Invited Commentaries
Commentary: tenofovir is superior to entecavir in HBeAg-positive chronic hepatitis B patients – authors’ reply L. Gao*, H. N. Trinh†, J. Li‡ & M. H. Nguyen§ *Department of Chemistry, Stanford University, Stanford, CA, USA. † San Jose Gastroenterology, San Jose, CA, USA. ‡ Palo Alto Medical Foundation, Mountain View, CA, USA. § Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA, USA. E-mail: [email protected] doi:10.1111/apt.12708
We agree with Bradshaw and Danta that the findings of this study should be confirmed in a prospective study with longer follow-up times and a greater number of patients, particularly for tenofovir.1, 2 As the study focuses on a real-life setting, our data may indeed reflect differences specific to the study population. We were also aware that entecavir has a much lower EC50 than tenofovir. However, the number of molecules of drug in a dose of tenofovir (300 mg) is 262 times that of entecavir (0.5 mg), which could help offset the higher EC50 of tenofovir and explain its efficacy. In addition, although there may be a small difference in weight between the hepatitis B (HB) eAg-positive entecavir and
Commentary: independent risk factors for recurrent neoplasia after endoscopic resection of early gastric cancer M. Yaghoobi*, Y. Yuan† & R. H. Hunt† *Division of Gastroenterology and Hepatology, Medical University of South Carolina and Ralph H. Johnson VA Medical Center, Charleston, SC, USA. † Division of Gastroenterology, Department of Medicine, McMaster University Health Science Centre, Hamilton, ON, Canada. E-mail: [email protected] doi:10.1111/apt.12686
We read with interest the report by Kwon et al.1 of their retrospective study which emphasises that both persistent H. pylori infection and old age (≥60) are independent risk factors for an increased incidence of metachronous gastric cancer. Their findings also complement our meta-analysis showing that H. pylori infection is strongly associated with early gastric cancer2 and that eradication Aliment Pharmacol Ther 2014; 39: 992-995 ª 2014 John Wiley & Sons Ltd
tenofovir groups, we did not have evidence that this is due to a greater proportion of the entecavir group having hepatic steatosis compared with the tenofovir group. Finally, regarding the possibility of increased entecavir resistance in nucleos(t)ide-na€ıve populations, the study cited3 observed mutations associated with entecavir resistance in only a single nucleos(t)ide-na€ıve patient; the patient in question achieved virological response without virological breakthrough during treatment with entecavir. The study also noted that ‘the probability of reaching undetectable HBV DNA under entecavir treatment was similar in patients with or without baseline mutation.’
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES 1. Bradshaw D, Danta M. Commentary: tenofovir is superior to entecavir in HBeAg-positive chronic hepatitis B patients. Aliment Pharmacol Ther 2014; 39: 992. 2. Gao L, Trinh HN, Li J, Nguyen MH. Tenofovir is superior to entecavir for achieving complete viral suppression in HBeAgpositive chronic hepatitis B patients with high HBV DNA. Aliment Pharmacol Ther 2014; 39: 629–37. 3. Koffi J, Egounlety R, Pradat P, et al. Impact of lamivudineresistance mutations on entecavir treatment outcome in hepatitis B. Eur J Gastroenterol Hepatol 2014; 26: 146–54.
