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Atul Humar - One of the best experts on this subject based on the ideXlab platform.
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the efficacy and safety of 200 days Valganciclovir cytomegalovirus prophylaxis in high risk kidney transplant recipients
American Journal of Transplantation, 2010Co-Authors: Atul Humar, Emily A. Blumberg, Alan G Jardine, Yvon Lebranchu, Flavio Vincenti, Jeffrey D Punch, Ajit P Limaye, Daniel Abramowicz, Athina Voulgari, Jane IvesAbstract:Late-onset cytomegalovirus (CMV) disease is a significant problem with a standard 3-month prophylaxis regimen. This multicentre, double-blind, randomized controlled trial compared the efficacy and safety of 200 days' versus 100 days' Valganciclovir prophylaxis (900 mg once daily) in 326 high-risk (D+/R-) kidney allograft recipients. Significantly fewer patients in the 200-day group versus the 100-day group developed confirmed CMV disease up to month 12 posttransplant (16.1% vs. 36.8%; p < 0.0001). Confirmed CMV viremia was also significantly lower in the 200-day group (37.4% vs. 50.9%; p = 0.015 at month 12). There was no significant difference in the rate of biopsy-proven acute rejection between the groups (11% vs. 17%, respectively, p = 0.114). Adverse events occurred at similar rates between the groups and the majority were rated mild-to-moderate in intensity and not related to study medication. In conclusion, this study demonstrates that extending Valganciclovir prophylaxis (900 mg once daily) to 200 days significantly reduces the incidence of CMV disease and viremia through to 12 months compared with 100 days' prophylaxis, without significant additional safety concerns associated with longer treatment. The number needed to treat to avoid one additional patient with CMV disease up to 12 months posttransplant is approximately 5.
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long term outcomes of cmv disease treatment with Valganciclovir versus iv ganciclovir in solid organ transplant recipients
American Journal of Transplantation, 2009Co-Authors: Anders Asberg, Mark D. Pescovitz, Atul Humar, Halvor Rollag, Alan G Jardine, H Mouas, Angelo A Bignamini, Huseyin Toz, I Dittmer, M MontejoAbstract:Though an important cause of morbidity and mortality in solid organ transplantation (SOT), the long-term outcomes of cytomegalovirus (CMV) disease treatment have not been well studied. In a randomized trial, 321 SOT recipients with CMV disease were followed 1 year after treatment with either twice daily intravenous ganciclovir or oral Valganciclovir (for 21 days) followed by once daily Valganciclovir until day 49 in all patients. Clinical and viral eradication of CMV disease was similar between groups. Clinical recurrence beyond day 49 was found in 15.1% and virological recurrence in 30.0%, no difference between groups (p > 0.77). In a multivariable logistic regression analysis, the only independent predictor for recurrence was failure to eradicate DNAemia by day 21 (clinical: OR 3.9 [1.3-11.3], p = 0.012; virological: OR 5.6 [2.5-12.6], p < 0.0001). Eight patients developed ganciclovir resistance, with no difference between groups (p = 0.62). Twenty patients (Valganciclovir: 11, ganciclovir: 9, p = 0.82) died, 12 due to infections, two involving CMV disease. There were no differences in long-term outcomes between treatment arms, further supporting the use of oral Valganciclovir for treatment of CMV disease. Persistent DNAemia at day 21, CMV IgG serostatus and development of resistance may be relevant factors for further individualization of treatment.
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cytomegalovirus resistance in solid organ transplant recipients treated with intravenous ganciclovir or oral Valganciclovir
Antiviral Therapy, 2009Co-Authors: Guy Boivin, Mark D. Pescovitz, Nathalie Goyette, Halvor Rollag, Alan G Jardine, Anders Asberg, Jane Ives, Anders Hartmann, Atul HumarAbstract:Background: The rate of cytomegalovirus (CMV) mutations conferring ganciclovir resistance was assessed in a trial comparing intravenous ganciclovir and oral Valganciclovir for treatment of CMV disease in solid organ transplant (SOT) recipients. Methods: Viral genes (UL97 and UL54) conferring ganciclovir resistance were amplified and sequenced from blood samples collected at days 0 (before therapy), 21 (end of induction) and 49 (end of maintenance). Results: The overall risk of developing a confirmed or probable ganciclovir resistance mutation during treatment was similar for patients treated with ganciclovir (2.3%) and Valganciclovir (3.6%; P=0.51). A persistent viral load at day 21 was associated with a significant risk of ganciclovir resistance by day 49 (odds ratio 11.83; P= 0 . 022 ). In multivariate analyses, presence of a confirmed ganciclovir resistance mutation was independently associated with virological failure (viral load ≥600 copies/ml) at days 21 and 49. One-third (3/9) of patients with confirmed CMV resistance mutations had recurrent CMV disease. The plasma half-life of confirmed ganciclovir-resistant UL97 mutants was significantly longer than that of wild-type strains, polymorphic variants and strains with mutations of unknown significance (P=0.045). Multiple UL54 mutations of unknown significance were found in clinical strains. Viral kinetic analysis of these latter strains revealed no effect (negative or positive) on in vivo viral fitness. Conclusions: Treatment with oral Valganciclovir or intravenous ganciclovir results in similar and low rates of resistance mutations in SOT recipients. Patients with drug-resistant CMV strains often have virological failure and might have unfavourable clinical outcomes.
