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• W2022377903 abstract "There is an urgent, and as yet unmet, need for therapy for cytomegalovirus (CMV) infection resistant to ganciclovir in solid organ and bone marrow transplantation. Since the recognition that CMV can emerge resistant to ganciclovir in solid organ or bone marrow transplant recipients, the approach to management has been difficult (1, 2). This need is because although rare, ganciclovir resistance in CMV infections in solid organ and bone marrow transplant recipients seems to be increasing slightly. In our own transplant programs, we have seen several cases in the past few years, whereas in the prior 15- to 18-year interval, during which ganciclovir was licensed and used clinically, we had the occurrence of one case of clinically resistant CMV disease in a bone marrow transplant recipient. Often we can induce a reduction in viral load and treat patients with ganciclovir resistance with Foscarnet or cidofovir, but maintaining intravenous Foscarnet therapy with its myriad of toxicities, including electrolyte imbalances, nephrotoxicity, and urethral ulceration may become dose limiting with long-term parenteral therapy, even in a maintenance phase (3). Cidofovir has significant long-term nephrotoxicity (4). In addition, emergence of cross resistance to either or both agents may occur (5). There are anecdotal reports of successful therapy using combinations of agents including continued use of ganciclovir in combination with sodium Foscarnet and the additional use of CMV immune globulin (5). Sometimes these efforts are successful, but often patients relapse or fail after initial success with viral suppression. In addition, it has been well documented that ganciclovir-resistant CMV disease is associated with poor outcomes in solid organ transplantation (1, 2). If one examines the American Society for Transplantation guidelines (6) or the recently published Transplantation Society guidelines (7), for the management of CMV infection due to resistant virus, there are nice algorithms to follow, but the evidence base on which agents or combinations to use, dosing guidelines, and the order in which to start agents is limited to anecdotal case series and expert opinion. Furthermore, we have been at a loss when ganciclovir resistance is followed by cidofovir and Foscarnet resistance (6–8). It had been hoped that maribavir, the benzimidazole l-riboside inhibitor of UL 97 kinase of CMV, known to be active against ganciclovir-resistant strains of CMV would be helpful in the management of such patients (9). Although there was a case series presented recently that compassionate use of maribavir may be somewhat helpful in the management of ganciclovir CMV (10), it is unclear whether this agent will remain available for compassionate use, or developed further, because of the lack of effectiveness in two prevention trials, one in stem-cell transplantation and the other in liver transplantation, in which maribavir did not meet targets for superiority at the dose chosen (Boeckh M, personal communication). It is against this back drop that the analysis by Avery et al. (11) in this issue of Transplantation is most welcome. They report the moderately successful use of leflunomide, an immunosuppressive agent that is currently licensed for use in rheumatoid arthritis. It was recognized to have some in vitro activity against CMV over a decade ago, acting at stages of viral assembly as opposed to DNA replication (12). Because of its different mechanism of action, leflunomide is active against ganciclovir-resistant strains in vitro (13). Case reports using leflunomide for both prevention and treatment of CMV infection and disease have been published previously, but as with any series of individual case reports, it has been difficult to interpret whether these patients would have responded anyway due to reductions in immunosuppression (14, 15). The report by Avery et al. is the largest series to date and gives the clinician enough details in prior management, and the context in which resistance developed, so that one is able to place the use of leflunomide in some framework, which should allow clinicians to tailor its use to their own practice. The authors choose a higher dose than has been reported previously, and they also followed levels and used a target level of the metabolite, teriflunomide, to monitor dosing (11). It would seem that patients more likely to respond had lower CMV viral loads when the drug was initiated. It should be noted that patients might have transient blips of CMV viremia, even using leflunomide, necessitating the introduction of additional agents. Once resuppressed, the authors were able to maintain viral suppression on single-agent leflunomide therapy. The take home message from this retrospective analysis is that leflunomide, perhaps in combination with other agents at induction may be useful, with a transition to leflunomide therapy for maintenance. Maintenance may require many months of treatment. Of those who responded with viral suppression, two thirds started treatment with leflunomide along with another agent. One advantage to leflunomide, of course, is the fact that it is an oral agent with adequate oral bioavailability. In this retrospective analysis, treatment-limiting toxicity was relatively frequent, 7 of the 17 patients had to discontinue therapy; diarrhea was the most common symptom. Other toxicities to be concerned about include anemia, neuropathic syndromes, and abnormal liver function tests. But the attribution of toxicity to leflunomide was difficult because of a number of potential confounding factors including the presence of resistant CMV and the development of other complications of their transplant such as graft versus host disease. Although leflunomide may offer some hope in the management of ganciclovir-resistant CMV, it is still not the answer in terms of drug development, because the response rates are only approximately 50%, and long-term toxicity can present problems. There still is an urgent need for additional new agents to prevent or treat CMV, especially ones without bone marrow or nephrotoxicity. In the meanwhile, the analysis by Avery et al. will serve as a useful starting point for future studies to help to guide clinicians in the management of these difficult patients. A randomized trial or group collaborative effort is needed to answer some of these questions, and I would urge drug development to think about the design of such studies and licensing authorities to also look at CMV drug development for CMV resistance in the same fashion as we look at HIV drug resistance to speed the development by the use of surrogate markers such as CMV viral loads to prove efficacy." @default.
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• W2022377903 date "2010-08-27" @default.
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• W2022377903 title "Leflunomide: A Small Step Forward in Meeting the Urgent Need for Treatment of Drug-Resistant Cytomegalovirus Infection" @default.
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