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doi: 10.1111/hel.12258
Keywords
peptic ulcer disease, resistance, compliance,
first line, second line, antimicrobial
susceptibility testing.
Reprint requests to: Anthony OConnor, Leeds
Gastroenterology Institute, Bexley Wing, St.
Jamess University Hospital, Leeds, UK. E-mail:
anthonyoconnor@nhs.net
Many interesting articles have been published from many parts of the world
over the last year assessing different issues around Helicobacter pylori eradication therapy. This article will address the published literature over the last
year pertaining to the topic of treatment of H. pylori infection. The main
themes that emerge are assessing the efficacy of standard triple therapy, as
well as exploring new first-line treatments, mainly optimized nonbismuthand bismuth-containing quadruple therapies with some promising data also
emerging on dual therapy. There was also considerable progress in investigating antibiotic resistance rates with much more data emerging from varied
parts of the world compared to recent years. There have also been advances
in the use of adjunctive therapies, especially probiotic therapies. Undoubtedly, the eradication of H. pylori remains a worthwhile goal to alleviate the
burden of diseases caused by the complications of this infection, including
dyspepsia, peptic ulcer disease, and gastric cancer.
Triple Therapy
A number of studies have been published this year, primarily from Asia, on standard triple therapy which
remains the regimen recommended in the majority of
published guidelines. A meta-analysis from China
showed suboptimal eradication rates in this part of the
world with a pooled rate of 74.5% which was inferior
when compared to sequential therapy with relative risk
(RR) = 0.863 [1]. Better, but still insufficient, eradication rates however were noted in Korea, with an overall eradication rate of 84% from 2005 to 2010 [2]. In
Japan, while rates remain clearly suboptimal, eradication rates by per-protocol (PP) analysis have not changed between 2001 and 2010 although there has been a
decline in eradication rates by intention-to-treat (ITT)
analysis [3]. Another Japanese group from a region of
higher clarithromycin resistance compared 7-day standard triple therapy with rabeprazole, amoxicillin, and
clarithromycin (RAC) to rabeprazole, amoxicillin, and
metronidazole (RAM). They found ITT eradication rates
of 73% in the RAC group and 91% in the RAM group
[4]. In other regions, a study in Nigeria found an eradication rate of 87% for triple therapy with no difference
between 7 and 10 days of treatment [5]. An interesting
study from Spain showed that when clarithromycin
54
Sequential Therapy
There have been several studies again this year examining sequential therapy, with the breadth of regions
where this regimen has been trialed growing. Over the
last year, several interesting randomized trials emerged
from East Asia. Sequential therapy consists of 5 days of
PPI therapy plus amoxicillin, followed by a further
2015 John Wiley & Sons Ltd, Helicobacter 20 (Suppl. S1): 5461
OConnor et al.
5 days of PPI with two other antibiotics, usually clarithromycin and metronidazole. A study from China
compared a 10-day sequential regimen with a quadruple bismuth-based regimen (esomeprazole, bismuth
subcitrate, tetracycline, and metronidazole) [10]. This
trial showed, by ITT analysis, eradication rates of 89%
for sequential and 93% for bismuth-based therapy
(p = .36). All patients in both arms who failed the firstline treatment were crossed over to the alternate regimen with 100% retreatment success. It was however
noted that the overall incidence of adverse events was
significantly higher in the bismuth-based group compared to the sequential therapy group (17 vs 8.1%). A
second Chinese randomized controlled trial (RCT) compared sequential therapy to standard triple therapy with
less impressive results [11]. In this study, there was no
significant difference between the eradication rates
achieved with standard triple therapy (66%) and
sequential therapy (72%). Although in this study
sequential therapy did have some advantages when
clarithromycin resistance was present, these were not
maintained when both clarithromycin and metronidazole resistance occurred. A third randomized study from
this part of the world, conducted in Taiwan, showed
that reversed sequential therapy where clarithromycin
and metronidazole were given first was equally effective [12]. In a retrospective study from Turkey, no significant difference was noted between eradication rates
with standard triple compared to sequential therapy (64
vs 71%), both being suboptimal [13]. In India, where
clarithromycin resistance rates are high, an RCT suggested that sequential therapy was more successful
when ciprofloxacin replaced clarithromycin (73.5 vs
66%) [14]. The systematic review evidence for sequential therapy was also updated this year, with a metaanalysis of 36 RCTs showing superior eradication rates:
84% for sequential therapy vs 75% for triple therapy,
with an RR for eradication of 1.14 (95% CI: 1.091.17)
[15].
