helicobacter

Helicobacter pylori eradication in children and adolescents by a oncedaily 6-day treatment with or without a proton pump inhibitor in adouble-blind randomized trial

Y. TINDBERG*, T. H. CASSWALL� , M. BLENNOW� , C. BENGTSSON§, M. GRANSTROM§ &

M. SORBERG–

*Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; �Division of Paediatrics,

Karolinska University Hospital (HS), Huddinge; �Sachs’s Department of Paediatrics, Soder Hospital, Karolinska Institutet,

Stockholm; §Department of Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm; –Department of

Medicine, Unit of Infectious Diseases, Karolinska University Hospital (KS), Solnd, Sweden

Accepted for publication 19 May 2004

SUMMARY

Aim: To evaluate two simplified Helicobacter pylori

eradication treatment alternatives for children and

adolescents.

Methods: Study subjects were identified by enzyme-

linked immunosorbent assay and immunoblot in a

family screening project. Helicobacter pylori infected

10–21 year olds were offered treatment, individuals

with abdominal pain underwent upper endoscopy and

those with peptic ulcers were excluded. Participants

were randomized to either azithromycin 500 mg daily

and tinidazole 500 mg two tablets daily in combination

with lansoprasole 30 mg daily for 6 days (ATL-group)

or with placebo (ATP-group). Urea Breath Test was

performed at inclusion and after a minimum of 6 weeks

after end of therapy.

Results: In total, 131 individuals were randomized, of

whom 31 (24%) had undergone upper endoscopy. Full

compliance was achieved in 93% (122 of 131). The

intention-to-treat eradication rate was 67% (44 of 66)

and 58% (38 of 65) for the ATL- and the ATP-group,

respectively.

Conclusion: The double-blind randomized clinical trial

did not identify a simplified, successful once daily

H. pylori treatment for children and adolescents. Thus,

twice daily proton pump inhibitor (PPI)-based triple

therapies for 7 days remain as the choice of treatment

in children. Further, powerful and controlled studies are

needed to elucidate the best treatment strategies for

H. pylori eradication in this age group.

INTRODUCTION

Helicobacter pylori infection has been shown to cause

chronic active gastritis and peptic ulcer disease (PUD) in

children and adults.1 An increasing amount of evidence

also supports the hypothesis that H. pylori is an

important cofactor in the development of gastric

cancer.2, 3 Furthermore, younger age at acquisition

has been suggested to increase the risk of developing

cancer later in life.4 Thus, strategies with the overall

aim to limit the burden of H. pylori infection and its

complications are warranted.

Prevention by treatment of childhood H. pylori infec-

tion has been suggested. The available data on efficacy

of different treatment regiments for eradication of

H. pylori infection in children and adolescents are,

however, sparse and have limitations. All published

Correspondence to: Dr T. H. Casswall, Children’s Hospital B57, Karolinska

University Hospital, Huddinge, SE-141 86 Stockholm, Sweden.

E-mail: [email protected]

Aliment Pharmacol Ther 2004; 20: 295–302. doi: 10.1111/j.1365-2036.2004.02077.x

� 2004 Blackwell Publishing Ltd 295

clinical trials in these age groups, with one recent

exception,5 have used an open study design, thus being

neither randomized nor double-blinded. A recent review

of these limited data on children,6 indicates that dual

therapies might be as effective as triple therapies, and

that longer courses of proton pump inhibitor (PPI)-based

triple therapies might not be better than shorter ones.

At present, there is no straightforward approach to

treat H. pylori infection in children. A Canadian

Consensus report suggests a 2-week course of a triple

regimen with a PPI in combination with two antibiot-

ics.7 A North American Paediatric Consensus report

suggests a triple or quadruple therapy given for 1 or

2 weeks,8 whereas the European Task Force9 felt that

the available data were too scarce for any recommen-

dation at all.

The Maastricht Consensus Report on the management

of H. pylori infection has stressed the need for further

studies to evaluate the efficacy as well as safety of

treatment regimens in all age groups.10 Also, the

importance of a high eradication rate (> 80%), high

tolerability and simplicity of the regimen for improved

compliance were stressed.

