64.1 % with standard quadruple therapy. On the other hand, a recent small study from Portugal [38] showed that triple therapy with 10 days of a PPI, amoxicillin, and doxycycline in 16 patients infected with known clarithromycin-, metronidazole-, and levofloxacinresistant H. pylori was completely ineffective, producing a 0 % cure rate.

Other possible first-line therapies With lower eradication rates noted using standard bismuth-based quadruple therapy, further research has been directed at modifying this regimen both by substituting the bismuth component with another antibiotic and by using different dosing strategies in an effort to increase cure rates. The outcome of this research has been the adoption of sequential, concomitant, and hybrid therapy. Sequential therapy was first proposed by Zullo et al [39] and consists of a total of 10 days of therapy, with the first 5 days comprising dual therapy with a PPI plus amoxicillin, and the following 5 days being made up of triple therapy with the PPI, clarithromycin, and metronidazole. Initial studies confirmed this regimen’s superiority to standard triple therapy in some populations. One randomized, multicenter study in Taiwan [40] compared 14 days of sequential therapy (7 days dual, 7 days triple), a 10-day conventional sequential regimen, and 14 days of clarithromycin-based triple therapy, and found eradication rates of 90.7 %, 87 %, and 84.5 %, respectively. Similar advantages of sequential over triple therapy have also been reported from Morocco [41], as well as in a systematic review [42]. However, some studies looking at sequential therapy have shown eradication rates below 80 % in Iranian [43], Indian [44], and Chinese [45] populations, and there has been concern that this complex regimen may be confusing to patients, leading to poor compliance with the intended dosing schedule. Concomitant or non-bismuth quadruple therapy is an alternative treatment for H. pylori that overcomes the complicated dosing schedule of a sequential regimen while appearing to be both safe and highly effective. A concomitant protocol consists of a PPI in addition to amoxicillin, clarithromycin, and metronidazole for 10–14 days. This regimen seems to perform well in areas of high clarithromycin resistance, with eradication rates approaching 90 % in one Spanish report [46], and there have been several recent reports comparing it with both triple and sequential therapy. Concomitant therapy has now been

Stomach (C Howden, Section Editor) shown to be superior to triple therapy in studies conducted in Spain [46], Japan [16], Korea [13], and Greece [17], with eradication rates greater than 90 %, compared with cure rates of 68–86 % with triple therapy in these populations. Other reports have also described nonsignificant trends toward better eradication rates with concomitant versus sequential therapy in Korean [47] and Chinese [48] populations. In addition, a randomized, multicenter trial of 276 patients in Spain [49•], comparing 10 days of concomitant versus 10 days of sequential therapy, showed a nonsignificant trend favoring concomitant treatment (86.9 % versus 81.2 % eradication rates), with equivalent compliance rates and safety profiles. These results were confirmed in a large review of 2,070 patients from 19 studies, which suggested eradication rates of 88 % with concomitant therapy [50]. The most recently introduced dosing modification for quadruple therapy is called hybrid or dual concomitant treatment, which is essentially a combination of a sequential and a concomitant approach, as first described by Hsu et al [51]. Hybrid therapy consists of dual therapy with a PPI and amoxicillin for 7 days, followed by concomitant quadruple therapy with the PPI, amoxicillin, clarithromycin, and metronidazole for 7 days. Hsu et al [51] reported greater than 95 % eradication rates with this regimen in a Taiwanese population. Further validation of these results in a Korean population revealed 85.9 % cure rates with hybrid therapy, compared with 82 % with sequential therapy, though the difference was not statistically significant [52]. Additional research has focused on shortening the duration of hybrid therapy to 10 and 12 days, in comparison with 14 days as initially proposed, and found similar cure rates of above 93 % across the board for all treatment durations in the Taiwanese population in which hybrid therapy was initially studied [53]. A recent Italian study [54] comparing concomitant, sequential, and hybrid dosing regimens yielded similar eradication rates of greater than 86 % for all three strategies, with no statistically significant differences being noted.

Second-line regimens Given that more than 10–20 % of patients do not achieve H. pylori eradication with typical first-line therapies, as reviewed above, multiple second-line therapies have been studied in an effort to find an optimal regimen to maximize cure rates. As a general rule, it is recommended not to repeat the first-line treatment (especially avoiding repeating metronidazole and clarithromycin, since resistance to these antibiotics is very common), and instead to use a second-line regimen that includes at least one different antibiotic than what was given previously. Current European Maastricht IV guidelines [11••] suggest use of bismuth-based quadruple therapy or a levofloxacin-based regimen following failure of traditional triple therapy. Levofloxacin-based treatment is also suggested by these guidelines after failure of initial quadruple therapy. Levofloxacin-based regimens have been studied extensively in recent years as both first and second-line therapies. Fluoroquinolone-based therapies with both moxifloxacin and levofloxacin have been investigated in many different forms, including triple, concomitant, and sequential regimens. Typical levofloxacin-based triple therapy consists of a PPI, amoxicillin, and levofloxacin for 10 days. A 2014 systematic review and meta-analysis of nine randomized, controlled trials of 1,275 patients compared levofloxacin-based triple therapy

