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Cytomegalovirus Prevention Strategies: All Are Not Created Equal, But Some More Unequal Than Others


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Luciano Potena, MD, PhD
University of Bologna
Cardiovascular Department
Bologna, ITALY
luciano.potena2@unibo.it




Cytomegalovirus (CMV) infection remains a major issue in the management of heart transplant recipients. The availability of highly effective oral antiviral drugs supported a generalized anti-CMV prophylaxis approach [1,2]-with several lines of evidence suggesting a protective effect of prophylaxis against indirect CMV-mediated graft injury [3-5]. However, the onset of under-diagnosed late CMV infection reveals that in some patients an important negative counterbalance to the desired protection of universal prophylaxis [6,7]. Indeed, a careful clinical practice approach highlights wide variability in CMV-related scenarios raising doubts on the real effectiveness of a prolonged "all for all" CMV prophylaxis strategy.

One scenario includes patients developing low white blood cell count while on valganciclovir prophylaxis: reduction of valganciclovir dose is not recommended because sub-therapeutic drug levels may favor ganciclovir-resistance development. On the other hand, reducing or withdrawing the antiproliferative agent (i.e. MMF or mTOR inhibitor) exposes the patient to the risk of rejection. In such situations the physician rarely gets it right.

Another scenario is the young lady on Tac and MMF, experiencing one or two early cellular rejection episodes, on six months prophylaxis, and living far away from the transplant center. After recovering from surgery and rejection she finally can go back to her hometown and returns for the scheduled follow-up visit at month 8 or 9 after transplant. This is when, 8 weeks after stopping prophylaxis, and without any transplant-specific medical contact, she presents with diarrhea, dehydration, kidney failure, high Tac levels and 500,000 CMV DNA copies/ml circulating.

Yet another consideration concerns the real risk of developing infection in the heart transplant population: according to studies on the pre-emptive approach and depending on the immunosuppression strategy, 20 to 50% of CMV seropositive heart recipients never show a single CMV positive blood sample. Thus a universal prophylaxis approach would overtreat a significant proportion of patients. The "prophylaxers" party defense is based on the fact that these are often indistinguishable from those who will indeed reactivate infection. But are they really indistinguishable?

These purposeful simplistic considerations aim to emphasize the highly variable CMV-recipient-graft relationship and support the concept that a "universal" therapeutic approach in disease prevention is not necessarily an effective shortcut, but favors mental laziness in avoiding the quest for "customized" strategies, based on the actual risk the patient has to develop an event. For example, it would be much easier distributing statin-enriched drinking water to enforce "universal" primary prevention against coronary artery disease than differentiate statin prescription after collecting full history and risk profile in the single patient (i.e. 40y old non-smoker female vs. 40y old smoker, diabetic male with a previous coronary angioplasty).

The main parameters to customize anti-CMV strategies include concomitant immunosuppression, feasibility of accurate CMV DNA monitoring, and the level of anti CMV immunity. Immunosuppression, induction strategy, in particular with thymoglobulin, portends a higher risk of subsequent CMV infection as compared to non-induction, while mTOR inhibitors are associated with a markedly lower risk of CMV infection and disease, as compared to MMF or AZA [8].

The availability of a local laboratory providing timely results of blood CMV PCR, and the compliance of recipients to frequent blood sampling (every 1-2 weeks for the first 3 post transplant months) usually allow prompt detection of viremia and planning of a pre-emptive treatment [9]. When frequent assays are not feasible, viral kinetics not captured may pose a higher risk of CMV syndrome or disease in heart recipients.

