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NDT Advance Access originally published online on April 20, 2006
Nephrology Dialysis Transplantation 2006 21(7):1757-1761; doi:10.1093/ndt/gfl151
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Editorial Comment

CMV prophylaxis—to do or not to do, that is the question

Ban Hock Tan

Department of Internal Medicine and Infectious Disease Unit, Singapore General Hospital, Singapore

Correspondence and offprint requests to: B. H. Tan. Email: tan.ban.hock{at}sgh.com.sg

Keywords: cytomegalovirus; ganciclovir prophylaxis; kidney transplantation; pre-emptive therapy



   Introduction
Top
 Introduction
Conclusion
 References
 
Cytomegalovirus (CMV) is the major microbe adversely affecting transplantation [1]. The CMV syndrome has been recognized from the early days of renal transplantation. In the pre-ganciclovir (GCV) era, the only treatment was reduction of immunosuppression [2].

In transplantation, preventing an infection is as important as, if not more important than, treating one; hence prophylaxis. Trimethorprim-sulfamethoxazole (TMP-SMX) prophylaxis has reduced the frequency of Pneumocystis pneumonia (PCP). In transplant recipients, CMV has both direct effects (e.g. colitis) and indirect ones. The latter include graft rejection and susceptibility to bacterial or fungal infection, among others [3].

There should, therefore, be no question regarding the importance of CMV prophylaxis in transplantation. If an agent is available that is effective, safe, easy to administer and not too expensive, then it should be given to every transplant recipient.

The role of prophylaxis is being questioned because of an attractive alternative: pre-emptive therapy (PRE). The therapy involves the administration of an anti-microbial agent to a population known to be at risk for active or severe disease by an epidemiological or a laboratory marker. Hence, the anti-CMV agent need not be administered to all transplant recipients, but could be selectively given to at-risk sub-populations; this potentially saves cost and reduces toxicity. If it is shown to be safe in practice, then it will seriously challenge the role of prophylaxis.

Indeed, this has been the case. Both prophylaxis and PRE reduce the incidence of CMV disease in transplant recipients. We now have to choose between them [4,5].

Prophylaxis
Early studies on prophylaxis consisted of passive immunization with CMV immunoglobulins (Ig). CMV Ig reduced the risk of CMV disease in transplant recipients but tended not to protect the most susceptible D+R– patients [6,7]. CMV Ig is expensive.

Prophylaxis with the anti-virals acyclovir (ACV), ganciclovir (GCV) and their pro-drugs, valacyclovir (VAC) and valganciclovir (VGC), also protects against CMV disease. Throughout the 1990s, data emerged that gave transplant physicians evolving options for CMV prophylaxis.

In a placebo-controlled randomized clinical trial (RCT) in renal transplant recipients, ACV reduced the rate of symptomatic CMV disease [8]. In allogeneic bone marrow transplant (BMT) recipients, i.v. ACV was superior to placebo in reducing the risk of CMV infection and disease [9]. When compared with GCV, however, ACV prophylaxis tended to be inferior [10,11].

The oral formulation of GCV, in an RCT for prophylaxis against CMV infection, proved superior to placebo, with the benefit extending to the D+R– sub-group [12].

Although ACV had been eclipsed by GCV throughout much of the 1990s, its pro-drug, VAC, protected seronegative renal recipients from CMV disease [13]. The VAC arm had a lower incidence of acute rejection. Critics of this study have highlighted problems such as the high rate of CMV disease in the placebo group [14].

The pro-drug VGC has also been shown to be safe and efficacious in transplant recipients [15–18].

Thus prophylaxis works, and several agents are available. But prophylaxis seems to imply universality; it is non-discriminatory. Every single transplant recipient gets PCP prophylaxis. However, transplant recipients differ in their risk for CMV disease. Universal prophylaxis, therefore, might be excessive, especially as GCV and VGC are not without toxicity [19], hence PRE.

