DOI: 10.1111/hel.

12410

REVIEW ARTICLE
Firmado digitalmente por Edson Guzman
Edson Guzman Nombre de reconocimiento (DN): cn=Edson Guzman, o, ou, email=edson_guzman@hotmail.com, c=<n
Fecha: 2017.09.15 20:19:29 -05'00'

Treatment of Helicobacter pylori infection 2017

Anthony O’Connor1 | Dominique Lamarque2 | Javier P. Gisbert3 | Colm O’Morain1

1
Department of Gastroenterology, Tallaght
Hospital/Trinity College Dublin, Dublin, Abstract
Ireland This review summarizes important studies regarding Helicobacter pylori therapy pub-
2
Hôpitaux Universitaires Paris Ile-de-France
lished from April 2016 to April 2017. The main themes that emerge involve studies
Ouest, Paris, France
3 assessing the efficacy of bismuth and nonbismuth quadruple regimens. While in recent
Gastroenterology Unit, Hospital
Universitario de La Princesa, Instituto years, much of the emphasis on the use of bismuth has focussed on its utility in a
de Investigación Sanitaria Princesa (IIS-
second-­line setting, an increasing number of studies this year have shown excellent
IP), Centro de Investigación Biomédica en
Red de Enfermedades Hepáticas y Digestivas efficacy in first-­line therapy. The efficacy of bismuth as a second-­line after sequential
(CIBEREHD), Madrid, Spain
and concomitant therapy was particularly noteworthy. Antibiotic resistance was more
Correspondence intensely studied this year than for a long time, and definite trends are presented re-
Anthony O’Connor, Department of
garding an increase in resistance, including the fact that clarithromycin resistance in
Gastroenterology, Tallaght Hospital/Trinity
College Dublin, Dublin, Ireland. particular is now at a level where the continued use of clarithromycin triple therapy
Email: Anthony.OConnor@amnch.ie
first-­line as a mainstream treatment is not recommended. Another exciting trend to
emerge this year is the utility of vonoprazan as an alternative to PPI therapy, especially
in resistant and difficult-­to-­treat groups.

KEYWORDS
bismuth, concomitant therapy, hybrid therapy, quadruple therapy, resistance, sequential therapy

1 |  INTRODUCTION
The last year has been an extremely busy period for research publi-
cations on the treatment of Helicobacter pylori, driven by a series of
articles in recent years suggesting that eradication rates with conven-
tional therapies have fallen to unacceptable levels. The most significant
paper of H. pylori treatment published this year was the fifth iteration
of the Maastricht Consensus Report.1 In this update, the importance
of collating knowledge on local resistance patterns is emphasized,
treatment regimens are extended to 14 days, standard proton-­pump
inhibitor (PPI)-­clarithromycin-­based triple therapy is limited to areas
of low clarithromycin resistance, and rescue therapy options are ex-
plored further. In particular, quadruple therapies, bismuth containing,
or otherwise are recommended as first-­line when clarithromycin resis-
tance exceeds 15% and as second-­line in low resistance areas. When
bismuth-­based therapies fail in high resistance countries, levofloxacin-­
based triple therapy is recommended. Antimicrobial susceptibility test-
ing (AST), standard or molecular is recommended after two treatment
failures. The North American Toronto consensus also favored 14-­day
2
regimens. This guideline recommended concomitant nonbismuth
quadruple therapy and traditional bismuth quadruple therapy as first-­
line regimens and also restricting standard PPI triple therapy to areas
with known low clarithromycin resistance. Recommended second-­
line therapies included bismuth quadruple therapy and levofloxacin-­
containing therapy. Rifabutin regimens were the preferred option for
rescue patients who have failed to respond to at least 3 prior options.
A network meta-­analysis of 30 systematic reviews ranked the
esomeprazole to be the most effective PPI, followed by rabeprazole,
while no difference was observed among the three old generations of
PPI for the eradication of H. pylori.3 A very large Swedish study looked
at 157, 915 eradication episodes in 140, 391 individuals (1.5% of the
Swedish population) and found good adherence to guidelines with
95.4% following the recommended regimen by national guidelines at
the particular time.4
Many studies have examined why eradication treatments fail.
The role of antibiotic resistance will be discussed later. A study from
Israel looked at the role of smoking and found the overall eradication
failure rates to be 34.8% in current smokers and 32.8% in subjects
who never smoked.5 In a multivariate analysis, eradication failure was
positively associated with current smoking, female gender, and low