Concomitant Therapy
Concomitant therapy is similar to sequential in that it
involves 1014 days of treatment with three antibiotics,
but in contrast to sequential therapy, all three antibiotics are taken along with the PPI for the full duration
of therapy. The concomitant regimen has been well
studied in both Europe and Asia over the last year. On
the basis that high-dose acid suppression and 14-day
duration of treatment can improve eradication rates by
up to 10%, a study from Spain looked at optimizing
therapy in this manner and comparing concomitant
(with PPI, amoxicillin, clarithromycin, and metronida-
2015 John Wiley & Sons Ltd, Helicobacter 20 (Suppl. S1): 5461
zole) to triple therapy (with PPI, amoxicillin, and clarithromycin) and found better eradication rates for the
concomitant method (90 vs 81%) [16]. In Italy, a study
compared sequential therapy on a head-to-head basis
with concomitant and hybrid therapy and found no significant difference in eradication rates (90% for
sequential, 86 % for concomitant, and 83 % for hybrid
therapy), although a beta error cannot be ruled out,
due to the small sample size of this study [17].
Regarding Asian studies, in three separate studies
from Korea, two nonrandomized and one randomized,
a contrasting outcome was noted when sequential and
concomitant therapies were compared. In the randomized trial of 10-day concomitant versus sequential regimens, eradication was achieved in 79% with
concomitant therapy and 71% with sequential therapy
[18]. In the first nonrandomized study, the regimens
were compared to two different triple regimes with
eradication rates of 76% for triple therapy with clarithromycin, 84% for triple therapy with metronidazole,
84% for the sequential group, and 94% for the concomitant group [19]. In a second study, sequential and
concomitant therapies were compared to one another
with concomitant therapy having superior eradication
rates (94 vs 82%) [20]. Concomitant therapy also did
better than triple or sequential therapy in a head-tohead comparison from Taiwan with ITT eradication
rates of 94, 82, and 89%, respectively [21]. In Singapore however, no difference was noted between
sequential, triple, and concomitant therapies (84 vs 83
vs 88%) [22].
One of the major reservations that have been raised
regarding the concomitant regimen is related to the
potential for increased costs given the long duration of
therapy with more drugs. To this end, a prospective
randomized trial was carried out on 200 treatmentnave patients in Lebanon in which standard dose
versus half-dose concomitant nonbismuth quadruple
therapy (NBQT) with rabeprazole 20 mg, amoxicillin
500 mg, metronidazole 250 mg, and clarithromycin
250 mg was given for 7 days [23]. Eradication occurred
in 78% in both groups on ITT analysis with no reduction in adverse events; however, treatment was naturally cheaper with the half-dose regimen.
Hybrid Therapy
Hybrid therapy is an attempt to combine the principle
of the induction phase of sequential therapy as a means
of overcoming resistance with the benefits of four
drugs, which is the characteristic of the concomitant
therapy. It involves using PPI and amoxicillin for
14 days, while clarithromycin and metronidazole or
55
OConnor et al.
