correspondence
Sharon D. Yeatts, Ph.D. Medical University of South Carolina
Charleston, SC
Robert Silbergleit, M.D. University of Michigan
Ann Arbor, MI Since publication of their article, the authors report no further potential conflict of interest. 1. Xiong Y, Mahmood A, Chopp M. Animal models of trau-
matic brain injury. Nat Rev Neurosci 2013;14:128-42. DOI: 10.1056/NEJMc1503138
imaging, whereas Khanna et al. emphasize the need to focus on molecular mechanisms of injury, rather than on gross clinical and radiologic observations. TBI has appropriately been termed “the most complicated disease of the most complex organ of the body.”2 Better characterization of the disease processes in individual patients may permit more appropriate targeting of therapy. Determination of benefit will require mechanistic end points, but proof of clinical effectiveness should be based on multidimensional assessments of outcome. Large international efforts are currently ongoing in these directions.3 The International Initiative for Traumatic Brain Injury Research, instituted in 2011 as a collaboration among major funding agencies, has provided a substantial stimulus to these efforts.4 Brett E. Skolnick, Ph.D.
Dr. Skolnick and colleagues reply: We appreciate the acknowledgment by Xydakis et al. of our efforts to avoid potential sources of bias while conducting a very large, complex, multinational clinical trial of TBI. We relied on the Glasgow Coma Scale score as the primary entry criterion and the Glasgow Outcome Scale score as the primary end point, because these instruments have been Hofstra North Shore–LIJ School of Medicine shown to be robust over several decades. We agree Hempstead, NY that they have their limitations, and we support [email protected] the concept of multidimensional approaches to Andrew I.R. Maas, M.D., Ph.D. classification of initial severity and of outcome.1 University Hospital Antwerp However, how exactly these new pieces of infor- Edegem, Belgium mation may best be used to improve TBI trial Raj K. Narayan, M.D. design and sensitivity remains to be determined. Hofstra North Shore–LIJ School of Medicine Xydakis et al. raise an important point regard- Hempstead, NY ing the need to evaluate patient subgroups on the for the SYNAPSE Steering Committee basis of relevant criteria, whether biomarkers or Since publication of their article, the authors report no furimaging components. Indeed, we performed ex- ther potential conflict of interest. tensive prespecified subgroup analyses (see Table 1. Manley GT, Maas AI. Traumatic brain injury: an interna2 of our article) and post hoc subgroup analyses. tional knowledge-based approach. JAMA 2013;310:473-4. We found no hint of a trend toward efficacy in 2. Marklund N, Hillered L. Animal modelling of traumatic injury in preclinical drug development: where do we go any of these analyses, in patients with diffuse brain from here? Br J Pharmacol 2011;164:1207-29. injury, mass lesions, or traumatic subarachnoid 3. Maas AI, Menon DK, Steyerberg EW, et al. Collaborative Euhemorrhage or in those undergoing surgery. It ropean NeuroTrauma Effectiveness Research in Traumatic Brain (CENTER-TBI): a prospective longitudinal observational would therefore seem unlikely that progesterone Injury study. Neurosurgery 2015;76:67-80. had any benefit in these subpopulations. 4. Tosetti P, Hicks RR, Theriault E, Phillips A, Koroshetz W, It is of interest that Xydakis et al. suggest a Draghia-Akli R. Toward an international initiative for traumatic potential role for characterizing patients on the brain injury research. J Neurotrauma 2013;30:1211-22. basis of pathoanatomical findings from neuro- DOI: 10.1056/NEJMc1503138
Preexposure Prophylaxis for HIV Infection To the Editor: The study by Marrazzo et al. (Feb. 5 issue)1 highlights the need for cautious monitoring during the rollout of preexposure prophylaxis against human immunodeficiency virus
(HIV) infection. In keeping with the maxim “first, do no harm,” the burden of proof against potential harm needs to be high, because people who qualify for preexposure prophylaxis are generally
n engl j med 372;18 nejm.org april 30, 2015
The New England Journal of Medicine Downloaded from nejm.org on August 13, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
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young and healthy. Tenofovir disoproxil fuma- Reed A. Siemieniuk, M.D. rate (TDF) may reduce bone mineral density2 and Isaac I. Bogoch, M.D. is associated with proximal renal tubulopathy, University of Toronto phosphate wasting, and resultant osteomalacia.3 Toronto, ON, Canada TDF may also have an effect on osteoblast func- [email protected] No potential conflict of interest relevant to this letter was retion.4 It is unclear whether TDF-related loss of ported. bone density is cumulatively dose-dependent, reversible, or more severe in geographic areas in 1. Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovirbased preexposure prophylaxis for HIV infection among African which vitamin D deficiency is prevalent — all of women. N Engl J Med 2015;372:509-18. which are factors that have long-term implica- 2. Liu AY, Vittinghoff E, Sellmeyer DE, et al. Bone mineral dentions for young patients. Although clinical trials sity in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco. have not identified any clear signal of harm, in- PLoS One 2011;6(8):e23688. tention-to-treat analyses underestimate the inci- 3. Mateo L, Holgado S, Mariñoso ML, et al. Hypophosphatemic dence of adverse effects, especially events with a osteomalacia induced by tenofovir in HIV-infected patients. Clin Rheumatol 2014 May 3 (Epub ahead of print). long lead time. This underestimation is greater 4. Grigsby IF, Pham L, Mansky LM, Gopalakrishnan R, Carlson when compliance with a study-drug regimen is AE, Mansky KC. Tenofovir treatment of primary osteoblasts allow, as it was in the study by Marrazzo et al. and ters gene expression profiles: implications for bone mineral density loss. Biochem Biophys Res Commun 2010;394:48-53. in other trials.5 As the role of preexposure pro- 5. Corneli AL, Deese J, Wang M, et al. FEM-PrEP: adherence phylaxis in the fight to end HIV infection appro- patterns and factors associated with adherence to a daily oral priately expands, scientific vigilance is required study product for pre-exposure prophylaxis. J Acquir Immune Defic Syndr 2014;66:324-31. for the early identification of any adverse conseDOI: 10.1056/NEJMc1502749 quences.
V122I Transthyretin Variant in Elderly Black Americans To the Editor: In their long-term analysis of black American carriers of the V122I allele in the transthyretin gene (TTR), Quarta et al. (Jan. 1 issue)1 confirm reported carrier frequencies2 but find a low prevalence of echocardiographic features of cardiomyopathy and no significant effect on mortality in spite of an increased incidence of heart failure. However, amyloid cardiomyopathy associated with the TTR V122I variant disproportionately afflicts elderly men,3 and only 11 men were included in the final analysis. The mortality trend in carriers older than 80 years of age and the disparate male dropout rate suggest that in a larger and older population, a significant risk of death among carriers might be detected. The inclusion of all the study participants in the multiple-imputation analysis might better handle the bias of missing data. The conclusion that the presence of the TTR V122I mutation “may be more benign than previously thought” could be premature and should not deter clinicians from identifying carriers of this variant who have cardiomyopathy and from monitoring them for heart failure and histochemical evidence of amyloidosis. In addition,
1768
such patients could be considered as candidates for trials of new therapeutics for TTR amyloidosis4 or, if necessary, for orthotopic heart transplantation. Frederick L. Ruberg, M.D. John L. Berk, M.D. Boston University School of Medicine Boston, MA
Marc J. Semigan, M.D. Massachusetts General Hospital Boston, MA Drs. Ruberg and Berk report having received consulting fees from Alnylam Pharmaceuticals. No other potential conflict of interest relevant to this letter was reported. 1. Quarta CC, Buxbaum JN, Shah AM, et al. The amyloidogenic
V122I transthyretin variant in elderly black Americans. N Engl J Med 2015;372:21-9. 2. Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant- sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 1997;336:466-73. 3. Connors LH, Prokaeva T, Lim A, et al. Cardiac amyloidosis in African Americans: comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J 2009;158:607-14. 4. Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 2013;310:2658-67. DOI: 10.1056/NEJMc1503222
n engl j med 372;18 nejm.org april 30, 2015
The New England Journal of Medicine Downloaded from nejm.org on August 13, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
Sharon D. Yeatts, Ph.D. Medical University of South Carolina
Charleston, SC
Robert Silbergleit, M.D. University of Michigan
Ann Arbor, MI Since publication of their article, the authors report no further potential conflict of interest. 1. Xiong Y, Mahmood A, Chopp M. Animal models of trau-
matic brain injury. Nat Rev Neurosci 2013;14:128-42. DOI: 10.1056/NEJMc1503138
imaging, whereas Khanna et al. emphasize the need to focus on molecular mechanisms of injury, rather than on gross clinical and radiologic observations. TBI has appropriately been termed “the most complicated disease of the most complex organ of the body.”2 Better characterization of the disease processes in individual patients may permit more appropriate targeting of therapy. Determination of benefit will require mechanistic end points, but proof of clinical effectiveness should be based on multidimensional assessments of outcome. Large international efforts are currently ongoing in these directions.3 The International Initiative for Traumatic Brain Injury Research, instituted in 2011 as a collaboration among major funding agencies, has provided a substantial stimulus to these efforts.4 Brett E. Skolnick, Ph.D.