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with standard triple therapy for first-line H. pylori treatment and revealed similar eradication rates of 80.2 % and 77.4 %, respectively [55]. Interestingly, subgroup analysis from this study showed that standard triple therapy was statistically superior in Asian populations, while levofloxacin-based triple therapy showed statistically significantly improved eradication rates in European countries. Because of increasing quinolone resistance with widespread use of this class of antibiotics for other types of infections, levofloxacin-based regimens have not been generally recommended for first-line therapy. However, evidence continues to mount that further supports the use of levofloxacin-based regimens for second-line therapy. A Spanish study recently assessed the use of 10 days of levofloxacin-based triple therapy as second-line treatment in 100 patients who had failed first-line non-bismuth quadruple sequential or concomitant regimens, and found eradication rates ranging from 71.4 % to 74.4 % [56]. Furthermore, a Taiwanese study showed that extending levofloxacin-based triple therapy from 10 to 14 days in a second-line treatment setting increased eradication rates from 68 % to 86 % [57]. When compared with standard quadruple therapy for second-line treatment in a meta-analysis, 10 days of levofloxacin-based triple therapy resulted in statistically significantly higher cure rates of 88.7 % versus 67.4 % with 7 days of quadruple therapy [58]. Interestingly, this meta-analysis again noted that levofloxacin-based regimens were more effective in European than in Asian populations and that the incidence of side effects was lower with levofloxacin treatment than with quadruple therapy.

Rescue therapies When first- and second-line therapies fail to eradicate H. pylori, several third-line therapies—also termed “rescue treatments” or “salvage treatments”—have been studied. In addition to the regimens already discussed, which can be used in different variations as salvage treatments, rifabutin-based triple therapy consisting of a PPI, amoxicillin, and rifabutin is exclusively used only as a thirdline treatment, because of rare myelotoxicity and the theoretical risk of potentially creating mycobacterial resistance if this therapy were to be used more routinely. Rifabutin was first found to be successful against metronidazole- and clarithromycin-resistant strains of H. pylori in vitro [59], and rifabutin-based triple therapy was subsequently shown to achieve a 73 % eradication rate in a meta-analysis of 1,008 patients [60]. Current European Maastricht IV guidelines [11••] suggest obtaining gastric biopsies for culture to determine antibiotic susceptibilities prior to initiation of third-line treatment, and several recent studies support this approach as a guide to choosing a rescue regimen. A Taiwanese group [61] employed polymerase chain reaction (PCR) genotyping to identify H. pylori resistance patterns in individual patients and then used a clarithromycin-, levofloxacin-, or tetracycline-based sequential regimen tailored on the basis of antibiotic susceptibility, with an overall eradication rate of 80.7 %. An Italian study [62] showed even better results, with culture-based susceptibility eradication rates of 90 % with levofloxacin-based triple therapy and 88.6 % with rifabutin-based triple therapy. Although culture-guided rescue therapy appears to be successful, the process can be expensive and is available only in a few specialized centers. For this reason, empiric third-line treatment has also been studied recently by

Stomach (C Howden, Section Editor) an Italian group [63], which reported successful eradication in up to 99.5 % of patients if the regimen chosen avoided repeating similar previously prescribed therapies. Another novel rescue therapy, recently studied in Japan [64], is dual therapy with rabeprazole 10 mg four times daily and amoxicillin 500 mg four times daily for 14 days, which achieved 63 % eradication rates. This regimen is postulated to be effective because a sustained intragastric pH greater than 4, which is probably achieved with highdose PPI therapy, has been associated with successful H. pylori eradication [65]. Spacing out amoxicillin dosing to four times daily, rather than twice daily, is based upon the pharmacokinetic profile of this antibiotic. Amoxicillin remains an important component in most H. pylori eradication regimens because of the rarity of amoxicillin resistance among H. pylori strains. Further study is needed to establish if this enhanced dual therapy has a role in H. pylori treatment in other populations.

Conclusions An abundance of research is taking place in an effort to modify traditional treatments and develop new regimens to improve H. pylori eradication rates. This research is important, given increasing antibiotic resistance, which has been slowly decreasing cure rates with conventional therapy to unacceptable levels in some populations. The most recently published European Maastricht IV guidelines [11••], which were developed from a 2010 conference incorporating 44 expert opinions from 24 different countries, do not take into account many of the newest developments discussed in this review, and should probably now be updated. Given the variation in H. pylori resistance patterns among different populations, it is difficult to create a universal algorithmic

Fig. 1. An algorithmic approach to H. pylori treatment.

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approach to therapy, but we have generated general guidelines, as depicted in Fig. 1. Ongoing research needs to be directed at further refining current regimens in different populations in order to maximize eradication rates. Areas of active interest include optimizing acid suppression, studying new combinations of current antibiotics, altering the length of therapy and dosing schedules, searching for H. pylori-specific antimicrobial agents, and better understanding the impact of adjuncts to treatment, such as statins or probiotics. Underpinning these approaches should be a more scientific attitude toward H. pylori eradication, with efforts directed at understanding local H. pylori eradication success rates and resistance patterns in order to better guide choices locally, rather than the often empiric approach that is taken today [66]. This is particularly important for the USA, where there is a great paucity of recent data on national or regional H. pylori resistance. Increasing the availability of culture-guided therapy should lead to more efficient treatment, particularly of refractory infections, which are an increasingly common clinical problem in this era of antibiotic overuse. Successful development of an H. pylori vaccine remains an elusive goal, but it would bypass any issues with antibiotic resistance altogether by preventing the acquisition of infection.

Compliance with Ethics Guidelines Conflict of Interest Jason Ferreira declares that he has no conflict of interest. Steven Moss has received payment for development of educational presentations, including service on speakers’ bureaus, from Otsuka America. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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Current Paradigm and Future Directions for Treatment of Helicobacter pylori Infection.

Once easily eradicated with triple or quadruple therapy, Helicobacter pylori infection has become increasingly resistant to traditional first-line tre...
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