Antimicrobial Resistance
Many studies on H. pylori primary antibiotic resistance
rates were carried out over the last year. They are summarized in Table 1 [2741]. Although molecular
in vitro testing gives a genotype that may not
Table 1 Helicobacter pylori resistance to antibiotics in the studies published during the last year worldwide
Author
Study design
Region
Amoxycillin
Clarithromycin
Metronidazole
Furazolidone
Biernat [27]
Lee [28]
Okamura [29]
Prospective
Prospective
Prospective
Poland
Korea
Japan
0
17.2%
n/s
42%
n/s
n/s
n/s
n/s
Camargo [30]
Systematic
Review
Prospective
Prospective
Latin
America
China
Germany
4%
24%
37.3%
<30 years
3150
>51
12%
53%
6.8%
n/s
37.5%
6.7%
USA
Picoli [34]
Peretz [35]
Almeida [36]
Pandya [37]
CrossSectional
Prospective
Prospective
Prospective
Prospective
Brazil
Israel
Portugal
India
Cheng [38]
Prospective
Taiwan
Karczewska
[39]
Karamanolis
[40]
Phan [41]
Prospective
Poland
Prospective
Greece
Prospective
Vietnam
Song [31]
Wuppenhorst
[32]
Shiota [33]
Tetracycline
Rifabutin
8% (Levo)
n/s
n/s
0
n/s
n/s
0
n/s
n/s
3%
15% (Levo)
6%
n/s
67.2%
29.4%
n/s
n/s
33.5% (Levo)
n/s
3.5%
n/s
14.2%
n/s
16.4%
20.3%
n/s
31.3% (Levo)
0.8%
n/s
11.1%
22.3%
50%
58.8%
n/s
70.5%
34.4%
83.8%
n/s
n/s
n/s
13.8%
n/s
2.3%
0.6%
53.8%
n/s
n/s
n/s
n/s
9.7%
33.3%
n/s
n/s
n/s
n/s
n/s
n/s
5.5% (Cipro)
n/s
33.9% (Levo)
50% (Cipro)
23.8% (Levo)
8% (Cipro)
5.1% (Gemi)
8.5% (Moxi)
6.8% (Levo)
5.8% (Levo)
n/s
n/s
n/s
42%
n/s
n/s
n/s
n/s
42.4%
76.1%
n/s
n/s
n/s
1.9%
2.3%
0.6%
72.5%
1.1%
57.9%
34.5%
35.2%
Fluoroquinolones
5.3%
41.3% (Levo)
56
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OConnor et al.
(20072014), clarithromycin resistance increased annually in a linear manner, while levofloxacin resistance
decreased annually and metronidazole resistance rates
were static. A very interesting study from Germany
looked at the difference in patterns of resistance based
on the topographic location of the gastric biopsies [42].
Discordant antibiotic susceptibility results were reported
between antrum and corpus isolates for different antibiotics in 15% of the patients and may account for some
treatment failures that occur even when treatment tailored to susceptibility is undertaken.
Bismuth Therapy
A study from Italy looked at the effect of adding bismuth to a 10-day triple therapy regimen consisting of
esomeprazole, amoxicillin, and doxycycline and found
that it significantly potentiated the eradication rates
achieving 89% (when 100 mg doxycycline was used)
and 92% (when 200 mg doxycycline was used) eradication rates by ITT analysis [43]. By contrast, the arms
of the study where bismuth was not used were less successful. The study design was to discontinue recruitment once six failures had been demonstrated in any
arm. This had been reached after 14 patients had been
enrolled in the arm with 100 mg doxycycline and 15
patients in the arm with 200 mg doxycycline.
A further study looked at the efficacy of bismuth as
a second-line regimen with metronidazole, tetracycline,
and PPI in comparison with dual therapy with moxifloxacin and amoxicillin. This revealed little difference
between the two combinations but a clear advantage
for prolonged durations of therapy for both, with eradication rates for 7-day bismuth, metronidazole, and
tetracycline of 66% compared to 71% for 14 days of
therapy (ITT) [44]. Following on from several recent
publications illustrating satisfactory eradication rates
with reduced-dose clarithromycin-based triple therapy
regimens, a letter published by a group from Lebanon
examined whether or not dose reduction of all components of a bismuth, tetracycline, esomeprazole, amoxicillin, and metronidazole would yield acceptable
eradication rates [45]. This was not the case, with
<65% achieving eradication (ITT). As a second-line
therapy in patients who have failed standard triple
therapy, one large study found quadruple therapy with
bismuth subcitrate potassium, omeprazole, metronidazole, and tetracycline hydrochloride, to yield ITT eradication rates ranging from 93 to 94% but with a high
rate of usually quite benign adverse events (67%) [46].
