EDITORIALS

The Current Role of Vonoprazan in Helicobacter pylori Treatment

(65.8% for VAC and 69.6% for VA). Bismuth quadruple
See “Vonoprazan triple and dual therapy for therapy (BQT) completely avoids the clarithromycin
Helicobacter pylori infection in the united states resistance issue and has achieved better success with real-
and Europe: randomized clinical trial,” by Chey world results of >90% success in Europe and 87% in the
WD, Mégraud F, Laine L, et al, on page 608. United States,10,11 although no head-to-head comparison
with vonoprazan regimens currently exits.
There are some limitations to this study. The comparison

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
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
increased rendering eradication more difficult.1,2 Clari- such as PAC in clarithromycin resistant infections is not very
thromycin resistance, in particular, has significantly grown useful information. However, the study does show that it
over time, thus decreasing the success rate of the commonly works just as well as an acceptable treatment (PAC) in
used proton pump inhibitor (PPI), amoxicillin, and clari- clarithromycin-susceptible infections. In addition, part of
thromycin triple therapy combination (PAC).3 Vonoprazan is the study was open label rather than double blind, but this
a potassium competitive acid blocker with stronger and is not too large of an issue given that the eradication rate is
longer lasting reduction of gastric acid secretion than PPIs.4 not a subjective outcome. Nevertheless, this study confirms
Higher acid suppression has been shown to be associated results from Asia with data from the United States and
with successful eradication of H pylori with triple therapy.5 Europe demonstrating a role for vonoprazan.
Vonoprazan combined with amoxicillin and clarithromycin What can we take back to our practice from this article?
(VAC) has also outperformed PAC in trials conducted in Asia Given the development of clarithromycin resistance detec-
confirming this theory.6 These trials suggest that more tion tests on stool, susceptibility testing is becoming easier,
potent acid suppression increased eradication of clari- more available, and more commonly used. For clari-
thromycin resistant strains by improving amoxicillin effec- thromycin sensitive strains, we can now confidently choose
tiveness. Omitting clarithromycin from this combination PAC or VAC (Figure 1) as treatment options. The clari-
(VA) produced similar results to VAC, suggesting that clar- thromycin in VAC is possibly not required in this setting,
ithromycin was an unnecessary antibiotic when treating but this study was not designed to see if VAC was superior
clarithromycin resistant infections.7 In this issue of Gastro- to VA for clarithromycin-susceptible organisms. In
enterology, Chey et al8 present the first results of vonopra- clarithromycin-resistant strains, I would feel more inclined
zan therapy for H pylori eradication from the United States to choose a regimen not containing clarithromycin, such as
and Europe. BQT. A high-dose dual therapy such as VA at the doses
In this randomized trial of 1046 patients, VA (which is provided in this study would be an alternative, although
essentially a high-dose dual therapy; it includes 1 g amoxi- further studies comparing the 2 regimens would be useful
cillin 3 times a day) and VAC were both compared with PAC. before choosing the latter over the very successful BQT. In
The comparisons were open label with VA and in double- situations where susceptibility testing is not feasible, but in
blind fashion with VAC. The vonoprazan regimens were the rare setting where resistance in the community is
found to be noninferior to PAC, with eradication success in known to be very low, one can now consider VAC instead of
78.5% and 84.7% versus 78.8%, respectively, in patients PAC because this strategy has the added advantage of
infected with clarithromycin- and amoxicillin-susceptible eradicating more of the clarithromycin-resistant strains. In
organisms. In patients with clarithromycin-resistant organ- areas of higher clarithromycin resistance rates (tradition-
isms, they demonstrated the superiority of both VA and VAC ally 15%) or those without known prevalence of clari-
versus PAC (69.6% and 65.8% vs 31.9%; P < .001). The thromycin resistance, the optimal choice would be to use
authors compared these new combinations with PAC, a the combination with the highest success rate such as BQT
commonly prescribed therapy in the United States and or concomitant non-BQT if bismuth is not available and
Europe, but this therapy is currently only recommended in there was a low rate of dual resistance to metronidazole
infection with confirmed clarithromycin-susceptible and clarithromycin. High-dose dual therapies including VA
infections.1–3,9 In fact, the results of the current study have not proven yet to have a high enough success rate to
reinforce this recommendation in that this treatment only be considered a first-line alternative, but certainly would be
eradicated 31.9% of clarithromycin-resistant infections. a good option in a population with a high prevalence of dual
The vonoprazan therapies were superior to this, but the resistance to metronidazole and clarithromycin. The
success rate was far from desirable at <70%. Again, one disadvantage when using either VAC or concomitant ther-
can see that the clarithromycin in the situation of a apy when susceptible profiles are not known is that one is
clarithromycin-resistant infection is an unnecessary often using an unnecessary antibiotic. Specifically in those
antibiotic as both had very similar eradication rates infected with clarithromycin-resistant organisms, one is