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oral Valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients
American Journal of Transplantation, 2007Co-Authors: Anders Asberg, Mark D. Pescovitz, Atul Humar, Halvor Rollag, Alan G Jardine, H Mouas, D Sgarabotto, Murat Tuncer, I L Noronha, Anders HartmannAbstract:Intravenous ganciclovir is the standard treatment for cytomegalovirus disease in solid organ transplant recipients. Oral Valganciclovir is a more convenient alternative. In a randomized, international trial, recipients with cytomegalovirus disease were treated with either 900 mg oral Valganciclovir or 5 mg/kg i.v. ganciclovir twice daily for 21 days, followed by 900 mg daily Valganciclovir for 28 days. A total of 321 patients were evaluated (Valganciclovir [n = 164]; i.v. ganciclovir [n = 157]). The success rate of viremia eradication at Day 21 was 45.1% for Valganciclovir and 48.4% for ganciclovir (95% CI -14.0% to +8.0%), and at Day 49; 67.1% and 70.1%, respectively (p = NS). Treatment success, as assessed by investigators, was 77.4% versus 80.3% at Day 21 and 85.4% versus 84.1% at Day 49 (p = NS). Baseline viral loads were not different between groups and decreased exponentially with similar half-lives and median time to eradication (21 vs. 19 days, p = 0.076). Side-effects and discontinuations of assigned treatment (18 of 321 patients) were comparable. Oral Valganciclovir shows comparable safety and is not inferior to i.v. ganciclovir for treatment of cytomegalovirus disease in organ transplant recipients and provides a simpler treatment strategy, but care should be taken in extrapolating to organ transplant recipients not properly represented in the present study.
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clinical impact of ganciclovir resistant cytomegalovirus infections in solid organ transplant patients
Transplant Infectious Disease, 2005Co-Authors: Guy Boivin, Atul Humar, Nathalie Goyette, Christian Gilbert, Emma CovingtonAbstract:Clinical consequences of ganciclovir resistant cytomegalovirus (CMV) infections were studied during 2 large prophylactic trials consisting of 100 days of Valganciclovir or ganciclovir prophylaxis in solid organ transplant (SOT) recipients. The first one involved 301 high-risk (CMV donor seropositive/recipient seronegative) SOT recipients excluding lung transplants followed for 12 months, whereas the second one involved 80 lung transplant patients evaluated over 6 months. Among the 7 patients (4 non-lung and 3 lung transplant patients) carrying viruses with known ganciclovir-resistance [corrected] mutations in blood, adverse clinical outcome was only observed in the lung transplant recipients. Additionally, no CMV resistance mutations were observed in non-lung transplant patients receiving Valganciclovir.
Richard F Jacobs - One of the best experts on this subject based on the ideXlab platform.
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Valganciclovir for symptomatic congenital cytomegalovirus disease
The New England Journal of Medicine, 2015Co-Authors: David W Kimberlin, Pablo J Sanchez, Penny Jester, Amina Ahmed, Ravit Aravboger, Marian G Michaels, Negar Ashouri, Janet A Englund, Benjamin Estrada, Richard F JacobsAbstract:BackgroundThe treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time. MethodsWe conducted a randomized, placebo-controlled trial of Valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear (“best-ear” hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline. ResultsA total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and...
