Prophylaxis and treatment of cytomegalovirus disease in recipients of solid organ transplants: Current approach and future challenges
Cytomegalovirus infection is a major cause of morbidity and mortality in solid-organ transplant recipients, in terms of cytomegalovirus disease itself and the associated outcomes of organ rejection and death. This review focuses on recent literature concerning prevention and treatment of cytomegalovirus disease in this population.
Two major strategies for the prevention of cytomegalovirus infection in solid-organ transplant recipients - preemptive and prophylactic treatment - are reviewed. Both strategies result in a lower incidence of cytomegalovirus disease when compared to a 'wait and treat' approach, and are generally considered cost-effective. Neither prophylaxis nor preemption has yet been shown to be superior. Newer trials are also reviewed, which are beginning to evaluate protocols of preemption or prophylaxis representative of current practice, as well as to explore alternative dosing strategies, the benefits of cytomegalovirus immune globulin, and the potential benefit of a longer course of prophylaxis. Concerns for the selection of ganciclovir-resistant strains of cytomegalovirus are also addressed.
The consensus is that there is benefit for the treatment of solid-organ transplant patients with an antiviral agent before clinical evidence of cytomegalovirus disease. So far, there has been no demonstration of the superiority of prophylactic or preemptive regimens, nor has the exact nature and dosing of the oral antiviral agent of choice been established.
Available from: Richard Buick
- "The validity of the SEQUENTIAL method was evaluated by using it in a project to produce neutralizing human mAbs against HCMV, a leading cause of morbidity and mortality in immunocompromised individuals and the most serious pathogenetic agent in transplant patients [15,36,37]. In the absence of other therapies such as vaccines , these patients are treated with antivirals, which are often associated with considerable side effects and the emergence of drug-resistant strains. "
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ABSTRACT: Human monoclonal antibodies (mAbs) generated as a result of the immune response are likely to be the most effective therapeutic antibodies, particularly in the case of infectious diseases against which the immune response is protective.Human cytomegalovirus (HCMV) is an ubiquitous opportunistic virus that is the most serious pathogenic agent in transplant patients. The available therapeutic armamentarium (e.g. HCMV hyperimmune globulins or antivirals) is associated with severe side effects and the emergence of drug-resistant strains; therefore, neutralizing human mAb may be a decisive alternative in the prevention of primary and re-activated HCMV infections in these patients.
The purpose of this study was to generate neutralizing mAb against HCMV from the immunological repertoire of immune donors. To this aim, we designed an efficient technology relying on two discrete and sequential steps: first, human B-lymphocytes are stimulated with TLR9-agonists and IL-2; second, after both additives are removed, the cells are infected with EBV. Using this strategy we obtained 29 clones secreting IgG neutralizing the HCMV infectivity; four among these were further characterized. All of the mAbs neutralize the infection in different combinations of HCMV strains and target cells, with a potency approximately 20 fold higher than that of the HCMV hyperimmune globulins, currently used in transplant recipients. Recombinant human monoclonal IgG1 suitable as a prophylactic or therapeutic tool in clinical applications has been generated.
The technology described has proven to be more reproducible, efficient and rapid than previously reported techniques, and can be adopted at low overall costs by any cell biology laboratory for the development of fully human mAbs for immunotherapeutic uses.
Available from: factsandcomparisons.com
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ABSTRACT: MEDICATION SAFETY Overlooked Renal Dosage Adjustments A retrospective analysis of 647 patients at hospital discharge com-pared required renal dosage adjust-ments to dosage actually prescribed. This study was conducted at VieCuri Medical Centre in Venlo, Netherlands. Patient demographics and renal function data were col-lected, and dosage adjustment needs were assessed via the pharmacy-supported discharge counseling ser-vice. The incidence of inappropriate dosing based on renal function was measured at hospital discharge. Thirty-seven percent of patients evaluated during the study period (237/647) had a creatinine clear-ance less than 51 mL/min/1.73 m 2 ; dosage adjustment was warranted in 23.9% (411/1,718) of prescrip-tions. When dosage adjustment should have been performed, more than 40% of prescriptions (169/411; 41.1%) were inappropri-ate for renal function (9.8% of pre-scriptions overall; 169/1,718). Fur-thermore, 60.4% (102/169) of inappropriate prescriptions pos-sessed the potential for moderate or severe clinical consequences, as evaluated by a panel of two clinical pharmacologists and one nephrolo-gist. Study authors also noted a lack of standardized dosing guidelines for agents requiring renal dosage adjustment. The authors also sug-gested that augmenting medication systems by adding dynamic renal dosing alerts would improve moni-toring. Summary: A comparison of suggested renal dosing and actual dosing at hospital discharge revealed that appropriate prescribing may be overlooked. van Dijk EA, Drabbe NRG, Kruijtbosch M, De Smet PAGM. Drug dosage adjust-ments according to renal function at hos-pital discharge. Ann Pharmacother. 2006;40:1254-1260.
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