reduces metachronous gastric lesions in patients with early gastric cancer who have undergone endoscopic mucosal dissection (ESD). However, the longest duration of follow-up in their study is 5 years and many of the lesions diagnosed during the follow-up period were likely present as pre-malignant lesions or microscopic malignancy at the time of eradication. This is supported by the lack of a significant difference in the rate of dysplasia in the two groups while an earlier change in the rate of dysplasia than cancer might be expected.3 Gastric carcinogenesis is a multifactorial process but, due to the nature of retrospective studies, many important environmental risk factors and bacterial and host genetics including socioeconomic status, smoking, dietary factors (e.g. processed meats, high salt intake), intake of anti-oxidants, nonsteroidal anti-inflammatory drugs or other medications, host genetic variants and family history, etc. were not studied. The observed difference in the rate of gastric cancer in the two groups could be 993
Invited Commentaries partially explained by some of these uninvestigated factors, such as virulence of H. pylori strain, which have been associated with both resistance to therapy and a higher risk of developing gastric cancer. As an example, we have shown that cagA status also influences the risk of gastric cancer.4 Furthermore, their sample size is relatively small for the study of more risk factors. We estimated a minimum of 194 patients would be required in each arm, rather than the 99 calculated by the authors, to achieve the power, based on the two references used in their study.5, 6 This difference is mainly due to the difference in their presumed rates (2% and 12% in each arm) as compared to the actual cumulative reported rates [2.8% (9/320) and 9.5% (30/322) respectively] in the studies referred to.5, 6 Moreover, there is likely insufficient power to study more than three predictors with only 31 cancer cases, as logistic regression models require a minimum of 10 events per variable.7 The authors included all nine predictors in the multivariate model instead of the most significant ones selected in their univariate analysis. In addition, one of their significant variables, ‘disease-free duration’, is not a risk factor and therefore should not be considered in the regression model. The authors did not interpret its significance, although they did indicate a ‘P < 0.05’. The proportion of diffuse-type gastric cancer was significantly higher in the persistent group as compared with the H. pylori-eradicated group (P = 0.03). The diffuse-type gastric cancer is believed to progress more rapidly than the intestinal type and is less commonly associated with chronic H. pylori infection.8 Kwon and colleagues do not provide information on the histological type of the metachronous lesions; were they similar to the primary cancer? We have recalculated the rates using only the intestinal-type gastric cancer and the difference is no longer significant (P = 0.11).
Commentary: independent risk factors for recurrent neoplasia after endoscopic resection of early gastric cancer – authors’ reply Y. H. Kwon & S. W. Jeon Division of Gastroenterology, Department of Internal Medicine, Kyungpook National University Medical Center, Daegu, South Korea. E-mail: [email protected] 994
The latest Asian-Pacific consensus on gastric cancer recommended H. pylori screening and treatment in highrisk subjects including those with a history of gastric cancer.9 Further large prospective studies investigating more important risk factors, and their interactions with H. pylori infection, would add invaluable information.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Kwon YH, Heo J, Lee HS, Cho CM, Jeon SW. Failure of Helicobacter pylori eradication and age are independent risk factors for recurrent neoplasia after endoscopic resection of early gastric cancer in 283 patients. Aliment Pharmacol Ther 2014; 39: 609–18. 2. Wang C, Yuan Y, Hunt RH. The association between Helicobacter pylori infection and early gastric cancer: a meta-analysis. Am J Gastroenterol 2007; 102: 1789–98. 3. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process–First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 1992; 52: 6735–40. 4. Huang JQ, Zheng GF, Sumanac K, Irvine EJ, Hunt RH. Metaanalysis of the relationship between cagA seropositivity and gastric cancer. Gastroenterology 2003; 125: 1636–44. 5. Fukase K, Kato M, Kikuchi S, et al. Japan Gast Study Group. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet 2008; 372: 392–7. 6. Uemura N, Mukai T, Okamoto S, et al. Effect of Helicobacter pylori eradication on subsequent development of cancer after endoscopic resection of early gastric cancer. Cancer Epidemiol Biomark Prev 1997; 6: 639–42. 7. Peduzzi P, Concato J, Kemper E, et al. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol 1996; 49: 1373–9. 8. Shah MA, Khanin R, Tang L, et al. Molecular classification of gastric cancer: a new paradigm. Clin Cancer Res 2011; 17: 2693–701. 9. Fock KM, Talley N, Moayyedi P, et al. Asia-Pacific Gastric Cancer Consensus Conference. Asia Pacific consensus guidelines on gastric cancer prevention. J Gastroenterol Hepatol 2008; 23: 351–65.
doi:10.1111/apt.12703
We thank Yaghoobi et al. for their interest1 in our study2 and we are pleased that our results complement their meta-analysis3 showing that Helicobacter pylori (H. pylori) infection is strongly associated with early gastric cancer.