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pharmacokinetic and pharmacodynamic assessment of oral Valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease
The Journal of Infectious Diseases, 2008Co-Authors: David W Kimberlin, Edward P Acosta, Pablo J Sanchez, James Homans, Richard F Jacobs, Jose R Romero, Sunil K Sood, Vish Agrawal, David Lang, Jill GriffinAbstract:Background. Intravenous ganciclovir administered for 6 weeks improves hearing outcomes in infants with symptomatic congenital cytomegalovirus (CMV) disease involving the central nervous system. Methods. Twenty-four subjects received antiviral therapy for 6 weeks. Serial pharmacokinetic assessments were performed after administration ofValganciclovir oral solution and of intravenous ganciclovir. Results. On the basis of a previous pharmacokinetic study of the use of intravenous ganciclovir in this population, a target AUC 12 (area under the concentration-time curve over a 12-h period) of 27 mg X h/L was defined. The median dose of oral Valganciclovir administered in the present trial was 16 mg/kg, which produced a geometric mean AUC 12 of 27.4 mg X h/L. The bioavailability of Valganciclovir was 41.1%. Of the 18 subjects who had detectable CMV in whole blood at baseline or during therapy, 11 had <4 log viral DNA copies/mL at baseline, and 7 had 3≥4 log viral DNA copies/mL at baseline; subjects who started the study with the higher viral burden experienced greater decreases in viral load but did not clear virus during the 42-day course of therapy. Neutropenia of grade 3 or 4 developed in 38% of subjects. Conclusions. In neonates with symptomatic congenital CMV disease, Valganciclovir oral solution provides plasma concentrations of ganciclovir comparable to those achieved with administration of intravenous ganciclovir. The results of the present study cannot be extrapolated to extemporaneously compounded liquid formulations of Valganciclovir.
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ganciclovir population pharmacokinetics in neonates following intravenous administration of ganciclovir and oral administration of a liquid Valganciclovir formulation
Clinical Pharmacology & Therapeutics, 2007Co-Authors: Edward P Acosta, Richard C Brundage, Jennifer R King, Pablo J Sanchez, S Sood, V Agrawal, James Homans, Richard F Jacobs, D Lang, Jose R RomeroAbstract:Cytomegalovirus (CMV) is the most common viral congenital infection, producing both sensorineural hearing loss and mental retardation. Our objective was to assess the population pharmacokinetics of a research-grade oral Valganciclovir solution in neonates with symptomatic congenital CMV disease. Twenty-four neonates received 6 weeks of antiviral therapy. Ganciclovir and Valganciclovir were measured by liquid chromatography/tandem mass spectroscopy. NONMEM version VI beta was used for population analyses. All profiles were consistent with a one-compartment model. Postnatal age, body surface area, and gender did not improve the model fit after body weight was taken into account. The typical value of clearance (l/h), distribution volume (l), and bioavailability of ganciclovir were 0.146 x body weight (WT)(1.68), 1.15 x WT, and 53.6%, respectively. Although these results cannot be extrapolated to extemporaneously compounded Valganciclovir preparations, they provide the foundation on which a commercial-grade Valganciclovir oral solution may be a viable option for administration to neonates.
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ganciclovir population pharmacokinetics in neonates following intravenous administration of ganciclovir and oral administration of a liquid Valganciclovir formulation
Clinical Pharmacology & Therapeutics, 2007Co-Authors: Edward P Acosta, Richard C Brundage, Jennifer R King, Pablo J Sanchez, S Sood, V Agrawal, James Homans, Richard F Jacobs, D Lang, Jose R RomeroAbstract:Cytomegalovirus (CMV) is the most common viral congenital infection, producing both sensorineural hearing loss and mental retardation. Our objective was to assess the population pharmacokinetics of a research-grade oral Valganciclovir solution in neonates with symptomatic congenital CMV disease. Twenty-four neonates received 6 weeks of antiviral therapy. Ganciclovir and Valganciclovir were measured by liquid chromatography/tandem mass spectroscopy. NONMEM version VI beta was used for population analyses. All profiles were consistent with a one-compartment model. Postnatal age, body surface area, and gender did not improve the model fit after body weight was taken into account. The typical value of clearance (l/h), distribution volume (l), and bioavailability of ganciclovir were 0.146 × body weight (WT)1.68, 1.15 × WT, and 53.6%, respectively. Although these results cannot be extrapolated to extemporaneously compounded Valganciclovir preparations, they provide the foundation on which a commercial-grade Valganciclovir oral solution may be a viable option for administration to neonates. Clinical Pharmacology & Therapeutics (2007) 81, 867–872. doi:10.1038/sj.clpt.6100150; published online 28 March 2007
Mark D. Pescovitz - One of the best experts on this subject based on the ideXlab platform.
