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• W2055615772 abstract "Cytomegalovirus (CMV) has long been regarded as one of the most significant opportunistic pathogens in organ transplant recipients. Up until the early 1980s, CMV disease accounted for 86% of febrile episodes and 65% of all infections; after rejection and surgical complications, it was the leading cause of posttransplant deaths (1). The last decade has witnessed a decline in CMV disease so substantial that these astonishingly high rates in the early years of organ transplantation seem virtually unfathomable. Refinement of immunosuppressive regimens and antiviral prophylaxis are the key variables contributing towards a decline in CMV-associated morbidity. Prophylaxis with valganciclovir has proven highly effective and is widely employed currently. However, with the increasing use of such an approach has come the recognition that although CMV disease can be effectively prevented during the period that antiviral prophylaxis is employed (i.e., the first 3 months), a significant proportion of patients—particularly the R-/D+ group—develop CMV disease upon discontinuation of prophylaxis. Late-onset CMV disease occurs in 5–18% of the organ transplant recipients receiving prophylaxis and has emerged as a significant posttransplant complication in the current era (2–4). Limited data exist with regards to the risk of late-onset CMV disease with preemptive therapy. Diaz-Pedroche et al. followed 324 high-risk seropositive kidney, heart, and liver transplant recipients using a CMV antigenemia-based surveillance protocol. Valganciclovir was employed as preemptive therapy for CMV antigenemia ≥25 cells/2×105 leukocytes; 50% of these patients had previously received T-cell antibody (basiliximab, an interleukin [IL]-2 receptor antibody or thymoglobulin for <6 days). This study is important for two reasons. First, the approach proved highly effective. At a median follow-up of 14 months, no episodes of CMV disease were observed during the period of surveillance monitoring or at anytime thereafter. Similar results were documented in two prior, albeit smaller, studies using valganciclovir as preemptive therapy (5, 6). Second, the logistics of conducting surveillance tests and initiating antiviral therapy in a timely manner are perceived by many as a major barrier to the implementation of the preemptive therapy approach (7). This study illustrates the feasibility of successfully implementing such a surveillance program in a large cohort of transplant recipients. Two important variables with regards to antiviral prophylaxis appear to influence the risk of late-onset CMV disease: the duration of therapy and the potency of the antiviral agent employed. In the absence of any form of antiviral prophylaxis, CMV disease occurs in ∼ 20–30% of the transplant recipients, with a vast majority of the episodes developing within 90 days posttransplant. Late-onset CMV disease was a rare event (0–5%) in the era of long-term use of acyclovir, an antiviral agent with poor activity against CMV (8–10). Oral ganciclovir, despite low bioavailability, is able to achieve serum concentrations adequate to prevent CMV disease. Upon cessation of prophylaxis, however, CMV disease has been documented in 2.5 to 7% of the patients receiving prolonged prophylaxis with oral ganciclovir (3, 11). However, it was not until valganciclovir came to be used as antiviral prophylaxis that late-onset CMV disease (5.5–18%) emerged as a more widely recognized entity in transplant recipients (2, 4, 12, 13). Based on these data, I suggest that the risk of late-onset CMV disease is low if a relatively less potent antiviral agent is employed for a prolonged period or if a potent drug is employed for short period as in preemptive therapy (Fig. 1). Use of a potent agent for a prolonged period appears to be associated with a higher risk for late-onset CMV disease (Fig. 1). Complete suppression of the virus with the long-term use of a potent agent may be less conducive to antigen-induced priming of host responses and therefore a greater likelihood of CMV disease.FIGURE 1.: Conceptual presentation of the risk of late-onset CMV disease with antiviral prophylaxis in organ transplant recipients; data compiled from (2–6, 8–13). The risk of late-onset CMV is low (0–5%) if a relatively less potent antiviral agent (acyclovir) is employed for a prolonged period (8, 9) or if a potent drug (valganciclovir) is used for a short period (0%) as in preemptive therapy (5, 6, 19). Long-term use of valganciclovir as prophylaxis appears to pose a higher risk (5.5–17%) for late-onset CMV disease (2, 3, 12, 13).Regardless of the prophylactic approach employed, long-term protective immunity against CMV is critically dependent on the adequate development of CMV-specific CD4+ T-helper and CD8+ cytotoxic T-cell responses. CMV-specific CD4+ T cells facilitate the generation and expansion of CMV-specific CD8+ cells that ultimately confer protection against CMV disease. Persistence of infection has also been shown to correlate with delayed maturation of CMV-specific antibodies, as determined by avidity assays. A potent antiviral agent, such as ganciclovir, has the potential to impair the recovery of viral-specific T-cell responses by suppression of antigen induced in vivo priming (14) or by its direct inhibitory effect on T-cell proliferation (15). Ganciclovir prophylaxis also delayed IgG seroconversion, inhibited antibody maturation, and impaired immunoglobulin class switching from IgM to IgG (16). Persistent CMV seronegativity at the end of prophylaxis was associated with a higher risk of late-onset CMV disease in R-/D+ organ transplant recipients who received prophylaxis for 100 days (17). Emerging data show that asymptomatic CMV replication that is not allowed to progress to symptomatic disease may facilitate T-cell mediated immune generation (18). In a study in allogeneic stem cell transplant recipients, preemptive therapy with ganciclovir was employed upon detection of CMV infection by antigenemia assay (18). Patients with CMV reactivation not only had enhanced lymphoid reconstitution, but had significantly better overall survival and lower nonrelapse-related mortality compared to patients without CMV reactivation (18). In liver transplant recipients, late-onset CMV disease in patients receiving prophylaxis with oral ganciclovir or valganciclovir correlated with an increased risk of mortality in the first posttransplant year (3). That there is an immunologic basis for adverse outcomes related to CMV in this setting remains to be determined, but is plausible given that mortality was not directly attributable to CMV disease but to superinfections (3). Thus, a clinical trial to compare preemptive therapy with prophylaxis, as suggested by Diaz-Pedroche, should assess not only direct and indirect outcomes associated with CMV, but also CMV-specific immune responses. The proposed immunologic benefits of controlled viral replication implicit in preemptive therapeutic approach are intriguing and warrant further characterization. These data would contribute substantially towards further elucidating the pathophysiologic basis of CMV and optimization of outcomes related to CMV in transplant recipients." @default.
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• W2055615772 date "2006-07-15" @default.
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• W2055615772 title "Optimization of Outcomes Related to Cytomegalovirus in Organ Transplant Recipients" @default.
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• W2055615772 doi "https://doi.org/10.1097/01.tp.0000228232.09678.6b" @default.
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