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Original Article
SMJ
Jadesada Lertsirimunkong, (Pharm.D.)*, Wiwat avornwattanayong, (B.Sc. in Pharm., R.Ph., LL.B., M.A.)**,
Yosita Napuk, (Pharm.D. Student)**, Watcharapong Ajcharoen, (Pharm.D. Student)**, Vipavee Chaisitsanguan,
(Pharm.D. Student)**, Supasuta Wachiranukornkul, (Pharm.D. Student)**
*Department of Pharmacy Administration, College of Pharmacy, Rangsit University, Pathum ani 12000, ailand, **Department of Community
Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, ailand.
Cost-effectiveness Analysis Comparing Vonoprazan-
based Triple Therapy with Proton Pump Inhibitor-
based Therapy in the Treatment of Helicobacter
pylori Infection in Thailand
ABSTRACT
Objective: Helicobacter pylori (H. pylori) infection is one of the leading causes of gastrointestinal diseases such as
dyspepsia, peptic ulcers. ailand has a 45.9% prevalence of the infection and an increasing rate of resistance to
clarithromycin, leading to standard treatments being less successful. Vonoprazan represents a novel drug oering
a new treatment regimen. Although vonoprazan has been available in ailand since 2019, its cost-eectiveness
has not been studied previously.
Materials and Methods: is study analysed the cost-eectiveness of vonoprazan-based triple therapy compared
with PPI-based therapy, in treating clarithromycin resistant H. pylori, by using the markov model from a societal
perspective.
Results: e total cost of vonoprazan-based triple therapy, levooxacin-PPI based triple therapy and concomitant-
PPI therapy were 784,932.08 baht, 783,863.65 baht and 783,874.55 baht respectively. e quality-adjusted life years
(QALYs) of vonoprazan-based triple therapy, levooxacin-PPI based triple therapy and concomitant-PPI therapy
were 25.1118 years, 25.1147 years and 25.1054 years respectively. e cost-eectiveness ratio (CER) of vonoprazan-
based triple therapy, levooxacin-PPI based triple therapy and concomitant-PPI therapy were 31,257.50 baht/
QALYs, 31,211.35 baht/QALYs and 31,223.34 baht per QALYs respectively.
Conclusion: erefore, levooxacin-PPI based triple therapy was found to be the most cost-eective regimen and
the dominant strategy compared with concomitant-PPI or vonoprazan-based triple therapy. It provided higher
QALYs and lower treatment costs. Levooxacin-PPI based triple therapy should be the rst choice of an alternative
strategy in treating clarithromycin-resistant H. pylori. e results of this study can be used by policymakers to help
inform their decisions.
Keywords: Cost-eectiveness; Vonoprazan; Proton pump inhibitors; Levooxacin; Concomitant; Helicobacter
pylori infection (Siriraj Med J 2021; 73: 823-831)
Corresponding author: Jadesada Lertsirimunkong
E-mail: jadesada.l@rsu.ac.th
Received 7 July 2021 Revised 21 September 2021 Accepted 1 October 2021
ORCID ID: https://orcid.org/0000-0003-2930-8810
http://dx.doi.org/10.33192/Smj.2021.107
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INTRODUCTION
Helicobactor pylori (H. pylori) is one of the leading
causes of gastrointestinal diseases such as peptic ulcers
and peptic cancer. is bacterium was found in the
gastrointestinal tract of more than 90% of peptic ulcer
patients. e worldwide prevalence of H. pylori infection
is about 66%. e prevalence in developing countries
is signicantly higher than in developed countries. At
present, ailand has a 45.9% prevalence of infection.
1
e incidence of infection in the Bangkok metropolitan
region is 74%, of which 50-80% are infections in adults.
2
For the treatment of H. pylori infection, the ailand
Consensus on Helicobacter pylori Management 2015
recommended using standard PPI-based triple therapy
for the rst regimen, including a proton pump inhibitor
and 2 antibiotics for 7-14 days. However, the eradication
rate of this regimen has since decreased below 80% due
to clarithromycin resistance.
3,4
In the Southeast Asia region, the country with the
highest rate of clarithromycin resistance has a resistance
rate of 43%, while ailand’s rate is about 14%.
5
In
2017, there was a conference to nd new guidelines
for H. pylori management in Asia called “Helicobacter
pylori management in ASEAN: e Bangkok consensus
report”. e conclusion of the report recommended that
any countries which have a clarithromycin resistance
rate of more than 10% should not use the standard
regimen and should switch to other non-clarithromycin
regimens instead.
