- Email: [email protected]
Treatment of Helicobacter pylori in Latin America
Correspondence
Treatment of Helicobacter pylori in Latin America Robert Greenberg and colleagues (Aug 6, p 507)1 are to be commended for doing a mass screening and treatment trial for Helicobacter pylori in the general population of Latin America. There is evidence to suggest that population screening and treatment can reduce the incidence of gastric cancer2 and lessen the economic burden from dyspepsia.3 However, we are not sure that Greenberg and colleagues’ conclusion that 14-day triple therapy is preferable to 5-day concomitant therapy in this setting is warranted. Eradication rates in other screening and treatment programmes have been variable, but are consistently between 60% and 80%,4 and the rates with triple versus concomitant treatment in Greenberg and colleagues’ study were 82·2% and 73·6%, respectively. This gives an absolute risk reduction for unsuccessful eradication of H pylori of only 8·6% with 14-day triple therapy, equating to a number needed to treat to prevent one failure of 12. Although this difference was statistically significant in Greenberg and colleagues’ primary analysis, the clinical significance is uncertain. Given the setting of the study—ie, countries with limited resources—we are surprised that the costs of eradication therapy were not discussed.
Most drug costs in all three groups of the trial will have been driven by the expense of clarithromycin, meaning that the regimen with the shortest duration of this antibiotic is likely to be the least costly. It would therefore seem more sensible to recommend the 5-day concomitant regimen for mass screening and treatment of the general population, in whom the benefits of successful eradication are less certain, and reserve 14-day triple therapy for individuals in whom there is definite evidence of benefit for H pylori eradication, such as those with peptic ulcer disease.5 We declare that we have no conflicts of interest.
Claire M Slater, *Alexander C Ford [email protected] Leeds Gastroenterology Institute, Leeds General Infirmary, Leeds LS1 3EX, UK 1
Greenberg ER, Anderson GL, Morgan DR, et al. 14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trial. Lancet 2011; 378: 507–14. Parsonnet J, Harris RA, Hack HM, et al. Modelling cost-effectiveness of Helicobacter pylori screening to prevent gastric cancer: a mandate for clinical trials. Lancet 1996; 348: 150–54. Ford AC, Forman D, Bailey AG, et al. A community screening program for Helicobacter pylori saves money: ten-year follow-up of a randomised controlled trial. Gastroenterology 2005; 129: 1910–17. You W-C, Brown LM, Zhang L, et al. Randomized double-blind factorial trial of three treatments to reduce the prevalence of precancerous gastric lesions. J Natl Cancer Inst 2006; 98: 974–83. Ford AC, Delaney BC, Forman D, et al. Eradication therapy in Helicobacter pylori positive peptic ulcer disease: systematic review and economic analysis. Am J Gastroenterol 2004; 99: 1833–55.
2
3
4
5
ST
Robert Greenberg and colleagues1 found that, in seven Latin American sites, the probability of Helicobacter pylori eradication with triple therapy lasting 14 days (TT-14) was 82·2%, which was 8·6% higher than with concomitant therapy lasting 5 days (CT-5) and 5·6% higher than with sequential therapy (ST). However, these data deserve further analysis. If we pool the eradication rates in each centre (figure), a significant dispersion can be seen across the countries, highlighted by the values of I2, showing heterogeneity.2 Part of this dispersion could possibly be due to the differing prevalence of resistant organisms in the individual countries. Furthermore, if the results are also analysed by country (webappendix), in Colombia, Mexico, and Nicaragua there was no significant difference between treatments tested. In the other three countries, the results were not homogeneous. In Chile, CT-5 was inferior to TT-14 and ST; in Costa Rica, ST was superior to CT-5; and in Honduras, TT-14 was superior to ST. However, the statistical differences are weak, as shown by the CIs, and probably reflect the small sample size enrolled in each group of each country, with a high likelihood of a type II error. This is also evident in the sensitivity analysis reported by Greenberg and colleagues in their table 4. Finally, an interesting aspect of this trial is that for the first time sequential therapy is compared with the standard triple therapy given for
TT-14
CT-5
Santiago (Chile)
84% (74–92)
86% (75–93)
66% (53–77)
Tùqueres (Colombia)
78% (67-87)
82% (71–90)
81% (70–89)
Guanacaste (Costa Rica)
90% (80–96)
87% (77–94)
77% (66–86)
Copan (Honduras)
82% (71–90)
94% (86–98)
86% (76–93)
Tapachula (Mexico)
67% (55–78)
77% (66–87)
72% (60–83)
Ciudad Obregon (Mexico)
66% (54–77)
77% (66–86)
68% (56–79)
Léon (Nicaragua)
68% (55–79)
72% (59–82)
64% (52–76)
Combined
77% (69–83)
82% (76–88)
74% (67–79)
50
70 90 110 Proportion (95% CI) I =72·8% (95% CI 23·4–85·6) 2
50
70 90 110 Proportion (95% CI) I =66·4% (95% CI 0–83·1) 2
Figure: Eradication rates by centre (random-effects model) ST=sequential therapy. TT-14=triple therapy lasting 14 days. CT-5=concomitant therapy lasting 5 days.