A separate study from Italy looked at second-line bismuth-based quadruple therapy with a different range
of antibiotics by randomizing participants taking
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Fluoroquinolones
A large number of studies looked at the role of fluoroquinolones, primarily levofloxacin, as both a first- and
second-line therapy against H. pylori. As a first-line
therapy, a systematic review was carried out of nine
RCTs including 1275 patients treated with levofloxacinbased triple therapy and 1237 patients with standard
triple therapy regimen. Eradication rate in the levofloxacin-based therapy group was 80% compared to 77%
in the standard triple therapy group (80 vs 77%). A difference was noted related to different geographic areas
with 7-day standard triple regimen being statistically
superior to 7-day levofloxacin-based scheme in the
Asian group (RR = 0.91, 95% CI = 0.860.97), but
levofloxacin-based triple therapy was superior regardless of treatment time in European countries
(RR = 1.15, 95% CI = 1.061.23) with no difference
observed regarding side effects [51]. A further systematic review reported the pooled OR by ITT for the levofloxacin triple regimen versus standard regimen was
1.28 (95% CI: 0.881.85) [52]. Two other original studies also compared fluoroquinolone-based triple therapy
to standard triple therapy. A study from Turkey noted
that the per-protocol (PP) eradication rate was 92% in
a levofloxacin triple therapy group, 92% in a moxifloxacin triple therapy group, and 82% in a clarithromycin triple therapy group, a statistically
significant difference for the combined fluoroquinolone-containing groups over clarithromycin [53].
57
Dual Therapy
A few studies this year looked at the role of enhanced
dual therapy in eradication. A multicenter RCT from
China examined the role of high-dose dual therapy
(HDDT) with rabeprazole 20 mg and amoxicillin
750 mg, 4 times/day for 14 days with that of standard
and sequential therapies both empiric and second-line
treatment [62]. By ITT analysis, H. pylori was eradicated
in 95.3% of patients in the HDDT group, 85% in the
sequential group, and 81% in the standard triple
58
OConnor et al.
Probiotics
Publications on probiotics in H. pylori eradication this
year can be divided into studies on various forms of
Lactobacilli species and systematic reviews. Regarding
Lactobacilli, one study found that L. plantarum XB7
secreted factors capable of modulating inflammation
during H. pylori infection, which may support a role for
it as an adjunctive therapy for treating H. pylori-associated disease [65]. Another suggested that Lactobacillus
reuteri was able to exert an inhibitory effect on H. pylori
growth and, when administered with eradication therapy, could lead to a significant reduction in antibioticassociated side effects, which may benefit compliance
[66]. L. reuteri has also been used as an eradication
agent per se, with pantoprazole in an open-label study,
but achieved a cure rate of only 14% by ITT analysis
[67]. Three meta-analyses have been published on the
role of probiotics as adjuvant treatments for H. pylori
infection. One showed pooled OR for the eradication
rates calculated by ITT analysis in the probiotic group
versus the control group of 1.67 (95%CI: 1.382.02)
with the incidence of diarrhea being significantly
reduced in the probiotic group (OR = 0.21 95%CI:
0.060.74) [68]. Two other reviews also noted very
similar findings with pooled eradication rates in probiotic supplementation groups significantly higher than
in controls and a significant difference between groups
in the overall incidence of side effects [69,70]. Interestingly, in one of the reviews, a subgroup analysis confirmed this finding only for four specific strains
(Lactobacillus acidophilus, Lactobacillus casei DN-114001,
Lactobacillus gasseri, and Bifidobacterium infantis 2036)
and for relatively ineffective antibiotherapies [69].
Furazolidone
Two studies this year examined the role of furazolidone
in H. pylori eradication. The largest study compared the
efficacy of furazolidone when used as part of a bismuth-based quadruple therapy to furazolidone as triple
therapy when given for 7 and 10 days in different arms
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OConnor et al.
References
Conclusion
There have been a many and varied number of studies
pertaining to H. pylori eradication treatment in the published literature over the last 12 months, often with
conflicting results, although several broad themes do
emerge. Outcomes for standard triple therapy have
been poor across most studies; however, when susceptibility testing is employed accurately, effective treatment
can still be delivered. The momentum behind sequential therapy as the regimen most likely to become preeminent has stalled somewhat, with more promising
results being noted in the published literature for both
bismuth- and nonbismuth (concomitant)-containing
quadruple therapies. In addition, a renewed interest in
HDDT based on amoxicillin delivered over prolonged
courses may help as the MIC is in a steady state and
amoxicillin resistance is rare. This may help overcome
some of the issues associated with rising rates of antibiotic resistance to macrolides and fluoroquinolones. Bismuth- and levofloxacin-based therapies have also
performed well as both primary and second-line eradication regimens and show promise when used in combination as a second-line treatment; however, issues
regarding resistance and availability may limit the
adoption of these agents in treatment protocols in some
regions. A concern is that most studies are coming from
areas with high infection rates. While not surprising, it
2015 John Wiley & Sons Ltd, Helicobacter 20 (Suppl. S1): 5461
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