序贯疗法幽门螺杆菌根除率更高

Articles www.thelancet.com Published online November 16, 2012 http://dx.doi.org/10.1016/S0140-6736(12)61579-7 1 Articles Published Online November 16, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61579-7 See Online/Comment http://dx.doi.org/10.1016/ S0140-6736(12)61849-2 Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (J-M Liou MD, C-C Chen MD, M-J Chen MD, P-H Tseng MD, H-P Wang MD, Prof J-T Lin MD, Y-C Lee MD, Prof M-S Wu MD); Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan (J-M Liou, Y-C Lee); Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin County, National Taiwan University College of Medicine, Yun-Lin County, Taiwan (C-C Chen, Y-J Fang MD, J-Y Lee MD, S-J Hsu MD); Department of Internal Medicine, E-DA Hospital and I-Shou University, Kaohsiung County, Taiwan (C-Y Chang MD, Y-C Hsu MD, C-H Tseng MD); Department of Medicine, National Yang-Ming University, School of Medicine, and Taipei Veterans General Hospital, Taipei, Taiwan (J-C Luo MD); Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan (W-H Chang MD); Institute of Biomedical Informatics, National Yang-Ming University, School of Medicine, and Taipei Veterans General Hospital, Taipei, Taiwan (Prof U-C Yang PhD); Department of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan (Prof C-T Shun MD); and Primary Care Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan (Prof M-S Wu MD) Sequential versus triple therapy for the fi rst-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial Jyh-Ming Liou, Chieh-Chang Chen, Mei-Jyh Chen, Chien-Chuan Chen, Chi-Yang Chang, Yu-Jen Fang, Ji–Yuh Lee, Shih-Jer Hsu, Jiing-Chyuan Luo, Wen-Hsiung Chang, Yao-Chun Hsu, Cheng-Hao Tseng, Ping-Huei Tseng, Hsiu-Po Wang, Ueng-Cheng Yang, Chia-Tung Shun, Jaw-Town Lin, Yi-Chia Lee, Ming-Shiang Wu, for the Taiwan Helicobacter Consortium Summary Background Whether sequential treatment can replace triple therapy as the standard treatment for Helicobacter pylori infection is unknown. We compared the effi cacy of sequential treatment for 10 days and 14 days with triple therapy for 14 days in fi rst-line treatment. Methods For this multicentre, open-label, randomised trial, we recruited patients (≥20 years of age) with H pylori infection from six centres in Taiwan. Using a computer-generated randomisation sequence, we randomly allocated patients (1:1:1; block sizes of six) to either sequential treatment (lansoprazole 30 mg and amoxicillin 1 g for the fi rst 7 days, followed by lansoprazole 30 mg, clarithromycin 500 mg, and metronidazole 500 mg for another 7 days; with all drugs given twice daily) for either 10 days (S-10) or 14 days (S-14), of 14 days of triple therapy (T-14; lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg for 14 days; with all drugs given twice daily). Investigators were masked to treatment allocation. Our primary outcome was the eradication rate in fi rst-line treatment by intention-to- treat (ITT) and per-protocol (PP) analyses. This trial is registered with ClinicalTrials.gov, number NCT01042184. Findings Between Dec 28, 2009, and Sept 24, 2011, we enrolled 900 patients: 300 to each group. The eradication rate was 90·7% (95% CI 87·4–94·0; 272 of 300 patients) in the S-14 group, 87·0% (83·2–90·8; 261 of 300 patients) in the S-10 group, and 82·3% (78·0–86·6; 247 of 300 patients) in the T-14 group. Treatment effi cacy was better in the S-14 group than it was in the T-14 group in both the ITT analysis (number needed to treat of 12·0 [95% CI 7·2–34·5]; p=0·003) and PP analyses (13·7 [8·3–40], p=0·003). We recorded no signifi cant diff erence in the occurrence of adverse eff ects or in compliance between the three groups. Interpretation Our fi ndings lend support to the use of sequential treatment as the standard fi rst-line treatment for H pylori infection. Funding National Taiwan University Hospital