6,7
is was in contrast to the 2015
ailand Consensus on Helicobacter pylori Management’s
recommendation of only using alternative rst-line
regimens (sequential therapy and concomitant-PPI
therapy) in patients whose rst-line regimen therapy
had been unsuccessful. Furthermore, the 2017 Bangkok
consensus report also recommended using concomitant-
PPI therapy over sequential therapy, due to the concern
that sequential therapy will have a lower ecacy if H. pylori
becomes resistant to clarithromycin and metronidazole at
the same time. e recommended second-line regimens
are levooxacin-PPI based triple therapy and bismuth
quadruple therapy, neither of which use clarithromycin.
However, following with the recommendation, bismuth
quadruple therapy has limitations of salt form of bismuth
and dosage. erefore, concomitant-PPI therapy and
levooxacin-PPI based triple therapy are more suitable
regimens for H. pylori infected patients in ailand.
It is not only drug resistance that aects the treatment
of H. pylori, but also pH levels in the stomach. Using an
anti-gastric acid secretion drug is essential for maintaining
stomach pH at 5 and for inhibiting H. pylori growth.
8,9
e novel drug Vonoprazan was rst used in a new
treatment regimen in ailand in 2019. e mechanism
is reversible H
+
,K
+
-
ATPase inhibitor.
10
A meta-analysis
study showed that vonoprazan-based triple therapy has an
era dication rate almost two-times higher than PPI-based
Triple erapy, especially in clarithromycin resistant
H. pylori infected patients.
11
us, vonoprazan-based triple
therapy represents an interesting alternative regimen to
eradicate clarithromycin resistant H. pylori. Until now
there has been no cost-eectiveness study carried out
comparing concomitant-PPI therapy, levooxacin-PPI
based triple therapy and vonoprazan-based triple therapy
in ailand. Consequently, the purpose of this study was
to assess the cost-eectiveness of vonoprazan-based triple
therapy compared with concomitant-PPI therapy and
levooxacin-PPI based triple therapy in the treatment
of clarithromycin resistant H. pylori infection.
MATERIALS AND METHODS
Study design
is study was a health economic evaluation using
a model-based structure and presented humanistic
outcomes in quality-adjusted life years (QALYs). e
analysis was assessed using cost-eectiveness ratio (CER)
and incremental cost-eectiveness ratio (ICER). e
perspective of this study was societal. Future costs and
utilities were discounted at 3% per year.
12
Intervention
is study compared three regimes of clarithromycin
resistant Helicobacter pylori infection treatment, approved
for use by the ailand Consensus of Helicobacter pylori
Management in 2015. e treatment included vonoprazan-
based triple therapy
13
(vonoprazan 20 mg, amoxicillin 750
mg and clarithromycin 250 mg, twice a day for 7 days) ,
levooxacin-PPI based triple therapy (levooxacin 500
mg once daily, amoxicillin 1 g twice daily, and standard
dose PPI twice daily for 14 days) and concomitant-PPI
therapy (standard dose PPI, amoxicillin 1 g, clarithromycin
500 mg and metronidazole 500 mg, twice a day for 10
days).
3
Decision model
is study used a Markov model to perform decision
analysis through Microsoft Excel 2016. The model
was developed from the 2015 ailand Consensus on
Helicobacter pylori Management
3
and the Helicobacter
pylori management in ASEAN: e Bangkok consensus
report.
7
is model was validated by two clinical experts in
gastrointestinal diseases, to ensure its appropriateness for
the treatment of H. pylori infection in ailand. Initially,
all patients were in a health status of H. pylori infection.
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Aer treatment, patients who returned a negative urea
breath test would have their health status recorded as
‘successful eradication’. If a positive urea breath test
result was returned, the health status was recorded as
‘failure from the rst regimen state’ and the patient
would go on to receive hybrid therapy. If a patient in a
successful eradication health state suered a reinfection,
they would return to the H. pylori infection health state
again. Patients in all health status could be changed to
the health status of death during the study. e model
is demonstrated in Fig 1.
for 7 days, followed by a standard dose PPI, amoxicillin
1 g, clarithromycin 500 mg and metronidazole 500 mg
twice a day for 7 days) because it is an eective therapy
in high clarithromycin resistant areas.
16
6. No treatment of side eects from any of the regimens
(diarrhea and taste disturbance in vonoprazan-based
triple therapy
15,17
, nausea and diarrhea in levooxacin-
PPI based triple therapy
18
, diarrhea and taste disturbance
in concomitant-PPI therapy
19-26
) was required as side
eects were mild.
27
7. All patients treated with hybrid therapy regimen
were assumed that have successful eradication.