Pre-emptive therapy
Schmidt et al. [20] subjected bone marrow transplant (BMT) recipients to a broncho-alveolar lavage (BAL) on day 35 and tested BAL fluid by shell vial cultures (SVC) for CMV. Patients who were CMV-positive were randomized to GCV or placebo. The rate of CMV pneumonia in the CMV-negative group (no prophylaxis) was 12%; the rate in the CMV-positive group randomized to placebo was 70% and the rate in the CMV-positive group randomized to GCV was 25%. No patient who completed the full course of GCV developed CMV pneumonia.

In an accompanying editorial, Rubin [21] coined the phrase PRE. Rubin and his colleagues [22] developed this strategy along another track: by defining the risk for CMV disease with an epidemiological (rather than a laboratory) marker, they elegantly demonstrated the benefits of PRE. At their institution, 121 antibody-positive transplant recipients receiving anti-lymphocyte antibody were randomized to either i.v. GCV or placebo. The reduction of CMV disease in the GCV arm was statistically significant [22].

PRE could not have taken off without advances in CMV diagnostics. The pp65 antigenaemia assay and the widespread application of PCR methodology provided clinicians with the means of monitoring CMV activity [23]. Studies showed these assays to be sensitive and specific, with good negative predictive values, which tended to be positive prior to symptoms [24–26].

Physicians subscribing to PRE could hold off giving GCV to all transplant recipients until there was pp65 antigenaemia or DNAemia. This strategy has proven efficacious in lowering the rates of CMV infection and disease, even in D+R– patients [27–30].

Problems with prophylaxis
Two problems have been identified as being related to prophylaxis: delayed CMV disease and GCV resistance.

Shibolet et al. [31] found that some transplant recipients developed CMV disease more than 2 years after transplantation; the occurrence of late CMV disease was not correlated with an early use of anti-viral prophylaxis or rejection episodes. In a trial that employed 100 days of VGC prophylaxis, 18% had developed CMV disease at the 12-month mark [15].

The non-discriminatory nature of prophylaxis violates a basic tenet of infectious diseases, as an antibiotic is administered for prolonged periods to all patients, regardless of their susceptibility to CMV infection. The consequence is GCV resistance. In a unit that had managed 240 organ transplant recipients with GCV prophylaxis for 100 days, Limaye et al. [32] noted that 17 developed CMV disease beyond 101 days post-transplant; five of them had GCV-resistant virus. VGC, through better bio-availability, may not be associated with similar problems, as suggested recently [33].

Problems with PRE
One weakness of PRE is that pp65 antigen or DNA may be detected just before, at the same time as or after the manifestations of disease. The opportunity to pre-empt is lost; one has to use treatment doses of GCV.

Paya et al. [34] followed liver transplant recipients with weekly PCR and SVC. When CMV DNA was detected, the patient was randomized to p.o. GCV or placebo. The study attempted to assess p.o. GCV's usefulness in PRE. The cumulative probability of CMV disease was zero in the GCV arm, 5% in the placebo arm. However, in 23% of D+R– patients, PCR positivity was detected so close temporally in relation to the onset of CMV infection that the use of p.o. GCV was precluded.

Although pp65 antigenaemia and CMV DNAemia generally precede the disease, this is not universally the case [23–25]. An explanation for this is the interval between the collection of the blood specimen and the result—this may be related to the (lack of) frequency of blood draws, or (lack of) frequency of PCR runs. The biological explanation might be the rapidity of viral replication in R– patients [35,36]. In immunocompromised patients, CMV's doubling time is about a day [36].

Prophylaxis vs PRE
Prophylaxis and PRE were compared in an RCT by Singh et al. [37]. Liver transplant recipients were randomized into two groups. One group received p.o. ACV. The other received i.v. GCV if the surveillance cultures yielded CMV. The ACV arm had more CMV disease. One wonders if this study showed the weakness of ACV rather than of the prophylactic strategy. Nevertheless, these investigators have provided impressive follow-up data suggesting the superiority of PRE: on using VGC in a pre-emptive approach, late-onset CMV disease was not seen. Indeed, no CMV disease was recorded after 189 person-years of follow-up [38]. Significantly, however, one meta-analysis suggested that prophylaxis reduced the rate of indirect effects of CMV disease, such as bacterial infections [39].