www.thelancet.com Vol 379 February 4, 2012
See Online for webappendix
40
60 80 100 Proportion (95% CI) I =60·4% (95% CI 0–80·3) 2
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
407
Correspondence
a full 14 days. Sequential therapy was less effective than has been reported in other trials,3 but a careful appraisal of the data shows that TT-14 was not remarkably better than ST: the number need to treat in favour of TT14 was 18, with a wide 95% CI (9–175) suggesting uncertainty in the true estimate of effect. In conclusion, caution should be exercised in the interpretation of these interesting but heterogeneous data. Carefully designed trials with documentation of resistance in individual patients and with a sufficiently large sample size from each country are necessary before any regimen can be determined as optimal in an individual Latin American country. NV has been a consultant to Takeda, AstraZeneca, and Ironwood. LG and DV declare that they have no conflicts of interest.
*Luigi Gatta, Nimish Vakil, Dino Vaira [email protected] Gastroenterology and Endoscopy Unit, Versilia Hospital, 55041 Lido di Camaiore, Lucca, Italy (LG); Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA (NV); Department of Medicine, Marquette University College of Health Sciences, Milwaukee, WI, USA (NV); and Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy (DV) 1
Greenberg ER, Anderson GL, Morgan DR, et al. 14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trial. Lancet 2011; 378: 507–14.
100
Grade A Grade B Grade C Grade F
90
Treatment success (%)
80 70 60 50 40 30 20 10 0 Honduras Costa Rica
Chile
Colombia Country
Mexico A
Mexico B
Nicaragua
Figure: Results of seven pilot studies done in six different countries with triple therapy Treatment result grade also shown. Grade A/B=good, C=acceptable, F=unacceptable.
408
2
3
Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–60. Gatta L, Vakil N, Leandro G, et al. Sequential therapy or triple therapy for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and children. Am J Gastroenterol 2009; 104: 3069–79.
In their multisite study, Robert Greenberg and colleagues1 attempted to identify a reliably effective treatment for Helicobacter pylori for use in Latin America. Each study site used locally available drugs and the regimens all contained clarithromycin or clarithromycin–metronidazole, despite the unacceptably low success of triple therapies elsewhere and a high expected prevalence of metronidazole resistance.2 The success of treatments for infectious diseases is mainly related to the absence of antimicrobial resistance and is predictable if one knows the pattern of resistance and the effect of resistance on the regimens tested.3,4 Greenberg and colleagues report that traditional triple therapy was the best of the three clarithromycincontaining regimens tested. However, they did not identify a reliably effective regimen overall and even their best regimen provided unacceptably low treatment results at four of the seven sites (figure).5 The absence of susceptibility data also prevented Greenberg and colleagues from showing why their results were so poor. Although they believed that they could not afford to do susceptibility testing, it is now clear that they could not afford not to. Overall, the study was well done but poorly conceived, confirming the old adage: “there is no right way to do the wrong thing”. Although Greenberg and colleagues’ conclusion that “standard 14-day triple-drug therapy is preferable to 5-day concomitant or 10-day sequential four-drug regimens as empirical therapy for H pylori infection in diverse Latin American populations” is literally true, we believe that it is irresponsible since, with one exception, the results were poor or unacceptably low.