Helicobacter. 2017;22(Suppl. 1):e12410. wileyonlinelibrary.com/journal/hel © 2017 John Wiley & Sons Ltd  |  1 of 10
https://doi.org/10.1111/hel.12410
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2 of 10       O’CONNOR et al.
socioeconomic status, but after controlling for socio-­
demographic
confounders, smoking was found to significantly increase the likeli-
hood of unsuccessful first-­
line treatment for H. pylori infection. A
Chinese study looking at the role of compliance with therapy found
that telephone follow-­up did not increase the H. pylori eradication
6
rate, but did improve compliance and satisfaction for the patients.
Other study with a view to resistance looked at whether previous an-
tibiotic use could predict failure. In one study where a clarithromycin-­
based regimen was used, the eradication failure rate in patients with
a history of macrolide use for >2 weeks was significantly higher than
if the duration of use was <2 weeks (44.8% vs 29.3%).7 Another study
from Korea identified that the regions that suffered the most signifi-
cant fall in eradication rates were those that had the highest rates of
8
macrolide prescriptions.
2 |  TRIPLE THERAPY
In addition to the comparative studies described elsewhere, a num-
ber of studies looked at the role that standard triple therapy can
play in H. pylori eradication treatment. A high-­quality meta-­analysis
examined the efficacy of triple therapy with amoxicillin and met-
ronidazole which showed that while overall they were less effica-
cious than clarithromycin-­based regimens (70% vs 77%), efficacy
was similar when drugs were administered for 14 days (80% vs
84%).9 An Italian study looked at the effect of PPI dose and found
eradication rates improved from 73.9% to 81.9% when double dose
(40 mg esomeprazole) twice daily was used compared to standard
(20 mg) dosing.10 In terms of safety, a Japanese study of 322 pa-
tient showed a 15% incidence of diarrhea and 2% risk of skin rash.11
A very interesting safety study looked at any association between
H. pylori eradication therapy and the development of osteoporosis,
a highly relevant topic in the context of recent data linking PPI use
12
to osteoporosis. An increase in the risk of developing osteoporosis
was found to be higher in the early H. pylori treatment (within 1 year
of diagnosis) cohort and also in the late H. pylori treatment cohort,
compared with controls; however, when the follow-­up period was
over 5 years, only the late eradication group exhibited a higher inci-
dence of osteoporosis. This may imply that early eradication could
reduce any potential influence of H. pylori infection on osteoporosis
either directly or by reducing PPI use. Finally, a study on a 14-­day
metronidazole-­based triple therapy from Uruguay reported an erad-
ication rate of 81%.13
3 |  SEQUENTIAL, CONCOMITANT, AND
HYBRID THERAPY
Sequential therapy consists of 5 days of PPI therapy plus amoxicil-
lin, followed by a further 5 days of PPI plus two other antibiotics,
usually clarithromycin and metronidazole.14 A very high-­
quality
meta-­analysis of 117 trials, comprising 32, 852 patients, including
17 H. pylori eradication regimens, subdivided patients into high and
low clarithromycin-­resistant populations.15 This found that sequential
therapy for 14 days had the highest effectiveness in high clarithro-
mycin resistance regions and hybrid therapy (HY) for 10 days or more
represented the most effective regimen in areas of low clarithromycin
resistance. The 7-­day triple therapy performed poorly in most regions.
Longer durations of therapy were associated with higher eradication
rates, but with a higher risk of events that lead to discontinuation.
These findings, however, do little to counteract reservations that
have been expressed in recent years that although sequential ther-
apy has now been studied extensively and in many parts of the world,
it has frequently been compared to 7-­day standard triple or “legacy”
therapy and that the comparator used does not reflect current best
practice.
As durations of therapy have been extended in the recent
Maastricht guidelines to 14 days, a comparison to 14-­day triple
therapy has become vital. A large randomized clinical trial in Taiwan
has shown that although sequential therapy performs better against
14-­
day triple therapy in patients with clarithromycin resistance
(62.5% vs 44.4%), overall eradication rates of sequential therapy
were not superior to 14-­day triple therapy (87.2% vs 85.7%) with
no difference in compliance or adverse events.16 Two randomized
studies from Korea of sequential therapy against 7-­day triple ther-
apy from the same region showed eradication rates of 81.9% vs
64.3% and 82.4% vs 70.8%, respectively, favoring the sequential
treatment.17,18 A further study from the United Arab Emirates also
