Cytomegalovirus Prevention: Prophylaxis and Preemptive Therapy (2007)

Despite widespread use of preventative measures, cytomegalovirus (CMV) infection and CMV disease continue to be a problem in solid-organ transplantation. The recent introduction of CMV prophylaxis has led to a decrease in the incidence of disease and has resulted in milder disease, most typically asymptomatic or mildly symptomatic viraemia. In consequence, severe CMV disease resulting in graft loss or death is becoming uncommon outside of certain transplant settings, such as the heavily immunocompromised patients or lung transplant recipients. This review will compare universal prophylaxis with preemptive therapy for the prevention of CMV disease in the solid-organ transplantation setting. Definition of Universal Prophylaxis and Preemptive Therapy Universal prophylaxis is defined as the initiation of antiviral therapy from the time of transplantation (or within the first few days) to all patients or to a subgroup of high-risk patients such as CMV donor (D)-positive, CMV recipient (R)-negative (D+R−) transplant recipients. In contrast, in a preemptive strategy, the patient is tested for CMV at regular intervals (usually weekly) and antiviral therapy is only initiated after a positive result. Therefore, CMV is detected when the patient still has low-level viral replication but no symptoms, and early intervention with antiviral therapy can prevent the onset of CMV disease (Fig. 1). Once initiated, preemptive therapy should be given until viremia is resolved and, once antiviral therapy has been stopped, there is a requirement to continue monitoring as 30% of patients will relapse.FIGURE 1.: Strategy for preemptive antiviral therapy in a posttransplant setting. Could have initiated preemptive therapy.The Impact of Prophylaxis Several randomized controlled trials and meta-analyses have clearly demonstrated the efficacy of prophylaxis, with a reduction in both the incidence of CMV organ disease and mortality associated with CMV (1). However, late-onset CMV disease (CMV disease occurring at least 3 months after solid-organ transplantation) is an increasing cause for concern (2, 3). In the absence of prophylaxis, most posttransplant CMV disease occurs in the first 12 weeks after transplantation (4). If prophylaxis is administered, the onset of either primary CMV disease in donor CMV-positive (D+) and recipient CMV-negative (R−) patients, or recurrence in recipient CMV-positive (R+) patients, is delayed (5, 6). Late-onset CMV disease may present with atypical symptoms, such as low-grade fever or absence of fever and grumbling malaise, and the diagnosis can be missed. As late-onset CMV disease occurs at least 3 months after transplant, patients are often no longer being followed regularly by the transplant center, but in the community, by physicians who may not be as familiar with the risks of CMV disease (7). This may also lead to a misdiagnosis. The PV16000 trial comparing valganciclovir (VGCV) with oral ganciclovir (GCV) prophylaxis in D+R− patients showed that prophylaxis was efficacious while patients received either therapy (Fig. 2) (8). However, once prophylaxis was stopped, patients began to develop CMV disease and, by day 180 after transplantation, there was approximately a 30% incidence of investigator-treated CMV disease in both treatment arms.FIGURE 2.: PV16000 trial showing investigator-treated CMV disease after cessation of prophylaxis.Options for Late-Onset CMV Disease There are a number of options available to deal with late-onset CMV disease. These include (1) doing nothing and accepting the risk of CMV disease and treating as it arises; (2) prolonging prophylaxis beyond the standard 3 months of therapy in an attempt to postpone or prevent late-onset CMV disease. (However, it is conceivable that prolonging prophylaxis may simply further extend the time to onset of CMV disease and increase the number of patients requiring therapy) (9); (3) alternative, more potent prophylaxis could be used to prevent CMV disease, but there are currently no new agents close to licensing or that have been proven to be superior to GCV or its derivatives; and (4) finally, the careful monitoring of high-risk patients with laboratory assays for CMV once they have completed prophylaxis is also a consideration (10). A recent study in kidney transplant recipients showed a significant reduction in the incidence of CMV disease in those patients receiving a longer, 24-week course of oral GCV compared with a historical cohort of patients receiving a 12-week course (9). The benefits of prolonging prophylaxis