That recommendation also ignored current data from Latin America on increasingly high rates of clarithromycin resistance. There was nothing useful to be gained by identifying the “best” of generally unacceptable therapies, and such “spin” on a failed study could potentially harm patients if followed blindly. DYG is supported in part by the Office of Research and Development Medical Research Service Department of Veterans Affairs (VA), Public Health Service grant DK56338 (which funds the Texas Medical Center Digestive Diseases Center), DK067366, and CA116845. He is an unpaid consultant for Novartis in relation to vaccine development for treatment or prevention of H pylori infection, a paid consultant for Otsuka Pharmaceuticals regarding diagnostic testing, and has received royalties on the Baylor College of Medicine patent covering materials related to 13C-urea breath test. AAT declares no conflicts of interest. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the VA or National Institutes of Health.
*David Y Graham, Alba A Trespalacios [email protected] Department of Medicine, Michael E DeBakey Veterans Affairs Medical Center, Houston, TX 77030, USA (DYG); Baylor College of Medicine, Houston, TX, USA (DYG); and Grupo de Enfermedades Infecciosas, Departamento de Microbiología, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia (AAT) 1
2
3
4
5
Greenberg ER, Anderson GL, Morgan DR, et al. 14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trial. Lancet 2011; 378: 507–14. Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut 2010; 59: 1143–53. Graham DY, Rimbara E. Understanding and appreciating sequential therapy for Helicobacter pylori eradication. J Clin Gastroenterol 2011; 45: 309–13. Rimbara E, Fischbach LA, Graham DY. Optimal therapy for Helicobacter pylori infections. Nat Rev Gastroenterol Hepatol 2011; 8: 79–88. Graham DY, Lu H, Yamaoka Y. A report card to grade Helicobacter pylori therapy. Helicobacter 2007; 12: 275–78.
Authors’ reply Claire Slater and Alexander Ford note that all three treatments compared in our trial achieved eradication probabilities similar to those reported from previous community-based programmes of Helicobacter pylori screening and treatment and that the less-expensive concomitant regimen might be preferable to the more effective, but www.thelancet.com Vol 379 February 4, 2012
Treatment of Helicobacter pylori in Latin America Robert Greenberg and colleagues (Aug 6, p 507)1 are to be commended for doing a mass screening and treatment trial for Helicobacter pylori in the general population of Latin America. There is evidence to suggest that population screening and treatment can reduce the incidence of gastric cancer2 and lessen the economic burden from dyspepsia.3 However, we are not sure that Greenberg and colleagues’ conclusion that 14-day triple therapy is preferable to 5-day concomitant therapy in this setting is warranted. Eradication rates in other screening and treatment programmes have been variable, but are consistently between 60% and 80%,4 and the rates with triple versus concomitant treatment in Greenberg and colleagues’ study were 82·2% and 73·6%, respectively. This gives an absolute risk reduction for unsuccessful eradication of H pylori of only 8·6% with 14-day triple therapy, equating to a number needed to treat to prevent one failure of 12. Although this difference was statistically significant in Greenberg and colleagues’ primary analysis, the clinical significance is uncertain. Given the setting of the study—ie, countries with limited resources—we are surprised that the costs of eradication therapy were not discussed.
Most drug costs in all three groups of the trial will have been driven by the expense of clarithromycin, meaning that the regimen with the shortest duration of this antibiotic is likely to be the least costly. It would therefore seem more sensible to recommend the 5-day concomitant regimen for mass screening and treatment of the general population, in whom the benefits of successful eradication are less certain, and reserve 14-day triple therapy for individuals in whom there is definite evidence of benefit for H pylori eradication, such as those with peptic ulcer disease.5 We declare that we have no conflicts of interest.
