Letters
2. Landrigan CP, Barger LK, Cade BE, Ayas NT, Czeisler CA. Interns’ compliance with accreditation council for graduate medical education work-hour limits. JAMA. 2006;296(9):1063-1070. 3. Drolet BC, Schwede M, Bishop KD, Fischer SA. Compliance and falsification of duty hours: reports from residents and program directors. J Grad Med Educ. 2013;5(3):368-373.
In Reply We evaluated the association of the 2011 Accreditation Council for Graduate Medical Education duty hour reforms with 30-day all-location mortality and 30-day allcause readmissions. This nationwide study evaluated 6 384 273 admissions from 2 790 356 patients at 3104 hospitals. We compared outcomes in more intensive teaching hospitals relative to less intensive or nonteaching hospitals. In the first year after the reforms, there were no significant associations between the 2011 duty hour reforms and patient outcomes. In our risk-adjusted models, the odds ratios for mortality were 1.00 (95% CI, 0.96-1.03) for combined medical conditions and 0.99 (95% CI, 0.94-1.04) for combined surgical conditions. Similarly, for readmissions, the adjusted odds ratios were 1.00 (95% CI, 0.97-1.02) for combined medical conditions and 1.00 (95% CI, 0.98-1.03) for combined surgical conditions. Because our findings showed odds ratios so close to 1, there would have to be a very large rate of noncompliance for our model to have missed an actual substantial effect on patient outcomes associated with the reforms because noncompliers, by definition, would have an odds ratio of 1. If we think of our results as a mixture of compliers and noncompliers, and we assume a noncompliance rate of 20%, it would only increase the upper 95% confidence bound of the mortality estimate for combined medical conditions from 1.03 to 1.04 (calculation based on the method of Freedman 1 and Zeger et al 2 ). Given the scope and strengths of our study, as well as the proximity of our odds ratio estimates to 1.0, it is extremely unlikely that any reasonable estimate of noncompliance would appreciably change our results. Furthermore, the 2 studies referenced by Dr HunterZinck described survey responses on violations of duty hour rules.3,4 Although we agree that compliance rates were likely not 100%, based on the data presented, we disagree with the conclusion that the rates are extremely low. Neither of the studies cited directly measured rates of hospital compliance with duty hour reforms or resident behavior. Instead they presented the percentage of residents or program directors that cited some noncompliance. Consider, for example, a teaching hospital that adopts the new reforms. Some of the residents within that hospital may violate the rules on rare occasions during the year. However, overall compliance rates may still be quite high. Indeed, Drolet et al 4 found that 90.7% of respondents reported that they either mostly or always agreed with the statement “I comply with ALL duty hour regulations.” Furthermore, a national survey found that there was significant concern among residents that the 2011 duty hour reforms may have led to an increase in medical errors.5 The fact that jama.com
such a concern existed suggests that there was enough compliance to justify this worry. Mitesh S. Patel, MD, MBA, MS Dylan S. Small, PhD Jeffrey H. Silber, MD, PhD Author Affiliations: University of Pennsylvania, Philadelphia. Corresponding Author: Mitesh S. Patel, MD, MBA, MS, University of Pennsylvania, 423 Guardian Dr, Philadelphia, PA 19104 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Freedman DA. Randomization does not justify logistic regression. Stat Sci. 2008;23:237-249. 2. Zeger SL, Liang KY, Albert PS. Models for longitudinal data: a generalized estimating equation approach. Biometrics. 1988;44(4):1049-1060. 3. Landrigan CP, Barger LK, Cade BE, Ayas NT, Czeisler CA. Interns’ compliance with accreditation council for graduate medical education work-hour limits. JAMA. 2006;296(9):1063-1070. 4. Drolet BC, Schwede M, Bishop KD, Fischer SA. Compliance and falsification of duty hours: reports from residents and program directors. J Grad Med Educ. 2013;5(3):368-373. 5. Sen S, Kranzler HR, Didwania AK, et al. Effects of the 2011 duty hour reforms on interns and their patients: a prospective longitudinal cohort study. JAMA Intern Med. 2013;173(8):657-662.
