The

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forts to prevent enactment of stricter firearm regulations. Lawmakers who run afoul of the NRA face political retribution. By obstructing the President’s nomination of Vivek Murthy as surgeon general, the NRA is taking its singleissue political blackmail to a new level. With the record of past surgeons general as their guide, senators should do what is right for the health of our country by confronting the NRA

of

m e dic i n e

and voting their own conscience. Dr. Murthy is an accomplished physician, policymaker, leader, and entrepreneur. He deserves the President’s continued backing and should be confirmed. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. This article was published on March 19, 2014, at NEJM.org. DOI: 10.1056/NEJMe1403374 Copyright © 2014 Massachusetts Medical Society.

Taming the Transplantation Troll by Targeting Terminase Paul D. Griffiths, M.D., D.Sc., and Vincent C. Emery, Ph.D. The immunosuppressive drugs required after stem-cell transplantation render patients susceptible to opportunistic infections. The most important of these infections, in terms of both abundance and severity, is cytomegalovirus (CMV), which has been dubbed the “troll of transplantation.”1 Fortunately, the clinical effects of CMV infection have been reduced by preemptive therapy. Levels of CMV DNA in the blood (viremia) are monitored with the use of polymerase-chainreaction (PCR) assays and, if viremia is detected, patients receive ganciclovir (or its prodrug valganciclovir) until viral DNA is no longer detectable.2 In addition to controlling overt CMV endorgan disease, since these agents are used only if viremia is detected, this strategy minimizes the bone marrow toxicity of ganciclovir and valganciclovir, which is clinically highly important after stem-cell transplantation.2 After solid-organ transplantation, these agents can be administered prophylactically with efficacy and safety that are similar to those of preemptive therapy.3,4 For patients who have undergone transplantation, drugs with reduced toxicity, improved potency, or both, as compared with ganciclovir and valganciclovir, are highly desirable. An appropriate study design2 in a placebo-controlled trial is to administer the experimental drug prophylactically and determine whether selected doses, as compared with placebo (the standard of care), can reduce the need for preemptive therapy. In this issue of the Journal, Chemaly et al.5 describe the phase 2 evaluation of a new antiCMV drug. In this study, the incidence of virologic failure decreased in a dose-dependent fashion: 36% in the placebo group, 21% in the group that received 60 mg per day, 19% in the 1844

group that received 120 mg per day, and 6% in the group that received 240 mg per day. The new drug in question is an inhibitor of a key enzymatic component of the “terminase complex.” Viral DNA is synthesized by means of rolling circle replication to produce long concatemers of DNA. As shown in Figure 1, these concatemers are analogous to individual coaches in a train. The unit-length DNA (like an individual coach) is actively packaged into a newly formed capsid until a defined sequence (analogous to a coupling between two coaches) is recognized, the DNA is cut, and the capsid is sealed.6,7 This cleavage is effected by terminase, which thus is a novel target both in the context of the virus (most other drugs in clinical use have targeted the viral DNA replication machinery) and in the context of the human host, because no such equivalent process is known to occur in human cells.8 Following successful phase 1 studies, this drug, letermovir, has passed its phase 2 evaluation with impressive results.5 One of the problems with performing CMV prophylaxis studies in a population of patients who have undergone stem-cell transplantation is deciding when to start therapy.2 Whereas prophylaxis in patients who have received solid-organ transplants can be initiated almost immediately after transplantation, in patients who have undergone stem-cell transplantation, prophylaxis has usually been initiated after engraftment (after the neutrophil count reaches a minimum threshold, usually ≥500 cells per cubic millimeter) because of the bone marrow toxicity of ganciclovir and valganciclovir.2 A new drug without such an adverse side-effect profile could be used much earlier after stem-cell transplantation; this was

