marginally improved ITT eradication rates overall (87.5%
[95% CI, 78.5%
–93.1%] vs 82.7% [95% CI, 73%–89.4%];
P
¼ .39), but eradication rates were much higher among
levo
floxacin-resistant strains (70.6% vs 37.5%).
52
After
prior treatment failure (including both standard triple and
nonbismuth quadruple therapies), BPAL had an ITT eradi-
cation success rate of 90% (95% CI, 86%
–94%) in a pro-
spective cohort study.
108
Decisions. The consensus group agreed that for pa-
tients who have previously failed to respond to H pylori
eradication therapy, levo
floxacin-containing therapy (usually
PAL) is an option. However, in light of evidence of higher
eradication rates with longer treatment durations,
106
the
consensus group recommended a 14-day regimen.
Statement 10. In patients who have previously
failed to respond to clarithromycin-containing
H py-
lori eradication therapy, we recommend against the
use of clarithromycin-containing regimens as sub-
sequent therapy. GRADE: Strong recommendation; quality
of evidence low. Vote: strongly agree, 100%.
Key evidence (
Supplementary Table 10
). As discussed
with statements 2 and 5, the ef
ficacy of clarithromycin-
containing regimens is highly affected by clarithromycin
resistance.
19,22,46,52
–55
More importantly, the prevalence of
secondary resistance is very high (up to 70% in some
series).
20,40
Decisions. As a result of resistance concerns, the
consensus group recommended against reuse of clari-
thromycin in patients who have already failed to respond to
a clarithromycin-containing regimen.
Statement 11. In patients who have previously
failed to respond to a levo
floxacin-containing H py-
lori eradication therapy, we recommend against the
use of levo
floxacin-containing regimens as subse-
quent therapy. GRADE: Strong recommendation; quality of
evidence low. Vote: strongly agree, 62.5%; agree, 37.5%.
Key evidence (
Supplementary Table 11
). As discussed
in statement 6, the ef
ficacy of levofloxacin-containing regi-
mens is highly affected by levo
floxacin resistance.
52,81
Studies have shown that the prevalence of secondary levo-
floxacin resistance is very high (up to 63% in some
series).
83,84
Decisions. As a result of resistance concerns, the
consensus group recommended against reusing levo
floxacin
in patients who have already failed to respond to a
levo
floxacin-containing regimen. Previous quinolone use is
also associated with levo
floxacin-resistant H pylori and
would be expected to reduce the therapeutic success of this
agent.
Statement 12. In patients who have previously
failed to respond to
H pylori eradication therapy, we
recommend against the use of sequential non-
bismuth quadruple therapy (PA followed by PMC) as
an option for subsequent therapy. GRADE: Strong
recommendation; quality of evidence very low. Vote: strongly
agree, 50%; agree, 50%.
Key evidence (
Supplementary Table 12
). Cohort data
have suggested that sequential nonbismuth quadruple
therapy can be effective after failure of previous eradication
therapy, but data are from a small number of patients (42
patients in total) and low quality.
109,110
As discussed in
statement 7, eradication success rates with this regimen
were low (
<80%) and inferior to concomitant administra-
tion when used in the
first-line setting (
Figure 2
).
69
In
addition, this strategy was associated with very low eradi-
cation of clarithromycin and dual clarithromycin and
metronidazole resistant strains (62% and 47%).
69
Decisions. The consensus group recommended that
sequential nonbismuth quadruple therapy not be used as
rescue therapy, because it is less ef
ficacious than other
therapies.
Statement 13. We recommend restricting the use
of rifabutin-containing regimens to cases in which at
least 3 recommended options have failed. GRADE:
Strong recommendation; quality of evidence very low. Vote:
strongly agree, 62.5%; agree, 37.5%.
Key evidence (
Supplementary Table 13
). A systematic
review of 21 studies assessing rescue therapy with
rifabutin-containing regimens found that the overall ITT
eradication success rate was 73% (95% CI, 67%
–79%).
111
The success rate was 79% for second-line regimens and
66% to 70% for third-line or greater regimens. The preva-
lence of resistance was low at 1.3%. Rifabutin triple therapy
for 10 days was shown to be effective in approximately one-
half of patients when used as fourth-line rescue therapy in a
cohort of 190 patients, with an ITT eradication rate of 52%
(95% CI, 45%
–59%).
112,113
Other issues and discussion. The most commonly stud-
ied rifabutin-containing regimen is PPI
þ amoxicillin þ
rifabutin [PAR]; current evidence suggests that 10 days may
be more effective than 7 days, but no additional bene
fit has
been shown with 14 days, which may increase the side ef-
fect burden.