Dr. Skolnick and colleagues reply: We appreciate the acknowledgment by Xydakis et al. of our efforts to avoid potential sources of bias while conducting a very large, complex, multinational clinical trial of TBI. We relied on the Glasgow Coma Scale score as the primary entry criterion and the Glasgow Outcome Scale score as the primary end point, because these instruments have been Hofstra North Shore–LIJ School of Medicine shown to be robust over several decades. We agree Hempstead, NY that they have their limitations, and we support [email protected] the concept of multidimensional approaches to Andrew I.R. Maas, M.D., Ph.D. classification of initial severity and of outcome.1 University Hospital Antwerp However, how exactly these new pieces of infor- Edegem, Belgium mation may best be used to improve TBI trial Raj K. Narayan, M.D. design and sensitivity remains to be determined. Hofstra North Shore–LIJ School of Medicine Xydakis et al. raise an important point regard- Hempstead, NY ing the need to evaluate patient subgroups on the for the SYNAPSE Steering Committee basis of relevant criteria, whether biomarkers or Since publication of their article, the authors report no furimaging components. Indeed, we performed ex- ther potential conflict of interest. tensive prespecified subgroup analyses (see Table 1. Manley GT, Maas AI. Traumatic brain injury: an interna2 of our article) and post hoc subgroup analyses. tional knowledge-based approach. JAMA 2013;310:473-4. We found no hint of a trend toward efficacy in 2. Marklund N, Hillered L. Animal modelling of traumatic injury in preclinical drug development: where do we go any of these analyses, in patients with diffuse brain from here? Br J Pharmacol 2011;164:1207-29. injury, mass lesions, or traumatic subarachnoid 3. Maas AI, Menon DK, Steyerberg EW, et al. Collaborative Euhemorrhage or in those undergoing surgery. It ropean NeuroTrauma Effectiveness Research in Traumatic Brain (CENTER-TBI): a prospective longitudinal observational would therefore seem unlikely that progesterone Injury study. Neurosurgery 2015;76:67-80. had any benefit in these subpopulations. 4. Tosetti P, Hicks RR, Theriault E, Phillips A, Koroshetz W, It is of interest that Xydakis et al. suggest a Draghia-Akli R. Toward an international initiative for traumatic potential role for characterizing patients on the brain injury research. J Neurotrauma 2013;30:1211-22. basis of pathoanatomical findings from neuro- DOI: 10.1056/NEJMc1503138
Preexposure Prophylaxis for HIV Infection To the Editor: The study by Marrazzo et al. (Feb. 5 issue)1 highlights the need for cautious monitoring during the rollout of preexposure prophylaxis against human immunodeficiency virus
(HIV) infection. In keeping with the maxim “first, do no harm,” the burden of proof against potential harm needs to be high, because people who qualify for preexposure prophylaxis are generally
n engl j med 372;18 nejm.org april 30, 2015
The New England Journal of Medicine Downloaded from nejm.org on August 13, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
1767
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
young and healthy. Tenofovir disoproxil fuma- Reed A. Siemieniuk, M.D. rate (TDF) may reduce bone mineral density2 and Isaac I. Bogoch, M.D. is associated with proximal renal tubulopathy, University of Toronto phosphate wasting, and resultant osteomalacia.3 Toronto, ON, Canada TDF may also have an effect on osteoblast func- [email protected] No potential conflict of interest relevant to this letter was retion.4 It is unclear whether TDF-related loss of ported. bone density is cumulatively dose-dependent, reversible, or more severe in geographic areas in 1. Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovirbased preexposure prophylaxis for HIV infection among African which vitamin D deficiency is prevalent — all of women. N Engl J Med 2015;372:509-18. which are factors that have long-term implica- 2. Liu AY, Vittinghoff E, Sellmeyer DE, et al. Bone mineral dentions for young patients. Although clinical trials sity in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco. have not identified any clear signal of harm, in- PLoS One 2011;6(8):e23688. tention-to-treat analyses underestimate the inci- 3. Mateo L, Holgado S, Mariñoso ML, et al. Hypophosphatemic dence of adverse effects, especially events with a osteomalacia induced by tenofovir in HIV-infected patients. Clin Rheumatol 2014 May 3 (Epub ahead of print). long lead time. This underestimation is greater 4. Grigsby IF, Pham L, Mansky LM, Gopalakrishnan R, Carlson when compliance with a study-drug regimen is AE, Mansky KC. Tenofovir treatment of primary osteoblasts allow, as it was in the study by Marrazzo et al. and ters gene expression profiles: implications for bone mineral density loss. Biochem Biophys Res Commun 2010;394:48-53. in other trials.5 As the role of preexposure pro- 5. Corneli AL, Deese J, Wang M, et al. FEM-PrEP: adherence phylaxis in the fight to end HIV infection appro- patterns and factors associated with adherence to a daily oral priately expands, scientific vigilance is required study product for pre-exposure prophylaxis. J Acquir Immune Defic Syndr 2014;66:324-31. for the early identification of any adverse conseDOI: 10.1056/NEJMc1502749 quences.
V122I Transthyretin Variant in Elderly Black Americans To the Editor: In their long-term analysis of black American carriers of the V122I allele in the transthyretin gene (TTR), Quarta et al. (Jan. 1 issue)1 confirm reported carrier frequencies2 but find a low prevalence of echocardiographic features of cardiomyopathy and no significant effect on mortality in spite of an increased incidence of heart failure. However, amyloid cardiomyopathy associated with the TTR V122I variant disproportionately afflicts elderly men,3 and only 11 men were included in the final analysis. The mortality trend in carriers older than 80 years of age and the disparate male dropout rate suggest that in a larger and older population, a significant risk of death among carriers might be detected. The inclusion of all the study participants in the multiple-imputation analysis might better handle the bias of missing data. The conclusion that the presence of the TTR V122I mutation “may be more benign than previously thought” could be premature and should not deter clinicians from identifying carriers of this variant who have cardiomyopathy and from monitoring them for heart failure and histochemical evidence of amyloidosis. In addition,
1768
such patients could be considered as candidates for trials of new therapeutics for TTR amyloidosis4 or, if necessary, for orthotopic heart transplantation. Frederick L. Ruberg, M.D. John L. Berk, M.D. Boston University School of Medicine Boston, MA
Marc J. Semigan, M.D. Massachusetts General Hospital Boston, MA Drs. Ruberg and Berk report having received consulting fees from Alnylam Pharmaceuticals. No other potential conflict of interest relevant to this letter was reported. 1. Quarta CC, Buxbaum JN, Shah AM, et al. The amyloidogenic
V122I transthyretin variant in elderly black Americans. N Engl J Med 2015;372:21-9. 2. Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant- sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 1997;336:466-73. 3. Connors LH, Prokaeva T, Lim A, et al. Cardiac amyloidosis in African Americans: comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J 2009;158:607-14. 4. Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 2013;310:2658-67. DOI: 10.1056/NEJMc1503222
n engl j med 372;18 nejm.org april 30, 2015
The New England Journal of Medicine Downloaded from nejm.org on August 13, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