The aim of the present study was to offer eradication

treatment to children and adolescents who had

participated in a family screening survey. The design

chosen was a double-blind, randomized-clinical trial of

two short and simple treatment regimens with the

aim to improve compliance and hence eradication

rates.

MATERIALS AND METHODS

Participants, study design and treatment regimens

A community-based seroepidemiological screening pro-

ject investigating determinants for H. pylori infection

among school children was performed in 1998–1999 in

the Stockholm area, Sweden.11 As an extension of this

study infection status in different family members were

assessed as plausible risk factors for infection in children

(unpublished data). Infection status was determined by

enzyme-linked immunosorbent assay (ELISA) and

immunoblot (Helico Blot 2.0, Genelabs, Singapore).8

All identified H. pylori infected children and adoles-

cents, being 10–21 years of age, were offered a

simplified eradication regimen within a clinical trial.

Helicobacter pylori infected individuals reporting abdominal

symptoms were offered upper endoscopy prior to

inclusion. Exclusion criteria were an identified PUD at

endoscopy, concurrent diseases where the study drugs

were contraindicated and use of antibiotics within the

previous 4 weeks. No children and adolescents reported

recent use of antacids.

Participants were included into the trial between

November 1999 and April 2000. Double-blind rand-

omization into two groups was made in blocks of eight.

One group received a triple therapy of azitromycin

500 mg once a day, tinidazole 500 mg two tablets once

a day and lansoprazole 30 mg once a day for 6 days

(ATL-group). The other group received a double therapy

of azitromycin 500 mg once a day, tinidazole 500 mg

two tablets once a day and placebo once a day for

6 days (ATP-group). A direct comparison with a 7 days

two-dose PPI-based triple therapy had been considered

either as one of two groups evaluated or as an added

third arm. However, a two-dose approach could not

have been placebo-controlled since we did not have

access to a placebo for all drugs. A third arm would

have resulted in a major loss of power, not judged

acceptable with the study population size.

The tablets were packed in an apodose (an individual

package with ready doses for each day) and prescribed

to be taken after dinner in order to reduce any

gastrointestinal discomfort during daytime. Side-effects

were documented in a diary during the 6 days of

treatment. At the end of the treatment, the diary and

the apodose were returned by mail to the project

coordinator in order to document adverse effects and

compliance. Current infection was confirmed by means

of a 13C-Urea Breath Test (UBT) at the day of inclusion

and monitored at least 6 weeks after finishing the

treatment.

13C-Urea breath test

Current infection was confirmed by means of a 13C-UBT

at the day of inclusion and monitored at least 6 weeks

after end of treatment. The UBT was performed after a

nights fasting without a prior test meal.12 Triple

samples of expiratory air were collected in screw-capped

glass tubes at baseline and 30 min after the ingestion of

100-mg 13C-Urea. Breath samples were refrigerated

until analysed by isotope ratio mass spectrometry

(BreathMat. Finnigan MAT, GmbH, Bremen, Germany).

The 13C-UBT results were calculated as the difference in

relative enrichment of 13CO2 between baseline and

30 min samples. Correction for body weight, and thus

296 Y. TINDBERG et al.

� 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20, 295–302

increased metabolism and CO2 production in children,

yielded results expressed as [(%/mmol) · kg], with a

grey zone for values between 0.10 and 0.20

[(%/mmol) · kg]. The correction corresponds to a cut-

off value at the 3.5 d per mil over baseline level and the

test yielded a sensitivity of 97% and a specificity of 96%

when compared with immunoblot (Helico Blot 2.0) in

the same child population.12 A sensitivity and specificity

of 100% for the 13C-UBT, with the same cut-off, had

previously also been established in 40 children

(5–16 years old) of mixed ethnicity, undergoing upper

endoscopy because of abdominal disorders and with

H. pylori status confirmed by histology, culture and

urease test on biopsies (unpublished data).

Culture

Patients undergoing upper endoscopy had biopsies

taken for culture (two from the corpus and two from

the antrum). The biopsies were inserted into separate,

labelled and sterile plastic tubes with 0.25 mL sterile

transport medium. The sealed tubes were immediately

frozen to )70 �C. The biopsies were homogenized and

inoculated onto prereduced blood agar and Campylobac-

ter agar base with 5% lysed horse blood supplemented

with vancomycin, polymyxin B and trimetoprim. The

plates were incubated under micro-aerobic conditions

(CampyGen, Oxoid Ltd, England, UK) and inspected on

days 3 and 7. Helicobacter pylori growth was identified

as Gram-negative curved rods producing catalase,

urease and oxidase.