Treatment to Prevent Hepatitis B Virus Reactivation in Patients With Lymphoma Receiving Chemotherapy To the Editor Dr Huang and colleagues1 showed the benefits of using a drug with a better resistance profile (entecavir) in preventing hepatitis B virus (HBV) reactivation in patients with lymphoma receiving chemotherapy who were seropositive for the hepatitis B surface antigen. Only 6.6% (n = 4) of patients experienced HBV reactivation in the entecavir group. Entecavir has an extremely favorable resistance profile with only 1.2% of patients experiencing viral breakthrough due to resistance after 5 years of treatment.2 In addition, high HBV DNA levels have been associated with increased risk of resistance.2 Patients included in this study were both treatment naive and had a baseline HBV DNA titer of less than 1000 copies/mL, which is very low. Considering these baseline characteristics, the viral breakthrough rate of 6.6% seems higher than what would be expected. One possible explanation for the relatively high breakthrough rate in this study is the widespread availability of lamivudine in China, which may have caused selection pressure leading to lamivudine-resistant viruses circulating in the community.3,4 Cross-resistance between lamivudine and entecavir is well-known, and even in the setting of lamivudine exposure with no documented resistance to lamivudine, the risk of entecavir resistance is increased.2,5 Thus, even if the patients in this study were treatment naive, they still could have been infected with a resistant virus, which may explain the relatively high breakthrough rate. The authors did not report the resistance profile of the patients who experienced viral reactivation. If entecavir resistance is demonstrated in these patients, this may have important clinical implications for countries with high lamivudine (Reprinted) JAMA March 24/31, 2015 Volume 313, Number 12
Copyright 2015 American Medical Association. All rights reserved.
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Letters
resistance rates. In such locales, performing a baseline resistance test or using drugs with little cross-resistance to lamivudine may need to be considered. Jihoon Baang, MD Author Affiliation: Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania. Corresponding Author: Jihoon Baang, MD, Department of Medicine, Temple University School of Medicine, 1316 W Ontario St, Philadelphia, PA 19140 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported being a former employee of Gilead Sciences (the maker of tenofovir, which is approved for the treatment of chronic HBV) during the period of January 2012 through February 2013; however, he currently does not have any relationship with the company. 1. Huang H, Li X, Zhu J, et al. Entecavir vs lamivudine for prevention of hepatitis B virus reactivation among patients with untreated diffuse large B-cell lymphoma receiving R-CHOP chemotherapy: a randomized clinical trial. JAMA. 2014;312(23):2521-2530. 2. European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol. 2012; 57(1):167-185. 3. Xu Z, Liu Y, Xu T, et al. Acute hepatitis B infection associated with drug-resistant hepatitis B virus. J Clin Virol. 2010;48(4):270-274. 4. Zhang Q, Liao Y, Cai B, et al. Incidence of natural resistance mutations in naïve chronic hepatitis B patients: a systematic review and meta-analysis. J Gastroenterol Hepatol. 2015;30(2):252-261. 5. Lee J-H, Cho Y, Lee DH, et al. Prior exposure to lamivudine increases entecavir resistance risk in chronic hepatitis B patients without detectable lamivudine resistance. Antimicrob Agents Chemother. 2014;58(3):1730-1737.
In Reply Dr Baang comments that the HBV reactivation rate of 6.6% with entecavir prophylaxis in our study was relatively higher than the reactivation rate of 1.2% after 5 years of entecavir treatment in patients with chronic HBV in the European Association for the Study of the Liver guidelines.1 We agree that this could be explained by cross-resistance between entecavir and lamivudine. The latter has been extensively used in China, which may cause transmission of lamivudineresistant viruses in the community. However, this study was conducted in patients with lymphoma who were receiving rituximab-containing chemotherapy. Rituximab is a human-mouse chimeric monoclonal antibody that specifically binds to the CD20 antigen located on pre-B and mature B lymphocytes, resulting in profound and durable B-cell depletion and secondary immunosuppression. Whether immunosuppression has an effect on virological breakthrough and drug resistance is unknown. To our knowledge, there is no investigation of the exact incidence of antiviral resistance to entecavir or lamivudine in immunosuppressed patients with chronic HBV. Another randomized clinical trial of entecavir prophylaxis in patients with lymphoma and resolved HBV receiving rituximab-based treatment reported a cumulative HBV reactivation rate of 4.3% at 18 months in the entecavir prophy-
1270
laxis group.2 The slightly higher rates of virological breakthrough in this study and our study possibly could be due to the relatively small sample size, with 41 and 61 patients in the entecavir prophylaxis groups, respectively. One of the limitations of our study was that the resistance mutations in patients with HBV reactivation were not tested. We will perform resistance testing in rituximabtreated patients who experience virological breakthrough and investigate whether immunosuppression has an influence on antiviral resistance. Tongyu Lin, MD He Huang, MD Xueying Li, MD Author Affiliations: Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China. Corresponding Author: Tongyu Lin, MD, Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Rd E, Guangzhou 510060, China ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol. 2012; 57(1):167-185. 2. Huang YH, Hsiao LT, Hong YC, et al. Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol. 2013;31(22): 2765-2772.
