- Email: [email protected]
Early bactericidal activity of new drug regimens for tuberculosis – Authors' reply
Correspondence
0
Δ log CFU/mL
–1 –2 –3
H2 H6 HREZ7 HRSZ3
–4 –5 0
7 Day
H2 HR2 HST3 HRSZ3 14
0
7
14 Day
21
28
Figure: Published trials of quantitative sputum microbiology in patients with pulmonary tuberculosis of 7–28 days’ duration Left: Across-trial comparisons of similar treatments, showing similar results. Right: Within-trial comparisons of distinct treatments, showing similar results during first 14 days. H=isoniazid; R=rifampicin, E=ethambutol; S=streptomycin, Z=pyrazinamide; T=thiacetazone. CFU=colony-forming units.
short-duration trials. The concept that such trials can inform the required duration of treatment is unsupported by clinical data. RSW is an employee and shareholder of Pfizer. CN is an employee and Chief Executive Officer of Sequella.
*Robert S Wallis, Carol Nacy robert.wallis@pfizer.com Pfizer, Groton, CT 06340, USA (RSW); and Sequella, Rockville, MD, USA (CN) 1
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Diacon AH, Dawson R, von Groote-Bidlingmaier F, et al. 14 day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. Lancet 2012; 380: 986–93. Wallis RS, Phillips M, Johnson JL, et al. Inhibition of INH-induced expression of M tuberculosis antigen 85 in sputum: a potential surrogate marker in TB chemotherapy trials. Antimicrob Agents Chemother 2001; 45: 1302–44. Brindle R, Odhiambo J, Mitchison DA. Serial counts of Mycobacterium tuberculosis in sputum as surrogate markers of the sterilising activity of rifampicin and pyrazinamide in treating pulmonary tuberculosis. BMC Pulm Med 2001; 1: 2. East and Central African-British Medical Research Council. Controlled clinical trial of 4 short-course regimens of chemotherapy (three 6-month and one 8-month) for pulmonary tuberculosis. Tubercle 1983; 64: 153–66. East African-British Medical Research Councils. Results at 5 years of a controlled comparison of a 6-month and a standard 18-month regimen of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 1977; 116: 3–8. Rustomjee R, Diacon AH, Allen J, et al. Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC 207 in pulmonary tuberculosis. Antimicrob Agents Chemother 2008; 52: 2831–35. Diacon AH, Dawson R, Hanekom M, et al. Early bactericidal activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients. Antimicrob Agents Chemother 2010; 54: 3402–07.
Authors’ reply We agree with Prasanta Mohapatra and colleagues and Zarir Udwadia that the efficacy of the PA-824moxifloxacin-pyrazinamide regimen must be shown in clinical trials that include patients with multidrugresistant (MDR) tuberculosis. Obviously, this regimen cannot be appropriate for all such patients because their isolates can harbour resistance beyond that to isoniazid and rifampicin, including moxifloxacin and pyrazinamide. A study of PA824-moxifloxacin-pyrazinamide over 8 weeks, which includes patients with MDR tuberculosis susceptible to moxifloxacin and pyrazinamide, is currently underway (ClinicalTrials. gov identifier NCT01498419). The results of our published study1 suggest that patients who receive PA-824-moxifloxacin-pyrazinamide, but neither isoniazid nor rifampicin, hitherto regarded as essential, will not be therapeutically disadvantaged in the ongoing study. Udwadia shares our enthusiasm for constructing a combination of at least three novel chemical entities that can be combined safely and to which resistance would be unlikely to occur naturally. Such a universal regimen would treat all forms of tuberculosis, thereby obviating the necessity for susceptibility testing for drugs currently in use. Until such a regimen becomes available, it remains important to use several drugs to
which a patient’s Mycobacterium tuberculosis isolate is sensitive, and susceptibility testing is essential for the correct treatment of all drugresistant tuberculosis. Robert Wallis and Carol Nacy seem to misunderstand the role of early bactericidal activity studies in our development pathway. All our current first-line antituberculosis drugs and regimens have shown efficacy, when appropriately tested, in mouse models, in 2-week early bactericidal activity studies, in 2-month clinical trials, and in long-term clinical trials.2,3 The mouse relapse model forms the initial basis for constructing any new regimen to advance into clinical evaluation. Hypotheses based on mouse studies must then continue to be supported by findings in short-term, intermediateterm, and long-term trials to remain viable. Our 2-week trial of the early bactericidal activity of PA-824moxifloxacin-pyrazinamide1 represents the first step in this systematic process. It remains an open, but extremely important, question as to exactly how well data based on sputum sampling in the early phase of treatment (whether for 2 weeks or for 2 months) predict long-term outcomes; unfortunately there is no single biomarker or shortterm study to provide definitive evidence of the necessary treatment duration to achieve cure.4 We believe that only after rigorous, methodical studies, such as our completed 2-week trial,1 our ongoing 2-month trial, and hopefully a future phase 3 trial, will we better understand the predictive capability of short-term clinical studies. We declare that we have no conflicts of interest.