Aliment Pharmacol Ther 2014; 39: 992-995 ª 2014 John Wiley & Sons Ltd
Commentary: tenofovir is superior to entecavir in HBeAg-positive chronic hepatitis B patients – authors’ reply L. Gao*, H. N. Trinh†, J. Li‡ & M. H. Nguyen§ *Department of Chemistry, Stanford University, Stanford, CA, USA. † San Jose Gastroenterology, San Jose, CA, USA. ‡ Palo Alto Medical Foundation, Mountain View, CA, USA. § Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA, USA. E-mail: [email protected] doi:10.1111/apt.12708
We agree with Bradshaw and Danta that the findings of this study should be confirmed in a prospective study with longer follow-up times and a greater number of patients, particularly for tenofovir.1, 2 As the study focuses on a real-life setting, our data may indeed reflect differences specific to the study population. We were also aware that entecavir has a much lower EC50 than tenofovir. However, the number of molecules of drug in a dose of tenofovir (300 mg) is 262 times that of entecavir (0.5 mg), which could help offset the higher EC50 of tenofovir and explain its efficacy. In addition, although there may be a small difference in weight between the hepatitis B (HB) eAg-positive entecavir and
Commentary: independent risk factors for recurrent neoplasia after endoscopic resection of early gastric cancer M. Yaghoobi*, Y. Yuan† & R. H. Hunt† *Division of Gastroenterology and Hepatology, Medical University of South Carolina and Ralph H. Johnson VA Medical Center, Charleston, SC, USA. † Division of Gastroenterology, Department of Medicine, McMaster University Health Science Centre, Hamilton, ON, Canada. E-mail: [email protected] doi:10.1111/apt.12686
We read with interest the report by Kwon et al.1 of their retrospective study which emphasises that both persistent H. pylori infection and old age (≥60) are independent risk factors for an increased incidence of metachronous gastric cancer. Their findings also complement our meta-analysis showing that H. pylori infection is strongly associated with early gastric cancer2 and that eradication Aliment Pharmacol Ther 2014; 39: 992-995 ª 2014 John Wiley & Sons Ltd
tenofovir groups, we did not have evidence that this is due to a greater proportion of the entecavir group having hepatic steatosis compared with the tenofovir group. Finally, regarding the possibility of increased entecavir resistance in nucleos(t)ide-na€ıve populations, the study cited3 observed mutations associated with entecavir resistance in only a single nucleos(t)ide-na€ıve patient; the patient in question achieved virological response without virological breakthrough during treatment with entecavir. The study also noted that ‘the probability of reaching undetectable HBV DNA under entecavir treatment was similar in patients with or without baseline mutation.’
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES 1. Bradshaw D, Danta M. Commentary: tenofovir is superior to entecavir in HBeAg-positive chronic hepatitis B patients. Aliment Pharmacol Ther 2014; 39: 992. 2. Gao L, Trinh HN, Li J, Nguyen MH. Tenofovir is superior to entecavir for achieving complete viral suppression in HBeAgpositive chronic hepatitis B patients with high HBV DNA. Aliment Pharmacol Ther 2014; 39: 629–37. 3. Koffi J, Egounlety R, Pradat P, et al. Impact of lamivudineresistance mutations on entecavir treatment outcome in hepatitis B. Eur J Gastroenterol Hepatol 2014; 26: 146–54.