Host immune capacity to control and respond to viral replication is a major factor influencing the risk for CMV infection and disease. The basic evidence of this concept is highlighted by the notion that CMV seronegative recipients of a CMV seropositive graft are those at highest risk to develop infection. Recently, assays on T-cell activation in response to CMV antigens pointed out a wide variability in the capacity of seropositive recipients to respond to and control CMV infection.[10] In particular, these data showed that T-cell mediated CMV immunity is progressively recovered after transplant, but with different patterns and timings, exposing the patient to variable risk of CMV infection and disease. In particular, recovery of immunity during the first month after transplant identifies patients who will most likely develop infection [11,12], and assay of immunity during asymptomatic viremia may help to discriminate between patients able to clear spontaneously the infection and those who will develop high-grade infection and disease [13]. Similarly, at the end of the prophylaxis period, assessment of CMV specific immunity can discriminate the risk of recipients to develop subsequent late CMV disease [14].

Although information deriving from immune-function assays is likely to be the most valuable to achieve effective customization of anti-CMV strategy, it must be remembered that studies validating the effectiveness of therapeutic approaches based on immune assay response are still lacking. Nevertheless, full consideration of these CMV risk parameters—immunosuppression, CMV monitoring facilities, and CMV specific immunity—may represent a starting point to overcome the "iron curtain" separating the universal prophylaxis and the pre-emptive parties, and moving towards an approach tailored on the risk estimation in the single patient ... while waiting for a CMV vaccine to become clinically available [15].

Disclosure Statement: The author received speaker's fees from Novartis Pharma.


References:

  1. Humar A, Lebranchu Y, Vincenti F, et al. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant 2010;10:1228-37.
  2. Kumar D, Humar A. Cytomegalovirus prophylaxis: how long is enough? Nat Rev Nephrol 2010;6:13-4.
  3. Potena L, Grigioni F, Magnani G, et al. Prophylaxis versus preemptive anti-cytomegalovirus approach for prevention of allograft vasculopathy in heart transplant recipients. J Heart Lung Transplant 2009;28:461-7.
  4. Potena L, Valantine HA. Cytomegalovirus-associated allograft rejection in heart transplant patients. Curr Opin Infect Dis 2007;20:425-31.
  5. Manuel O, Kralidis G, Mueller NJ, et al. Impact of antiviral preventive strategies on the incidence and outcomes of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 2013;13:2402-10.
  6. Reischig T, Hribova P, Jindra P, et al. Long-term outcomes of pre-emptive valganciclovir compared with valacyclovir prophylaxis for prevention of cytomegalovirus in renal transplantation. J Am Soc Nephrol 2012;23:1588-97.
  7. Sun HY, Wagener MM, Singh N. Prevention of posttransplant cytomegalovirus disease and related outcomes with valganciclovir: a systematic review. Am J Transplant 2008;8:2111-8.
  8. Kobashigawa J, Ross H, Bara C, et al. Everolimus is associated with a reduced incidence of cytomegalovirus infection following de novo cardiac transplantation. Transpl Infect Dis 2012.
  9. Emery VC, Sabin CA, Cope AV, et al. Application of viral-load kinetics to identify patients who develop cytomegalovirus disease after transplantation. Lancet 2000;355:2032-6.
  10. 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.
  11. Tu W, Potena L, Stepick-Biek P, et al. T-cell immunity to subclinical cytomegalovirus infection reduces cardiac allograft disease. Circulation 2006;114:1608-15.
  12. Petrisli E, Potena L, Bianchi IG, et al. 402 Reconstitution of CMV-Specific Immunity after Heart Transplantation Is Modulated by mTOR Inhibition, but Not by Antiviral Strategy. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2012;31:S143.
  13. Lisboa LF, Kumar D, Wilson LE, et al. Clinical utility of cytomegalovirus cell-mediated immunity in transplant recipients with cytomegalovirus viremia. Transplantation 2012;93:195-200.
  14. Manuel O, Husain S, Kumar D, et al. Assessment of cytomegalovirus-specific cell-mediated immunity for the prediction of cytomegalovirus disease in high-risk solid-organ transplant recipients: a multicenter cohort study. Clin Infect Dis 2013;56:817-24.
  15. Griffiths PD, Stanton A, McCarrell E, et al. Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial. Lancet 2011;377:1256-63.



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