for reducing late-onset CMV disease should be clarified through the IMPACT clinical trial (NCT00294515), which is a randomized controlled trial that will compare 3 months of VGCV therapy followed by 3 months of placebo versus 6 months of VGCV prophylaxis (11). The primary outcome of the IMPACT trial is to determine the incidence of CMV disease at 12 and 24 months after transplantation (11). Molecular diagnostic tests such as quantitative polymerase chain reaction (PCR) are well-established tools for assessing the need to initiate preemptive therapy. However, quantitative PCR was found to be less useful when performed after a course of prophylaxis (12). In the PV16000 study, after 3 months of prophylaxis with either VGCV or oral GCV, all patients were tested using quantitative CMV PCR every 2 to 4 weeks to investigate whether the use of PCR could predict late-onset CMV disease (13). PCR had a sensitivity of only 38% and a specificity of 60% in predicting late-onset CMV disease. It is possible that more frequent PCR testing may have resulted in better test characteristics but, beyond 3 months after transplantation, it may be difficult to persuade patients to return on a regular basis to be tested for CMV viremia. Host Response and CMV Disease It is well established that CD4+ and CD8+ cytotoxic T lymphocytes (CTLs) are important in the control of CMV in solid-organ transplant recipients (14, 15). There are a number of assays available that measure CTL responses, including Elispot and HLA tetramer assays, although they are not routinely used in the posttransplantation setting. It is anticipated that, should a CMV-specific CTL assay become commercially available, measuring cellular immunity may become standard practice in the management of transplant recipients. Simpler assays, such as tests for CMV seroconversion in the D+/R– transplant recipient (a measure of humoral immune responses), do not appear to be predictive of late-stage CMV disease (12). In one study (12), CMV seroconversion was tested at a number of time points after transplantation in CMV D+/R− patients. Late-onset CMV disease was found in 13.2% of CMV-seropositive patients who seroconverted by 3 months compared with 17.8% of patients who remained seronegative at 3 months after transplantation. These data suggest that, after transplantation, CMV seroconversion is not a good predictor of protection from disease. However, in the same study, 6 months after transplant, the risk of developing late-onset CMV disease (between 6 and 12 months) was extremely low in CMV-seropositive subjects, occurring in 1.3% compared with 10% in seronegative individuals (16). Taken together the data suggest that seroconversion is a marker for some degree of protection against the virus but is insufficiently specific to be used as a diagnostic predictor of CMV disease in D+/R− patients. Preemptive Therapy There are both advantages and disadvantages associated with preemptive therapy. A specifically targeting drug should theoretically lead to less drug-associated toxicity and to a lower cost of antiviral therapy per patient (5). It is anticipated that preemptive therapy may result in less late-onset CMV disease; it is also well suited to populations of patients at low risk of CMV disease. Furthermore, there is a possibility of fewer drug-resistant viruses emerging with preemptive therapy (5), although this has not been clearly established in head-to-head clinical trials with prophylaxis (17). The disadvantages of preemptive therapy include the logistics associated with routine testing of solid-organ transplant recipients. It is simpler to prescribe 3 months of prophylaxis than to monitor every week for the emergence of CMV replication. Other questions surrounding preemptive therapy include: (1) What tests should be used to monitor CMV status? (2) How often and for how long should a patient be monitored? (3) What drug, at what dose and what duration should be used? Concerns remain in relation to the impact of preemptive therapy on the indirect effects of CMV and on the interaction of CMV with other herpesviruses (1, 18). Intravenous (IV) GCV has been shown to be effective for the preemptive treatment of CMV viremia, but it is difficult to administer in asymptomatic CMV-infected patients because of the requirement of hospitalization or home IV therapy. Studies suggest that oral GCV may result in suboptimal therapy, leading to antiviral drug resistance and treatment failure (19). Use of the newer agent VGCV for preemptive strategies is currently under investigation (20–22). Several studies have suggested that there