The
n e w e ng l a n d j o u r na l
of
m e dic i n e
data, protocols, and clinical-study reports should Michael Rosenblatt, M.D. be made available on request to qualified re- Merck searchers pursuing legitimate research projects Whitehouse Station, NJ [email protected] for medicines and indications approved in the United States and the European Union. Second, for the Chief Medical Officers Roundtable Barron reports being an employee of Hoffmann–La Roche there should be public disclosure of synopses of andDr.Genentech and holding stock and stock options in Roche; clinical-study reports after approval in the United and Dr. Rosenblatt, being an employee of and holding stock and States and the European Union. Third, summa- stock options in Merck. No other potential conflict of interest ries that are written in lay language should be relevant to this letter was reported. provided to patients involved in clinical trials. 1. Eichler H-G, Pétavy F, Pignatti F, Rasi G. Access to patientlevel trial data — a boon to drug developers. N Engl J Med 2013; Fourth, procedures should be adopted to imple- 369:1577-9. ment these principles. And fifth, researchers need 2. Nisen P, Rockhold F. Access to patient-level data from to make a commitment to publish study results, GlaxoSmithKline clinical trials. N Engl J Med 2013;369:475-8. Rawal B, Deane BR. Clinical trial transparency: an assesswhether negative or positive. The CMOR fully 3. ment of the disclosure of results of company-sponsored trials supports the sharing of patient-level clinical trial associated with new medicines approved recently in Europe. data, by all who generate such data, in the inter- Curr Med Res Opin 2013 November 11 (Epub ahead of print). 4. EFPIA and PhRMA. Principles for responsible clinical trial est of patients. data sharing: our commitment to patients and researchers (http:// phrma.org/sites/default/files/pdf/PhRMAPrinciplesForResponsible Hal Barron, M.D. ClinicalTrialDataSharing.pdf).
Hoffmann–La Roche South San Francisco, CA
DOI: 10.1056/NEJMc1315673
Maraviroc and JC Virus–Associated Immune Reconstitution Inflammatory Syndrome To the Editor: The immune reconstitution inflammatory syndrome (IRIS) can be a serious complication in immunocompromised patients in whom progressive multifocal leukoencephalopathy (PML) has developed. IRIS occurs in such patients when their immunocompromised state reverses.1 Although restored immune surveillance is vital for clearing the JC virus that causes PML, improved management strategies for IRIS are needed because of its potential for considerable complications and death. The common, though unproven, use of glucocorticoids to treat IRIS may limit JC viral clearance.2 Because of the indirect implication of chemokine receptor 5– positive (CCR5+) T cells in IRIS pathophysiology,3 we used the small-molecule CCR5 antagonist maraviroc, which has been approved for the treatment of human immunodeficiency virus (HIV) infection to inhibit CCR5-dependent viral docking, in a patient with multiple sclerosis who presented with natalizumab-associated PML and features that were expected to predict the development of IRIS.4,5 A 49-year-old, HIV-negative woman with relapsing–remitting multiple sclerosis and a score of 2.5 on the Expanded Disability Status Scale 486
(EDSS, which ranges from 0 to 10, with higher scores indicating more severe disability) had received 43 infusions of natalizumab monotherapy over a period of 3.6 years. She received a diagnosis of PML after presenting with an episode of aphasia and seizure. She was considered at risk for severe IRIS because of the multilobar PML (Fig. 1A and 1B) and an elevated JC viral load in the cerebrospinal fluid (130,000 copies per milliliter) as measured by means of a polymerasechain-reaction assay (Focus Diagnostics). Oral maraviroc at a dose of 300 mg twice daily was initiated shortly after plasmapheresis. No glucocorticoids or other immunomodulating therapy was given throughout the course of the PML illness. The patient was monitored closely with frequent clinical and imaging evaluations. Serial cerebrospinal fluid analyses showed that maraviroc treatment was associated with a selective decrease in CCR5+ immune cells in the cerebrospinal fluid (see the Figure in the Supplementary Appendix, available with the full text of this letter at NEJM.org). These findings suggest that maraviroc functionally inhibits CCR5-dependent immune-cell trafficking into the central nervous system (CNS). The patient’s condition remained
n engl j med 370;5 nejm.org january 30, 2014
The New England Journal of Medicine Downloaded from nejm.org on September 12, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
A
C
B
D
E
Figure 1. Sequential Magnetic Resonance Images of the Brain. When the patient presented for treatment, axial fluid-attenuated inversion recovery images showed multilobar progressive multifocal leukoencephalopathy (Panels A and B). A T1-weighted image after gadolinium infusion showed frank immune reconstitution inflammatory syndrome (IRIS) after the patient discontinued maraviroc (Panel C). After the patient began to receive maraviroc again, a T1-weighted image after gadolinium infusion showed regression of IRIS (Panel D). A T1-weighted image after gadolinium infusion obtained 2 months after gradual discontinuation of maraviroc showed stable lesions with no enhancement (Panel E).