111,114
For this reason, this is the only regimen
for which a duration of therapy of 10 days may be sug-
gested; however, this suggestion is based on a small number
of patients who were treated.
Rifabutin-containing regimens should be reserved for
patients with multiple treatment failures. Because eradication
in the rescue setting is low, there are concerns about adverse
events, especially myelotoxicity, and cost is also an issue. In
addition, although the prevalence of resistance is low, there
are theoretical concerns that overuse may increase the
prevalence of rifabutin-resistant mycobacteria in the com-
munity, for which this agent is currently very important.
111
Decisions. The consensus group agreed that rifabutin-
containing regimens may be useful in the rescue setting
but appear to be less safe than other regimens and should
be reserved for patients with multiple previous failures (eg,
PBMT, PAMC, and PAL).
Other
statements/comments. PAMC
as
rescue
therapy. The consensus group concluded that there was
insuf
ficient evidence to support or refute the efficacy of
PAMC as a second-line option and thus was unable to
recommend for or against this regimen as a rescue therapy.
In a small Japanese study, the ITT eradication rate with
PAMC after failure of PAC triple therapy was 88.5%,
compared with 82.7% with PAM.
115
No data were found
assessing the use of this regimen after failure of bismuth
quadruple therapy.
July 2016
Toronto Consensus for
H pylori Treatment
61
The role of acid suppression. Acid suppression plays an
important role in eradication of H pylori infection. Successful
eradication has been shown to be closely related to the
degree of acid inhibition, with a cohort study using triple
therapy (PAC) showing a signi
ficantly higher mean gastric
pH in patients with versus without successful eradication
(6.4 vs 5.2; P
¼ .013).
116
It has been suggested that achieving more potent acid
inhibition can improve treatment success. Meta-analyses
of RCTs have shown higher eradication rates with triple
therapy using a standard-dose PPI twice daily versus
once daily (13 studies; 83.9% vs 77.7%; P
< .01)
117
and
with a high-dose (eg, esomeprazole 40 mg twice daily)
versus standard-dose PPI (eg, esomeprazole 20 mg
twice daily) (6 studies; 82% vs 74%; P
¼ .03).
118
In
addition, a meta-analysis of 35 studies showed higher
eradication rates with esomeprazole (82.3% vs 77.6%;
odds ratio, 1.32; 95% CI, 1.01
–1.73) and rabeprazole
(80.5% vs 76.2%; odds ratio, 1.21; 95% CI, 1.02
–1.42)
compared with
first-generation PPIs (omeprazole, lanso-
prazole, pantoprazole).
119
Another potential method to improve acid inhibition
would be to use newer, more potent antisecretory agents.
Potassium-competitive acid blockers inhibit gastric H
þ
/
K
þ
–adenosine triphosphatase in a K
þ
competitive but
reversible manner and thus do not require prior proton
pump activation to achieve their antisecretory effect.
120,121
One of these agents, vonoprazan, was recently approved in
Japan for a number of gastrointestinal diseases, including
eradication of H pylori infection.
121
Data suggest that the
pH 4 holding time with this drug is equivalent to esome-
prazole 20 mg 4 times daily.
122,123
Superior clinical ef
ficacy
of this more potent acid suppressant in triple therapy
regimens has been shown in
first-line and second-line
settings.
124
For example, vonoprazan-based triple therapy
with amoxicillin and clarithromycin had greater eradication
success rates (92.6% vs 75.9%; P
< .0001) than the same
lansoprazole-based treatment due to the difference in
eradication of clarithromycin-resistant cases (82.0% vs
40.0%; P
< .0001), although treatment success in the
presence of clarithromycin resistance is still far from
desirable.
124
High-dose dual therapy. Further evidence for increased
ef
ficacy with greater acid suppression comes from a study
of high-dose PPI dual therapy.
50
Despite the recognized
inadequacy of standard-dose PPI dual therapy,
125
a large
RCT reported signi
ficantly higher ITT eradication rates
with high-dose PPI dual therapy (amoxicillin 750 mg 4
times a day and rabeprazole 20 mg 4 times a day for 14
days; 95.3%) as
first-line treatment compared with either
10-day sequential (85.3%) or 7-day standard triple ther-
apy (80.7%) and as second-line treatment (89.3%)
compared with sequential (51.8%) but not levo
floxacin-
based triple therapy (78.6%).