E-test

Minimal inhibitory concentrations (MIC) for metroni-

dazole, clarithromycin, amoxicillin were determined

with E-test (Biodisk AB, Solna, Sweden) on paper disc

method (PDM) agar plates (Biodisk AB) after 72 h

incubation at 37 �C under microaerobic conditions

(CampyGen). Metronidazole and clarithromycin E-test

MIC was performed since tinidazole and azithromycin

E-test is not available. Since National Commitee for

Clinical Laboratory Standards (NCCLS) does not have

H. pylori breakpoint recommendations for metroni-

dazole, amoxicillin the breakpoints used were

R > 1 lg/mL for clarithromycin and amoxicillin, and

R > 4 lg/mL for metronidazole according to the rec-

ommendations of the Swedish Reference Group for

Antibiotics (SRGA, http://www.srga.org).

Histology

A histological grading of inflammation and density of

H. pylori on biopsies was performed according to the

revised Sydney System.13 Briefly, the grade of inflam-

mation and H. pylori density was graded as 0–3

arbitrary units, where 0 was no presence of inflamma-

tion, and 1, 2 and 3 were indicating mild, moderate and

severe histological changes, respectively.

Ethical clearance

The study was approved by the local ethic committee at

Huddinge University Hospital and the Swedish Medical

Drug Agency. Written informed consent was obtained

in each case, either from the parents of the children or

from the participants themselves when over 18 years of

age.

Statistical analyses

The power calculation was based on the assumption

that 150 children and adolescents would be included in

the present clinical trial (230 identified by screening

and approximately 33% loss to follow-up). With a

90–95% eradication rate for the triple therapy group

(ATL), as previously reported in adults, and with

75 children and adolescents in each group, we would

be able to detect a 15–20% lower eradication rate, with

a type I error of 0.05 and a type II error of 0.2, for the

dual therapy group (ATP). Statistical analyses were

performed before breaking the treatment code and thus

being blinded to treatment group as well as block size.

Student’s t-test was used to compare the two study

groups. Chi-square analyses were performed for com-

parison of eradication rates and side-effects in the two

treatment groups.

RESULTS

Overall, 172 H. pylori infected 10–21-year-old children,

adolescents and young adults were identified in a

previous epidemiological screening survey and offered

treatment within the present clinical trial. Of the

42 individuals not participating in the present trial,

12 children had moved from the Stockholm region and

13 children declined participation. Eight children had

received treatment for H. pylori infection from another

physician before the clinical trial was started. Two

SIMPLIFIED H. PYLORI ERADICATION THERAPY IN ADOLESCENTS 297


children were excluded, one due to anaemia and one

due to prior poliomyelitis. Of the 36 individuals who

underwent upper endoscopy, five children were exclu-

ded from the treatment trial due to PUD (14%).

Furthermore, one child was excluded due to a negative

UBT at inclusion.

In total, 131 individuals were included in the

treatment trial. There were no statistical significant

differences in characteristics of the patients after

randomization to the two treatment groups, as shown

in Table 1. Age varied between 10.4 and 21.7 (mean

14.3; s.d. 2.7) years. Antibodies against CagA and VacA

were found in 60% and 75%, respectively, among the

participants. A majority of the children had a non-

European mother (Table 1).

Full compliance was achieved in 122 (93%) of the

participants. Eight patients did not follow the stipulated

treatment time, three due to side-effects and five due to

misunderstanding of instructions. One included and

randomized child did not start the treatment at all.

Diarrhoea, metallic taste and nausea were common in

both groups (Table 2). Side-effects were usually mild

apart from in three cases where the participants

withdrew because of diarrhoea.

The eradication rate in the two groups is shown in

Table 3. The small difference in efficacy between the

two treatment groups was not statistically significant.