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editorials

Host nucleus

Newly synthesized cytomegalovirus capsid

Portal protein Terminase complex cleaves DNA at a specific sequence

One copy of viral DNA

Concatemer of DNA with multiple genome copies

One copy of viral DNA

Figure 1. Structure of Cytomegalovirus. Viral DNA, synthesized as a long, multiunit, concatemeric DNA molecule, is packaged into the capsid through a specialized portal protein that replaces one of the pentons in the icosahedral capsid. This packaging is an active process that consumes ATP. When the capsid is full, the terminase complex cleaves the DNA at specific sequences. The process is then repeated for another capsid. The long concatemeric DNA, which contains cleavage signals recognizable by the terminase complex, can be thought of as a train comprising individual identical coaches, each of which can be released when the terminase complex cleaves the couplings between them.

aptly shown in the study by Chemaly et al., in which a substantial number of patients were already CMV-positive according to PCR analysis at a central laboratory at the time of screening, day 1 of treatment, or both. Given the safety profile of letermovir, earlier use in patients who have undergone stem-cell transplantation is warranted. The discrepancy between testing for CMV in a central laboratory and in a local laboratory in this study identifies another area where progress needs to be made, both for consistent pa-

tient care and in the design of multicenter clinical trials. The adoption of the universal World Health Organization standard9 for CMV detection in PCR assays should help to address this issue. Naturally, the results presented by Chemaly and colleagues are only the beginning of this exciting new development in the therapeutic control of CMV infection. Given the potent antiviral effect of letermovir, the issue of drug resistance will need to be investigated, especially in patients with breakthrough viremia during the

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editorials

prophylactic period, and the incidence of postprophylaxis infection and late CMV disease must be assessed. Nevertheless, the potential availability of a new class of antiviral drug with high potency and a low side-effect profile, and one that could be used alongside existing therapy, is a welcome development. The safety and potency of these agents should be assessed in babies born with congenital CMV infection for whom ganciclovir and valganciclovir are the current treatments.10 It also offers the possibility of evaluating combination therapy with these agents in patients who have undergone transplantation to see whether the troll of transplantation can finally be suppressed into hiding. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From the Centre for Virology, University College London Medical School, London (P.D.G.), and the Department of Microbial and Cellular Sciences, University of Surrey, Guildford (V.C.E.) — both in the United Kingdom. 1. Balfour HH Jr. Cytomegalovirus: the troll of transplantation.

Arch Intern Med 1979;139:279-80.

2. Marty FM, Boeckh M. Maribavir and human cytomegalovirus

— what happened in the clinical trials and why might the drug have failed? Curr Opin Virol 2011;1:555-62. 3. Owers DS, Webster AC, Strippoli GF, Kable K, Hodson EM. Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev 2013;2:CD005133. 4. Kotton CN, Kumar D, Caliendo AM, et al. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2013;96: 333-60. 5. Chemaly RF, Ullmann AJ, Stoelben S, et al. Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. N Engl J Med 2014;370:1781-9. 6. Newcomb WW, Juhas RM, Thomsen DR, et al. The UL6 gene product forms the portal for entry of DNA into the herpes simplex virus capsid. J Virol 2001;75:10923-32. 7. Brown JC, Newcomb WW. Herpesvirus capsid assembly: insights from structural analysis. Curr Opin Virol 2011;1:142-9. 8. Bogner E. Human cytomegalovirus terminase as a target for antiviral chemotherapy. Rev Med Virol 2002;12:115-27. 9. Fryer JF, WHO Expert Committee on Biological Standardization. Collaborative study to evaluate the proposed 1st WHO international standard for human cytomegalovirus (HCMV) for nucleic acid amplification (NAT)-based assays. Geneva: World Health Organization, 2010. (Publication no. WHO/BS/10.2138.) 10. Kimberlin DW, Lin CY, Sánchez PJ, et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr 2003;143:16-25. DOI: 10.1056/NEJMe1401567 Copyright © 2014 Massachusetts Medical Society.

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Taming the transplantation troll by targeting terminase.

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