PRE—biologically superior?
In BMT recipients, recovery of CD8+ cells is important for preventing CMV disease [40]. The BMT recipients who received GCV prophylaxis failed to recover CD8+ and CD4+ CMV-specific T-cell responses [41]. Space does not permit a detailed discussion of CMV immunology, but in GCV-treated persons, not all viral antigens may be available to activate T-cell responses. It might appear that allowing low-grade viral replication, so that the full repertoire of viral antigens is expressed, helps immune recovery. But data in BMT recipients may not be applicable to solid organ transplant recipients.

Late CMV disease may also be related to the ongoing need for immunosuppression. The calcineurin inhibitors have been described as an in vivo PCR [3]. Ciclosporin does not by itself re-activate latent virus, while the anti-lymphocyte antibodies do. Once the actively replicating virus is present, however, ciclosporin, tacrolimus and rapamycin may promote viral replication. A combination of these theories suggests that following the patient closely for evidence of viral activity and suppressing the virus when activity is detected might help with immune reconstitution, while taking care of the in vivo PCR effects of the calcineurin inhibitors.

Cost
Kusne et al. [28] showed that PRE was cost-effective compared with prophylaxis. Singhal et al. [42] studied a ‘targeted prophylaxis’ approach against prophylaxis and found that the former cost £1587 less per life-year. They recommended liver transplant units to adopt a targeted strategy. Because their ‘targeted prophylaxis’ arm did not include the cost of monitoring pp65 antigenaemia or DNAemia, this is not quite PRE as is commonly practised. However, their article suggests that targeted approaches save money.



   Conclusion
Top
 Introduction
 Conclusion
References
 
Technology provides choices that can be bewildering. Until the case for or against each strategy can be made convincingly through an adequately-powered RCT (and the end points should include the direct and indirect effects of CMV), we clinicians will have to find a middle path that incoporates elements of both strategies. Patients at highest risk of CMV disease—D+R– or recipients of anti-lymphocye antibodies—may need prophylaxis, while other patients may be followed by the pre-emptive mode.

Conflicts of interest statement. None declared.