*Andreas H Diacon, Peter R Donald, Carl M Mendel [email protected] Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063, 7505 Tygerberg, South Africa (AHD); Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa (PRD); and Global Alliance for TB Drug Development, New York, NY, USA (CMM)
www.thelancet.com Vol 381 January 12, 2013
Correspondence
1
2
3
4
Diacon AH, Dawson R, von Groote-Bidlingmaier F, et al. 14 day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. Lancet 2012; 380: 986–93. Jindani A, Aber VR, Edwards EA, Mitchison DA. The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis 1980; 121: 939–49. Ma Z, Lienhardt C, McIlleron H, Nunn AJ, Wang X. Global tuberculosis drug development pipeline: the need and the reality. Lancet 2010; 375: 2100–09. Wallis RS, Pai M, Menzies D, et al. Biomarkers and diagnostics for tuberculosis: progress, needs, and translation into practice. Lancet 2010; 375: 1920–37.
Stem-cell-based, tissue-engineered tracheal replacement in a child Martin Elliott and colleagues (Sept 15, p 994)1 report the third case of transplantation of a tissueengineered airway. These three case reports have been published over the past 4 years in The Lancet by more-or-less the same research group. The first paper2 reported on a decellularised tracheal allotransplant which was repopulated ex vivo by use of a complex bioreactor. The second3 involved a synthetic tracheal prosthesis that had been repopulated by use of an in-vivo tissue-engineering technique. The third paper1 switched to a decellularised allotransplant with in-vivo repopulation. However, the working mechanism of the tissueengineered airway remains unclear. There are no experimental studies available on how the avascular constructs become revascularised and remucosalised, and the different approaches within the three cases are confusing. We know that an airway defect can be temporarily repaired with a synthetic tube or stent wrapped with vascularised omentum.4 Hence, it is important to assess the individual contribution of the tissues interposed between stent and omentum. An essential part of the tissue-engineered trachea seems to be www.thelancet.com Vol 381 January 12, 2013
the chondrocyte differentiation within the cartilaginous trachea. Therefore, a comparison between cartilaginous and membranous trachea would have been informative. However, the available CT scans are difficult to interpret: the cartilaginous and membranous trachea cannot be distinguished, and whether the airway is still supported by the Nitinol stent after 12 months is not clear. How the different components— omentum, stent, and tissueengineered airway—contribute to the outcome of the procedure is therefore still uncertain. I declare that I have no conflicts of interest.
Pierre R Delaere [email protected] Department of Otorhinolaryngology Head & Neck Surgery, University Hospital K U Leuven, 3000 Leuven, Belgium 1
2
3
4
Elliott M J, De Coppi P, Speggiorin S, et al. Stem-cell-based, tissue engineered tracheal replacement in a child: a 2-year follow-up study. Lancet 2012; 380: 994–1000. Macchiarini P, Junglebluth P, Go T, et al. Clinical transplantation of a tissue-engineered airway. Lancet 2008; 372: 2023–30. Jungebluth P, Alici E, Baiguera S, et al. Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study. Lancet 2011; 378: 1997–2004. Delaere PR. Tracheal transplantation. Curr Opin Pulm Med 2012; 18: 313–20.