is no difference between IV GCV and oral VGCV in reducing CMV viral load (22, 23). Recently the results of a large multicenter trial comparing IV GCV with oral VGCV for the treatment of CMV disease were reported (23a). In 321 evaluated patients, both medications had comparable success rates for the eradication of viremia and a similar safety profile. A detailed analysis of viral kinetics in the two treatment arms demonstrated no significant differences in time to viral eradication and the rate of decline in viral load. Considerations for Prophylaxis and Preemptive Therapy Of concern for both prophylaxis and preemptive therapy is whether the overuse of antiviral drugs could lead to the development of more drug-resistant viruses. The risk factors for the emergence of GCV-resistant CMV include treatment of D+R– patients, prolonged oral GCV, and use of more potent immunosuppression, such as depleting antibody therapy (24). However, in the PV16000 study the emergence of GCV-resistant viruses was extremely rare. Overall, genotypic GCV-resistant viruses emerged in two (0.7%) patients, and in the subgroup that developed CMV disease, the incidence of GCV resistance was 2 of 88 (2.3%) patients (25). However, in certain subpopulations of transplant patients antiviral drug resistance rates of up to 10% have been reported, especially in D+R− lung transplant patients on potent immunosuppressive regimens (26, 27). The two alternative therapies for use in patients with GCV-resistant viruses, foscarnet and cidofovir, both have considerable toxicities which limit their use. The benefits and weaknesses of prophylaxis versus preemptive therapy are summarized in Table 1. There is evidence that both prophylaxis and preemptive therapy are effective in reducing CMV disease, with more evidence to support the role of prophylaxis in reducing the indirect effects of CMV (1, 18). However, there is a concern that prophylaxis is more likely to predispose patients to late-onset CMV disease than preemptive therapy (3, 6, 28). The controversy between the two treatments will not be resolved until results from large randomized clinical trials comparing prophylaxis versus preemptive therapy are performed. Results from such a trial should include the impact that the therapies have on the indirect effects of CMV to establish a global strategy for the treatment of CMV in solid organ transplantation.TABLE 1: Comparison of the effectiveness of prophylaxis versus preemptive therapyGuidelines Guidelines published in the October 2004 issue of the American Journal of Transplantation (29) recommend universal prophylaxis with VGCV or IV or oral GCV in D+R− kidney, liver, pancreas, or heart transplant recipients. Valacyclovir is also recommended in renal transplant recipients. It was noted that there is a Food and Drug Administration caution for the use of VGCV in liver transplantation as a consequence of subgroup analysis from the PV16000 trial indicating a higher incidence of tissue invasive disease in this group. In R+ kidney, liver, pancreas, and heart transplants the guidelines recommend prophylaxis with GCV or VGCV, but valacyclovir may also be an option in renal transplantation. Preemptive therapy with IV GCV or oral VGCV is also an option in R+ transplant recipients after a positive CMV test. In lung or heart and lung D+R− or R+ transplant patients, the guidelines recommend 3 months of universal prophylaxis with IV GCV or VGCV. Oral GCV is an option in R+ patients. In D+R− patients, prophylaxis may be extended to six months, and, in some patients, the physician may choose to add in CMV-specific immunoglobulin to the antiviral prophylaxis regimen. What Does the Future Hold? Selective immunosuppressive therapy that contains inherent antiviral properties is an exciting area of research (30). The other area of promise is novel preventative strategies, such as multi-epitope DNA vaccines and cell-mediated therapeutic modalities (31, 32). However, both strategies are in the experimental phase and some way from becoming an option for the prevention and treatment of CMV disease in transplant recipients. ACKNOWLEDGMENTS The author acknowledges and thanks the editorial team from International Medical Press for their help in the preparation of this article. The articles in this supplement summarize the findings of a CME-accredited symposium entitled “CMV: The Facts Revealed,” which was jointly sponsored by International Medical Press, the Center for Accredited Healthcare Education (CAHE) and the Institute for Medical and Nursing Education (IMNE) with an independent educational grant from Roche Inc.