   References
Top
 Introduction
 Conclusion
 References
 

  1. Slifkin M, Doron S, Snydman DR. Viral prophylaxis in organ transplant recipients. Drugs 2004; 64: 2763–2792[CrossRef][Medline]
  2. Tobin JOH. Cytomegalovirus infection. In: Weatherall DJ, Ledingham JGG, Warrell DA, eds. Oxford Textbook of Medicine, 2nd edn. Oxford University Press, Oxford: 1987, 5.76–5.80
  3. Rubin RH. Infections in the organ transplant recipient. In: Rubin RH, Young LS, eds. Clinical Approach to Infection in the Compromised Host, 4th edn. Kluwer Academic/Plenum, New York:2002, 573–680
  4. Singh N. Late-onset cytomegalovirus disease as a significant complication in solid organ transplant recipients receiving antiviral prophylaxis: a call to heed the mounting evidence. Clin Infect Dis 2005; 40: 704–708[Medline]
  5. Snydman DR. Counterpoint: prevention of cytomegalovirus (CMV) infection and CMV disease in recipients of solid organ transplants: the case for prophylaxis. Clin Infect Dis 2005; 40: 709–712[Medline]
  6. Snydman DR, Werner BG, Heinze-Lacey B et al. Use of cytomegalovirus immune globulin to prevent cytomegalovirus disease in renal-transplant recipients. New Engl J Med 1987; 317: 1049–1054[Abstract]
  7. Saliba F, Gugenheim J, Samuel D et al. Incidence of cytomegalovirus infection and effects of cytomegalovirus immune globulin prophylaxis after orthotopic liver transplantation. Transplant Proc 1987; 19: 4081–4082[Medline]
  8. Balfour HH,Jr, Chace BA, Stapleton JT et al. A randomized, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. New Engl J Med 1989; 320: 1381–1387[Abstract]
  9. Meyers JD, Reed EC, Shepp DH et al. Acyclovir for the prevention of cytomegalovirus infection and disease after allogeneic marrow transplantation. New Engl J Med 1988; 318: 70–75[Abstract]
  10. Martin M, Manex R, Linden P et al. A prospective randomized trial comparing sequential ganciclovir-high dose acyclovir to high dose acyclovir for the prevention of cytomegalovirus disease in adult liver transplant recipients. Transplantation 1994; 58: 779–785[Web of Science][Medline]
  11. Badley AD, Seaberg EC, Porayko MK et al. Prophylaxis of cytomegalovirus infection after liver transplantation. Transplantation 1997; 64: 66–73[CrossRef][Web of Science][Medline]
  12. Gane E, Saliba F, Valdecasas GJC et al. Randomised trial of efficacy and safety of oral ganciclovir in the prevention of cytomegalovirus disease in liver-transplant recipients. Lancet 1997; 350: 1729–1733[CrossRef][Web of Science][Medline]
  13. Lowance D, Neumayer HH, Legendre CM et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. New Engl J Med 1999; 340: 1462–1470[Abstract/Free Full Text]
  14. Kuypers DRJ, Vanrenterghem YFC. Prophylaxis of cytomegalovirus infection in renal transplantation: new data for an old problem. Nephrol Dial Transplant 1999; 14: 2304–2308[Free Full Text]
  15. Paya C, Humar A, Dominguez E et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 2004; 4: 611–620[CrossRef][Web of Science][Medline]
  16. Gabardi S, Magee CC, Baroletti SA et al. Efficacy and safety of low-dose valganciclovir for prevention of cytomegalovirus disease in renal transplant recipients: a single-center, retrospective analysis. Pharmacotherapy 2004; 24: 1323–1330[CrossRef][Medline]
  17. Ciancio G, Burke GW, Mattiazzi A et al. Cytomegalovirus prophylaxis with valganciclovir in kidney, pancreas-kidney, and pancreas transplantation. Clin Transplant 2004; 18: 402–406[Medline]
  18. Gruber SA, Garnick J, Morawski K et al. Cytomegalovirus prophylaxis with valganciclovir in African-American renal allograft recipients based on donor/recipient serostatus. Clin Transplant 2005; 19: 273–278[CrossRef][Medline]
  19. Crumpacker CS. Ganciclovir. New Engl J Med 1996; 335: 721–729[Free Full Text]
  20. Schmidt GM, Horak DA, Niland JC et al. A randomized, controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants. New Engl J Med 1991; 324: 1005–1011[Abstract]
  21. Rubin RH. Preemptive therapy in immunocompromised hosts. New Engl J Med 1991; 324: 1057–1059[Medline]
  22. Hibberd PL, Tolkoff-Rubin NE, Conti D et al. Preemptive ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus antibody-positive renal transplant recipients. Ann Intern Med 1995; 123: 18–26[Abstract/Free Full Text]
