Mei-Jyh Chen

Sequential versus triple therapy for the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial

BACKGROUND Whether sequential treatment can replace triple therapy as the standard treatment for Helicobacter pylori infection is unknown. We compared the efficacy of sequential treatment for 10 days and 14 days with triple therapy for 14 days in first-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 first 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 first-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 efficacy 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 significant difference in the occurrence of adverse effects or in compliance between the three groups. INTERPRETATION Our findings lend support to the use of sequential treatment as the standard first-line treatment for H pylori infection. FUNDING National Taiwan University Hospital and National Science Council.

Levofloxacin-based and clarithromycin-based triple therapies as first-line and second-line treatments for Helicobacter pylori infection: a randomised comparative trial with crossover design

Background The efficacy of a levofloxacin-based regimen as the first-line treatment and a clarithromycin-based regimen as the second-line treatment for Helicobacter pylori infection remains unknown. The aim of this study was to assess the eradication rates of these two regimens using different administration sequences. Methods Eligible patients were randomised to receive LAL: levofloxacin (750 mg once a day), amoxicillin (1000 mg twice a day) and lansoprazole (30 mg twice a day) for 7 days, or CAL: clarithromycin (500 mg twice a day), amoxicillin (1000 mg twice a day) and lansoprazole (30 mg twice a day) for 7 days. Patients with positive [13C]urea breath test after treatment were retreated with the rescue regimen in a crossover manner for 10 days. Result When used as first-line treatment (n=432), the eradication rates of LAL (n=217) and CAL (n=215) were 74.2 and 83.7% (p=0.015) in the intent-to-treat (ITT) analysis, and 80.1 and 87.4% (p=0.046) in the per-protocol (PP) analysis, respectively. When used as second-line treatment, the eradication rates of LAL (n=26) and CAL (n=40) were 76.9 and 60% (p=0.154) in the ITT analysis, and 80 and 61.5% (p=0.120) in the PP analysis, respectively. The overall eradication rates of CAL followed by LAL were better than the reverse sequence in both the ITT analysis (93% vs 85.3%, p=0.01) and the PP analysis (97.6% vs 92.5%, p=0.019). The eradication rate was significantly lower in the presence of levofloxacin resistance in the LAL group (50% vs 84.4%, p=0.018) and clarithromycin resistance in the CAL group (44.4% vs 90.7%, p=0.002). Conclusion CAL achieved a higher eradication rate than LAL as the first-line treatment, but not as the second-line treatment. The strategy of using CAL as the initial treatment and LAL as the rescue regimen achieved higher eradication rates than the reverse sequence. Clinical trial number NCT00816140.

Validation of the World Health Organization quality of life instrument in patients with HIV infection

We studied the reliability and validity of the World Health Organization quality of life (WHOQOL) assessment instrument in patients with human immunodeficiency virus (HIV) infection. WHOQOL-BREF was used to assess 136 HIV-infected outpatients. The results were analyzed and compared with data from 213 healthy persons. The Cronbachs α for internal consistency ranged from 0.74 to 0.85 across domains in HIV-infected patients. The test–retest reliability ranged from 0.64 to 0.79 across domains at average 4-week retest interval. Factor analysis identified four major factors: social, psychological, environment, and physical, consistent with the four domains of the instrument. The scores of all four domains correlated positively with self-evaluated health status and happiness (r range: 0.52–0.60 and 0.55–0.73 across domains, respectively), and correlated negatively with the number and severity of symptoms (r range: −0.40 to −0.47 and −0.41 to −0.52, respectively). The scores of physical, psychological and social domains, but not the environment domain, discriminated between healthy persons and HIV-infected patients (all p < 0.01). We conclude that the WHOQOL-BREF can be a useful quality-of-life instrument in patients with HIV infection.

Efficacy of genotypic resistance-guided sequential therapy in the third-line treatment of refractory Helicobacter pylori infection: a multicentre clinical trial

OBJECTIVES The efficacy of sequential therapy and the applicability of genotypic resistance to guide the selection of antibiotics in the third-line treatment of Helicobacter pylori have not been reported. We aimed to assess the efficacy of genotypic resistance-guided sequential therapy in third-line treatment. METHODS Genotypic and phenotypic resistances were determined in patients who failed at least two eradication therapies by PCR with direct sequencing and agar dilution test, respectively. The patients were retreated with sequential therapy containing esomeprazole and amoxicillin for the first 7 days, followed by esomeprazole and metronidazole plus clarithromycin, levofloxacin or tetracycline for another 7 days (all twice daily), according to genotypic resistance determined using gastric biopsy specimens. Eradication status was determined by the (13)C-urea breath test. Trial registered at clinicaltrials.gov (identifier: NCT01032655). RESULTS The overall eradication rate was 80.7% (109/135, 95% CI 73.3%-86.5%) in the intention-to-treat analysis. The presence of amoxicillin resistance (OR 6.83, 95% CI 1.62-28.86, P = 0.009) and prior sequential therapy (OR 4.77, 95% CI 1.315-17.3, P = 0.017), but not tetracycline resistance (tetracycline group), were associated with treatment failure. The eradication rates in patients who received clarithromycin-, levofloxacin- and tetracycline-based sequential therapies were 78.9% (15/19), 92.2% (47/51) and 71.4% (25/35) in strains susceptible to clarithromycin, levofloxacin and tetracycline, respectively. CONCLUSIONS A simple molecular method guiding sequential therapy can achieve a high eradication rate in the third-line treatment of refractory H. pylori infection.

