EDITORIALS
The Current Role of Vonoprazan in Helicobacter pylori Treatment
See “Vonoprazan triple and dual therapy for
Helicobacter pylori infection in the united states
and Europe: randomized clinical trial,” by Chey
WD, Mégraud F, Laine L, et al, on page 608.
O ver the last several years, indications for treating
Helicobacter pylori have increased, but the pro-
portion of organisms resistant to certain antibiotics has also
increased rendering eradication more difficult.1,2 Clari-
thromycin resistance, in particular, has significantly grown
over time, thus decreasing the success rate of the commonly
used proton pump inhibitor (PPI), amoxicillin, and clari-
thromycin triple therapy combination (PAC).3 Vonoprazan is
a potassium competitive acid blocker with stronger and
longer lasting reduction of gastric acid secretion than PPIs.4
Higher acid suppression has been shown to be associated
with successful eradication of H pylori with triple therapy.5
Vonoprazan combined with amoxicillin and clarithromycin
(VAC) has also outperformed PAC in trials conducted in Asia
confirming this theory.6 These trials suggest that more
potent acid suppression increased eradication of clari-
thromycin resistant strains by improving amoxicillin effec-
tiveness. Omitting clarithromycin from this combination
(VA) produced similar results to VAC, suggesting that clar-
ithromycin was an unnecessary antibiotic when treating
clarithromycin resistant infections.7 In this issue of Gastro-
enterology, Chey et al8 present the first results of vonopra-
zan therapy for H pylori eradication from the United States
and Europe.
In this randomized trial of 1046 patients, VA (which is
essentially a high-dose dual therapy; it includes 1 g amoxi-
cillin 3 times a day) and VAC were both compared with PAC.
The comparisons were open label with VA and in double-
blind fashion with VAC. The vonoprazan regimens were
found to be noninferior to PAC, with eradication success in
78.5% and 84.7% versus 78.8%, respectively, in patients
infected with clarithromycin- and amoxicillin-susceptible
organisms. In patients with clarithromycin-resistant organ-
isms, they demonstrated the superiority of both VA and VAC
versus PAC (69.6% and 65.8% vs 31.9%; P < .001). The
authors compared these new combinations with PAC, a
commonly prescribed therapy in the United States and
Europe, but this therapy is currently only recommended in
infection with confirmed clarithromycin-susceptible
infections.1–3,9 In fact, the results of the current study
reinforce this recommendation in that this treatment only
eradicated 31.9% of clarithromycin-resistant infections.
The vonoprazan therapies were superior to this, but the
success rate was far from desirable at <70%. Again, one
can see that the clarithromycin in the situation of a
clarithromycin-resistant infection is an unnecessary
antibiotic as both had very similar eradication rates
Gastroenterology 2022;163:572–585
(65.8% for VAC and 69.6% for VA). Bismuth quadruple
therapy (BQT) completely avoids the clarithromycin
resistance issue and has achieved better success with real-
world results of >90% success in Europe and 87% in the
United States,10,11 although no head-to-head comparison
with vonoprazan regimens currently exits.
There are some limitations to this study. The comparison
is not to the current standard of care for clarithromycin-
resistant infections or those of unknown susceptibility.
Finding that a treatment is better than an unacceptable one
such as PAC in clarithromycin resistant infections is not very
useful information. However, the study does show that it
works just as well as an acceptable treatment (PAC) in
clarithromycin-susceptible infections. In addition, part of
the study was open label rather than double blind, but this
is not too large of an issue given that the eradication rate is
not a subjective outcome. Nevertheless, this study confirms
results from Asia with data from the United States and
Europe demonstrating a role for vonoprazan.
What can we take back to our practice from this article?
Given the development of clarithromycin resistance detec-
tion tests on stool, susceptibility testing is becoming easier,
more available, and more commonly used. For clari-
thromycin sensitive strains, we can now confidently choose
PAC or VAC (Figure 1) as treatment options. The clari-
thromycin in VAC is possibly not required in this setting,
but this study was not designed to see if VAC was superior
to VA for clarithromycin-susceptible organisms. In
clarithromycin-resistant strains, I would feel more inclined
to choose a regimen not containing clarithromycin, such as
BQT. A high-dose dual therapy such as VA at the doses
provided in this study would be an alternative, although
further studies comparing the 2 regimens would be useful
before choosing the latter over the very successful BQT. In
situations where susceptibility testing is not feasible, but in
the rare setting where resistance in the community is
known to be very low, one can now consider VAC instead of
PAC because this strategy has the added advantage of
eradicating more of the clarithromycin-resistant strains. In
areas of higher clarithromycin resistance rates (tradition-
ally 15%) or those without known prevalence of clari-
thromycin resistance, the optimal choice would be to use
the combination with the highest success rate such as BQT
or concomitant non-BQT if bismuth is not available and
there was a low rate of dual resistance to metronidazole
and clarithromycin. High-dose dual therapies including VA
have not proven yet to have a high enough success rate to
be considered a first-line alternative, but certainly would be
a good option in a population with a high prevalence of dual
resistance to metronidazole and clarithromycin. The
disadvantage when using either VAC or concomitant ther-
apy when susceptible profiles are not known is that one is
often using an unnecessary antibiotic. Specifically in those
infected with clarithromycin-resistant organisms, one is
 EDITORIALS

Figure 1. Proposed algorithm for the first-line treatment of H pylori infection. Certain facts may alter the selection of treatment.