showed such a result (84.6% vs 68%).19 Two systematic reviews and
meta-­analyses of sequential therapy vs triple therapy found sequen-
tial treatment to be significantly more effective (82% vs 75% and
84.1% vs 75.1%, respectively).20,21 However, on subgroup analysis,
both confirmed no benefit for sequential when longer triple therapy
regimens were used. A study in which N-­acetylcysteine (NAC) was
used as an adjunct to sequential therapy showed overall very poor
eradication rates but an improvement when NAC was used (58.0%
vs 67.3%).22
Concomitant therapy is similar to sequential in that it involves
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.23 A study from Spain this year showed it to be superior
to 10-­day triple therapy (85.9% vs 65.7%).24 A meta-­analysis of stud-
ies from regions of China found concomitant therapy to be superior
to triple therapies of varying (but usually 7-­day) regimens (91.2% vs
77.9%), but not significantly different from sequential therapy, albeit
with better compliance for concomitant therapy.25 Several studies this
year compared sequential to concomitant therapy, with concomitant
therapy showing superiority overall. An interesting paper from China
reported an 86.1% eradication rate for concomitant therapy but also
looked in depth at patients who failed eradication with this regimen.26
They noted eradication was significantly higher in the group that re-
ceived an esomeprazole-­based regimen compared with the group that
received an omeprazole-­
based regimen and that the omeprazole-­
based regimen was an independent risk factor for treatment failure as
were CYP2C19 extensive metabolizer status, as well as clarithromycin
and metronidazole resistance.
O’CONNOR et al.
In a Korean study, where 10-­and 14-­day sequential and concomi-
tant regimes were all used, all four regimens revealed eradication rates
greater than 90% with the highest rate (98.5%) being for 14-­day con-
comitant therapy.27 A second Korean study compared triple therapy
with sequential and concomitant regimens and found eradication rates
of 62.6%, 70.6%, and 77.8%.28 In a Greek prospective study, concomi-
tant therapy outperformed sequential therapy by 89.1% vs 78.7%.29 A
further study from Saudi Arabia focussing on patients with perforated
duodenal ulcers also suggested a trend toward improved eradication
rates for concomitant rather than sequential therapy (81.8% vs 71.4%),
but it did not reach statistical significance.30 The inverse was seen in
a study from Slovenia where 10-­day sequential therapy (94.3% erad-
ication) was significantly better than 7-­day triple therapy (83.6%) in
31
a clinical setting with low rates of resistance. Concomitant therapy
achieved eradication in 91.7% in this population, showing significant
superiority over standard triple therapy only in the subgroup of pa-
tients with clarithromycin-­resistant strains.
Hybrid therapy is an attempt to combine the principle of the in-
duction phase of sequential therapy as a means of overcoming resis-
tance 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 equivalent are added for
the final 7 days.32 A prospective study this year of hybrid therapy as
a first-­line regimen was disappointing, revealing an eradication rate
33
of 77%. A systematic review published this year reported 77%-­97%
eradication with hybrid therapy and excellent compliance with low ad-
verse event rates.34
A head-­to-­head trial of hybrid vs concomitant therapy was car-
ried out in Iran which demonstrated eradication rates of 87.3% for
hybrid therapy compared to 80.9% for sequential.35 One systematic
review of 12 trials comparing sequential, concomitant and hybrid ther-
apies showed no significant difference in eradication rates between
the treatments with similarly high compliance rates and acceptable
36
adverse event rates. Another network meta-­analysis carried out of
Korean studies compared conventional triple therapy for 7 days, stan-
dard sequential therapy for 10 days, hybrid therapy for 10-­14 days,
and concomitant therapy for 10-­14 days and reported eradication
37
rates of 71.1%, 76.2%, 79.4% and 78.3%, respectively.
4 | LEVOFLOXACIN-­ AND OTHER
FLUOROQUINOLONE-­B ASED THERAPIES
Numerous articles have been published in the last year examining
multiple different aspects of the use of levofloxacin as a means
of eradicating H. pylori infection. Levofloxacin has primarily been
considered as a second-­line treatment but may be used as primary
therapy also. A large meta-­analysis of 4,574 patients from 41 tri-
als, including 16 trials in the first-­line treatment and 25 trials in
the second-­line treatment published last year revealed a cumula-
tive eradication rate of 80.7% in the first-­line treatment and 74.5%
line treatment.38 Subgroup analysis in this study
in the second-­
showed a decline in eradication rates after 2012, presumably due to
|
      3 of 10