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long term outcomes of cmv disease treatment with Valganciclovir versus iv ganciclovir in solid organ transplant recipients
American Journal of Transplantation, 2009Co-Authors: Anders Asberg, Mark D. Pescovitz, Atul Humar, Halvor Rollag, Alan G Jardine, H Mouas, Angelo A Bignamini, Huseyin Toz, I Dittmer, M MontejoAbstract:Though an important cause of morbidity and mortality in solid organ transplantation (SOT), the long-term outcomes of cytomegalovirus (CMV) disease treatment have not been well studied. In a randomized trial, 321 SOT recipients with CMV disease were followed 1 year after treatment with either twice daily intravenous ganciclovir or oral Valganciclovir (for 21 days) followed by once daily Valganciclovir until day 49 in all patients. Clinical and viral eradication of CMV disease was similar between groups. Clinical recurrence beyond day 49 was found in 15.1% and virological recurrence in 30.0%, no difference between groups (p > 0.77). In a multivariable logistic regression analysis, the only independent predictor for recurrence was failure to eradicate DNAemia by day 21 (clinical: OR 3.9 [1.3-11.3], p = 0.012; virological: OR 5.6 [2.5-12.6], p < 0.0001). Eight patients developed ganciclovir resistance, with no difference between groups (p = 0.62). Twenty patients (Valganciclovir: 11, ganciclovir: 9, p = 0.82) died, 12 due to infections, two involving CMV disease. There were no differences in long-term outcomes between treatment arms, further supporting the use of oral Valganciclovir for treatment of CMV disease. Persistent DNAemia at day 21, CMV IgG serostatus and development of resistance may be relevant factors for further individualization of treatment.
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cytomegalovirus resistance in solid organ transplant recipients treated with intravenous ganciclovir or oral Valganciclovir
Antiviral Therapy, 2009Co-Authors: Guy Boivin, Mark D. Pescovitz, Nathalie Goyette, Halvor Rollag, Alan G Jardine, Anders Asberg, Jane Ives, Anders Hartmann, Atul HumarAbstract:Background: The rate of cytomegalovirus (CMV) mutations conferring ganciclovir resistance was assessed in a trial comparing intravenous ganciclovir and oral Valganciclovir for treatment of CMV disease in solid organ transplant (SOT) recipients. Methods: Viral genes (UL97 and UL54) conferring ganciclovir resistance were amplified and sequenced from blood samples collected at days 0 (before therapy), 21 (end of induction) and 49 (end of maintenance). Results: The overall risk of developing a confirmed or probable ganciclovir resistance mutation during treatment was similar for patients treated with ganciclovir (2.3%) and Valganciclovir (3.6%; P=0.51). A persistent viral load at day 21 was associated with a significant risk of ganciclovir resistance by day 49 (odds ratio 11.83; P= 0 . 022 ). In multivariate analyses, presence of a confirmed ganciclovir resistance mutation was independently associated with virological failure (viral load ≥600 copies/ml) at days 21 and 49. One-third (3/9) of patients with confirmed CMV resistance mutations had recurrent CMV disease. The plasma half-life of confirmed ganciclovir-resistant UL97 mutants was significantly longer than that of wild-type strains, polymorphic variants and strains with mutations of unknown significance (P=0.045). Multiple UL54 mutations of unknown significance were found in clinical strains. Viral kinetic analysis of these latter strains revealed no effect (negative or positive) on in vivo viral fitness. Conclusions: Treatment with oral Valganciclovir or intravenous ganciclovir results in similar and low rates of resistance mutations in SOT recipients. Patients with drug-resistant CMV strains often have virological failure and might have unfavourable clinical outcomes.
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oral Valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients
American Journal of Transplantation, 2007Co-Authors: Anders Asberg, Mark D. Pescovitz, Atul Humar, Halvor Rollag, Alan G Jardine, H Mouas, D Sgarabotto, Murat Tuncer, I L Noronha, Anders HartmannAbstract:Intravenous ganciclovir is the standard treatment for cytomegalovirus disease in solid organ transplant recipients. Oral Valganciclovir is a more convenient alternative. In a randomized, international trial, recipients with cytomegalovirus disease were treated with either 900 mg oral Valganciclovir or 5 mg/kg i.v. ganciclovir twice daily for 21 days, followed by 900 mg daily Valganciclovir for 28 days. A total of 321 patients were evaluated (Valganciclovir [n = 164]; i.v. ganciclovir [n = 157]). The success rate of viremia eradication at Day 21 was 45.1% for Valganciclovir and 48.4% for ganciclovir (95% CI -14.0% to +8.0%), and at Day 49; 67.1% and 70.1%, respectively (p = NS). Treatment success, as assessed by investigators, was 77.4% versus 80.3% at Day 21 and 85.4% versus 84.1% at Day 49 (p = NS). Baseline viral loads were not different between groups and decreased exponentially with similar half-lives and median time to eradication (21 vs. 19 days, p = 0.076). Side-effects and discontinuations of assigned treatment (18 of 321 patients) were comparable. Oral Valganciclovir shows comparable safety and is not inferior to i.v. ganciclovir for treatment of cytomegalovirus disease in organ transplant recipients and provides a simpler treatment strategy, but care should be taken in extrapolating to organ transplant recipients not properly represented in the present study.