and National Science Council. Introduction Helicobacter pylori is an important cause of peptic ulcer disease and gastric cancer, but eradication rates with standard triple therapy have decreased to less than 80% in many countries.1–5 Several strategies have been proposed to increase the eradication rate, including the extending of treatment duration to 14 days, the use of a four-drug regimen (quadruple, sequential, and concomi tant treat- ments), and the use of novel antibiotics such as levofl oxacin.6–13 Sequential treatment, which consists of a proton-pump inhibitor and amoxicillin for the fi rst 5 days, followed by a proton-pump inhibitor plus clarith romycin and metronidazole (or tinidazole) for another 5 days, has been shown to be more eff ective than triple therapy for 7 days or 10 days.11–13 The effi cacy of sequential treatment seemed to be aff ected less by clarithromycin resistance than is triple therapy and has the potential to become the standard fi rst-line treatment for H pylori infection.15,16 However, several concerns need to be resolved before sequential treatment can replace triple therapy as the standard treatment.15,16 First, most of the studies did not do susceptibility tests and their results cannot be generalised to other countries where the prevalence of antibiotic resistance is diff erent. Second, few studies compared sequential treatment with triple therapy for 14 days, which is recommended by US guidelines.4,15 Two studies from Latin America and South Korea that compared sequential treatment for 10 days with triple therapy for 14 days, however, showed contra dictory results.9,17 The reasons behind the contradictory results were unknown because susceptibility tests were not done.9,17,18 Third, whether extending the duration of sequential treatment from 10 days to 14 days would be more eff ective than triple therapy for 14 days is unknown. Fourth, despite the fact that knowing how to re-treat patients who fail sequential treatment is important, few studies addressed this issue.19 Finally, how to choose the best regimen on the basis of the prevalence of antibiotic resistance in diff erent geographical areas is unknown. To address these issues, we did a randomised controlled trial to compare the effi cacy of sequential treatment for 10 days and 14 days with triple therapy for 14 days in fi rst- line treatment. We extensively assessed factors that might aff ect eradication rates, such as anti biotic resis- tance, host CYP2C19 polymorphisms, and bacterial virulence factors (CagA and VacA). We also assessed the Articles 2 www.thelancet.com Published online November 16, 2012 http://dx.doi.org/10.1016/S0140-6736(12)61579-7 effi cacy of the modifi ed sequential treat ment containing levofl oxacin in patients who failed sequential treatment and triple therapy.20 We constructed a decision model to estimate the effi cacies of three regimens in the sensitivity analysis according to the prevalence of antibiotic resis- tance, aiming to solve the heterogeneity of treatment effi cacies seen in previous studies. Methods Study design and participants For this multicentre, open-label, randomised trial, we recruited participants from gastroenterology clinics in six medical centres in Taiwan. Study staff recruited potential participants and explained to them the purpose of the trial and eligibility requirements for enrolment. Patients were eligible for recruitment if they were aged 20 years or older and had documented H pylori infection. Patients with any one of the following criteria were excluded from the study: previous eradi- cation treatment for H pylori, his tory of gas trectomy, contraindication or previous allergic reactions to the study drugs, pregnant or lactating women, use of antibiotics within the previous 4 weeks, and severe concurrent diseases or malignancy. Participants provided