The intention-to-treat (ITT) eradication rate in the triple

therapy group (ATL) was 67% (95% CI: 55–78%) when

compared with an eradication rate of 58% (95% CI:

46–70%) in the dual therapy group (ATP). The per

Table 1. Characteristics of patients after randomization to treat-

ment groups

ATL group ATP group

Number of children included 66 65

Age

Mean years (s.d.) 14.0 (2.5) 14.5 (2.8)

Range 10.4–20.9 10.7–21.7

Gender

Male (%) 29 (44) 35 (54)

Female (%) 37 (56) 30 (46)

Laboratory characteristics

Mean enzyme-linked

immunosorbent

assay (ELISA) at inclusion (s.d.)

0.73 (0.36) 0.71 (0.35)

Antibodies against VacA (%) 37 (56) 41 (63)

Antibodies against CagA (%) 48 (74) 50 (77)

Mean 13C-Urea Breath

Test (13C-UBT) at inclusion (s.d.)

1.16 (0.7) 1.13 (0.8)

Upper endoscopy

and culture performed (%)

13 (20) 18 (28)

Ethnic origin

Child born in Scandinavia (%) 42 (64) 32 (50)

Maternal origin

Scandinavian (%) 6 (9) 4 (6)

Middle East (%) 30 (45) 24 (37)

Africa (%) 19 (29) 22 (34)

Other (%) 11 (17) 15 (23)

Table 2. Compliance and tolerance of treatment by group

ATL group

[n (%)]

ATP group

[n (%)]

Number of children included 66 (100) 65 (100)

Compliance

Full compliance 62 (94) 60 (92)

Withdrawal before first dose 1 (2) 0

Withdrawal after third doses 3 (4) 5 (8)

Reported side-effects

Diarrhoea 31 (48) 21 (32)

Metallic taste 18 (28) 27 (42)

Nausea 37 (57) 25 (38)

Vomiting 3 (5) 5 (8)

Dizziness 12 (18) 12 (18)

Constipation 6 (9) 5 (8)

Dermatological reactions 4 (6) 1 (2)

Other 17 (26) 12 (18)

ATL, azithromycin + tinidazole + lansoprazole once daily for 6 days.

ATP, azithromycin + tinidazole + placebo once daily for 6 days.

Table 3. Helicobacter pylori eradication rate

by treatment group in 131 included study

subjects

ATL group

Eradication rate

(%, 95% CI) (n/N)

ATP group

Eradication

rate (%, 95% CI) (n/N)

Intention-to-treat (ITT) 66.7, 55.3–78.1* (44/66) 58.5, 46.5–70.5 (38/65)

Per protocol treatment (PPT) 67.7, 56.1–79.3** (42/62) 55.0, 42.4–67.6 (33/60)



* ATL vs. ATP – P ¼ 0.3.

** ATL vs. ATP – P ¼ 0.1.



protocol analysis yielded a similar result, i.e. 68% (95%

CI: 56–79%) vs. 55% (95% CI: 42–68%) for the ATL

and ATP group, respectively (Table 3).

Three individuals taking only three doses of ATP and

two taking four or five doses of ATP were all H. pylori-

negative at follow-up. Three participants took less than

six doses of ATL, two having their infection cleared and

one remaining infected.

As all participants received the same dosage over the

whole range of ages, the possible impact of age on

eradication therapy was tested. As shown in Table 4,

neither older age nor the ensuing higher weight had

any effect for treatment outcome in either group.

All 31 children undergoing upper endoscopy were

H. pylori-positive at culture of their biopsies. Of these, 12

(39%) had strains with resistance against antibiotics,

four of 13 (31%) and eight of 18 (44%) in the ATL- and

ATP-group, respectively. Clarithromycin resistance was

seen in two of 31 (6%) of the isolates whereas

metronidazole resistance was noted in 10 of 31 (32%).

All except one isolate (MIC: 64 lg/mL) were highly

resistant to metronidazole with MIC-values >256 lg/

mL. No isolates were found to have a combined

resistance pattern. Also, no ampicillin resistance was

noted. Eradication was achieved in eight of 12 (67%) of

participants in spite of infection with a resistant strain

(Table 5). Histology showed mild-to-severe chronic

antral gastritis in all patients while a less pronounced

inflammation was seen in the corpus area.