Authors’ reply Although there is overlap between authors and subject in the three Lancet papers Pierre Delaere cites,1–3 these represent three projects by different groups, separately assembled to achieve specific goals. Moreover, we reported the longest follow-up and the first transplantation in a child.1 The different, but congruent, approaches used in each case represent an evolution in thought, not just by the authors, but by the wider world of regenerative medicine, which has moved with astonishing pace since the first of these papers was published. Additionally, the approaches reflect the different acute needs of individual patients (who would have otherwise died), treated under compassionate-
use licences.4 They are not mutually exclusive. We are pleased that Delaere points out how little is known about the precise mechanisms by which these grafts integrate and maintain function. This is a point we make in these papers and calls for considerable reversetranslational discovery science so that we can learn more about the interaction between the cells and tissues we and others5 are applying successfully to patients. The technologies available for such study in man are limited, and require specific investment. For example, safe and effective means to track implanted stem cells and their progeny are required. We agree that formal clinical trials are needed to follow these important but, as Delaere points out, one-off, case reports. There will probably always be a need for the compassionate use of evolving techniques. Such uses provide not only hope for an individual, but useful clues to inform the necessary laboratory science. We declare that we have no conflicts of interest.
*Martin A Birchall, Martin J Elliott, Mark Lowdell, Paolo De Coppi [email protected] Royal National Throat Nose and Ear Hospital, UCL Ear Institute, London WC1X 8DA, UK (MAB); Department of Cardiothoracic Surgery, Great Ormond Street, Hospital for Children, London, UK (MJE); Paul O’Gorman Laboratory of Cellular Therapeutics, Department of Haematology, Royal Free Hospital, London, UK (ML); and Department of Surgery, Great Ormond Street, Hospital for Children, London, UK (PDC) 1
2
3
4
5
Elliott M J, De Coppi P, Speggiorin S, et al. Stem-cell-based, tissue engineered tracheal replacement in a child: a 2-year follow-up study. Lancet 2012; 380: 994–1000. Macchiarini P, Junglebluth P, Go T, et al. Clinical transplantation of a tissue-engineered airway. Lancet 2008; 372: 2023–30. Jungebluth P, Alici E, Baiguera S, et al. Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study. Lancet 2011; 378: 1997–2004. Lowdell MW, Birchall M, Thrasher AJ. Use of compassionate-case ATMP in preclinical data for clinical trial applications. Lancet 2012; 379: 2341. Raya-Rivera A, Esquiliano DR, Yoo JJ, Lopez-Bayghen E, Soker S, Atala A. Tissue-engineered autologous urethras for patients who need reconstruction: an observational study. Lancet 2011; 377: 1175–82.
113
0
Δ log CFU/mL
–1 –2 –3
H2 H6 HREZ7 HRSZ3
–4 –5 0
7 Day
H2 HR2 HST3 HRSZ3 14
0
7
14 Day
21
28
Figure: Published trials of quantitative sputum microbiology in patients with pulmonary tuberculosis of 7–28 days’ duration Left: Across-trial comparisons of similar treatments, showing similar results. Right: Within-trial comparisons of distinct treatments, showing similar results during first 14 days. H=isoniazid; R=rifampicin, E=ethambutol; S=streptomycin, Z=pyrazinamide; T=thiacetazone. CFU=colony-forming units.
short-duration trials. The concept that such trials can inform the required duration of treatment is unsupported by clinical data. RSW is an employee and shareholder of Pfizer. CN is an employee and Chief Executive Officer of Sequella.
*Robert S Wallis, Carol Nacy robert.wallis@pfizer.com Pfizer, Groton, CT 06340, USA (RSW); and Sequella, Rockville, MD, USA (CN) 1
2
3
4
5
6
7
112
Diacon AH, Dawson R, von Groote-Bidlingmaier F, et al. 14 day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. Lancet 2012; 380: 986–93. Wallis RS, Phillips M, Johnson JL, et al. Inhibition of INH-induced expression of M tuberculosis antigen 85 in sputum: a potential surrogate marker in TB chemotherapy trials. Antimicrob Agents Chemother 2001; 45: 1302–44. Brindle R, Odhiambo J, Mitchison DA. Serial counts of Mycobacterium tuberculosis in sputum as surrogate markers of the sterilising activity of rifampicin and pyrazinamide in treating pulmonary tuberculosis. BMC Pulm Med 2001; 1: 2. East and Central African-British Medical Research Council. Controlled clinical trial of 4 short-course regimens of chemotherapy (three 6-month and one 8-month) for pulmonary tuberculosis. Tubercle 1983; 64: 153–66. East African-British Medical Research Councils. Results at 5 years of a controlled comparison of a 6-month and a standard 18-month regimen of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 1977; 116: 3–8. Rustomjee R, Diacon AH, Allen J, et al. Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC 207 in pulmonary tuberculosis. Antimicrob Agents Chemother 2008; 52: 2831–35. Diacon AH, Dawson R, Hanekom M, et al. Early bactericidal activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients. Antimicrob Agents Chemother 2010; 54: 3402–07.