stable, without clinical or imaging evidence of overt IRIS. Approximately 2 months after plasmapheresis, she inadvertently stopped taking maraviroc for 5 days and presented with cognitive and behavioral changes. Features on brain magnetic resonance imaging (MRI) were consistent with IRIS that involved all visible PML lesions (Fig. 1C). Oral maraviroc at a dose of 300 mg twice daily was reintroduced (without glucocorticoids), with close clinical and imaging follow-up. The patient’s cognitive and behavioral abnormalities steadily improved, though mild deficits persisted, and features of IRIS on imaging attenuated over weeks (Fig. 1D). The dose of maraviroc was reduced to 150 mg twice daily because of imaging evidence of IRIS regression, and the dose was eventually tapered off after 7 months once the lesions on MRI were stable and no lonn engl j med 370;5
ger showed gadolinium enhancement (Fig. 1E). Repeat cerebrospinal fluid analysis at 10 months was negative for JC virus. The patient survived both her PML infection and IRIS with few persisting sequelae; at 1 year after the initiation of maraviroc, she had an EDSS score of 3.0 and she continued to have mild cognitive deficits. No new multiple sclerosis disease activity was noted, and no new therapy for multiple sclerosis was introduced. Our findings, which implicate CCR5+ immune cells as mediators of IRIS, suggest that without the use of glucocorticoids, maraviroc contributed both to initial prevention of IRIS and to active treatment of IRIS once it was established. Our data on selective reduction in the proportions of CCR5+ immune-cell subsets in the cerebrospinal fluid show that maraviroc may selectively
nejm.org
january 30, 2014
The New England Journal of Medicine Downloaded from nejm.org on September 12, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
487
The
n e w e ng l a n d j o u r na l
limit trafficking into the CNS compartment in vivo and highlight the potential for selective targeting of immune-cell chemotaxis and trafficking in the management of complex immunologic disorders. Paul S. Giacomini, M.D. Ayal Rozenberg, M.D.
m e dic i n e
words (excluding references) and must be received within 3 weeks after publication of the article. • Letters not related to a Journal article must not exceed 400 words. • A letter can have no more than five references and one figure or table. • A letter can be signed by no more than three authors.
Imke Metz, M.D.
• Financial associations or other possible conflicts of interest must be disclosed. Disclosures will be published with the letters. (For authors of Journal articles who are responding to letters, we will only publish new relevant relationships that have developed since publication of the article.)
Georg-August University Göttingen, Germany
• Include your full mailing address, telephone number, fax number, and e-mail address with your letter.
David Araujo, M.D.
• All letters must be submitted at authors.NEJM.org.
McGill University Montreal, QC, Canada
Letters that do not adhere to these instructions will not be considered. We will notify you when we have made a decision about possible publication. Letters regarding a recent Journal article may be shared with the authors of that article. We are unable to provide prepublication proofs. Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it in the Journal’s various print and electronic publications and in collections, revisions, and any other form or medium.