Gastroenterology 2022;163:572–585
 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 1. Malfertheiner P, Mégraud F, O’Morain CA, et al. Man-
when using concomitant therapy in metronidazole resistant agement of Helicobacter pylori infection – the Maastricht
infections. Rifabutin-containing regimens are also alterna- V/Florence Consensus Report. Gut 2017;66:6–30.
tives (Figure 1); however, we tend to reserve this for fail- 2. Chey WD, Leontiadis GL, Howden CW, et al. ACG Clin-
ures given the potential of bone marrow suppression, ical Guideline: Treatment of Helicobacter pylori infection.
although this seems to be less of an issue than originally Am J Gastroenterol 2017;112:212–238.
thought.12,13 3. Fallone CA, Chiba N, Veldhuyzen van Zanten S, et al. The
Further studies with vonoprazan regimens are desired Toronto Consensus for the Treatment of Helicobacter
to further define their role in the armamentarium against H pylori infection in adults. Gastroenterology 2016;
pylori infection. High-dose dual therapy with VA may have a 151:51–69.
role in first-line therapy, but more studies are required in 4. Scarpignato C, Hunt RH. Acid suppressant therapy: a
this setting to see if it achieves success as frequently as BQT. step forward with potassium-competitive acid blockers.
Perhaps tweaking the doses of this dual therapy may also Curr Treat Options Gastroenterol 2021;19:94–132.
prove fruitful. In addition, the role of increased acid sup- 5. Sugimoto M, Furuta T, Shirai N, et al. Evidence that the
pression by PPI substitution with vonoprazan should be degree and duration of acid suppression are related to
examined in other H pylori regimens, including BQT and Helicobacter pylori eradication by triple therapy. Heli-
perhaps in combination with amoxicillin and metronidazole, cobacter 2007;12:317–323.
levofloxacin, or rifabutin. 6. Lyu Q-J, Pu Q-H, Zhong X-F, Zhang J. Efficacy and
safety of vonoprazan-based versus proton pump
CARLO A. FALLONE inhibitor-based triple therapy for Helicobacter pylori
Division of Gastroenterology Eradication: a meta-analysis of randomized clinical trials.
McGill University Health Center BioMed Res Int 2019;2019:9781212.
McGill University 7. Li M, Oshima T, Horikawa T, et al. Systematic review with
Montreal, Quebec, Canada meta-analysis: vonoprazan, a potent acid blocker, is