rising resistance and surprisingly, better eradication rates when lev-
ofloxacin was given once daily rather than twice. A first-­line study
conducted in Iran this year found levofloxacin to be more effective
than clarithromycin when given for two weeks as part of a triple
therapy regimen (75% vs 51.7%).39 In Portugal, where resistance
rates to both levofloxacin and clarithromycin are high, higher eradi-
cation rates were observed for clarithromycin than for levofloxacin
as part of first-­line sequential regimens (90% vs 79%).40
A separate randomized clinical trial examined whether levofloxacin-­
based second-­line therapy was more effective if delivered as part of a
10-­day triple regimen or sequential regimen and found that eradica-
tion rates were superior with sequential 90.2% vs 80.5%.41 Another
study investigated whether levofloxacin could be used with bismuth
as part of a quadruple regimen when a non-­bismuth-­based quadruple
regimen had failed to achieve eradication as first-­line, and found a suc-
cess rate of 73.5%.42
As a third-­line treatment, extended courses of levofloxacin-­based
therapies were examined in two separate studies from Korea which
yielded divergent results. In one study, eradication rates were noted
of 58.3% for 7-­day therapy, 68.2% for 10-­day therapy, and 93.3% for
14-­day therapy.43 In a separate study though no significant difference
was noted between different treatment durations with the best rates
seen for 7-­day therapy at 80.6% compared to 64% for 10 days and
68.8% for 14 days.44 A study of levofloxacin used in concomitant ther-
apy compared to standard sequential therapy for patients with type 2
diabetes, often considered to be a difficult-­to-­treat group, reported
96.4% vs 81.4% eradication rates in favor of the levofloxacin arm.45
Another group in Australia looked at difficult-­to-­treat patients with
a median of 2 and up to 7 failed eradication attempts and reported
90% cure for levofloxacin-­based triple therapy.46 In Egypt, a novel
quadruple combination of levofloxacin, nitazoxanide, doxycycline,
and omeprazole prescribed for 14 days led to a successful eradica-
tion of H. pylori in 83% of patients who had previously failed first-­line
therapy.47
Other fluoroquinolone antibiotics have also been tested
with respect to H. pylori eradication this year. Sitafloxacin in par-
ticular was the subject of three studies in Japan. One of which
looked at using sitafloxacin with four times daily rabeprazole in
metronidazole-­
resistant patients and found eradication rates of
93.7% even though levofloxacin resistance was 42%.48 Two other
studies of sitafloxacin as a third-­line agent were reported. As a tri-
ple regime with esomeprazole and amoxicillin, eradication rates for
third-­line were 83% in one study and 70.3% in a separate study
which looked solely at patients harboring the gyrA mutation, which
is associated with fluoroquinolone resistance.49,50 Another fluoro-
quinolone, gemifloxacin, was observed to have an eradication rate
of 91.4% in 120 patients when used as part of a bismuth-­based
quadruple therapy.51 A systematic review and meta-­analysis of 16
studies on all quinolone-­containing rescue therapies reported 10-­
day levofloxacin-­amoxicillin-­PPI triple therapy to achieve eradica-
tion rates of 80%. Regarding the moxifloxacin-­amoxicillin-­PPI triple
therapy, efficacy was higher when administered for 14 days instead
of 7 days (80% vs 63%). Only two levofloxacin-­and bismuth-­based
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4 of 10       O’CONNOR et al.
quadruple regimens reported eradication rates greater than 90%
with similar safety in all treatments.52
5 |  BISMUTH-­B ASED THERAPY
Bismuth is a commonly used agent in H. pylori eradication therapy,
usually with metronidazole, tetracycline, and PPI and as part of a first-­
or second-­line treatment. The utility of such regimens has been some-
what hampered by difficulties with the supply and availability of both
bismuth itself and also tetracycline. A very high-­quality study of over
5,000 patients which compared 10-­day concomitant therapy, 10-­day
bismuth quadruple therapy, and 14-­day triple therapy observed the
best eradication rates in the bismuth-­based therapy arm (90.4%) com-
pared to 85.9% for 10-­day concomitant therapy and 83.7% for 14-­day
triple therapy, albeit with a higher frequency of adverse events 67%,
58% and 47%, respectively.53 A separate Chinese study also showed
superiority for bismuth-­based therapy, this time compared to 10-­day
triple therapy (86.1% vs 58.4%).54 A further study in Korea differed
though with superior eradication rates being seen for 10-­day se-
quential therapy than 14-­day bismuth-­based quadruple therapy.55 In
Turkey, a further study compared two different bismuth-­based quad-
ruple regimens (one with clarithromycin and one with metronidazole)