McGill University Montreal, QC, Canada
Nathalie Arbour, Ph.D. University of Montreal Montreal, QC, Canada
Amit Bar-Or, M.D. McGill University Montreal, QC, Canada [email protected]
for the Maraviroc in Multiple Sclerosis– Associated PML–IRIS (MIMSAPI) Group Members of the MIMSAPI Group are listed in the Supplementary Appendix, available at NEJM.org. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. 1. Tan IL, McArthur JC, Clifford DB, Major EO, Nath A. Im-
mune reconstitution inflammatory syndrome in natalizumabassociated PML. Neurology 2011;77:1061-7. 2. Antoniol C, Jilek S, Schluep M, et al. Impairment of JCVspecific T-cell response by corticotherapy: effect on PML-IRIS management? Neurology 2012;79:2258-64. 3. Schwab N, Höhn KG, Schneider-Hohendorf T, et al. Immunological and clinical consequences of treating a patient with natalizumab. Mult Scler 2012;18:335-44. 4. Delbue S, Elia F, Carloni C, et al. JC virus load in cerebrospinal fluid and transcriptional control region rearrangements may predict the clinical course of progressive multifocal leukoencephalopathy. J Cell Physiol 2012;227:3511-7. 5. Yousry TA, Pelletier D, Cadavid D, et al. Magnetic resonance imaging pattern in natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol 2012;72:779-87. DOI: 10.1056/NEJMc1304828 Correspondence Copyright © 2014 Massachusetts Medical Society.
instructions for letters to the editor
Letters to the Editor are considered for publication, subject to editing and abridgment, provided they do not contain material that has been submitted or published elsewhere. Please note the following: • Letters in reference to a Journal article must not exceed 175
488
of
corrections ERCP for Gallstone Pancreatitis (January 9, 2014;370:150-7). In the second paragraph of the Clinical Use section (page 153), the third sentence should have begun, “An INR below 1.5 is preferred . . . ,” rather than “An INR above 1.5 . . . .” The article is correct at NEJM.org. A Randomized Trial of Prolonged Co-trimoxazole in HIV- Infected Children in Africa (January 2, 2014;370:41-53). In the second paragraph of the introduction (page 42), the third sentence, beginning, “However,” should have ended, “. . . may discontinue co-trimoxazole,” rather than “. . . may discontinue ART.” In the first paragraph of Methods (page 42), in the second sentence, “trimethoprim” and “sulfamethoxazole” were reversed in all instances. The parenthetical in that sentence should have read, “(once-daily doses of 200 mg of sulfamethoxazole and 40 mg of trimethoprim, 400 mg of sulfamethoxazole and 80 mg of trimethoprim, or 800 mg of sulfamethoxazole and 160 mg of trimethoprim for a body weight of 5 to 15, 15 to 30, or >30 kg, respectively).” The article is correct at NEJM.org. Calcium Supplements and Fracture Prevention (October 17, 2013;369:1537-43). In the second paragraph of the Potential Harms of Calcium Intake subsection of Strategies and Evidence (page 1541), the number of trials mentioned in the second sentence should have been 11, rather than 15, and the parenthetical at the end of the sentence should have read, “(odds ratio, 1.27; 95% CI, 1.01 to 1.59)22,” rather than “(odds ratio, 1.31; 95% CI, 1.02 to 1.67).22” In the sixth sentence, beginning “In a subsequent meta-analysis,” the final parenthetical should have read, “(odds ratio, 1.24; 95% CI, 1.07 to 1.45),” rather than “(odds ratio, 1.21; 95% CI, 1.01 to 1.44).” The article is correct at NEJM.org.