50
It is unknown how this
regimen would compare with PBMT. This regimen may
prove to be advantageous given the low prevalence of
amoxicillin resistance, but the consensus group felt that
more evidence was needed (eg, compared with 14-day
PBMT or PAMC
first-line therapy, compared with PBMT
in rescue therapy and in other countries) before a state-
ment on this therapy could be developed. However, high-
dose dual PPI therapy for 14 days may be an option
when both dual metronidazole/clarithromycin resistance
and levo
floxacin resistance are suspected, such as in a
patient with multiple previous failures to respond to
therapy.
Supplemental Therapy
Statement 14. In patients with
H pylori infection,
we recommend against routinely adding probiotics
to eradication therapy for the purpose of reducing
adverse events. GRADE: Strong recommendation; quality
of evidence very low. Vote: strongly agree, 87.5%; agree,
12.5%.
Statement 15. In patients with
H pylori infection,
we recommend against adding probiotics to eradi-
cation therapy for the purpose of increasing eradi-
cation rates. GRADE: Strong recommendation; quality of
evidence very low. Vote: strongly agree, 62.5%; agree, 37.5%.
Key evidence (
Supplementary Table 14
). A meta-
analysis
of
10
trials
concluded
that
Lactobacillus-
containing
and
Bi
fidobacterium-containing
probiotic
preparations during H pylori eradication therapy may have
bene
ficial effects on eradication rate and incidence of total
side effects.
126
However, this analysis was rated low-quality
evidence due to serious limitations, inconsistency, and
indirectness (the majority of trials assessed the impact of
probiotic supplementation when added to triple rather than
quadruple therapy).
Two RCTs have reported no improvement in eradication
rates with the addition of probiotics to quadruple therapy
in adults.
127,128
When added to sequential nonbismuth
quadruple therapy, there was no signi
ficant impact on
eradication rates; however, side effects and compliance
were improved compared with placebo.
127
When added to
bismuth quadruple therapy, a multi-strain probiotic com-
pound showed no bene
ficial effects on efficacy (ITT eradi-
cation rate, 76.6% vs 81.1%; P
¼ .029) or overall tolerability
(P
¼ .851) compared with placebo.
128
There was a signi
fi-
cant reduction in diarrhea but an increase in abdominal
pain.
Other issues and discussion. Although some studies
suggest possible bene
ficial effects, these results are incon-
sistent across studies and there are a number of concerns
with use of probiotics.
129
Formulations are not standardized
and contain different bacterial strains in different combi-
nations and at different concentrations; therefore, studies
are needed to determine which, if any, speci
fic formulations
may actually have bene
ficial effects. Use of probiotics also
increases the cost and complexity of an already complex
treatment regimen.
Decisions. The consensus group concluded that the ev-
idence does not convincingly show that probiotics will in-
crease the ef
ficacy of the recommended eradication
therapies and they should not be used for this purpose. In
contrast, although not recommended routinely for the pre-
vention of adverse events, they may be potentially useful,
and unlikely harmful, in certain high-risk cases to prevent
diarrhea or Clostridium dif
ficile infection.
62
Fallone et al
Gastroenterology Vol. 151, No. 1
Future Directions
The lack of availability of data on local susceptibility
patterns and eradication success rates was identi
fied as a
knowledge gap that has a major impact on the choice of
therapy and hence best management. Periodic susceptibility
testing should be considered by health authorities, and cli-
nicians should be encouraged to record their successes.
These data should be published or presented at conferences
to help monitor susceptibility on an ongoing basis.
There is a need for well-conducted, head-to-head RCTs
on the ef
ficacy of concomitant nonbismuth therapy versus
PBMT as
first-line treatment, as well as studies on 10-day
versus 14-day regimens. In addition, more data are
needed on the ef
ficacy of rescue therapies after failure of
concomitant or PBMT
first-line treatment.
As discussed in statement 8, there continues to be a need
to determine the optimal doses of drugs included in the
recommended regimens, including the effects of various
doses of metronidazole (500 mg 3 times daily vs 500 mg 4
times a day) for PBMT. The role of more potent acid sup-
pression through higher or more frequent doses, or the use
of newer antisecretory agents such as vonoprazan, requires
further study.
The increasing prevalence of resistance and increasing
rates of failure of current therapies emphasize the need to
continue
developing
and
evaluating
new
regimens.
Moxi
floxacin-containing triple therapies have been studied
in some parts of the world.
130
–133
Several meta-analyses of
RCTs have reported that this regimen is better tolerated
than bismuth quadruple therapy and is as effective in the
first-line setting
130
and more effective in the second-line
setting.