DISCUSSION

Clinical trials evaluating efficacy and safety of H. pylori

eradication therapies have been warranted in all age

groups.10 Data from clinical trials in children and

adolescents are, however, sparse. The present study of

131 included patients is, to our knowledge, the largest

double-blind randomized clinical trial of H. pylori

eradication among paediatric patients so far. In order

to simplify the treatment with the aim to improve

compliance and hence eradication rates we evaluated

two one-dose per day therapies with or without a PPI

for 6 days. The difference in eradication rate between

the dual therapy (58%) and the triple therapy (67%)

was not statistically significant in the ITT analysis or in

the per protocol analysis were the eradication rate was

55% and 68% for the two groups, respectively.

With the aim to find a one-dose per day therapy

characteristics of various antibiotics, such as half time

(t 12) and intracellular activity, were taken into account.

Azithromycin was considered as an alternative to

clarithromycin based on its t 12 of 2–4 days and its

intracellular activity in gastric mucosa,14 although not

being detectable in gastric juice.15 Studies in adults

have shown high eradication rates when using azith-

romycin in combination therapies,16, 17 also when used

for only 3 days,18 although others have reported

inferior results.19, 20 We used a dose of 500 mg

azithromycin per day and a higher dose might have

improved the eradication rate as shown in adults.21

However, the mean age of our patients was 14 years

and neither older age nor the ensuing higher weight

had any effect on treatment outcome in either group.

The choice of tinidazol was governed by a slightly

longer t 12 of 12–13 h when compared with 8 h for

metronidazol and previous reports of a good effect in

other studies.22, 23 The pharmacological data of a long

t 12 for both antibiotics and studies in vitro indicating that

lansoprazole may act synergetic on azitromycin24

motivated our choice of a one-dose per day 6 days

PPI-based triple therapy that in theory would be

comparable with a twice daily 7 days therapy.

Table 4. The effect of age and weight on Helicobacter pylori

eradication by treatment group

ATL group

Eradicated/total (%)

ATP group

Eradicated/total (%)

Age group (years)

10–12 20/29 (69) 13/25 (52)

13–17 20/30 (67) 17/28 (61)

18–22 4/6 (67) 7/11 (64)

Weight groups (kg)

<45 11/15 (73) 8/15 (53)

45–59 22/34 (65) 21/32 (66)

>60 11/16 (69) 11/20 (55)



Table 5. Eradication results in 12 patients with resistant Heli-

cobacter pylori strains

ATL group

Eradicated/total

ATP group

Eradicated/total

Metronidazole resistance 3/3 4/7

Claritromycin resistance 0/1 1/1

Total 3/4 5/8





Previous reports have indicated that a PPI might not

be needed when eradicating H. pylori infection in

children,25, 26 although higher doses and a longer

period of treatment with two antibiotics might be

needed. Our use of two antibiotics with a long half-

time and the observations that azitromycin is highly

retained in the target tissue14 and less sensitive to

acidity than other antibiotics, including other macro-

lides27 encouraged us to test a combination without a

PPI. In order to be able to use all identified infected

children to test two simplified regimens we decided to

use our previous finding of an eradication rate of 88%

among children treated with omeprazole, clarithromy-

cin and metronidazol twice daily for 7 days28 as a

historical control.

Adding a PPI to one of the groups improved the cure

rates by 9% in the ITT analysis and by 13% in the per

protocol analysis. However, the present outcome with a

poorer eradication rate than expected for the triple

therapy and a relatively small difference in results

between the two groups did, however, not allow for

verifying the observed differences with statistical signi-

ficance. In a recent French study, adding a PPI to

amoxicillin and clarithromycin increased the eradica-

tion rate from 10 to 74%.5 The large difference in

outcome using dual therapies might be explained by

differences in resistance patterns among bacterial

strains, in dosage of drugs or in mechanisms of action

for the antibiotics used. With a poorer result than

expected even for our tested triple therapy group, ATL,

and the present study design, it is not possible to

ascertain whether our result is due to the shorter

duration of the therapy, to the use of once daily

treatment or to a combination of both. In a parallel

study conducted in Vietnam in adult patients with

PUD,29 we found also that a once daily treatment was

inferior to a twice daily, in spite of possible gains in

compliance. In the Vietnamese study, adding a PPI

improved the eradication rates significantly but only

when the infection was caused by a strain that was

highly resistant to metronidazole (MIC: > 265 lg/mL).