Metronidazole resistance is fairly common, but bismuth quadruple therapy can overcome much of the metronidazole resis-
tance. It, however, has a large pill burden. Levofloxacin resistance is quite high in certain regions and should only be used with
caution, given recent warnings from the US Food and Drug Administration of aortic rupture in susceptible individuals. Rifabutin
can cause some bone marrow suppression. Nonbismuth concomitant quadruple therapy uses an unnecessary antibiotic,
which is not desired because of antibiotic stewardship. PPI, proton pump inhibitor.

using clarithromycin unnecessarily with either of the 2 References

regimens and one is using metronidazole unnecessarily
when using concomitant therapy in metronidazole resistant
infections. Rifabutin-containing regimens are also alterna-
tives (Figure 1); however, we tend to reserve this for fail-
ures given the potential of bone marrow suppression,
although this seems to be less of an issue than originally
thought.12,13
Further studies with vonoprazan regimens are desired
to further define their role in the armamentarium against H
pylori infection. High-dose dual therapy with VA may have a
role in first-line therapy, but more studies are required in
this setting to see if it achieves success as frequently as BQT.
Perhaps tweaking the doses of this dual therapy may also
prove fruitful. In addition, the role of increased acid sup-
pression by PPI substitution with vonoprazan should be
examined in other H pylori regimens, including BQT and
perhaps in combination with amoxicillin and metronidazole,
levofloxacin, or rifabutin.
CARLO A. FALLONE
Division of Gastroenterology
McGill University Health Center
McGill University
Montreal, Quebec, Canada
1. Malfertheiner P, Mégraud F, O’Morain CA, et al. Man-
agement of Helicobacter pylori infection – the Maastricht
V/Florence Consensus Report. Gut 2017;66:6–30.
2. Chey WD, Leontiadis GL, Howden CW, et al. ACG Clin-
ical Guideline: Treatment of Helicobacter pylori infection.
Am J Gastroenterol 2017;112:212–238.
3. Fallone CA, Chiba N, Veldhuyzen van Zanten S, et al. The
Toronto Consensus for the Treatment of Helicobacter
pylori infection in adults. Gastroenterology 2016;
151:51–69.
4. Scarpignato C, Hunt RH. Acid suppressant therapy: a
step forward with potassium-competitive acid blockers.
Curr Treat Options Gastroenterol 2021;19:94–132.
5. Sugimoto M, Furuta T, Shirai N, et al. Evidence that the
degree and duration of acid suppression are related to
Helicobacter pylori eradication by triple therapy. Heli-
cobacter 2007;12:317–323.
6. Lyu Q-J, Pu Q-H, Zhong X-F, Zhang J. Efficacy and
safety of vonoprazan-based versus proton pump
inhibitor-based triple therapy for Helicobacter pylori
Eradication: a meta-analysis of randomized clinical trials.
BioMed Res Int 2019;2019:9781212.
7. Li M, Oshima T, Horikawa T, et al. Systematic review with
meta-analysis: vonoprazan, a potent acid blocker, is

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EDITORIALS
superior to proton-pump inhibitors for eradication of
clarithromycin-resistant strains of Helicobacter pylori.
Helicobacter 2018;23:e12495.
8. Chey WD, Mégraud F, Laine L, et al. Vonoprazan triple
and dual therapy for Helicobacter pylori infection in the
united states and Europe: randomized clinical trial.
Gastroenterology 2022;163:608–619.
9. Fallone CA, Moss SF, Malfertheiner P. Reconciliation of
recent H. pylori treatment guidelines in a time of increasing
antibiotic resistance. Gastroenterology 2019;157:44–53.