written informed consent before enrolment. This trial was approved by the Institutional Review Board of each hospital. Randomisation and masking Using a permuted block randomisation with a block size of six, we randomly allocated eligible patients to receive one of the following regimens (1:1:1): sequential treat- ment for 14 days (S-14), sequential treatment for 10 days (S-10), or triple therapy for 14 days (T-14; all given twice daily). An independent research assistant at the National Taiwan University Hospital generated the computerised random number sequence. The sequence was concealed in an opaque envelope until the inter vention was assigned. Envelopes were kept at the National Taiwan University Hospital. After the written informed consents were obtained from eligible patients, the independent research assistant telephoned study staff to give them each patient’s treatment allo cation. All investigators were masked to the random isation sequence. Patients who Correspondence to: Dr Yi-Chia Lee, 7 Chung-Shan S Road, Taipei 10002, Taiwan yichialee@ntu.edu.tw and Dr Ming-Shiang Wu, 7 Chung-Shan S Road, Taipei 10002 Taiwan mingshiang@ntu.edu.tw Figure 1: Trial profi le ITT=intention-to-treat. PP=per-protocol. MS-14=modifi ed sequential treatment containing levofl oxacin. S-10=sequential treatment for 10 days. S-14=sequential treatment for 14 days. T14=triple therapy for 14 days. Fi rs t- lin e t re at m en t Se co nd -li ne tr ea tm en t 2553 screened for eligibility 1653 excluded 1406 Helicobacter pylori negative 98 refused 149 not eligible 900 randomly allocated 300 assigned to S-10 (ITT population) 300 assigned to T-14 (ITT population) 10 lost to follow-up and took <80% of drugs 2 lost to follow-up but took ≥80% of drugs 3 took <80% drugs 8 lost to follow-up and took <80% of drugs 6 lost to follow-up but took ≥80% of drugs 7 took <80% drugs 285 completed follow-up (PP analysis) 279 completed follow-up (PP analysis) 39 S-14 failed first-line treatment 53 S-14 failed first-line treatment 12 lost to follow-up 2 refused further treatment 14 lost to follow-up 4 refused further treatment 25 given MS-14 35 given MS-14 6 lost to follow-up 300 assigned to S-14 (ITT population) 4 lost to follow-up and took <80% of drugs 5 lost to follow-up but took ≥80% of drugs 6 took <80% drugs 285 completed follow-up (PP analysis) 28 S-14 failed first-line treatment 9 lost to follow-up 3 refused further treatment 16 given MS-14 1 lost to follow-up 15 completed follow-up 25 completed follow-up 29 completed follow-up Articles www.thelancet.com Published online November 16, 2012 http://dx.doi.org/10.1016/S0140-6736(12)61579-7 3 remained positive for H pylori after the initial treatment were retreated with modifi ed sequential treatment for 14 days (MS-14). Procedures Study treatment regimens were all given twice a day and contained the following: S-14 (lansoprazole 30 mg and amoxicillin 1 g for the fi rst 7 days, followed by lansoprazole 30 mg, clarithromycin 500 mg, and metro- nidazole 500 mg for another 7 days), S-10 (lansoprazole 30 mg and amoxicillin 1 g for the fi rst 5 days, followed by lansoprazole 30 mg, clarithromycin 500 mg, and metro- nidazole 500 mg for another 5 days), T-14 (lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg for 14 days). MS-14 was also given twice a day and contained lansoprazole 30 mg and amoxicillin 1 g for the fi rst 7 days, followed by lansoprazole 30 mg, metronidazole 500 mg, and levofl oxacin 250 mg for another 7 days. Before enrolment, the status of H pylori infection in patients with upper gastrointestinal symptoms was deter mined by rapid urease test, histology, culture, and serology. Patients with positive results in at least two of these tests were eligible for enrolment. Asymptomatic individuals who underwent cancer screening were also eligible for enrolment if they