n engl j med 370;5 nejm.org january 30, 2014
The New England Journal of Medicine Downloaded from nejm.org on September 12, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
n e w e ng l a n d j o u r na l
of
m e dic i n e
data, protocols, and clinical-study reports should Michael Rosenblatt, M.D. be made available on request to qualified re- Merck searchers pursuing legitimate research projects Whitehouse Station, NJ [email protected] for medicines and indications approved in the United States and the European Union. Second, for the Chief Medical Officers Roundtable Barron reports being an employee of Hoffmann–La Roche there should be public disclosure of synopses of andDr.Genentech and holding stock and stock options in Roche; clinical-study reports after approval in the United and Dr. Rosenblatt, being an employee of and holding stock and States and the European Union. Third, summa- stock options in Merck. No other potential conflict of interest ries that are written in lay language should be relevant to this letter was reported. provided to patients involved in clinical trials. 1. Eichler H-G, Pétavy F, Pignatti F, Rasi G. Access to patientlevel trial data — a boon to drug developers. N Engl J Med 2013; Fourth, procedures should be adopted to imple- 369:1577-9. ment these principles. And fifth, researchers need 2. Nisen P, Rockhold F. Access to patient-level data from to make a commitment to publish study results, GlaxoSmithKline clinical trials. N Engl J Med 2013;369:475-8. Rawal B, Deane BR. Clinical trial transparency: an assesswhether negative or positive. The CMOR fully 3. ment of the disclosure of results of company-sponsored trials supports the sharing of patient-level clinical trial associated with new medicines approved recently in Europe. data, by all who generate such data, in the inter- Curr Med Res Opin 2013 November 11 (Epub ahead of print). 4. EFPIA and PhRMA. Principles for responsible clinical trial est of patients. data sharing: our commitment to patients and researchers (http:// phrma.org/sites/default/files/pdf/PhRMAPrinciplesForResponsible Hal Barron, M.D. ClinicalTrialDataSharing.pdf).
Hoffmann–La Roche South San Francisco, CA
DOI: 10.1056/NEJMc1315673
Maraviroc and JC Virus–Associated Immune Reconstitution Inflammatory Syndrome To the Editor: The immune reconstitution inflammatory syndrome (IRIS) can be a serious complication in immunocompromised patients in whom progressive multifocal leukoencephalopathy (PML) has developed. IRIS occurs in such patients when their immunocompromised state reverses.1 Although restored immune surveillance is vital for clearing the JC virus that causes PML, improved management strategies for IRIS are needed because of its potential for considerable complications and death. The common, though unproven, use of glucocorticoids to treat IRIS may limit JC viral clearance.2 Because of the indirect implication of chemokine receptor 5– positive (CCR5+) T cells in IRIS pathophysiology,3 we used the small-molecule CCR5 antagonist maraviroc, which has been approved for the treatment of human immunodeficiency virus (HIV) infection to inhibit CCR5-dependent viral docking, in a patient with multiple sclerosis who presented with natalizumab-associated PML and features that were expected to predict the development of IRIS.4,5 A 49-year-old, HIV-negative woman with relapsing–remitting multiple sclerosis and a score of 2.5 on the Expanded Disability Status Scale 486
(EDSS, which ranges from 0 to 10, with higher scores indicating more severe disability) had received 43 infusions of natalizumab monotherapy over a period of 3.6 years. She received a diagnosis of PML after presenting with an episode of aphasia and seizure. She was considered at risk for severe IRIS because of the multilobar PML (Fig. 1A and 1B) and an elevated JC viral load in the cerebrospinal fluid (130,000 copies per milliliter) as measured by means of a polymerasechain-reaction assay (Focus Diagnostics). Oral maraviroc at a dose of 300 mg twice daily was initiated shortly after plasmapheresis. No glucocorticoids or other immunomodulating therapy was given throughout the course of the PML illness. The patient was monitored closely with frequent clinical and imaging evaluations. Serial cerebrospinal fluid analyses showed that maraviroc treatment was associated with a selective decrease in CCR5+ immune cells in the cerebrospinal fluid (see the Figure in the Supplementary Appendix, available with the full text of this letter at NEJM.org). These findings suggest that maraviroc functionally inhibits CCR5-dependent immune-cell trafficking into the central nervous system (CNS). The patient’s condition remained
n engl j med 370;5 nejm.org january 30, 2014
The New England Journal of Medicine Downloaded from nejm.org on September 12, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
A
C
B
D
E
Figure 1. Sequential Magnetic Resonance Images of the Brain. When the patient presented for treatment, axial fluid-attenuated inversion recovery images showed multilobar progressive multifocal leukoencephalopathy (Panels A and B). A T1-weighted image after gadolinium infusion showed frank immune reconstitution inflammatory syndrome (IRIS) after the patient discontinued maraviroc (Panel C). After the patient began to receive maraviroc again, a T1-weighted image after gadolinium infusion showed regression of IRIS (Panel D). A T1-weighted image after gadolinium infusion obtained 2 months after gradual discontinuation of maraviroc showed stable lesions with no enhancement (Panel E).