Plasma Insulin-Like Growth Factor-Binding Protein-2 Levels as Diagnostic and Prognostic Biomarker of Colorectal Cancer

CONTEXT Overexpression of IGF-II and IGF-binding protein (IGFBP)-2 has been reported in several cancers. OBJECTIVE We aimed to assess the roles of plasma IGF-II and IGFBP-2 levels as diagnostic and prognostic biomarkers and the impact of loss of imprinting (LOI) of IGF-II on the survival of colorectal cancer (CRC). DESIGN We conducted a case control and prospective cohort study for diagnostic and prognostic values, respectively. PATIENTS AND SETTING Plasma levels of IGF-II and IGFBP-2 were measured in 162 patients with CRC before surgery, in paired 15 patients after curative surgery, in 24 patients with advanced colon polyps, and in 114 healthy controls between 2003 and 2006 in National Taiwan University Hospital. RESULTS The area under the curve values of using IGFBP-2 as a diagnostic marker for advanced colon polyp and CRC were 0.654 [95% confidence interval (CI) = 0.547-0.76; P = 0.017] and 0.815 (95% CI = 0.766-0.864; P < 0.001), respectively. The sensitivity and specificity for diagnosing CRC were 80.2 and 64%, respectively, if the cutoff value of IGFBP-2 was 377 ng/ml. In the multivariate Cox proportional hazards regression model, higher IGFBP-2 levels were associated with increased risk of mortality [hazard ratio (HR) = 2.46; P = 0.017], whereas higher IGF-II levels were associated with reduced risk of mortality (HR = 0.42; P = 0.044). LOI of IGF-II was associated with increased risk of mortality (HR = 7.91; P = 0.014) in patients with stage IV disease. CONCLUSIONS IGFBP-2 is a potential diagnostic and prognostic biomarker of CRC. LOI of IGF-II is significantly associated with poor prognosis in patients with stage IV disease.

The Primary Resistance of Helicobacter pylori in Taiwan after the National Policy to Restrict Antibiotic Consumption and Its Relation to Virulence Factors—A Nationwide Study

Objective The Taiwan Government issued a policy to restrict antimicrobial usage since 2001. We aimed to assess the changes in the antibiotic consumption and the primary resistance of H. pylori after this policy and the impact of virulence factors on resistance. Methods The defined daily dose (DDD) of antibiotics was analyzed using the Taiwan National Health Insurance (NHI) research database. H. pylori strains isolated from treatment naïve (N=1395) and failure from prior eradication therapies (N=360) from 9 hospitals between 2000 and 2012 were used for analysis. The minimum inhibitory concentration was determined by agar dilution test. Genotyping for CagA and VacA was determined by PCR method. Results The DDD per 1000 persons per day of macrolides reduced from 1.12 in 1997 to 0.19 in 2008, whereas that of fluoroquinolones increased from 0.12 in 1997 to 0.35 in 2008. The primary resistance of amoxicillin, clarithromycin, metronidazole, and tetracycline remained as low as 2.2%, 7.9%, 23.7%, and 1.9% respectively. However, the primary levofloxacin resistance rose from 4.9% in 2000–2007 to 8.3% in 2008–2010 and 13.4% in 2011–2012 (p=0.001). The primary resistance of metronidazole was higher in females than males (33.1% vs. 18.8%, p<0.001), which was probably attributed to the higher consumption of nitroimidazole. Neither CagA nor VacA was associated with antibiotic resistance. Conclusions The low primary clarithromycin and metronidazole resistance of H. pylori in Taiwan might be attributed to the reduced consumption of macrolides and nitroimidazole after the national policy to restrict antimicrobial usage. Yet, further strategies are needed to restrict the consumption of fluoroquinolones in the face of rising levofloxacin resistance.

Genotypic Resistance in Helicobacter pylori Strains Correlates with Susceptibility Test and Treatment Outcomes after Levofloxacin- and Clarithromycin-Based Therapies