had a positive ¹³C urea breath test (¹³C-UBT). Post-treatment H pylori status was assessed by ¹³C-UBT at least 6 weeks after completion of treatment. All patients were asked to stop treatment with proton-pump inhibitor and histamine-2 blocker for at least 2 weeks before their ¹³C-UBT. The urea kit (which contained 75 mg ¹³C-urea) was dissolved in water and mixed with orange juice. Baseline and 30 min breath samples were assayed with an infrared spectrometer that produced computer-generated results in the Taipei Institute of Pathology (Taipei City, Taiwan). Positive and negative results were defi ned according to results of our previous validation study21 as a Δ value of 4 units or higher for positive and less than 2·5 units for negative. Patients with inconclusive results received another ¹³C-UBT at least 2 weeks after the inconclusive test until the results were conclusive. The primary endpoint of the study was H pylori eradication rates in fi rst-line treatment. The secondary endpoints were the frequency of adverse events and treatment compliance. The patients were informed of the common side-eff ects from the study drugs before treatment and were asked to record these symptoms during treatment in provided diaries. A standardised interview was also arranged at the end of treatment to assess the adverse events and compliance. Compliance was recorded as low when less than 80% of pills were taken. The biopsy specimens were cultured on plates con- taining Brucella chocolate agar with 7% sheep blood and incubated for 7 days under microaerobic conditions. The minimum inhibitory concentrations were assessed by agar dilution test in the central laboratory in National Taiwan University Hospital. We defi ned resistance breakpoints for every antibiotic (amoxicillin ≥0·5 mg/L, S-14 group (N=300) S-10 group (N=300) T-14 group (N=300) Men 165 (55%) 159 (53%) 167 (56%) Mean age in years (SD) 53·7 (12·5) 52·8 (13·8) 53·3 (14·1) Cigarette smoking 59 (20%) 68 (23%) 67 (22%) Alcohol drinking (>40mL) 77 (26%) 71 (24%) 74 (25%) Peptic ulcer disease 193 (64%) 209 (70%) 197 (66%) Body-mass index of 27 or greater 63 (21%) 52 (17%) 66 (22%) CYP2C19 (poor metaboliser) 43/286 (15%) 27/286 (9%) 38/287 (13%) CagA-positive 147/177 (83%) 157/191 (82%) 144/183 (79%) 23S rRNA mutation 15/178 (8%) 15/192 (8%) 21/183 (11%) GyrA mutation 16/172 (9%) 23/190 (12%) 17/179 (9%) Clarithromycin resistance 16/177 (9%) 18/192 (9%) 21/183 (11%) Metronidazole resistance 39/177 (22%) 46/192 (24%) 48/183 (26%) Amoxicillin resistance 4/177 (2%) 4/192 (2%) 5/183 (3%) Levofl oxacin resistance 17/177 (10%) 22/192 (11%) 22/183 (12%) Helicobacter pylori test Serology 293/298 (98%) 292/295 (99%) 291/298 (98%) Rapid urease test 235/253 (93%) 237/255 (93%) 239/252 (95%) Histology 252/263 (96%) 254/264 (96%) 248/262 (95%) Culture 181/234 (77%) 195/235 (83%) 184/230 (80%) Urea breath test 66/66 (100%) 65/65 (100%) 70/70 (100%) Data are number of patients (%) or patients positive/patients tested (%), unless otherwise stated. S-10=sequential treatment for 10 days. S-14=sequential treatment for 14 days. T-14=triple therapy for 14 days. Table 1: Baseline characteristics S-14 group S-10 group T-14 group p value Eradication after fi rst-line treatment ITT analysis (n/N [%; 95% CI]) 272/300 (90·7%; 87·4–94·0)* 261/300 (87·0%; 83·2–90·8) 247/300 (82·3%; 78·0–86·6)* 0·011 PP analysis (n/N [%; 95% CI]) 269/285 (94·4%; 91·7–97·1)†‡ 258/285 (90·5%; 87·1–93·9)‡ 243/279 (87·1%; 83·2–91·0)†‡ 0·012 Eradication after second-line treatment ITT analysis (n/N [%; 95% CI]) 283/300 (94·3%; 91·7–97·0) 283/300 (94·3%; 91·7–97·0) 275/300 (91·7%; 88·6–94·8) 0·31 PP analysis (n/N [%; 95% CI]) 280/284 (98·6%; 96·4–99·4) 280/285 (98·2%; 96·0–99·2) 271/273 (99·3%; 97·4–100) 0·56 ITT=intention-to-treat. PP=per-protocol. S-10=sequential treatment for 10 days. S-14=sequential treatment