8. e mortality rate of H. pylori infection was
determined by the age range according to the ai mortality
rate
28
due to H. pylori is not a signicant risk factor for
death from any cause.
29
Time Horizon
As most previous studies have examined H. pylori
induced dyspepsia or peptic ulcers in patients aged 18-
65 years
19,30
, the Markov model used in this study was
developed to follow the treatment of H. pylori infection
over a lifetime, from age 18 until death. In 2020, the
average life expectancy in ailand was 75.7 years.
31
A
cycle length of 6 weeks was considered appropriate to cover
the period of clinical treatment, adverse drug reactions
and H. pylori eradication, that was evaluated through
the urea breath test at 4-6 weeks aer the completion
of treatment. H. pylori infection could relapse within 1
year.
32
Probability of clinical outcomes
A systematic search up to September 2020 was
conducted in Pubmed, Cochrane library, Science Direct
and Scopus databases. e keywords were “Vonoprazan,
Levooxacin triple therapy, Concomitant-PPI therapy,
H. pylori or Helicobacter pylori” with “And” and ltered
by randomized controlled trial, meta-analysis, full text
and English published literature. Studies were identied
as eligible for inclusion if they met the following criteria
(i) published in English (ii) randomized control trial,
systematic review, or meta-analysis. e studies were
excluded if they met any of the following exclusion criteria
(i) the outcome was not eradication rate (ii) prevalence
of clarithromycin-resistant H. pylori was not similar to
that found in ailand (iii) not one of the treatment
regimens recommended for use in ailand (iv) did not
analyse eradication rate by intention to treat analysis. All
searched literature was evaluated and given a JADAD
quality assessment score. e transitional probabilities
are shown in Table 1.
Fig 1. Markov model structure of treatment for patients with
H. pylori infection
Assumption of the model
1. Patient did not withdraw from any treatment
during the study and remained until the end of the
treatment.
2. Asymptomatic patients or patients with dyspepsia,
who were conrmed to be infected with H. pylori and failed
from the standard rst-line treatment, were recruited.
3. Patients with H. pylori infection health status
who failed the standard rst-line treatment (Amoxicillin,
Clarithromycin and PPI
3
and treated by vonoprazan-based
triple therapy, levooxacin-PPI based triple therapy or
concomitant-PPI therapy.
4. A successful eradication health status was conrmed
by the negative results of a urea breath test conducted
at least 4 weeks aer treatment.
14,15
5. Patients whose vonoprazan-based triple therapy,
levooxacin-PPI based triple therapy or concomitant-
PPI therapy treatment failed, were switched to a hybrid
therapy regimen (standard dose PPI and amoxicillin 1 g
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Parameters Distribution Mean ± SE References
Transitional probabilities
Levooxacin-PPI based triple therapy
Success Beta 0.8481 ± 0.0404 18
Failure Beta 0.1519 ± 0.0404 18
Relapse Beta 0.0061 ± 0.0041 32
Vonoprazan-based triple therapy
Success Beta 0.7809 ± 0.0310 14, 15, 33
Failure Beta 0.2191 ± 0.0310 14, 15, 33
Relapse Beta 0.0061 ± 0.0041 32
Concomitant-PPI therapy
Success Beta 0.8286 ± 0.0083 19-26, 34
Failure Beta 0.1714 ± 0.0083 19-26, 34
Relapse Beta 0.0061 ± 0.0041 32
Probabilities of side effects
Levooxacin-PPI based triple therapy
Nausea Beta 0.0253 ± 0.0177 18
Diarrhea Beta 0.0380 ± 0.0215 18
Vonoprazan-based triple therapy
Diarrhea Beta 0.1172 ± 0.0161 15, 17
Taste disturbance Beta 0.0399 ± 0.0098 15, 17
Concomitant-PPI therapy
Diarrhea Beta 0.1639 ± 0.0089 19-26
Taste disturbance Beta 0.2212 ± 0.0100 19-26
Costs (Baht)
Medicine costs
Omeprazole 20 mg (per tablet) Gamma 0.6245 ± 0.0624 35
Amoxicillin 250 mg (per tablet) Gamma 6.0432± 0.6043 36
Amoxicillin 500 mg (per tablet) Gamma 1.7122 ± 0.1712 35
Clarithromycin 250 mg (per tablet) Gamma 31.0200 ± 3.1020 35
Clarithromycin 500 mg (per tablet) Gamma 13.5368 ± 1.3537 35
Levooxacin 500 mg (per tablet) Gamma 18.1296 ± 1.8130 35
Vonoprazan 20 mg (per tablet) Gamma 112.6251 ± 11.2625 36
Metronidazole 250 mg (per tablet) Gamma 0.3324 ± 0.0332 36
Laboratory cost
Urea Breath Test (per test) Gamma 3,100.00 ± 310.00 37-39
Gastrointestinal Endoscopy (per test) Gamma 1,712.24 ± 171.22 40
Biopsy (per test) Gamma 805.76 ± 80.58 40
Urease (per test) Gamma 40.29 ± 4.03 40
Treatment and additional procedures
OPD service (per visit) Gamma 120.86 ± 12.09 40
OPD prescription (per visit) Gamma 70.50 ± 7.05 40
Direct non-medical cost
Travel (per visit) Gamma 315.49 ± 31.55 41
Food (per visit) Gamma 63.14 ± 6.31 41
Utility
H. pylori Infection Beta 0.9000 ± 0.0006 42
Nausea Beta 0.6000 ± 0.0500 43
Diarrhea Beta 0.8970 ± 0.0157 44
Taste disturbance Beta 0.9410 ± 0.2356 45
TABLE 1. Parameters used in Markov model.
