Helicobacter pylori treatment results in Slovenia in the period 2013-2015 as a part of European Registry on Helicobacter pylori Management

Helicobacter pylori (H. pylori) is the cause of the most common chronic bacterial infection in the world, affecting over 50% of the world’s population.1 Approximately 20% of infected patients will develop peptic ulcer disease, mucosa associated lymphoid tissue lymphoma or gastric cancer at some point in their lives.2 The WHO’s International Agency for Research on Cancer classified H. pylori as a definite (group 1) carcinogen.3,4H. pylori is the leading infectious cause of cancer worldwide and it was estimated that some 660 000 new cancer cases globally were directly attributable to H. pylori infection in 2008, which accounts for 33% of all infection-associated cancers, including 46% in developed regions and 29% in the developing regions.5

Several national guidelines have recommended eradication in all H. pylori-infected individuals to prevent the spread of infection and reduce the future burden of H. pylori-induced diseases, particularly gastric cancer.6,7 In the Kyoto consensus on H. pylori gastritis the recommendation is to treat all H. pylori infected patients independent of whether clinical manifestations are present.8

The basis of modern H. pylori therapy is a proton pump inhibitor (PPI) plus two / three antibiotics for 7–14 days.2 The desired eradication rate is > 90%, the acceptable eradication rate for first line therapy is > 80%.9

The treatment success depends on H. pylori’s susceptibility to antibiotics and patient’s compliance. H. pylori resistance rate to antibiotics as well as treatment results should be carefully recorded and those results should guide the therapy in a certain country or region.2 The European Registry on H. pylori management (Hp-EuReg) has been introduced in 2013 with the idea to collect treatment results, side effects, patients’ compliance and antimicrobial susceptibility in different European countries. Thirty one countries and 280 recruiting investigators are included in the Hp-EuReg. So far, more than 15.000 patients have been included, and 12.270 patients have finished follow-up.10

We would like to present the Slovenian data collected in Hp-EuReg from April 16^th 2013 to May 15^th 2016.

Data was collected in seven medical institutions in Slovenia from April 16 ^th 2013 to May 15 ^th 2016 for 1774 patients (Table 1).

Table 1

Medical institutions participating in the Slovenian part of EU-HpReg

Two hundred and fifty-five (14.4%) patients were excluded from the analysis because they either had incomplete/invalid data (e.g.: missing age, gender, compliance data etc.) or because they were treated within the last year of this analysis and the outcome of their treatment was not yet registered.

All the remaining 1519 patients were eligible for further analysis in the modified intention to treat (mITT) group; 918 (60.4%) were female patients and 601 (39.6%) were male patients (Table 2; p = 0.00).

Table 2

Demographic data for modified intention to treat (mITT) patient group

Out of those, 1346 patients had their outcome registered and were eligible for analysis in the per protocol (PP) group.

There were 173 patients (11.4%) who did not have their outcome recorded and were treated more than a year prior to this analysis. We consider that group a drop out patients group. We do not know if these patients took their therapy or whether they had the UBT done in the primary medical care and because of that did not return to their gastroenterologist, which can be a realistic option.

Only in 56 patients who took part in a RCT, primary H. pylori resistance to antibiotics was recorded (Table 3). The highest resistance rate was for metronidazole (M; 28.6%), resistance rate to clarithromycin (C) was 14.3% and to amoxicillin (A) was 3.6%. All the other antimicrobial susceptibility tests have been performed in treatment failure patients. The percentage of resistance to different antibiotics rose with the number of treatment attempts.

Table 3

Helicobacter pylori antibiotic resistance

Ten different 7–14 days triple combinations were used in 1305 patients as a first line treatment. The majority of patients (1.154) were treated accordingly to our therapeutic guidelines (Table 4) with 7 day triple therapies: PPI clarithromycin / amoxicillin / metronidazole. The eradication rate for PPI + Clarithromycin + Amoxicillin was 72.0% for the mITT group vs. 88.1% for the PP group. The eradication rate in 7 day PPI + Clarithromycin + Metronidazole was 84.4% for the mITT group vs. 85.2% for the PP group. No significant differences were found regarding the type of PPI used.

Table 4

First line treatment results for treatment regimens with more than 15 patients

Six different triple 7–14 days treatments were used in 176 patients whose H. pylori was not eradicated with the first line treatment (Table 5). The majority of them used 14 days PPI 40 mg bid, Amoxicillin (A) 1000 mg bid, and Levofloxacin (L) 500 mg oid with 92.3% eradication rate PP and 87.1% eradication rate mITT. This treatment is according to our guidelines the recommended one for second line. Dropout rate for the second treatment attempt was 6.3%.

Table 5

Second line treatment results for treatment regimens with more than 15 patients

Bismuth is not available in Slovenia and those that need third or fourth line treatment regimen should buy it in Germany or in any other country in Europe where it is available. At the moment this treatment is not reimbursed (Tables 6,7). Dropout rate after third line therapy was 18.2%. Seven patients were treated with fourth line treatment regimen (Table 7), one was treated with fifth, and one with sixth line treatment. No drop out has been recorded in the group with four or more treatment attempts.