stable, without clinical or imaging evidence of overt IRIS. Approximately 2 months after plasmapheresis, she inadvertently stopped taking maraviroc for 5 days and presented with cognitive and behavioral changes. Features on brain magnetic resonance imaging (MRI) were consistent with IRIS that involved all visible PML lesions (Fig. 1C). Oral maraviroc at a dose of 300 mg twice daily was reintroduced (without glucocorticoids), with close clinical and imaging follow-up. The patient’s cognitive and behavioral abnormalities steadily improved, though mild deficits persisted, and features of IRIS on imaging attenuated over weeks (Fig. 1D). The dose of maraviroc was reduced to 150 mg twice daily because of imaging evidence of IRIS regression, and the dose was eventually tapered off after 7 months once the lesions on MRI were stable and no lonn engl j med 370;5
ger showed gadolinium enhancement (Fig. 1E). Repeat cerebrospinal fluid analysis at 10 months was negative for JC virus. The patient survived both her PML infection and IRIS with few persisting sequelae; at 1 year after the initiation of maraviroc, she had an EDSS score of 3.0 and she continued to have mild cognitive deficits. No new multiple sclerosis disease activity was noted, and no new therapy for multiple sclerosis was introduced. Our findings, which implicate CCR5+ immune cells as mediators of IRIS, suggest that without the use of glucocorticoids, maraviroc contributed both to initial prevention of IRIS and to active treatment of IRIS once it was established. Our data on selective reduction in the proportions of CCR5+ immune-cell subsets in the cerebrospinal fluid show that maraviroc may selectively
nejm.org
january 30, 2014
The New England Journal of Medicine Downloaded from nejm.org on September 12, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
487
The
n e w e ng l a n d j o u r na l
limit trafficking into the CNS compartment in vivo and highlight the potential for selective targeting of immune-cell chemotaxis and trafficking in the management of complex immunologic disorders. Paul S. Giacomini, M.D. Ayal Rozenberg, M.D.
m e dic i n e
words (excluding references) and must be received within 3 weeks after publication of the article. • Letters not related to a Journal article must not exceed 400 words. • A letter can have no more than five references and one figure or table. • A letter can be signed by no more than three authors.
Imke Metz, M.D.
• Financial associations or other possible conflicts of interest must be disclosed. Disclosures will be published with the letters. (For authors of Journal articles who are responding to letters, we will only publish new relevant relationships that have developed since publication of the article.)
Georg-August University Göttingen, Germany
• Include your full mailing address, telephone number, fax number, and e-mail address with your letter.
David Araujo, M.D.
• All letters must be submitted at authors.NEJM.org.
McGill University Montreal, QC, Canada
Letters that do not adhere to these instructions will not be considered. We will notify you when we have made a decision about possible publication. Letters regarding a recent Journal article may be shared with the authors of that article. We are unable to provide prepublication proofs. Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it in the Journal’s various print and electronic publications and in collections, revisions, and any other form or medium.