reduces metachronous gastric lesions in patients with early gastric cancer who have undergone endoscopic mucosal dissection (ESD). However, the longest duration of follow-up in their study is 5 years and many of the lesions diagnosed during the follow-up period were likely present as pre-malignant lesions or microscopic malignancy at the time of eradication. This is supported by the lack of a significant difference in the rate of dysplasia in the two groups while an earlier change in the rate of dysplasia than cancer might be expected.3 Gastric carcinogenesis is a multifactorial process but, due to the nature of retrospective studies, many important environmental risk factors and bacterial and host genetics including socioeconomic status, smoking, dietary factors (e.g. processed meats, high salt intake), intake of anti-oxidants, nonsteroidal anti-inflammatory drugs or other medications, host genetic variants and family history, etc. were not studied. The observed difference in the rate of gastric cancer in the two groups could be 993
Invited Commentaries partially explained by some of these uninvestigated factors, such as virulence of H. pylori strain, which have been associated with both resistance to therapy and a higher risk of developing gastric cancer. As an example, we have shown that cagA status also influences the risk of gastric cancer.4 Furthermore, their sample size is relatively small for the study of more risk factors. We estimated a minimum of 194 patients would be required in each arm, rather than the 99 calculated by the authors, to achieve the power, based on the two references used in their study.5, 6 This difference is mainly due to the difference in their presumed rates (2% and 12% in each arm) as compared to the actual cumulative reported rates [2.8% (9/320) and 9.5% (30/322) respectively] in the studies referred to.5, 6 Moreover, there is likely insufficient power to study more than three predictors with only 31 cancer cases, as logistic regression models require a minimum of 10 events per variable.7 The authors included all nine predictors in the multivariate model instead of the most significant ones selected in their univariate analysis. In addition, one of their significant variables, ‘disease-free duration’, is not a risk factor and therefore should not be considered in the regression model. The authors did not interpret its significance, although they did indicate a ‘P < 0.05’. The proportion of diffuse-type gastric cancer was significantly higher in the persistent group as compared with the H. pylori-eradicated group (P = 0.03). The diffuse-type gastric cancer is believed to progress more rapidly than the intestinal type and is less commonly associated with chronic H. pylori infection.8 Kwon and colleagues do not provide information on the histological type of the metachronous lesions; were they similar to the primary cancer? We have recalculated the rates using only the intestinal-type gastric cancer and the difference is no longer significant (P = 0.11).
Commentary: independent risk factors for recurrent neoplasia after endoscopic resection of early gastric cancer – authors’ reply Y. H. Kwon & S. W. Jeon Division of Gastroenterology, Department of Internal Medicine, Kyungpook National University Medical Center, Daegu, South Korea. E-mail: [email protected] 994
The latest Asian-Pacific consensus on gastric cancer recommended H. pylori screening and treatment in highrisk subjects including those with a history of gastric cancer.9 Further large prospective studies investigating more important risk factors, and their interactions with H. pylori infection, would add invaluable information.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Kwon YH, Heo J, Lee HS, Cho CM, Jeon SW. Failure of Helicobacter pylori eradication and age are independent risk factors for recurrent neoplasia after endoscopic resection of early gastric cancer in 283 patients. Aliment Pharmacol Ther 2014; 39: 609–18. 2. Wang C, Yuan Y, Hunt RH. The association between Helicobacter pylori infection and early gastric cancer: a meta-analysis. Am J Gastroenterol 2007; 102: 1789–98. 3. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process–First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 1992; 52: 6735–40. 4. Huang JQ, Zheng GF, Sumanac K, Irvine EJ, Hunt RH. Metaanalysis of the relationship between cagA seropositivity and gastric cancer. Gastroenterology 2003; 125: 1636–44. 5. Fukase K, Kato M, Kikuchi S, et al. Japan Gast Study Group. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet 2008; 372: 392–7. 6. Uemura N, Mukai T, Okamoto S, et al. Effect of Helicobacter pylori eradication on subsequent development of cancer after endoscopic resection of early gastric cancer. Cancer Epidemiol Biomark Prev 1997; 6: 639–42. 7. Peduzzi P, Concato J, Kemper E, et al. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol 1996; 49: 1373–9. 8. Shah MA, Khanin R, Tang L, et al. Molecular classification of gastric cancer: a new paradigm. Clin Cancer Res 2011; 17: 2693–701. 9. Fock KM, Talley N, Moayyedi P, et al. Asia-Pacific Gastric Cancer Consensus Conference. Asia Pacific consensus guidelines on gastric cancer prevention. J Gastroenterol Hepatol 2008; 23: 351–65.
doi:10.1111/apt.12703
We thank Yaghoobi et al. for their interest1 in our study2 and we are pleased that our results complement their meta-analysis3 showing that Helicobacter pylori (H. pylori) infection is strongly associated with early gastric cancer.
Aliment Pharmacol Ther 2014; 39: 992-995 ª 2014 John Wiley & Sons Ltd