and obtained clearly superior eradication rates for both (95.4% and
93.9%) compared to triple therapy (64.7%).56 A study from Italy using
®
Pylera (a three-­in-­one capsule containing potassium bismuth subci-
trate 140 mg, metronidazole 125 mg, and tetracycline 125 mg) three
capsules q.i.d. plus PPI for 10 days yielded eradication rates of 92.7%
in treatment-­naïve patients and a remarkable 96.0% in patients who
had failed previous treatment.57
More novel variations of first-­line bismuth-­based therapy were also
reported this year. A group from China reported two separate prospec-
tive studies from a region with high antibiotic resistance rates looking at
bismuth-­based quadruple therapy for 14 days with minocycline, amox-
icillin, and in one case rabeprazole and the other esomeprazole. The ra-
beprazole group had eradication rates of 87.5% in first-­line therapy and
58
82.9% for second-­line. The group receiving esomeprazole reported
59
85.5% eradication rates in first-­line therapy and 82.8% for second-­line.
A study from Croatia reported eradication rates of 80.64% for bismuth
quadruple therapy with pantoprazole, metronidazole, and moxifloxa-
cin.60 Other studies examined combining levofloxacin and bismuth. One
such study reported eradication rates of 86.7% for one week of qua-
druple therapy including bismuth and levofloxacin compared to 72.2%
for clarithromycin and bismuth and 75.56% for levofloxacin-­based triple
therapy in first-­line patients.61 A different Chinese group observed sim-
ilar eradication rates for a bismuth-­based quadruple therapy whether
62
amoxicillin or cefuroxime was used (83.5% vs 81.0%).
Some reports focussed solely on the role of bismuth as second-­
line therapy, a high-­quality US study found the use of metronidazole
and amoxicillin provided similar eradication rates (88.5% vs 87.7%) to
classical bismuth quadruple therapy but with superior safety and com-
pliance.63 In France, a study of Pylera® as second-­line therapy showed
similar high efficacy to that reported in Italy with 83% achieving
eradication.64 In Korea, an interesting study noted that although erad-
ication rates of 73.9% were observed, a multivariate analysis showed
that diabetes mellitus was strongly associated with H. pylori eradica-
tion therapy failure.65
6 | DUAL THERAPY
Enhanced dual therapy may also be a useful option for H. pylori
eradication and has been studied more in recent years. Two Asian
studies addressed the question this year. As a first-­line option, a
Korean group gave ilaprazole 40 mg tablets twice a day and amoxi-
cillin 750 mg tablets 4 times a day for 14 days and reported a
cure rate of 79.3%.66 A meta-­analysis of the use of dual therapy
as a rescue therapy for H. pylori compared to a series of guideline-­
recommended rescue therapies found rates of eradication (81.3%
vs 81.5%) as well as compliance and adverse events to be com-
parable with recommended rescue treatments from international
guidelines.67
7 | RIFABUTIN
Rifabutin can be a useful option for H. pylori eradication treatment
although its use is limited by potentially severe adverse events such
as myelotoxicity and concerns regarding promoting the spread of
multidrug-­resistant tuberculosis. Nonetheless, in difficult scenarios, it
is of some benefit. A study from Japan found in third-­or fourth-­line
therapy that 83.3% achieved eradication after 10 days of rifabutin-­
based triple therapy and 94.1% after 14 days.68 A separate pilot study
from Italy reported 96.6% for a 10-­day bismuth-­based quadruple regi-
men containing rifabutin compared to 66.7 in the 10-­day rifabutin-­
based triple therapy arm.69 Less impressive results were found in a
12-­patient cohort in Korea in whom only 50% achieved eradication
although this study was significantly skewed by the fact that some
patients received therapy for 7 days and others 14 days.70 In a large
study from Italy looking at 254 patients harboring triple-­resistant
(clarithromycin, metronidazole, levofloxacin) strains 82.9% of the pa-
tients were cured with a rifabutin-­based triple therapy.71
8 | ANTIMICROBIAL RESISTANCE
A significant and welcome increase was noted over the last year in the
number of studies addressing the important topic of antimicrobial re-
sistance in H. pylori infection. These are summarized in Table 1.72-92 A
key message emerging is the relentless rise in antibiotic resistance, es-
pecially to clarithromycin and levofloxacin. Although the pace of this
increase appears to be variable, the trend is a clear one. In many re-
gions of western Europe such as Ireland, Germany, and France where
clarithromycin resistance had previously been low, recent studies have
shown an increase in rates above the level of 20% (now 15%) where
it has long been considered that clarithromycin-­based triple therapy
O’CONNOR et al. |
      5 of 10