At the end all patients that start their treatment and comply with the treatment regimens were cured of their H. pylori infection.

High dropout rate - 11.4% - in the Slovenian Hp-EuReg data is the first important message. This percentage is lower than in the EU Hp-EuReg (13%).10 Some logistic reasons can influence this high dropout rate. All 66 patients (3.73% of all patients) from University Medical Centre did not come back to their gastroenterologist. They were most probably controlled by their general practitioner, but we are not aware of their UBT results. And many more dropout patients from other medical centers could be treated in the same way. Real patients’ compliance was never an issue, also in our previous reports / studies.12,13

H. pylori resistance to clarithromycin is still low in Slovenia. It was 10.5% in a recently published study and 25.9% for metronidazole.12 In our Hp-EuReg data primary resistance to clarithromycin was recorded in a small subgroup of patients and was 14.3% and 28.6% for metronidazole. That can explain the still relatively good eradication results for 7 day triple therapy (TT). The PP eradication rate for PPI A C was 88.7% (72.0% mITT) and 85.2% PP for PPI C M (84.4% mITT). This is an acceptable eradication rate in PP analysis, but still not satisfactory, because it did not reach > 90% eradication rate. In some other parts of the world due to the increasing incidence of H. pylori resistance to clarithromycin, the cure rates of 7 day triple therapy (TT) have decreased to less than 80%, which is considered to be unacceptably low (14). Maastricht IV suggest not to use 7 day triple therapy in countries with H. pylori resistance to clarithromycin over 15%. Our H. pylori resistance rate to clarithromycin is still under this value, but we must continue to audit eradication rates with triple therapies in Slovenia as well as continuously measure primary H. pylori resistance rate to clarithromycin and other antibiotics.

Ten different 7-14 days triple combinations were used as a first line therapy. In our last H. pylori treatment guidelines⁷ only two TT (PPI A C and PPI C M) were recommended. This shows us that real clinical practice in Slovenia is not ideal, which was also recognized in some other countries shown in Hp-EuReg data.10

We did not show any benefits of esomeprazole over other PPIs in the eradication rates as was shown in some other studies.10,15 Because Caucasians have higher prevalence of high metabolizers (56%-81%) compared to Asians, higher doses of esomeprazole or rabeprazole are recommended, as they can control gastric pH adequately and allow better antibiotic efficacy.16,17

When H. pylori infection is found, it is very important to control the eradication rate and prescribe second or even further treatments to cure the infection.2 In our data, dropout rate for second line therapy is still too high (6.3%). Results in Hp-EuReg are even worse with only 27% of first line eradication failures being retreated.10 In Maastricht IV quadruple bismuth therapy is recommended as the second line treatment in low clarithromycin resistant regions.2 The fact is that this therapy is not available in Slovenia at this moment. That is why the majority of second line treatments were 14 days PPI A L. In the National recommendation7 only 14 day therapy should be used as a second line treatment. But in real practice, gastroenterologists use therapies from 7-14 days. This variations need to be corrected, because longer duration of second line therapies mean also better cure rates.2,18 Our eradication rate for PPI A L is 92.3% in PP group and 87.1% in mITT group, which is a satisfactory result. We know that this is due to low H. pylori resistance to quinolones in Slovenia (3.1–4.4%).19,20

Other possible second line treatment could also be sequential or non-bismuth concomitant therapy with PPI and all three antibiotics (C, M, E). This therapy has been proven to be very effective (> 90% by ITT) in Slovenia10 but is not used at the moment in clinical practice. These therapies can be effective also in the regions with H. pylori resistance to clarithromycin > 15%.21,22,23 Only if dual resistance to clarithromycin and metronidazole is > 15%, the eradication rate of non-bismuth quadruple therapies will be impaired and bismuth quadruple therapies should be used.24

In the third and fourth line treatment PPI A L was used in some patients not treated with this regimen before, as well as bismuth quadruple therapies. Some patients were treated with 14 day therapies, but not all, which should also be corrected.

In Maastricht recommendations culture and antibiotic susceptibility should be done after two unsuccessful therapeutic attempts2, but we seldom use this approach. The reason for this is non-reimbursement for culture by our National health fund.

One patient has been treated for the fifth time and one for the sixth time, both successfully. So finally all patients who were compliant with the prescribed therapeutic regimens were eradicated of H. pylori infection in the end, which is similar to our and international previously published data.13,25

Hp-EuReg is a very important clinical registry which helps us audit real clinical practice in the field of H. pylori eradication as well as collect eradication rates for different first, second line and beyond treatments. From the analysis of our Slovenian data we can figure out some clinically important conclusions:

Seven days PPI A/M /C results has unacceptable low mITT eradication rates. Treatment duration should be prolonged to 14 days.

Dropout rate is too high. We must provide all general practitioners with the possibility to use urea breath test or monoclonal stool antibody test in all patients with H. pylori eradication therapies. No patients should be without confirmation of eradication success.

Treatment failures of the first line regimen should be retreated according to National guidelines, that is with 14 day PPI A L regimen

Primary H. pylori resistance to antibiotics and treatment results should be continuously monitored