Authors’ reply We agree with Prasanta Mohapatra and colleagues and Zarir Udwadia that the efficacy of the PA-824moxifloxacin-pyrazinamide regimen must be shown in clinical trials that include patients with multidrugresistant (MDR) tuberculosis. Obviously, this regimen cannot be appropriate for all such patients because their isolates can harbour resistance beyond that to isoniazid and rifampicin, including moxifloxacin and pyrazinamide. A study of PA824-moxifloxacin-pyrazinamide over 8 weeks, which includes patients with MDR tuberculosis susceptible to moxifloxacin and pyrazinamide, is currently underway (ClinicalTrials. gov identifier NCT01498419). The results of our published study1 suggest that patients who receive PA-824-moxifloxacin-pyrazinamide, but neither isoniazid nor rifampicin, hitherto regarded as essential, will not be therapeutically disadvantaged in the ongoing study. Udwadia shares our enthusiasm for constructing a combination of at least three novel chemical entities that can be combined safely and to which resistance would be unlikely to occur naturally. Such a universal regimen would treat all forms of tuberculosis, thereby obviating the necessity for susceptibility testing for drugs currently in use. Until such a regimen becomes available, it remains important to use several drugs to
which a patient’s Mycobacterium tuberculosis isolate is sensitive, and susceptibility testing is essential for the correct treatment of all drugresistant tuberculosis. Robert Wallis and Carol Nacy seem to misunderstand the role of early bactericidal activity studies in our development pathway. All our current first-line antituberculosis drugs and regimens have shown efficacy, when appropriately tested, in mouse models, in 2-week early bactericidal activity studies, in 2-month clinical trials, and in long-term clinical trials.2,3 The mouse relapse model forms the initial basis for constructing any new regimen to advance into clinical evaluation. Hypotheses based on mouse studies must then continue to be supported by findings in short-term, intermediateterm, and long-term trials to remain viable. Our 2-week trial of the early bactericidal activity of PA-824moxifloxacin-pyrazinamide1 represents the first step in this systematic process. It remains an open, but extremely important, question as to exactly how well data based on sputum sampling in the early phase of treatment (whether for 2 weeks or for 2 months) predict long-term outcomes; unfortunately there is no single biomarker or shortterm study to provide definitive evidence of the necessary treatment duration to achieve cure.4 We believe that only after rigorous, methodical studies, such as our completed 2-week trial,1 our ongoing 2-month trial, and hopefully a future phase 3 trial, will we better understand the predictive capability of short-term clinical studies. We declare that we have no conflicts of interest.
*Andreas H Diacon, Peter R Donald, Carl M Mendel [email protected] Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063, 7505 Tygerberg, South Africa (AHD); Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa (PRD); and Global Alliance for TB Drug Development, New York, NY, USA (CMM)
www.thelancet.com Vol 381 January 12, 2013
Correspondence
1
2
3
4
Diacon AH, Dawson R, von Groote-Bidlingmaier F, et al. 14 day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. Lancet 2012; 380: 986–93. Jindani A, Aber VR, Edwards EA, Mitchison DA. The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis 1980; 121: 939–49. Ma Z, Lienhardt C, McIlleron H, Nunn AJ, Wang X. Global tuberculosis drug development pipeline: the need and the reality. Lancet 2010; 375: 2100–09. Wallis RS, Pai M, Menzies D, et al. Biomarkers and diagnostics for tuberculosis: progress, needs, and translation into practice. Lancet 2010; 375: 1920–37.