T A B L E   1   Helicobacter pylori resistance to antibiotics in the studies published during the last year worldwide

Author Region AMO, % CLA, % MET, % LEV, % TET, % RIF, % FUR, %

72
Bouihat Morocco 0 29 40 11 0 0 –
73
Li China 0.06 16.4 75.2 6.7 – – 0.06
Miftahussurur74 Indonesia 5.2 9.1 46.7 31.2 2.6 – –
75
Miftahussurur Nepal 0 21.4 88.1 42.9 0
Brennan76 Ireland – 51.9 – 9.3 – – –
77
Ferenc Poland – 55.2 56.7 5.9 – – –
Sanches78 Brazil – 16.9 – 13.5 – – –
Quek79 Vietnam 10.4 85.5 37.8 24.4 23.8 – –
Djennane-­Hadibi80 Algeria – 33 – – – – –
81
Regnath Germany 0.8 23.2 28.7 – – 13.3 –
Trespalacios-­ Colombia – – – 18.2 – – –
Rangél82
Zemali83 Reunion – 12.3 – – – – –
84
Ducournau France 0.7 22.2 45.9 15.4 0 0.7 –
Han85 China – 20.2 99.5 23.4 – – –
86
Zollner-­Schwetz Austria – 17.2 10.2 9.4 – – –
Park87 USA – 32.3 – – – – –
88
Tamayo Spain – 17.6 – – – – –
Goudarzi89 Iran 27.7 43.1 73.8 13.4 29.2 23.1 –
90
Gunnarsdottir Iceland 0 9 1 4 0 – –
Boehnke91 Peru 32.9 35.5 61.8 53.9 3.9 46.1 –
Alarcón-­Millán92 Mexico – 17.8 – – – – –