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Costs
All costs were expressed in ai Baht and are shown
in Table 1. Drugs and laboratory costs were obtained
from the drug’s median price in ailand and National
Drug Information and the service charge of public health
services aliated with the Ministry of Public Health,
ailand.
35,40
e costs of metronidazole 250 mg, amoxicillin
250 mg and vonoprazan 20 mg, were obtained from the
Department of Internal Trade, Ministry of Commerce,
ailand.
36
e urea breath test cost was obtained from
3 hospitals and the mean cost calculated.
37-39
Direct
non-medical costs were obtained from the standard
cost lists for health technology assessment.
41
All costs
were adjusted to 2021 values using the consumer price
index from the Bureau of Trade and Economic indices,
e Ministry of Commerce, ailand.
46
Utility values
e health outcomes were measured in utility weights
for dierent health states and adverse drug reactions,
ranging from 0 (death) to 1 (perfect health). Utility
weights were multiplied by life expectancy to generate
quality-adjusted life-years (QALYs).
Utility values of diarrhea and taste disturbance
were estimated based on the disability weights (DW) of
diarrhea and taste disturbance from the previous study
44,45
that using the calculation, utility weight = 1-DW. Utility
values of H. pylori Infection and nausea were obtained
from a previous study.
42,43
All utility values are shown
in Table 1.
Sensitivity analysis
e one-way sensitivity analysis was performed
through Microso Excel 2016. e parameter values
were changed one by one, usually to a low and a high
value. e results are presented in a tornado diagram to
demonstrate how a change in the value of one parameter
impacts the model results shown as the ICER values.
A Monte Carlo Simulation was used for probabilistic
sensitivity analysis in Microso Excel 2016. All variables
were randomized 1,000 times by probability distribution,
and the incremental cost-eectiveness ratio (ICER)
estimated. e net monetary benet (NMB) was used to
assess the cost-eectiveness in probabilistic sensitivity
analyses. e NMB calculation of vonoprazan-based
triple therapy compared with proton pump inhibitor-
based therapy was formulated as follows
12
NMB = ([QALYs
Vonoprazan-based triple therapy
- QALYs
Proton pump
inhibitor-based therapy
] x Willingness to Pay [WTP])-(Costs
Vonoprazan-
based triple therapy
-Costs
Proton pump inhibitor-based therapy
)
e results were presented as a cost-eectiveness
plane between incremental QALYs and incremental cost,
and the cost-eectiveness acceptability curve between
probabilities of vonoprazan-based triple therapy and
proton pump inhibitor-based therapy, and willingness
to pay (WTP).
RESULTS
Cost-eectiveness Analysis
e results in Table 2 show that the total costs
of vonoprazan-based triple therapy, levooxacin-PPI
based triple therapy and concomitant-PPI therapy
were 784,932.08 baht, 783,863.65 baht and 783,874.55
baht respectively while the quality-adjusted life years
(QALYS) were 25.1118 years, 25.1147 years and 25.1054
years respectively. e cost-eectiveness ratio (CER)
of vonoprazan-based triple therapy with levooxacin-
PPI based triple therapy were 31,257.50 baht/QALYs,
31,211.35 baht/QALYs and 31,223.34 baht per QALYs
respectively. When comparing vonoprazan-based triple
therapy with levooxacin-PPI based triple therapy, the
results revealed that levooxacin-PPI based triple therapy
is a dominant strategy because it delivers greater QALYs
and has a lower cost. When comparing vonoprazan-based
triple therapy with concomitant-PPI therapy, the results
revealed that the ICER was 165,239.06 baht per QALYs.