  23. The TH, van der Bij W, van den Berg AP et al. Cytomegalovirus antigenemia. Rev Infect Dis 1990; 12 [Suppl 7]S733–S744
  24. Mazzulli T, Rubin RH, Ferraro MJ et al. Cytomegalovirus antigenemia: clinical correlations in transplant recipients and in persons with AIDS. J Clin Microbiol 1993; 31: 2824–2827[Abstract/Free Full Text]
  25. Tanabe K, Tokumoto T, Ishikawa N et al. Comparative study of cytomegalovirus (CMV) antigenemia assay, polymerase chain reaction, serology, and shell vial assay in the early diagnosis and monitoring of CMV infection after renal transplantation. Transplantation 1997; 64: 1721–1725[CrossRef][Medline]
  26. Wolf DG, Spector SA. Early diagnosis of human cytomegalovirus disease in transplant recipients by DNA amplification in plasma. Transplantation 1993; 56: 330–334[Medline]
  27. Gotti E, Suter F, Baruzzo S et al. Early ganciclovir therapy effectively controls viremia and avoids the need for cytomegalovirus (CMV) prophylaxis in renal transplant patients with cytomegalovirus antigenemia. Clin Tansplant 1996; 10: 550–555
  28. Kusne S, Grossi P, Irish W et al. Cytomegalovirus pp65 antigenemia monitoring as a guide for preemptive therapy: a cost effective strategy for prevention of cytomegalovirus disease in adult liver transplant recipients. Transplantation 1999; 68: 1125–1131[CrossRef][Web of Science][Medline]
  29. Singh N, Paterson DL, Gayowski T et al. Cytomegalovirus antigenemia directed pre-emptive prophylaxis with oral versus i.v. ganciclovir for the prevention of cytomegalovirus disease in liver transplant recipients. Transplantation 2000; 70: 717–722[Medline]
  30. Sagedal S, Nordal KP, Hartman A et al. Pre-emptive therapy of CMVpp65 antigen positive renal transplant recipients with oral ganciclovir: a randomized, comparative study. Nephrol Dial Transplant 2003; 18: 1899–1908[Abstract/Free Full Text]
  31. Shibolet O, Ilan Y, Kalish Y et al. Late cytomegalovirus disease following liver transplantation. Transpl Int 2003; 16: 861–865[CrossRef][Medline]
  32. Limaye AP, Corey L, Koelle DM et al. Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants. Lancet 2000; 356: 645–649[CrossRef][Web of Science][Medline]
  33. Boivin G, Goyette N, Gilbert C et al. Absence of cytomegalovirus-resistance mutations after valganciclovir prophylaxis, in a prospective multicenter study of solid-organ transplant recipients. J Infect Dis 2004; 189: 1615–1618[CrossRef][Medline]
  34. Paya CV, Wilson JA, Espy MJ et al. Preemptive use of oral ganciclovir to prevent cytomegalovirus infection in liver transplant recipients: a randomized, placebo-controlled trial. J Infect Dis 2002; 185: 854–860[CrossRef][Medline]
  35. Emery VC, Hassan-Walker AF, Burroughs AK et al. Human cytomegalovirus (HCMV) replication dynamics in HCMV-naive and -experienced immunocompromised hosts. J Infect Dis 2002; 185: 1723–1728[CrossRef][Medline]
  36. Emery VC, Griffiths PD. Prediction of cytomegalovirus load and resistance patterns after antiviral chemotherapy. Proc Natl Acad Sci USA 2000; 97: 8039–8044[Abstract/Free Full Text]
  37. Singh N, Yu VL, Mieles L et al. High-dose acyclovir compared with short-course preemptive ganciclovir therapy to prevent cytomegalovirus disease in liver transplant recipients. A randomized trial. Ann Intern Med 1994; 120: 375–381[Abstract/Free Full Text]
  38. Singh N. Delayed occurrence of cytomegalovirus disease in organ transplant recipients receiving antiviral prophylaxis: are we winning the battle only to lose the war?. Eur J Clin Microbiol Infect Dis 2002; 21: 643–646[CrossRef][Medline]
  39. Kalil AC, Levitsky J, Lyden E et al. Meta-analysis: the efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients. Ann Intern Med 2005; 143: 870–880[Abstract/Free Full Text]
  40. Reusser P, Riddell SR, Meyers JD et al. Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. Blood 1991; 78: 1373[Abstract/Free Full Text]
  41. Li CR, Greenberg PD, Gilbert MJ et al. Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. Blood 1994; 83: 1971–1979[Abstract/Free Full Text]
  42. Singhal S, Khan OA, Bramble RA et al. Cytomegalovirus disease following liver transplantation: an analysis of prophylaxis strategies. J Infect 2003; 47: 104–109[Medline]
Received for publication: 7.12.05
Accepted in revised form: 6. 3.06


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