AMO: amoxicillin, CLA: clarithromycin, MET: metronidazole, LEV; levofloxacin, TET: tetracycline, RIF: rifamycin, FUR: furazodilodone

ought to be abandoned as a primary treatment strategy.76,81,84 In con-
86
trast, resistance in Austria remains low.
The correlation between in vivo and in vitro resistance in H. pylori
has long been questioned. An interesting paper from a French group
this year showed a good correlation between the clarithromycin resis-
tance detected by phenotypic methods and the associated mutations
for clarithromycin resistance and also that no patients receiving Pylera
developed resistance to tetracycline.84
A study from Poland looked at tailoring initial triple therapy based
on AST to amoxicillin, clarithromycin, levofloxacin, and metronidazole
and found that, when such a strategy was employed, eradication rates
were significantly better (95.5% vs 86.6%).77 This strategy has previ-
ously been used predominantly for third-­line or “rescue” therapies. A
meta-­analysis on this topic was conducted this year which concluded
that cure rates, using susceptibility-­guided treatment, were 72% and
that the evidence in favor of such a rescue therapy is currently insuffi-
cient to recommend its use.93
9 | PROBIOTICS
Several articles this year described the effect of probiotic treatment
on H. pylori eradication therapy. Regarding probiotics, there were a
few original studies that reported interesting results as well as three
meta-­analyses. A study of 159 patients in Turkey treated with se-
quential therapy revealed that 86.8% of patients in the group receiv-
ing probiotics alongside the sequential therapy achieved eradication
compared to 70.8% without.94 When used with quadruple bismuth-­
based therapy, the provision of probiotic and prebiotic supplemen-
tation also led to greater eradication rates (92.1% vs 63.2%).95 The
proposed benefits of probiotic supplementation are thought by some
to lie in altering the microbiome in such a manner as to limit diarrhea
side effects, thus improving tolerance, compliance and eradication
rates. One study this year analyzed the microbiome of patients receiv-
ing probiotics compared to those receiving just eradication therapy
alone.96 The overall alterations in microbiota, as revealed by metagen-
ome sequencing, were similar, but the proportional shift in functional
gene families was greater in the antibiotic group than in the probiotic
only group leading to functional alterations of gut microbiota which
may link to the reduction in intestinal irritation and maintenance of
bacterial diversity observed following probiotic supplementation with
antibiotic therapy.
One high-­quality meta-­analysis probed into the individual strains
used in the relevant studies and showed that four multistrain pro-
biotics significantly improved H. pylori eradication rates, five sig-
nificantly prevented any adverse reactions and three significantly
reduced antibiotic-­
associated diarrhea, but only two probiotic
mixtures (Lactobacillus acidophilus/Bifidobacterium animalis and an
 |
6 of 10       O’CONNOR et al.

T A B L E   2   Helicobacter pylori eradication rates in studies where vonoprazan was used

Eradication with Second-­line with

Author N Study design Formulation vonoprazan Eradication with PPI vonoprazan

Suzuki100 661 Retrospective Triple with AMO, CLA 89.1% 70.9% –

Murakami101 641 Prospective Triple with AMO, CLA 92.6% 79.9% 98%
Ono102 88 Retrospective Triple with MET, CLA 92.9% 46.2% –
Kajihara103 209 Retrospective Triple with AMO, CLA 94.6% 86.7% –
Sakurai104 1353 Retrospective Triple with AMO, CLA 87.9% 71.6% 96.1%
Yamada105 2507 Retrospective Triple with AMO, CLA/ 85.7% 73.2% 89.4%
MET
Matsumoto106 420 Prospective Triple with AMO, CLA 100% CLA-­Sens, 89.6% CLA-­Sens, –
76.1% CLA-­Resistant 40.2% CLA-­Resistant
Fukuda107 669 Retrospective Triple with AMO, CLA 91.4% – 100%
108
Noda 1451 Prospective Triple with AMO, CLA 89.7% 73.9% –
Shichijo109 2715 Retrospective Triple with AMO, CLA 87.2% 72.4% –
110
Shinozaki 573 Retrospective Triple with AMO, CLA 83% 66% –
Maruyama111 141 Prospective Triple with AMO, CLA 95.8% 69.6% –

PPI, proton-­pump inhibitor; AMO, amoxicillin; CLA, clarithromycin; MET, metronidazole.