Guidelines for Letters Letters discussing a recent JAMA article should be submitted within 4 weeks of the article's publication in print. Letters received after 4 weeks will rarely be considered. Letters should not exceed 400 words of text and 5 references and may have no more than 3 authors. Letters reporting original research should not exceed 600 words of text and 6 references and may have no more than 7 authors. They may include up to 2 tables or figures but online supplementary material is not allowed. All letters should include a word count. Letters must not duplicate other material published or submitted for publication. Letters not meeting these specifications are generally not considered. Letters being considered for publication ordinarily will be sent to the authors of the JAMA article, who will be given the opportunity to reply. Letters will be published at the discretion of the editors and are subject to abridgement and editing. Further instructions can be found at http://jama.com/public /InstructionsForAuthors.aspx. A signed statement for authorship criteria and responsibility, financial disclosure, copyright transfer, and acknowledgment and the ICMJE Form for Disclosure of Potential Conflicts of Interest are required before publication. Letters should be submitted via the JAMA online submission and review system at http: //manuscripts.jama.com. For technical assistance, please contact [email protected]. Section Editor: Jody W. Zylke, MD, Deputy Editor.
JAMA March 24/31, 2015 Volume 313, Number 12 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a BYU Harold B Lee Library User on 05/19/2015
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2. Landrigan CP, Barger LK, Cade BE, Ayas NT, Czeisler CA. Interns’ compliance with accreditation council for graduate medical education work-hour limits. JAMA. 2006;296(9):1063-1070. 3. Drolet BC, Schwede M, Bishop KD, Fischer SA. Compliance and falsification of duty hours: reports from residents and program directors. J Grad Med Educ. 2013;5(3):368-373.
In Reply We evaluated the association of the 2011 Accreditation Council for Graduate Medical Education duty hour reforms with 30-day all-location mortality and 30-day allcause readmissions. This nationwide study evaluated 6 384 273 admissions from 2 790 356 patients at 3104 hospitals. We compared outcomes in more intensive teaching hospitals relative to less intensive or nonteaching hospitals. In the first year after the reforms, there were no significant associations between the 2011 duty hour reforms and patient outcomes. In our risk-adjusted models, the odds ratios for mortality were 1.00 (95% CI, 0.96-1.03) for combined medical conditions and 0.99 (95% CI, 0.94-1.04) for combined surgical conditions. Similarly, for readmissions, the adjusted odds ratios were 1.00 (95% CI, 0.97-1.02) for combined medical conditions and 1.00 (95% CI, 0.98-1.03) for combined surgical conditions. Because our findings showed odds ratios so close to 1, there would have to be a very large rate of noncompliance for our model to have missed an actual substantial effect on patient outcomes associated with the reforms because noncompliers, by definition, would have an odds ratio of 1. If we think of our results as a mixture of compliers and noncompliers, and we assume a noncompliance rate of 20%, it would only increase the upper 95% confidence bound of the mortality estimate for combined medical conditions from 1.03 to 1.04 (calculation based on the method of Freedman 1 and Zeger et al 2 ). Given the scope and strengths of our study, as well as the proximity of our odds ratio estimates to 1.0, it is extremely unlikely that any reasonable estimate of noncompliance would appreciably change our results. Furthermore, the 2 studies referenced by Dr HunterZinck described survey responses on violations of duty hour rules.3,4 Although we agree that compliance rates were likely not 100%, based on the data presented, we disagree with the conclusion that the rates are extremely low. Neither of the studies cited directly measured rates of hospital compliance with duty hour reforms or resident behavior. Instead they presented the percentage of residents or program directors that cited some noncompliance. Consider, for example, a teaching hospital that adopts the new reforms. Some of the residents within that hospital may violate the rules on rare occasions during the year. However, overall compliance rates may still be quite high. Indeed, Drolet et al 4 found that 90.7% of respondents reported that they either mostly or always agreed with the statement “I comply with ALL duty hour regulations.” Furthermore, a national survey found that there was significant concern among residents that the 2011 duty hour reforms may have led to an increase in medical errors.5 The fact that jama.com