Stem-cell-based, tissue-engineered tracheal replacement in a child Martin Elliott and colleagues (Sept 15, p 994)1 report the third case of transplantation of a tissueengineered airway. These three case reports have been published over the past 4 years in The Lancet by more-or-less the same research group. The first paper2 reported on a decellularised tracheal allotransplant which was repopulated ex vivo by use of a complex bioreactor. The second3 involved a synthetic tracheal prosthesis that had been repopulated by use of an in-vivo tissue-engineering technique. The third paper1 switched to a decellularised allotransplant with in-vivo repopulation. However, the working mechanism of the tissueengineered airway remains unclear. There are no experimental studies available on how the avascular constructs become revascularised and remucosalised, and the different approaches within the three cases are confusing. We know that an airway defect can be temporarily repaired with a synthetic tube or stent wrapped with vascularised omentum.4 Hence, it is important to assess the individual contribution of the tissues interposed between stent and omentum. An essential part of the tissue-engineered trachea seems to be www.thelancet.com Vol 381 January 12, 2013
the chondrocyte differentiation within the cartilaginous trachea. Therefore, a comparison between cartilaginous and membranous trachea would have been informative. However, the available CT scans are difficult to interpret: the cartilaginous and membranous trachea cannot be distinguished, and whether the airway is still supported by the Nitinol stent after 12 months is not clear. How the different components— omentum, stent, and tissueengineered airway—contribute to the outcome of the procedure is therefore still uncertain. I declare that I have no conflicts of interest.
Pierre R Delaere [email protected] Department of Otorhinolaryngology Head & Neck Surgery, University Hospital K U Leuven, 3000 Leuven, Belgium 1
2
3
4
Elliott M J, De Coppi P, Speggiorin S, et al. Stem-cell-based, tissue engineered tracheal replacement in a child: a 2-year follow-up study. Lancet 2012; 380: 994–1000. Macchiarini P, Junglebluth P, Go T, et al. Clinical transplantation of a tissue-engineered airway. Lancet 2008; 372: 2023–30. Jungebluth P, Alici E, Baiguera S, et al. Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study. Lancet 2011; 378: 1997–2004. Delaere PR. Tracheal transplantation. Curr Opin Pulm Med 2012; 18: 313–20.
Authors’ reply Although there is overlap between authors and subject in the three Lancet papers Pierre Delaere cites,1–3 these represent three projects by different groups, separately assembled to achieve specific goals. Moreover, we reported the longest follow-up and the first transplantation in a child.1 The different, but congruent, approaches used in each case represent an evolution in thought, not just by the authors, but by the wider world of regenerative medicine, which has moved with astonishing pace since the first of these papers was published. Additionally, the approaches reflect the different acute needs of individual patients (who would have otherwise died), treated under compassionate-
use licences.4 They are not mutually exclusive. We are pleased that Delaere points out how little is known about the precise mechanisms by which these grafts integrate and maintain function. This is a point we make in these papers and calls for considerable reversetranslational discovery science so that we can learn more about the interaction between the cells and tissues we and others5 are applying successfully to patients. The technologies available for such study in man are limited, and require specific investment. For example, safe and effective means to track implanted stem cells and their progeny are required. We agree that formal clinical trials are needed to follow these important but, as Delaere points out, one-off, case reports. There will probably always be a need for the compassionate use of evolving techniques. Such uses provide not only hope for an individual, but useful clues to inform the necessary laboratory science. We declare that we have no conflicts of interest.
*Martin A Birchall, Martin J Elliott, Mark Lowdell, Paolo De Coppi [email protected] Royal National Throat Nose and Ear Hospital, UCL Ear Institute, London WC1X 8DA, UK (MAB); Department of Cardiothoracic Surgery, Great Ormond Street, Hospital for Children, London, UK (MJE); Paul O’Gorman Laboratory of Cellular Therapeutics, Department of Haematology, Royal Free Hospital, London, UK (ML); and Department of Surgery, Great Ormond Street, Hospital for Children, London, UK (PDC) 1
2
3
4
5
Elliott M J, De Coppi P, Speggiorin S, et al. Stem-cell-based, tissue engineered tracheal replacement in a child: a 2-year follow-up study. Lancet 2012; 380: 994–1000. Macchiarini P, Junglebluth P, Go T, et al. Clinical transplantation of a tissue-engineered airway. Lancet 2008; 372: 2023–30. Jungebluth P, Alici E, Baiguera S, et al. Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study. Lancet 2011; 378: 1997–2004. Lowdell MW, Birchall M, Thrasher AJ. Use of compassionate-case ATMP in preclinical data for clinical trial applications. Lancet 2012; 379: 2341. Raya-Rivera A, Esquiliano DR, Yoo JJ, Lopez-Bayghen E, Soker S, Atala A. Tissue-engineered autologous urethras for patients who need reconstruction: an observational study. Lancet 2011; 377: 1175–82.
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