In the present study, a lower rate of high resistance to

metronidazole was noted when compared with Viet-

nam, but the results in children and adolescents who

had undergone upper endoscopy imply that PPI will

help to overcome high-grade resistance (three of three

eradicated with PPI and four of seven without).

Furthermore, a recent meta-analysis,30 not available

at the time of planning the present study, has shown

that a twice-a-day PPI is more effective than a once-

a-day PPI for H. pylori eradication in adults. It cannot be

excluded that this would improve the results also in this

age group.

The present simplified regimen allowed for good

compliance and per protocol analysis in 93% of the

participants. One child, without symptoms, was lost to

follow-up since he did not even start the treatment. Five

withdrawals were reported due to misunderstood

instructions and another three due to diarrhoea.

Although expected gastrointestinal side-effects and

metallic taste were frequently reported, no severe or

unexpected side-effects occurred.

Gastric biopsies were available for 31 children and

adolescents presenting with abdominal symptoms but

with no signs of PUD at upper endoscopy. Resistance

against clarithromycin and metronidazole was found in

two (6%) and 10 (32%) participants, respectively. The

reported corresponding resistance pattern for other

European countries varies between 17 and 45% for

clarithromycin and 18 and 43% for metronidazole.31

Also, clarithromycin resistance seems to be increasing

over time.32

The present clinical trial was based predominantly on

asymptomatic individuals, mainly as a result of a

previous epidemiological survey where the local ethics

committee wanted a reasonable follow-up of identified

infected participants. Thus, we believed that a controlled

clinical trial after upper endoscopy in all symptomatic

children would be the best way to meet the demands of

the involved families, the local ethics committee and the

recommendations in the Maastricht Consensus.10

The question as whether to treat H. pylori infections in

childhood or not is complex. The consensus reports on

the management of H. pylori infection among children

have not been able to state a recommendation for a test-

and-treat approach7–9 basically since no clinical picture

indicating a need to screen for the infection has been

identified. Children with abdominal symptoms indica-

ting a need for invasive examination should, however,

be offered treatment after positive investigation. Treat-

ment of asymptomatic infected individuals, irrespective

of age, is more controversial. However, recent studies

that have been able to show a strong association

between H. pylori infection and later development of

gastric adenocarcinoma2, 3 and the indication that long

time H. pylori infection might increases the risk of later

cancer development33, 34 are likely to result in further

discussions.



One limitation of the present study is the low

frequency of biopsies because of the limited number

of children referred to upper endoscopy. Thus, we do

not know if the low eradication rate is a result of

resistant bacterial strains in asymptomatic partici-

pants. However, upper endoscopy in all symptomatic

participants should guarantee that no PUDs were

included. Since it has been suggested that H. pylori

infection is more difficult to clear in adult patients

with chronic active gastritis than with PUD,35 the

study population of predominantly asymptomatic

10–21 year olds might be part of the explanation of

our rather poor outcome.

In conclusion, our double-blind randomized-clinical

trial in H. pylori infected children and adolescent was

not able to identify a simplified one-dose per day

eradication therapy with an acceptable eradication rate,

i.e. > 80%. In combination with our results from

Vietnam, we conclude that (i) twice daily treatment is

needed for high eradication rates also in children; (ii) a

PPI is important in case of high degree of metronidazole

resistance. Such a treatment will have to be used for

children also in Europe since most children in our study,

as in other European studies, have a non-European

background and thus more likely to harbour metroni-

dazole-resistant strains. In order to elucidate the best

approach to successful H. pylori treatment strategies in

children and adolescents, further powerful and con-

trolled clinical trials seem to be needed.

ACKNOWLEDGEMENTS

Authors thank Carl Axel Persson for advice when

planning the study, Malin Swartling for skilful assist-

ance in the clinical fieldwork and Mats Bergstrom for

the 13C-UBT analyses. The study was supported by

Pfizer Ltd, Sweden, and Wyeth-Lederle Nordic Ltd by the

gift of study drugs.

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