130,131
However, moxi
floxacin is affected by the
same high prevalence of
fluoroquinolone resistance as lev-
o
floxacin (see statement 6). Bismuth quadruple therapy
with a PPI, amoxicillin, and clarithromycin (PBAC)
134
–137
or
levo
floxacin (BPAL; see statement 9) may be an effective
alternative to PBMT.
52,108
Eradication success rates with
PBAC have been widely variable, ranging from 55% to 96%
in RCTs.
134
–137
In addition, this regimen will likely be
affected by clarithromycin resistance.
Further study on high-dose PPI dual therapy (amoxicillin
750 mg 4 times a day and rabeprazole 20 mg 4 times a day
for 14 days)
50
and other high-dose dual regimens is
required before they can be recommended.
In certain countries, some agents are not available;
therefore, alternative regimens may be required for treat-
ment failure. For example, if bismuth and levo
floxacin are
not available, high-dose PPI dual therapy or PAM can be
considered. Further studies on these and other alternatives
are required for those who fail to respond to treatment.
Limitations of the Consensus
There are some limitations of this consensus that should
be mentioned. It would have been ideal if the consensus
panel also included primary care physicians, patients, or
other stakeholders, although their potential viewpoints
were discussed at the face-to-face meeting before every
vote. In addition, it was decided not to search for data
before 2008 to avoid confounding of data from earlier
studies that had higher eradication success rates likely as a
result of lower antibiotic resistance. However, this cutoff
can be viewed as a shortcoming, especially in the rare
instance when no new data were available. Older studies
and meta-analyses were used as a discussion point when
presenting newer studies and newer meta-analyses, because
we did not want to completely ignore older data. The older
data were only used in decision making if newer data did
not exist for that particular statement. We believe this
approach was valid because it puts more emphasis on more
recent data while not ignoring data published before 2008.
Finally, the systematic evaluation of evidence relied on
studies in which the populations had variable percentages of
antibiotic resistance. This would affect the success rates of
the different regimens and conclusions may not be gener-
alizable
to
speci
fic practice populations.
57
Similarly,
different studies may have used different doses, dosing in-
tervals, and relationships to meals that are not taken into
account when combining results from different studies.
Some of these factors may also play a role in determining
outcome and have not been addressed by this consensus.
Summary
Based on evidence of higher eradication rates with regi-
mens of longer duration and increasing failure of shorter
treatment durations, the consensus group strongly recom-
mended that all H pylori eradication regimens be given
for 14 days. Recommended
first-line strategies include
Figure 3. Algorithm for eradication therapies for
first-line and
rescue treatments. *Some members of the consensus group
advocated against the repeat use of PBMT, whereas others
suggested it may be useful to reserve rifabutin for fourth-line
use (see statement 8). Optimized refers to using a higher dose
of PPI or metronidazole. See
Tables 1
and
2
for more details
on regimens and dosing.
July 2016
Toronto Consensus for
H pylori Treatment
63
traditional quadruple bismuth therapy (PBMT), concomitant
nonbismuth quadruple therapy (PAMC), and the restricted
use of PPI triple therapy (PAC or PMC) to regions with
known low clarithromycin resistance or high eradication
success rates (
Table 1
and
Figure 3
). Levo
floxacin triple
therapy (PAL) and sequential nonbismuth quadruple ther-
apy (PA followed by PMC) were not recommended for
first-
line treatment.
Potential strategies for subsequent therapy for patients
who fail to respond treatment are shown in
Figure 3
. The
choice of second-line treatment depends on previous anti-
biotic exposure. If there is no previous metronidazole
exposure, PBMT and levo
floxacin-containing therapies are
both options. If the patient was previously exposed to
metronidazole, PAL is the preferred second-line option. If
PAL has failed, then PBMT is the next option even if previ-
ously exposed to metronidazole. An optimized PBMT with
higher-dose PPI and metronidazole 500 mg 4 times a day
could be considered an option if the patient has previously
failed to respond to regular PBMT and PAL, especially if one
wanted to avoid rifabutin. However, there is not a large
body of evidence for this, and some members of the group
argued that repeating PBMT would not be useful. The use of
rifabutin-containing regimens should be restricted to pa-
tients who have failed to respond to at least 3 prior options.
Regarding nonbismuth quadruple therapy, there were
insuf
ficient data to make a recommendation regarding
concomitant PAMC as rescue therapy, but sequential ther-
apy (PA followed by PMC) was not recommended.
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