McGill University Montreal, QC, Canada
Nathalie Arbour, Ph.D. University of Montreal Montreal, QC, Canada
Amit Bar-Or, M.D. McGill University Montreal, QC, Canada [email protected]
for the Maraviroc in Multiple Sclerosis– Associated PML–IRIS (MIMSAPI) Group Members of the MIMSAPI Group are listed in the Supplementary Appendix, available at NEJM.org. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. 1. Tan IL, McArthur JC, Clifford DB, Major EO, Nath A. Im-
mune reconstitution inflammatory syndrome in natalizumabassociated PML. Neurology 2011;77:1061-7. 2. Antoniol C, Jilek S, Schluep M, et al. Impairment of JCVspecific T-cell response by corticotherapy: effect on PML-IRIS management? Neurology 2012;79:2258-64. 3. Schwab N, Höhn KG, Schneider-Hohendorf T, et al. Immunological and clinical consequences of treating a patient with natalizumab. Mult Scler 2012;18:335-44. 4. Delbue S, Elia F, Carloni C, et al. JC virus load in cerebrospinal fluid and transcriptional control region rearrangements may predict the clinical course of progressive multifocal leukoencephalopathy. J Cell Physiol 2012;227:3511-7. 5. Yousry TA, Pelletier D, Cadavid D, et al. Magnetic resonance imaging pattern in natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol 2012;72:779-87. DOI: 10.1056/NEJMc1304828 Correspondence Copyright © 2014 Massachusetts Medical Society.
instructions for letters to the editor
Letters to the Editor are considered for publication, subject to editing and abridgment, provided they do not contain material that has been submitted or published elsewhere. Please note the following: • Letters in reference to a Journal article must not exceed 175
488
of
corrections ERCP for Gallstone Pancreatitis (January 9, 2014;370:150-7). In the second paragraph of the Clinical Use section (page 153), the third sentence should have begun, “An INR below 1.5 is preferred . . . ,” rather than “An INR above 1.5 . . . .” The article is correct at NEJM.org. A Randomized Trial of Prolonged Co-trimoxazole in HIV- Infected Children in Africa (January 2, 2014;370:41-53). In the second paragraph of the introduction (page 42), the third sentence, beginning, “However,” should have ended, “. . . may discontinue co-trimoxazole,” rather than “. . . may discontinue ART.” In the first paragraph of Methods (page 42), in the second sentence, “trimethoprim” and “sulfamethoxazole” were reversed in all instances. The parenthetical in that sentence should have read, “(once-daily doses of 200 mg of sulfamethoxazole and 40 mg of trimethoprim, 400 mg of sulfamethoxazole and 80 mg of trimethoprim, or 800 mg of sulfamethoxazole and 160 mg of trimethoprim for a body weight of 5 to 15, 15 to 30, or >30 kg, respectively).” The article is correct at NEJM.org. Calcium Supplements and Fracture Prevention (October 17, 2013;369:1537-43). In the second paragraph of the Potential Harms of Calcium Intake subsection of Strategies and Evidence (page 1541), the number of trials mentioned in the second sentence should have been 11, rather than 15, and the parenthetical at the end of the sentence should have read, “(odds ratio, 1.27; 95% CI, 1.01 to 1.59)22,” rather than “(odds ratio, 1.31; 95% CI, 1.02 to 1.67).22” In the sixth sentence, beginning “In a subsequent meta-analysis,” the final parenthetical should have read, “(odds ratio, 1.24; 95% CI, 1.07 to 1.45),” rather than “(odds ratio, 1.21; 95% CI, 1.01 to 1.44).” The article is correct at NEJM.org.
n engl j med 370;5 nejm.org january 30, 2014
The New England Journal of Medicine Downloaded from nejm.org on September 12, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