When compared levooxacin-PPI based triple therapy
and concomitant-PPI therapy, the results revealed that
levooxacin-PPI based triple therapy was a dominant
strategy because of greater QALYs and lower cost.
TABLE 2. Results
Treatment regimens Total costs QALYs CER
(Baht) (Years) (Baht/QALY)
Vonoprazan-based triple therapy 784,932.08 25.1118 31,257.50
Levooxacin-PPI based triple therapy 783,863.65 25.1147 31,211.35
Concomitant-PPI therapy 783,874.55 25.1054 31,223.34
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Sensitivity analysis
e one-way sensitivity analysis in Fig 2 is presented
in a tornado diagram. e probability of relapse from
levooxacin-PPI based triple therapy had the most impact
on the ICER. e probabilistic sensitivity analysis in
Fig 3 presents the incremental cost and the QALYs
of vonoprazan-based triple therapy compared with
levooxacin-PPI based therapy as a cost-eectiveness
plane. Each variable was randomized 1,000 times by
Fig 3. Cost-eectiveness plane between vonoprazan-based triple therapy and levooxacin-PPI based triple therapy
the Monte Carlo simulations. e base-case ICER is
represented by a yellow dot in the gure and falls in
quadrant 2 which mean levooxacin-PPI based triple
therapy was a dominant strategy because of greater QALYs
and lower cost. is revealed that levooxacin-PPI based
therapy was more cost-eective than vonoprazan-based
triple therapy. Nevertheless, the widely distributed ICERs
in the cost-eectiveness plane shows uncertain results.
Fig 2. Tornado diagram showing the results of one-way sensitivity analysis
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DISCUSSION
is study is the rst economic evaluation of the
use of vonoprazan-based triple therapy and proton
pump inhibitor-based therapy in clarithromycin-resistant
H. pylori eradication. An increasing rate of resistance
to clarithromycin has led to standard treatments being
less successful in Thailand. The results showed that
levooxacin-PPI based triple therapy is the most cost-
eective regimen. Although levooxacin-PPI based triple
therapy has a high eradication rate, it also increases
the chances of levooxacin resistance, which is now a
reserved antibiotic for the treatment of drug-resistant
tuberculosis and other infection diseases. In order to
prevent drug resistance, this drug is not widely used.
3
erefore, vonoprazan-based triple therapy represents
an interesting alternative therapy. Although it is not a
cost-eective regimen at present, vonoprazan-based triple
therapy will become more cost eective if it contributes
to an increased eradication rate. A study by Yamasaki T.
found that if the dosage of clarithromycin was increased
from 400 mg to 800 mg, the eradication rate would be
increased from 86.7% to 97.8%
47
and a randomized
controlled trial phase 3
15
conrmed that the ecacy
of vonoprazan-based triple therapy in clarithromycin
resistant H. pylori was higher than PPI-based triple therapy.
Whereas, a study involving ai people found that the
H. pylori eradication rate of vonoprazan-based triple
therapy was 63.2%
14
, which is lower than that reported
in foreign studies. is could be because vonoprazan
is mainly metabolized via CYP3A4. As the genes of
ai people may include enzyme enhancers, this would
render Vonoprazan-based triple therapy less eective.
48
erefore, a possible area for further study is to compare
the ecacy or the cost-eectiveness of using vonoprazan,
with high dose clarithromycin (greater than 800 mg per
day). e limitation of this study was scope to focusing
on the ecacy of vonoprazan-based triple therapy and
the proton pump inhibitor-based therapy. Other factors
such as compliance
4
and gastrointestinal pH while taking
the drug
49
which could aect the treatment were not
considered.
CONCLUSION
Levooxacin-PPI based triple therapy in clarithromycin-
resistant H. pylori is a more cost-eective and dominant
strategy. It was found to deliver higher QALYs at lower
treatment costs from a societal perspective. Levooxacin-PPI
based triple therapy should be the rst-choice alternative
strategy in treating clarithromycin-resistant H. pylori.
e results of this study could contribute to informed
decision making by policymakers.
is study has been reviewed and approved by
the Human Research Ethics Committee of Silpakorn
University (COE Number: COE 64.0113-003)
ACKNOWLEDGEMENTS
We would also like to thank Assoc. Prof. Dr. Srisombat
Nawanopparatsak and Dr. Kittiyot Yotsombut for their
recommendations in the development of the decision
model, as well as Mr. Paul Mines for proofreading the
article.
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