such a concern existed suggests that there was enough compliance to justify this worry. Mitesh S. Patel, MD, MBA, MS Dylan S. Small, PhD Jeffrey H. Silber, MD, PhD Author Affiliations: University of Pennsylvania, Philadelphia. Corresponding Author: Mitesh S. Patel, MD, MBA, MS, University of Pennsylvania, 423 Guardian Dr, Philadelphia, PA 19104 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Freedman DA. Randomization does not justify logistic regression. Stat Sci. 2008;23:237-249. 2. Zeger SL, Liang KY, Albert PS. Models for longitudinal data: a generalized estimating equation approach. Biometrics. 1988;44(4):1049-1060. 3. Landrigan CP, Barger LK, Cade BE, Ayas NT, Czeisler CA. Interns’ compliance with accreditation council for graduate medical education work-hour limits. JAMA. 2006;296(9):1063-1070. 4. Drolet BC, Schwede M, Bishop KD, Fischer SA. Compliance and falsification of duty hours: reports from residents and program directors. J Grad Med Educ. 2013;5(3):368-373. 5. Sen S, Kranzler HR, Didwania AK, et al. Effects of the 2011 duty hour reforms on interns and their patients: a prospective longitudinal cohort study. JAMA Intern Med. 2013;173(8):657-662.
Treatment to Prevent Hepatitis B Virus Reactivation in Patients With Lymphoma Receiving Chemotherapy To the Editor Dr Huang and colleagues1 showed the benefits of using a drug with a better resistance profile (entecavir) in preventing hepatitis B virus (HBV) reactivation in patients with lymphoma receiving chemotherapy who were seropositive for the hepatitis B surface antigen. Only 6.6% (n = 4) of patients experienced HBV reactivation in the entecavir group. Entecavir has an extremely favorable resistance profile with only 1.2% of patients experiencing viral breakthrough due to resistance after 5 years of treatment.2 In addition, high HBV DNA levels have been associated with increased risk of resistance.2 Patients included in this study were both treatment naive and had a baseline HBV DNA titer of less than 1000 copies/mL, which is very low. Considering these baseline characteristics, the viral breakthrough rate of 6.6% seems higher than what would be expected. One possible explanation for the relatively high breakthrough rate in this study is the widespread availability of lamivudine in China, which may have caused selection pressure leading to lamivudine-resistant viruses circulating in the community.3,4 Cross-resistance between lamivudine and entecavir is well-known, and even in the setting of lamivudine exposure with no documented resistance to lamivudine, the risk of entecavir resistance is increased.2,5 Thus, even if the patients in this study were treatment naive, they still could have been infected with a resistant virus, which may explain the relatively high breakthrough rate. The authors did not report the resistance profile of the patients who experienced viral reactivation. If entecavir resistance is demonstrated in these patients, this may have important clinical implications for countries with high lamivudine (Reprinted) JAMA March 24/31, 2015 Volume 313, Number 12
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a BYU Harold B Lee Library User on 05/19/2015
1269
Letters
resistance rates. In such locales, performing a baseline resistance test or using drugs with little cross-resistance to lamivudine may need to be considered. Jihoon Baang, MD Author Affiliation: Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania. Corresponding Author: Jihoon Baang, MD, Department of Medicine, Temple University School of Medicine, 1316 W Ontario St, Philadelphia, PA 19140 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported being a former employee of Gilead Sciences (the maker of tenofovir, which is approved for the treatment of chronic HBV) during the period of January 2012 through February 2013; however, he currently does not have any relationship with the company. 1. Huang H, Li X, Zhu J, et al. Entecavir vs lamivudine for prevention of hepatitis B virus reactivation among patients with untreated diffuse large B-cell lymphoma receiving R-CHOP chemotherapy: a randomized clinical trial. JAMA. 2014;312(23):2521-2530. 2. European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol. 2012; 57(1):167-185. 3. Xu Z, Liu Y, Xu T, et al. Acute hepatitis B infection associated with drug-resistant hepatitis B virus. J Clin Virol. 2010;48(4):270-274. 4. Zhang Q, Liao Y, Cai B, et al. Incidence of natural resistance mutations in naïve chronic hepatitis B patients: a systematic review and meta-analysis. J Gastroenterol Hepatol. 2015;30(2):252-261. 5. Lee J-H, Cho Y, Lee DH, et al. Prior exposure to lamivudine increases entecavir resistance risk in chronic hepatitis B patients without detectable lamivudine resistance. Antimicrob Agents Chemother. 2014;58(3):1730-1737.