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EDITORIALS
superior to proton-pump inhibitors for eradication of 12. Gisbert JP. Rifabutin for the treatment of Helicobacter
clarithromycin-resistant strains of Helicobacter pylori. Pylori infection: a review. Pathogens 2021;10:15.
Helicobacter 2018;23:e12495. 13. Nyssen OP, Vaira D, Saracino IM, et al. Experi-
8. Chey WD, Mégraud F, Laine L, et al. Vonoprazan triple ence with rifabutin-containing therapy in 500 pa-
and dual therapy for Helicobacter pylori infection in the tients from the European Registry on Helicobacter
united states and Europe: randomized clinical trial. pylori Management (Hp-EuReg). J Clin Med 2022;
Gastroenterology 2022;163:608–619. 11:1658.
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. Correspondence
Address correspondence to: Carlo A. Fallone, Division of Gastroenterology,
10. Nyssen OP, Bordin D, Tepes B, et al. European Registry McGill University Health Center, McGill University, 1001 Decarie Blvd, Room
on Helicobacter pylori management (Hp-EuReg): pat- D05.7154, Montreal, Quebec H4A 3J1, Canada. e-mail:
terns and trends in first-line empirical eradication [email protected].
prescription and outcomes of 5 years and 21 533 Conflicts of interest
patients. Gut 2021;70:40–54. The author discloses no conflicts.
11. Alsamman MA, Vecchio EC, Shawwa K, et al. Retro- Most current article
spective analysis confirms tetracycline quadruple as best
© 2022 by the AGA Institute.
Helicobacter pylori regimen in the USA. Dig Dis Sci 2019; 0016-5085/$36.00
64:2893–2898. https://doi.org/10.1053/j.gastro.2022.06.076

Novel, Emerging Risk Factors for Colorectal Cancer Remain

Understudied
1.14–1.27) and CRC in those diagnosed at ages 50 years
See “Association between metabolic syndrome (HR, 1.19; 95% confidence interval, 1.17–1.21). Higher body
and the risk of colorectal cancer diagnosed mass index and waist circumference were also associated
before 50 years according to tumor location,” by with increased risk of early-onset CRC. In reporting HR es-
Jin EH, Han K, Lee DH, et al, on page 637. 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

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
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
States and in other parts of the world.1 More recently, colon, distal colon, and rectum, which suggests that
incidence rates have started to increase in adults ages metabolic syndrome is associated with early-onset CRC
50–54 years old.2 Despite broad recognition in the medical throughout the colon and rectum.
and public health communities about the increasing This large study in a well-characterized cohort provides
morbidity and mortality associated with early-onset CRC, further evidence that many of the same risk factors associ-
the factors driving this increase are largely unknown. Many ated with CRC, overall, are also associated with early-onset
studies have investigated risk of early-onset CRC associated CRC. However, it falls short of shedding additional light on
with traditional, well-known risk factors for CRC , including the factors that are driving the global increase in early-onset
a Western diet,3 heavy alcohol use,4 tobacco use,5 sedentary CRC, as well as continued increases among adults aged
behavior,6 obesity,7,8 and diabetes.7 In this issue of Gastro- 50–54 in some regions of the world. Early-onset CRC does
enterology, Jin et al9 continued this line of research by using not have a stronger association with metabolic syndrome
the South Korean National Health Insurance Service data- than later onset CRC and, although the prevalence of
base to conduct a cohort study of more than 5.7 million metabolic syndrome and obesity have increased globally
adults ages 20–49 years and more than 4.1 million adults over the same time period that early-onset CRC incidence
aged 50 years investigating the association of obesity and has increased, recent evidence suggests that traditional risk
metabolic syndrome with early-onset CRC. Importantly, the factors explain only 10% of the increase in early-onset
magnitude of the association for each of these established CRCs.10 There are likely new, emerging risk factors for
CRC risk factors was compared between age groups (aged CRC that remain undiscovered.11,12 However, to date, there
20–49 years vs 50 years). Also, among those in the 20–49 is a dearth of studies evaluating novel risk factors, and
years age group, hazard ratio (HR) estimates were pre- studies that extend beyond traditional CRC risk factors are
sented separately by anatomic site (proximal colon, distal critically needed to address the alarming rise in early-onset
colon, and rectum). Jin et al9 reported that metabolic syn- CRC and more recent increases in CRC after age 50 years.
drome was similarly associated with an increased risk of A key epidemiologic clue that should act to guide future
early-onset CRC (HR, 1.20; 95% confidence interval, investigations of risk factors is that early-onset CRC

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