Claire M Slater, *Alexander C Ford [email protected] Leeds Gastroenterology Institute, Leeds General Infirmary, Leeds LS1 3EX, UK 1
Greenberg ER, Anderson GL, Morgan DR, et al. 14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trial. Lancet 2011; 378: 507–14. Parsonnet J, Harris RA, Hack HM, et al. Modelling cost-effectiveness of Helicobacter pylori screening to prevent gastric cancer: a mandate for clinical trials. Lancet 1996; 348: 150–54. Ford AC, Forman D, Bailey AG, et al. A community screening program for Helicobacter pylori saves money: ten-year follow-up of a randomised controlled trial. Gastroenterology 2005; 129: 1910–17. You W-C, Brown LM, Zhang L, et al. Randomized double-blind factorial trial of three treatments to reduce the prevalence of precancerous gastric lesions. J Natl Cancer Inst 2006; 98: 974–83. Ford AC, Delaney BC, Forman D, et al. Eradication therapy in Helicobacter pylori positive peptic ulcer disease: systematic review and economic analysis. Am J Gastroenterol 2004; 99: 1833–55.
2
3
4
5
ST
Robert Greenberg and colleagues1 found that, in seven Latin American sites, the probability of Helicobacter pylori eradication with triple therapy lasting 14 days (TT-14) was 82·2%, which was 8·6% higher than with concomitant therapy lasting 5 days (CT-5) and 5·6% higher than with sequential therapy (ST). However, these data deserve further analysis. If we pool the eradication rates in each centre (figure), a significant dispersion can be seen across the countries, highlighted by the values of I2, showing heterogeneity.2 Part of this dispersion could possibly be due to the differing prevalence of resistant organisms in the individual countries. Furthermore, if the results are also analysed by country (webappendix), in Colombia, Mexico, and Nicaragua there was no significant difference between treatments tested. In the other three countries, the results were not homogeneous. In Chile, CT-5 was inferior to TT-14 and ST; in Costa Rica, ST was superior to CT-5; and in Honduras, TT-14 was superior to ST. However, the statistical differences are weak, as shown by the CIs, and probably reflect the small sample size enrolled in each group of each country, with a high likelihood of a type II error. This is also evident in the sensitivity analysis reported by Greenberg and colleagues in their table 4. Finally, an interesting aspect of this trial is that for the first time sequential therapy is compared with the standard triple therapy given for
TT-14
CT-5
Santiago (Chile)
84% (74–92)
86% (75–93)
66% (53–77)
Tùqueres (Colombia)
78% (67-87)
82% (71–90)
81% (70–89)
Guanacaste (Costa Rica)
90% (80–96)
87% (77–94)
77% (66–86)
Copan (Honduras)
82% (71–90)
94% (86–98)
86% (76–93)
Tapachula (Mexico)
67% (55–78)
77% (66–87)
72% (60–83)
Ciudad Obregon (Mexico)
66% (54–77)
77% (66–86)
68% (56–79)
Léon (Nicaragua)
68% (55–79)
72% (59–82)
64% (52–76)
Combined
77% (69–83)
82% (76–88)
74% (67–79)
50
70 90 110 Proportion (95% CI) I =72·8% (95% CI 23·4–85·6) 2
50
70 90 110 Proportion (95% CI) I =66·4% (95% CI 0–83·1) 2
Figure: Eradication rates by centre (random-effects model) ST=sequential therapy. TT-14=triple therapy lasting 14 days. CT-5=concomitant therapy lasting 5 days.
www.thelancet.com Vol 379 February 4, 2012
See Online for webappendix
40
60 80 100 Proportion (95% CI) I =60·4% (95% CI 0–80·3) 2
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
407
Correspondence
a full 14 days. Sequential therapy was less effective than has been reported in other trials,3 but a careful appraisal of the data shows that TT-14 was not remarkably better than ST: the number need to treat in favour of TT14 was 18, with a wide 95% CI (9–175) suggesting uncertainty in the true estimate of effect. In conclusion, caution should be exercised in the interpretation of these interesting but heterogeneous data. Carefully designed trials with documentation of resistance in individual patients and with a sufficiently large sample size from each country are necessary before any regimen can be determined as optimal in an individual Latin American country. NV has been a consultant to Takeda, AstraZeneca, and Ironwood. LG and DV declare that they have no conflicts of interest.
*Luigi Gatta, Nimish Vakil, Dino Vaira [email protected] Gastroenterology and Endoscopy Unit, Versilia Hospital, 55041 Lido di Camaiore, Lucca, Italy (LG); Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA (NV); Department of Medicine, Marquette University College of Health Sciences, Milwaukee, WI, USA (NV); and Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy (DV) 1
Greenberg ER, Anderson GL, Morgan DR, et al. 14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trial. Lancet 2011; 378: 507–14.