ABSTRACT The accuracy of genotypic resistance to levofloxacin (gyrA mutations) and its agreement with treatment outcomes after levofloxacin-based therapy have not been reported. We aimed to assess the correlation. Helicobacter pylori strains isolated from patients who received levofloxacin-based and clarithromycin-based triple therapies in a previous randomized trial were analyzed for point mutations in gyrA and 23S rRNA. PCR followed by direct sequencing was used to assess the gyrA and 23S rRNA mutations. An agar dilution test was used to determine the MICs of clarithromycin and levofloxacin. We found that the agreement between genotypic and phenotypic resistance to levofloxacin was best when the MIC breakpoint was >1 μg/ml (kappa coefficient, 0.754). The eradication rates in patients with and without gyrA mutations were 41.7% and 82.7%, respectively (P = 0.003). The agreement between genotypic and phenotypic resistance to clarithromycin was best when the MIC breakpoint was >2 μg/ml (kappa, 0.694). The eradication rates in patients with and without 23S rRNA mutations were 7.7% and 93.5%, respectively (P < 0.001). The agreements (kappa coefficient) between therapeutic outcomes after clarithromycin-based triple therapy and genotypic and phenotypic resistance were 0.671 and 0.356, respectively. The agreements (kappa coefficient) between therapeutic outcomes after levofloxacin-based triple therapy and genotypic and phenotypic resistance were 0.244 and 0.190, respectively. In conclusion, gyrA and 23S rRNA mutations in H. pylori strains appeared to be better markers than phenotypic resistance in the prediction of treatment outcomes. The optimal breakpoints for levofloxacin and clarithromycin resistance appeared to be >1 μg/ml and >2 μg/ml, respectively.

Risk factors for incident diabetes mellitus among HIV-infected patients receiving combination antiretroviral therapy in Taiwan: a case-control study.

Recent studies suggest that patients with HIV infection are at increased risk for incident diabetes mellitus (DM). We investigated the incidence and risk factors of DM among HIV‐infected patients receiving combination antiretroviral therapy (CART) in Taiwan.

Sequential therapy for 10 days versus triple therapy for 14 days in the eradication of Helicobacter pylori in the community and hospital populations: a randomised trial

Objective Significant heterogeneity was observed in previous trials that assessed the efficacies of sequential therapy for 10 days (S10) versus triple therapy for 14 days (T14) in the first-line treatment of Helicobacter pylori. We aimed to compare the efficacy of S10 and T14 and assess the factors affecting their efficacies. Design We conducted this open-label randomised multicentre trial in eight hospitals and one community in Taiwan. 1300 adult subjects with H pylori infection naïve to treatment were randomised (1:1) to receive S10 (lansoprazole and amoxicillin for the first 5 days, followed by lansoprazole, clarithromycin and metronidazole for another 5 days) or T14 (lansoprazole, amoxicillin and clarithromycin for 14 days). All drugs were given twice daily. Successful eradication was defined as negative 13C-urea breath test at least 6 weeks after treatment. Our primary outcome was the eradication rate by intention-to-treat (ITT) and per-protocol (PP) analyses. Antibiotic resistance was determined by agar dilution test. Results The eradication rates of S10 and T14 were 87.2% (567/650, 95% CI 84.4% to 89.6%) and 85.7% (557/650, 95% CI 82.8% to 88.2%) in the ITT analysis, respectively, and were 91.6% (556/607, 95% CI 89.1% to 93.4%) and 91.0% (548/602, 95% CI 88.5% to 93.1%) in the PP analysis, respectively. There were no differences in compliance or adverse effects. The eradication rates in strains susceptible and resistant to clarithromycin were 90.7% and 62.2%, respectively, for S10, and were 91.5% and 44.4%, respectively, for T14. The efficacy of T14, but not S10, was affected by CYP2C19 polymorphism. Conclusions S10 was not superior to T14 in areas with low clarithromycin resistance. Trial registration number NCT01607918.

Empirical modified sequential therapy containing levofloxacin and high-dose esomeprazole in second-line therapy for Helicobacter pylori infection: a multicentre clinical trial

OBJECTIVES Sequential therapy appears to achieve a higher Helicobacter pylori eradication rate than triple therapy. We assessed the efficacy and tolerability of modified sequential therapy containing levofloxacin and high-dose esomeprazole in second-line therapy. METHODS Patients who failed first-line triple therapy with clarithromycin, amoxicillin and a proton pump inhibitor were eligible in this multicentre trial. Eligible patients were treated with esomeprazole 40 mg and amoxicillin 1 g for the first 5 days, followed by esomeprazole 40 mg, levofloxacin 250 mg and metronidazole 500 mg for another 5 days (all given twice daily). Eradication was confirmed with a (13)C-urea breath test 6 weeks after therapy. Drug susceptibility, presence/absence of gyrA mutation and CYP2C19 genotype were also determined. RESULTS A total of 142 patients were enrolled. The eradication rate was 95.1% [135/142, 95% confidence interval (CI) 91.5%-98.6%] in the intention-to-treat analysis and 96.4% (133/138, 95% CI 93.3%-99.5%) in the per protocol analysis. Four patients (2.8%) failed to take at least 80% of the drugs due to adverse effects. The eradication rates were 50% (4/8) and 97.7% (43/44) in patients with and without metronidazole resistance, respectively (P = 0.001). The eradication rates were 84.6% (11/13) and 95.1% (58/61) in patients with and without gyrA mutation, respectively (P = 0.210). The eradication rates were not affected by the CYP2C19 polymorphism (P = 0.421). CONCLUSIONS This modified sequential therapy achieved an excellent eradication rate (>95%) in second-line treatment and the eradication rate appeared to be affected by metronidazole resistance.