In Reply Dr Baang comments that the HBV reactivation rate of 6.6% with entecavir prophylaxis in our study was relatively higher than the reactivation rate of 1.2% after 5 years of entecavir treatment in patients with chronic HBV in the European Association for the Study of the Liver guidelines.1 We agree that this could be explained by cross-resistance between entecavir and lamivudine. The latter has been extensively used in China, which may cause transmission of lamivudineresistant viruses in the community. However, this study was conducted in patients with lymphoma who were receiving rituximab-containing chemotherapy. Rituximab is a human-mouse chimeric monoclonal antibody that specifically binds to the CD20 antigen located on pre-B and mature B lymphocytes, resulting in profound and durable B-cell depletion and secondary immunosuppression. Whether immunosuppression has an effect on virological breakthrough and drug resistance is unknown. To our knowledge, there is no investigation of the exact incidence of antiviral resistance to entecavir or lamivudine in immunosuppressed patients with chronic HBV. Another randomized clinical trial of entecavir prophylaxis in patients with lymphoma and resolved HBV receiving rituximab-based treatment reported a cumulative HBV reactivation rate of 4.3% at 18 months in the entecavir prophy-
1270
laxis group.2 The slightly higher rates of virological breakthrough in this study and our study possibly could be due to the relatively small sample size, with 41 and 61 patients in the entecavir prophylaxis groups, respectively. One of the limitations of our study was that the resistance mutations in patients with HBV reactivation were not tested. We will perform resistance testing in rituximabtreated patients who experience virological breakthrough and investigate whether immunosuppression has an influence on antiviral resistance. Tongyu Lin, MD He Huang, MD Xueying Li, MD Author Affiliations: Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China. Corresponding Author: Tongyu Lin, MD, Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Rd E, Guangzhou 510060, China ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol. 2012; 57(1):167-185. 2. Huang YH, Hsiao LT, Hong YC, et al. Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol. 2013;31(22): 2765-2772.
Guidelines for Letters Letters discussing a recent JAMA article should be submitted within 4 weeks of the article's publication in print. Letters received after 4 weeks will rarely be considered. Letters should not exceed 400 words of text and 5 references and may have no more than 3 authors. Letters reporting original research should not exceed 600 words of text and 6 references and may have no more than 7 authors. They may include up to 2 tables or figures but online supplementary material is not allowed. All letters should include a word count. Letters must not duplicate other material published or submitted for publication. Letters not meeting these specifications are generally not considered. Letters being considered for publication ordinarily will be sent to the authors of the JAMA article, who will be given the opportunity to reply. Letters will be published at the discretion of the editors and are subject to abridgement and editing. Further instructions can be found at http://jama.com/public /InstructionsForAuthors.aspx. A signed statement for authorship criteria and responsibility, financial disclosure, copyright transfer, and acknowledgment and the ICMJE Form for Disclosure of Potential Conflicts of Interest are required before publication. Letters should be submitted via the JAMA online submission and review system at http: //manuscripts.jama.com. For technical assistance, please contact [email protected]. Section Editor: Jody W. Zylke, MD, Deputy Editor.
JAMA March 24/31, 2015 Volume 313, Number 12 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a BYU Harold B Lee Library User on 05/19/2015
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