10. Nyssen OP, Bordin D, Tepes B, et al. European Registry
on Helicobacter pylori management (Hp-EuReg): pat-
terns and trends in first-line empirical eradication
prescription and outcomes of 5 years and 21 533
patients. Gut 2021;70:40–54.
11. Alsamman MA, Vecchio EC, Shawwa K, et al. Retro-
spective analysis confirms tetracycline quadruple as best
Helicobacter pylori regimen in the USA. Dig Dis Sci 2019;
64:2893–2898.
Novel, Emerging Risk Factors for Colorectal Cancer Remain
Understudied
See “Association between metabolic syndrome
and the risk of colorectal cancer diagnosed
before 50 years according to tumor location,” by
Jin EH, Han K, Lee DH, et al, on page 637.
F or more than 3 decades, colorectal cancer (CRC)
incidence rates have been increasing rapidly among
adults <50 years of age (ie, early-onset CRC) in the United
States and in other parts of the world.1 More recently,
incidence rates have started to increase in adults ages
50–54 years old.2 Despite broad recognition in the medical
and public health communities about the increasing
morbidity and mortality associated with early-onset CRC,
the factors driving this increase are largely unknown. Many
studies have investigated risk of early-onset CRC associated
with traditional, well-known risk factors for CRC , including
a Western diet,3 heavy alcohol use,4 tobacco use,5 sedentary
behavior,6 obesity,7,8 and diabetes.7 In this issue of Gastro-
enterology, Jin et al9 continued this line of research by using
the South Korean National Health Insurance Service data-
base to conduct a cohort study of more than 5.7 million
adults ages 20–49 years and more than 4.1 million adults
aged 50 years investigating the association of obesity and
metabolic syndrome with early-onset CRC. Importantly, the
magnitude of the association for each of these established
CRC risk factors was compared between age groups (aged
20–49 years vs 50 years). Also, among those in the 20–49
years age group, hazard ratio (HR) estimates were pre-
sented separately by anatomic site (proximal colon, distal
colon, and rectum). Jin et al9 reported that metabolic syn-
drome was similarly associated with an increased risk of
early-onset CRC (HR, 1.20; 95% confidence interval,
574
12. Gisbert JP. Rifabutin for the treatment of Helicobacter
Pylori infection: a review. Pathogens 2021;10:15.
13. Nyssen OP, Vaira D, Saracino IM, et al. Experi-
ence with rifabutin-containing therapy in 500 pa-
tients from the European Registry on Helicobacter
pylori Management (Hp-EuReg). J Clin Med 2022;
11:1658.
Correspondence
Address correspondence to: Carlo A. Fallone, Division of Gastroenterology,
McGill University Health Center, McGill University, 1001 Decarie Blvd, Room
D05.7154, Montreal, Quebec H4A 3J1, Canada. e-mail:
carlo.fallone@mcgill.ca.
Conflicts of interest
The author discloses no conflicts.
Most current article
© 2022 by the AGA Institute.
0016-5085/$36.00
https://doi.org/10.1053/j.gastro.2022.06.076
1.14–1.27) and CRC in those diagnosed at ages 50 years
(HR, 1.19; 95% confidence interval, 1.17–1.21). Higher body
mass index and waist circumference were also associated
with increased risk of early-onset CRC. In reporting HR es-
timates for early-onset CRC by anatomic site, the authors
stress that “dose-response (ie, per number of metabolic
syndrome components) associations were significant in
distal colon and rectal cancers, though not for proximal
colon cancers.” However, metabolic syndrome, overall, was
significantly associated with early-onset CRC in the proximal
colon, distal colon, and rectum, which suggests that
metabolic syndrome is associated with early-onset CRC
throughout the colon and rectum.
This large study in a well-characterized cohort provides
further evidence that many of the same risk factors associ-
ated with CRC, overall, are also associated with early-onset
CRC. However, it falls short of shedding additional light on
the factors that are driving the global increase in early-onset
CRC, as well as continued increases among adults aged
50–54 in some regions of the world. Early-onset CRC does
not have a stronger association with metabolic syndrome
than later onset CRC and, although the prevalence of
metabolic syndrome and obesity have increased globally
over the same time period that early-onset CRC incidence
has increased, recent evidence suggests that traditional risk
factors explain only 10% of the increase in early-onset
CRCs.10 There are likely new, emerging risk factors for
CRC that remain undiscovered.11,12 However, to date, there
is a dearth of studies evaluating novel risk factors, and
studies that extend beyond traditional CRC risk factors are
critically needed to address the alarming rise in early-onset
CRC and more recent increases in CRC after age 50 years.
A key epidemiologic clue that should act to guide future
investigations of risk factors is that early-onset CRC