Antiviral dosing and efficacy for prophylaxis of cytomegalovirus disease in solid organ transplant recipients.
ABSTRACT The implications of the findings from clinical studies and pharmacokinetic analyses of the antiviral agent valganciclovir for dosing of the drug to prevent cytomegalovirus (CMV) disease in solid organ transplant recipients are reviewed.
Valganciclovir, an oral prodrug of ganciclovir, is as effective as oral ganciclovir for preventing CMV disease, although prophylaxis with either agent may delay CMV disease. Dosage reduction is required for both drugs in patients with renal impairment to prevent high plasma ganciclovir concentrations and toxicity. A valganciclovir dosage of 900 mg/day is required in patients with normal renal function, especially those at high risk for CMV disease, to provide adequate systemic ganciclovir exposure. Some studies suggest that a lower dosage might suffice for patients at a low risk for CMV disease.
Valganciclovir dosing should be based on renal function to avoid toxicity.
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ABSTRACT: Viruses depend on the host cell to provide the energy and biomolecular subunits necessary for production of viral progeny. We have previously reported that human cytomegalovirus (HCMV) infection induces dramatic changes to central carbon metabolism, including glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid biosynthesis, and nucleotide biosynthesis. Here, we explore the mechanisms involved in HCMV-mediated glycolytic activation. We find that HCMV virion binding and tegument protein delivery are insufficient for HCMV-mediated activation of glycolysis. Viral DNA replication and late-gene expression, however, are not required. To narrow down the list of cellular pathways important for HCMV-medicated activation of glycolysis, we utilized pharmaceutical inhibitors to block pathways reported to be both involved in metabolic control and activated by HCMV infection. We find that inhibition of calmodulin-dependent kinase kinase (CaMKK), but not calmodulin-dependent kinase II (CaMKII) or protein kinase A (PKA), blocks HCMV-mediated activation of glycolysis. HCMV infection was also found to target calmodulin-dependent kinase kinase 1 (CaMKK1) expression, increasing the levels of CaMKK1 mRNA and protein. Our results indicate that inhibition of CaMKK has a negligible impact on immediate-early-protein accumulation yet severely attenuates production of HCMV viral progeny, reduces expression of at least one early gene, and blocks viral DNA replication. Inhibition of CaMKK did not affect the glycolytic activation induced by another herpes virus, herpes simplex virus type 1 (HSV-1). Furthermore, inhibition of CaMKK had a much smaller impact on HSV-1 replication than on that of HCMV. These data suggest that the role of CaMKK during the viral life cycle is, in this regard, HCMV specific. Taken together, our results suggest that CaMKK is an important factor for HCMV replication and HCMV-mediated glycolytic activation.Journal of Virology 11/2010; 85(2):705-14. · 4.65 Impact Factor
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ABSTRACT: We have previously reported that human cytomegalovirus (HCMV) infection induces large-scale changes to host cell glycolytic, nucleic acid, and phospholipid metabolism. Here we explore the viral mechanisms involved in fatty acid biosynthetic activation. Our results indicate that HCMV targets ACC1, the rate-limiting enzyme of fatty acid biosynthesis, through multiple mechanisms. HCMV infection was found to activate ACC1 expression, increasing the abundance of both ACC1 mRNA and protein. Viral gene expression but not viral DNA replication was found to be necessary for HCMV-mediated induction of ACC1 levels. HCMV infection was also found to increase the proteolytic processing of SREBP-2, a transcription factor whose proteolytic cleavage is known to activate a variety of phospholipid metabolic genes. Processing of SREBP-2 was found to be dependent on mTOR activity; pharmaceutical inhibition of mTOR blocked HCMV-induced SREBP-2 processing and prevented the induction of fatty acid biosynthesis and ACC1 expression. Independent of the increases in ACC1 expression, HCMV infection also induced ACC1's enzymatic activity. Inhibition of ACC1 through either RNA interference (RNAi) or inhibitor treatment was found to attenuate HCMV replication, and HCMV replication was sensitive to ACC1 inhibition even at the later stages of infection, suggesting a late role for fatty acid biosynthesis during HCMV replication. These findings indicate that HCMV infection actively modulates numerous functional aspects of a key metabolic regulatory enzyme that is important for high-titer viral replication.Journal of Virology 04/2011; 85(12):5814-24. · 4.65 Impact Factor
Article: Valganciclovir[Show abstract] [Hide abstract]
ABSTRACT: Valganciclovir has widely become the agent of choice for the prevention of cytomegalovi-rus in recipients of organ transplants. Optimal dosing is needed to achieve efficacy and avoid toxicity. For subjects at high risk of cytomegalovirus, it is strongly suggested that full-dose (based on renal function) valganciclovir be used. While low-dose valganciclovir appears to be efficacious in some reports, the recommendations are based on inadequate-ly designed trials and must be taken with caution. Unfortunately, because of the sample size needed, it is not likely that the efficacy of reduced-dose valganciclovir will be ade-quately tested in well-controlled trials. The duration of prophylaxis, particularly whether prophylaxis should be extended beyond three months, continues to be an important ques-tion and is the subject of a well-designed clinical trial of which we anxiously await the results.Drugs 07/2001; 61(8). · 4.13 Impact Factor