eight-­strain mixture) had significant efficacy for all three outcomes.97
A separate meta-­analysis which emphasized the heterogeneity of the
13 studies identified that pooled relative risk of eradication was sig-
nificantly higher in the probiotic supplementation group than in the
control group and the incidence of total antibiotic-­related side effects
was lower in the probiotic supplementation group than in the control
group.98 A further meta-­analysis of 30 randomized clinical trials with
significant heterogeneity found eradication rates improved by 12.2%
when probiotics were used in supplementation.99
10 | VONOPRAZAN
PPI, and second-­line eradication rate of 98%.101 In another study of
penicillin-­allergic patients, vonoprazan with clarithromycin and metro-
nidazole led to cure in 92.9% of cases compared to 46.2% in patients
who received those antibiotics with PPI.102 One cost-­effectiveness
study was carried out which showed in a population where vono-
prazan triple therapy achieved 94.6% eradication rates compared to
86.7% for PPI-­based therapy that the vonoprazan option cost 1155.4
Japanese yen (approx. €10) higher than PPI.103 On this basis, the cost-­
effectiveness ratio of vonoprazan was less than PPI (360.1 vs 379.4,
Japanese yen per percent) and incremental cost-­effectiveness ratio of
vonoprazan was 147.0 JPY/1.28 Euro per percent.

Vonoprazan is a first-­
in-­
class orally bioavailable potassium-­
competitive acid blocker (P-­CAB) which has been developed for the
treatment and prevention of acid-­
related diseases. It inhibits the
H+, K+-­ATPase-­mediated gastric acid secretion in a reversible and
potassium-­competitive manner and is thought to possess more po-
tent inhibitory effects than PPI offering a potential benefit for H. pylori
eradication. A raft of literature has emerged from Japan in the last
year where this agent is approved for use, all of which have found su-
100-111
periority for vonoprazan over PPI in triple therapy formats. This
is summarized in Table 2. It is noteworthy, however, that vonoprazan
has been tested in triple therapies only and not in other regimens such
as quadruple therapy, sequential therapy, or with bismuth.
One high impact retrospective study of more than 600 patients
showed eradication rates of 89.1% for vonoprazan when used as a triple
therapy with amoxicillin and clarithromycin compared to 70.9% when
PPI was used with no significant difference in the incidence of adverse
101
events. A separate prospective study on a similar number of patients
which included 50 undergoing second-­line therapy yielded a first-­line
eradication rate of 92.6% with vonoprazan compared to 75.9% with
11 | CONCLUSION
There have been many and varied number of studies pertaining to
H. pylori eradication treatment in the published literature over the last
12 months, often with diverse results, although several broad themes
do emerge. Clarithromycin resistance rates are increasing in all regions
of the world and this threatens the viability of clarithromycin based tri-
ple therapies even when given at longer durations. Bismuth and non-­
bismuth concomitant quadruple therapies seem in most cases to show a
clear advantage over sequential therapies which have performed poorly
against triple therapy regimens of 14 days duration and cannot be
adopted for first-­line H. pylori eradication treatment. The evidence base
behind longer courses of treatment regardless of the regimen grows
ever more solid. This is copper-­fastened by a new systematic review of
all optimisation strategies for H. pylori eradication that shows the most
direct way to optimize a treatment is using higher doses of drugs unless
it has been shown that lower doses are equally effective. This applies
to the use of potent acid inhibition and/or higher antibiotic doses-­
especially by increasing the number of daily intakes-­and lengthening
O’CONNOR et al.
treatments up to 14 days.112 Bismuth based therapies are performing
very well across numerous regions and the more novel pairings of it
either as part of a “single triple” capsule or with other antibiotics may
well enable clinicians to overcome some of the issues around tetracy-
cline supply that have hampered the widespread adoption of bismuth
based therapy. Levofloxacin and rifabutin remain useful alternatives,
especially in rescue therapy settings. Excellent results for studies using
vonoprazan has been a very noteworthy development this year but this
will need to be robustly examined in regions outside Japan and also
compared with regimens other than standard triple therapy.
D ISCLOSURE S OF I N TE RE S TS
The authors declare no conflict of interest.
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How to cite this article: O’Connor A, Lamarque D, Gisbert JP,
O’Morain C. Treatment of Helicobacter pylori infection 2017.
Helicobacter. 2017;22(Suppl. 1):e12410.
https://doi.org/10.1111/hel.12410