for 14 days. T-14=triple therapy for 14 days. *p=0·003 for S-14 vs T-14. †p=0·003 for S-14 vs T-14. ‡In the six patients in the S-14 group, three patients in the S-10 group, and seven patients in the T-14 group who took less than 80% of the study drugs, H pylori eradication was successfully achieved in three patients, three patients, and four patients, respectively. Table 2: Helicobacter pylori eradication in fi rst-line and second-line treatments Articles 4 www.thelancet.com Published online November 16, 2012 http://dx.doi.org/10.1016/S0140-6736(12)61579-7 clarithromycin ≥1 mg/L, levofl oxacin ≥1 mg/L, and metronidazole ≥8 mg/L).8,22 The genotypes of gyrA and 23S rRNA were established by PCR followed by direct sequencing with the automatic sequencer (ABI PRISM 3100 Genetic Analyzer; Applied Biosystems, Foster City, CA, USA).22 The CagA gene and the VacA signal region (signal region 1 and 2) and midregion (midregion 1 and 2) mosaics were determined by PCR as described previously.23 Genotyping for the CYP2C19 polymorphism was done with the SEQUENOM MassARRAY System (Sequenom, Sand Diego, CA, USA) in the Taiwan National Genotyping Centre.24 Statistical analysis On the basis of fi ndings from a previous meta-analysis,15 we hypothesised that there would be about a 10% diff erence in the eradication rates between the three study regimens. Findings from a previous study sug- gested that the eradication rate with T-14 would be about 85%,25 so our original sample size estimation was for at least 155 individuals in each group, giving a power of 80% and a 0·05 two-sided type 1 error, assuming 10% loss to follow-up. After an interim report, we decided to increase the sample size to a conservative estimate of 300 individuals in each group, which would give a power of 90% in rejecting the null hypothesis and to adjust the type 1 error for multiple comparisons with Bonferroni correction. We made this decision to increase the precision of our study and to ensure an overall nominal signifi cance level of 0·05, assuming 15% loss to follow- up. We did intention-to-treat (ITT) and per-protocol (PP) analyses in the assess ment of the primary endpoint. All randomised patients were included in the ITT analysis. All individuals who violated the study protocol, such as patients not taking at least 80% of treatment drugs, or with unknown post-treatment H pylori status were excluded from the PP analysis. Patients who did not return for a follow-up ¹³C-UBT were recorded as treatment failures. We compared categorical data using the χ² test or Fisher’s exact test, as appropriate. We compared continuous data with the Student’s t test and gave results as mean (SD). For the primary endpoint, we adjusted for multiple comparisons by setting a Bonferroni-corrected α level of 0·01. For secondary variables, we did exploratory ana lyses by setting an α level of 0·05 without adjustment for multiple comparisons. We used SPSS (version 12.0 for Microsift Windows) for all statistical analyses. To assess factors aff ecting eradication rates, we did a multiple logistic regression analyses with the following predictors of interest: clarithromycin resistance, metro- nidazole resistance, amoxicillin resistance, age, sex, peptic ulcer disease, and smoking. We did not include patients with missing data in the regression analyses. After identifi cation of factors associated with treat- ment failure, we constructed a decision model (not described in the protocol) to elucidate the heterogeneity Figure 2: Effi cacies of fi rst-line and second-line Helicobacter pylori treatments ITT=intention to treat. PP=per protocol. MS-14=modifi ed sequential treatment containing levofl oxacin. S-10=sequential treatment for 10 days. S-14=sequential treatment for 14 days. T14=triple therapy for 14 days. Absolute diff erences in the effi cacy of fi rst-line and secon