The new england journal of medicine

editorials

Vivek Murthy for Surgeon General Gregory D. Curfman, M.D., Stephen Morrissey, Ph.D., Debra Malina, Ph.D., and Jeffrey M. Drazen, M.D.

Surgeons general of the have often may be delayed or withdrawn altogether. How championed important causes that improve the could this have happened to such a distinguished nation’s health. Leroy Burney and and highly qualified nominee? took on the issue of smoking and health. C. Everett The answer lies with the National Rifle Asso- Koop championed the treatment of HIV-AIDS as ciation (NRA). It is of great concern to us and to a medical condition. With the nomination of many other members of the health care com- Dr. Vivek Murthy, who aims to take on the epi- munity that Murthy’s nomination is in jeopardy demic of obesity, President is striv- because of NRA opposition. The NRA opposes ing to continue this tradition. Murthy solely on the grounds that he has advo- Murthy, whose parents immigrated to the cated reasonable and mainstream forms of gun United States from India, has lived the American regulation, including an assault-weapons ban, a dream. He was educated at two of our nation’s limit on ammunition sales, and required safety most prestigious universities, earning his under- training. Given that there are more than 30,000 graduate degree at Harvard and both an M.D. firearm deaths in the United States each year, and an M.B.A. degree at Yale. He currently prac- Murthy’s views on potential safeguards are un- tices medicine at Boston’s Brigham and Women’s surprising. Hospital and is a member of the faculty of Har- This is the first time that the NRA has flexed vard Medical School. its political muscle over the appointment of a Murthy was one of the founders and is cur- surgeon general. The NRA has taken this action rently the president of Doctors for America, an even though the surgeon general has no author- organization focused on broadening access to ity over firearm regulation and even though high-quality health care. In his impressive career, Murthy made it clear in his testimony before the he has been strongly committed to disease pre- Senate HELP Committee that if he is confirmed, vention and health promotion, having served on his principal focus will be on the important na- the Presidential Advisory Group on Prevention, tional problem of obesity prevention, not firearm Health Promotion, and Integrative and Public policy. Still, 10 Senate Democrats are apparently Health. He cofounded Visions Worldwide, a non- prepared to vote against Murthy’s confirmation profit organization working on HIV prevention because of his personal views on firearms — a and education. He is the chair of TrialNetworks, demonstration of just how much political power an initiative that assists drug developers with our legislators have ceded to the NRA. clinical trials. The critical question is this: Should a special- On February 27, a bipartisan group of senators interest organization like the NRA have veto on the Health, Education, Labor, and Pensions power over the appointment of the nation’s top (HELP) Committee approved Murthy’s nomina- doctor? The very idea is unacceptable. tion for surgeon general and forwarded it for a Despite the continuing American tragedy of vote by the full Senate. But now, astonishingly, mass shootings — Newtown, Aurora, Fort Hood, the nomination appears to be in jeopardy and Virginia Tech — the NRA has redoubled its ef-

n engl j med 370;19 nejm.org may 8, 2014 1843 The New England Journal of Medicine Downloaded from nejm.org by NICOLETTA TORTOLONE on May 7, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. The new england journal of medicine

forts to prevent enactment of stricter firearm and voting their own conscience. Dr. Murthy is regulations. Lawmakers who run afoul of the an accomplished physician, policymaker, leader, NRA face political retribution. By obstructing and entrepreneur. He deserves the President’s the President’s nomination of Vivek Murthy as continued backing and should be confirmed. surgeon general, the NRA is taking its single- Disclosure forms provided by the authors are available with issue political blackmail to a new level. With the full text of this article at NEJM.org. the record of past surgeons general as their This article was published on March 19, 2014, at NEJM.org. guide, senators should do what is right for the DOI: 10.1056/NEJMe1403374 health of our country by confronting the NRA 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 group that received 120 mg per day, and 6% in stem-cell transplantation render patients suscep- the group that received 240 mg per day. The new tible to opportunistic infections. The most im- drug in question is an inhibitor of a key enzy- portant of these infections, in terms of both matic component of the “terminase complex.” abundance and severity, is cytomegalovirus (CMV), Viral DNA is synthesized by means of rolling which has been dubbed the “troll of transplanta- circle replication to produce long concatemers of tion.”1 Fortunately, the clinical effects of CMV DNA. As shown in Figure 1, these concatemers infection have been reduced by preemptive ther- are analogous to individual coaches in a train. apy. Levels of CMV DNA in the blood (viremia) The unit-length DNA (like an individual coach) are monitored with the use of polymerase-chain- is actively packaged into a newly formed capsid reaction (PCR) assays and, if viremia is detected, until a defined sequence (analogous to a cou- patients receive ganciclovir (or its prodrug val- pling between two coaches) is recognized, the ganciclovir) until viral DNA is no longer detect- DNA is cut, and the capsid is sealed.6,7 This able.2 In addition to controlling overt CMV end- cleavage is effected by terminase, which thus is organ disease, since these agents are used only a novel target both in the context of the virus if viremia is detected, this strategy minimizes (most other drugs in clinical use have targeted the bone marrow toxicity of ganciclovir and val- the viral DNA replication machinery) and in the ganciclovir, which is clinically highly important context of the human host, because no such after stem-cell transplantation.2 After solid-organ equivalent process is known to occur in human transplantation, these agents can be administered cells.8 Following successful phase 1 studies, this prophylactically with efficacy and safety that are drug, letermovir, has passed its phase 2 evalua- similar to those of preemptive therapy.3,4 For pa- tion with impressive results.5 tients who have undergone transplantation, drugs One of the problems with performing CMV with reduced toxicity, improved potency, or both, prophylaxis studies in a population of patients as compared with ganciclovir and valganciclovir, who have undergone stem-cell transplantation is are highly desirable. An appropriate study design2 deciding when to start therapy.2 Whereas prophy- in a placebo-controlled trial is to administer the laxis in patients who have received solid-organ experimental drug prophylactically and determine transplants can be initiated almost immediately whether selected doses, as compared with pla- after transplantation, in patients who have under- cebo (the standard of care), can reduce the need gone stem-cell transplantation, prophylaxis has for preemptive therapy. usually been initiated after engraftment (after In this issue of the Journal, Chemaly et al.5 the neutrophil count reaches a minimum thresh- describe the phase 2 evaluation of a new anti- old, usually ≥500 cells per cubic millimeter) be- CMV drug. In this study, the incidence of viro- cause of the bone marrow toxicity of ganciclovir logic failure decreased in a dose-dependent and valganciclovir.2 A new drug without such an fashion: 36% in the placebo group, 21% in the adverse side-effect profile could be used much group that received 60 mg per day, 19% in the earlier after stem-cell transplantation; this was

1844 n engl j med 370;19 nejm.org may 8, 2014 The New England Journal of Medicine Downloaded from nejm.org by NICOLETTA TORTOLONE on May 7, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.