100
Grade A Grade B Grade C Grade F
90
Treatment success (%)
80 70 60 50 40 30 20 10 0 Honduras Costa Rica
Chile
Colombia Country
Mexico A
Mexico B
Nicaragua
Figure: Results of seven pilot studies done in six different countries with triple therapy Treatment result grade also shown. Grade A/B=good, C=acceptable, F=unacceptable.
408
2
3
Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–60. Gatta L, Vakil N, Leandro G, et al. Sequential therapy or triple therapy for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and children. Am J Gastroenterol 2009; 104: 3069–79.
In their multisite study, Robert Greenberg and colleagues1 attempted to identify a reliably effective treatment for Helicobacter pylori for use in Latin America. Each study site used locally available drugs and the regimens all contained clarithromycin or clarithromycin–metronidazole, despite the unacceptably low success of triple therapies elsewhere and a high expected prevalence of metronidazole resistance.2 The success of treatments for infectious diseases is mainly related to the absence of antimicrobial resistance and is predictable if one knows the pattern of resistance and the effect of resistance on the regimens tested.3,4 Greenberg and colleagues report that traditional triple therapy was the best of the three clarithromycincontaining regimens tested. However, they did not identify a reliably effective regimen overall and even their best regimen provided unacceptably low treatment results at four of the seven sites (figure).5 The absence of susceptibility data also prevented Greenberg and colleagues from showing why their results were so poor. Although they believed that they could not afford to do susceptibility testing, it is now clear that they could not afford not to. Overall, the study was well done but poorly conceived, confirming the old adage: “there is no right way to do the wrong thing”. Although Greenberg and colleagues’ conclusion that “standard 14-day triple-drug therapy is preferable to 5-day concomitant or 10-day sequential four-drug regimens as empirical therapy for H pylori infection in diverse Latin American populations” is literally true, we believe that it is irresponsible since, with one exception, the results were poor or unacceptably low.
That recommendation also ignored current data from Latin America on increasingly high rates of clarithromycin resistance. There was nothing useful to be gained by identifying the “best” of generally unacceptable therapies, and such “spin” on a failed study could potentially harm patients if followed blindly. DYG is supported in part by the Office of Research and Development Medical Research Service Department of Veterans Affairs (VA), Public Health Service grant DK56338 (which funds the Texas Medical Center Digestive Diseases Center), DK067366, and CA116845. He is an unpaid consultant for Novartis in relation to vaccine development for treatment or prevention of H pylori infection, a paid consultant for Otsuka Pharmaceuticals regarding diagnostic testing, and has received royalties on the Baylor College of Medicine patent covering materials related to 13C-urea breath test. AAT declares no conflicts of interest. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the VA or National Institutes of Health.
*David Y Graham, Alba A Trespalacios [email protected] Department of Medicine, Michael E DeBakey Veterans Affairs Medical Center, Houston, TX 77030, USA (DYG); Baylor College of Medicine, Houston, TX, USA (DYG); and Grupo de Enfermedades Infecciosas, Departamento de Microbiología, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia (AAT) 1
2
3
4
5
Greenberg ER, Anderson GL, Morgan DR, et al. 14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trial. Lancet 2011; 378: 507–14. Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut 2010; 59: 1143–53. Graham DY, Rimbara E. Understanding and appreciating sequential therapy for Helicobacter pylori eradication. J Clin Gastroenterol 2011; 45: 309–13. Rimbara E, Fischbach LA, Graham DY. Optimal therapy for Helicobacter pylori infections. Nat Rev Gastroenterol Hepatol 2011; 8: 79–88. Graham DY, Lu H, Yamaoka Y. A report card to grade Helicobacter pylori therapy. Helicobacter 2007; 12: 275–78.
Authors’ reply Claire Slater and Alexander Ford note that all three treatments compared in our trial achieved eradication probabilities similar to those reported from previous community-based programmes of Helicobacter pylori screening and treatment and that the less-expensive concomitant regimen might be preferable to the more effective, but www.thelancet.com Vol 379 February 4, 2012