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pharmacokinetic profile of ganciclovir after its oral administration and from its prodrug Valganciclovir in solid organ transplant recipients
Clinical Pharmacokinectics, 2005Co-Authors: Hugh Wiltshire, Carlos V. Paya, Mark D. Pescovitz, Atul Humar, Kenneth Washburn, Emily A. Blumberg, Sarapee Hirankarn, Colm Farrell, Edward A Dominguez, Barbara D. AlexanderAbstract:Background Valganciclovir (Valcyte/sR) has recently been approved for the prevention of cytomegalovirus (CMV) disease in high-risk (CMV donor positive [D+1/recipient negative [R−]) solid organ transplant (SOT) recipients. Large-scale studies describing the pharmacokinetics of Valganciclovir in SOT recipients are lacking. A recent randomised, double-blind study of Valganciclovir in 364 D+/R− (intent-to-treat population) SOT recipients provided valuable data on which a population pharmacokinetic analysis was performed.
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efficacy and safety of Valganciclovir vs oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients
American Journal of Transplantation, 2004Co-Authors: Carlos V. Paya, Atul Humar, Kenneth Washburn, Emily A. Blumberg, Barbara D. Alexander, Richard B. Freeman, Nigel Heaton, Ed Dominguez, Mark D. PescovitzAbstract:We compared the efficacy and safety of Valganciclovir with those of oral ganciclovir in preventing cytomegalovirus (CMV) disease in high-risk seronegative solid organ transplant (SOT) recipients of organs from seropositive donors (D+/R-). In this randomised, prospective, double-blind, double-dummy study, 364 CMV D+/R- patients received Valganciclovir 900 mg once daily or oral ganciclovir 1000 mg three times a day (tid) within 10 days of transplant and continued through 100 days. CMV disease, plasma viremia, acute graft rejection, graft loss and safety were analyzed up to 6 and 12 months post-transplant. Endpoint committee-defined CMV disease developed in 12.1% and 15.2% of Valganciclovir and ganciclovir patients, respectively, by 6 months, though with a difference in the relative efficacy of Valganciclovir and ganciclovir between organs (i.e. an organ type-treatment interaction). By 12 months, respective incidences were 17.2% and 18.4%, and the incidence of investigator-treated CMV disease events was comparable in the Valganciclovir (30.5%) and ganciclovir (28.0%) arms. CMV viremia during prophylaxis was significantly lower with Valganciclovir (2.9% vs. 10.4%; p=0.001), but was comparable by 12 months (48.5% Valganciclovir vs 48.8% ganciclovir). Time-to-onset of CMV disease and to viremia were delayed with Valganciclovir; rates of acute allograft rejection were generally lower with Valganciclovir. Except for a higher incidence of neutropenia with Valganciclovir (8.2%, vs 3.2% ganciclovir) the safety profile was similar for both drugs. Overall, once-daily oral Valganciclovir was as clinically effective and well-tolerated as oral ganciclovir tid for CMV prevention in high-risk SOT recipients.
Alan G Jardine - One of the best experts on this subject based on the ideXlab platform.
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the efficacy and safety of 200 days Valganciclovir cytomegalovirus prophylaxis in high risk kidney transplant recipients
American Journal of Transplantation, 2010Co-Authors: Atul Humar, Emily A. Blumberg, Alan G Jardine, Yvon Lebranchu, Flavio Vincenti, Jeffrey D Punch, Ajit P Limaye, Daniel Abramowicz, Athina Voulgari, Jane IvesAbstract:Late-onset cytomegalovirus (CMV) disease is a significant problem with a standard 3-month prophylaxis regimen. This multicentre, double-blind, randomized controlled trial compared the efficacy and safety of 200 days' versus 100 days' Valganciclovir prophylaxis (900 mg once daily) in 326 high-risk (D+/R-) kidney allograft recipients. Significantly fewer patients in the 200-day group versus the 100-day group developed confirmed CMV disease up to month 12 posttransplant (16.1% vs. 36.8%; p < 0.0001). Confirmed CMV viremia was also significantly lower in the 200-day group (37.4% vs. 50.9%; p = 0.015 at month 12). There was no significant difference in the rate of biopsy-proven acute rejection between the groups (11% vs. 17%, respectively, p = 0.114). Adverse events occurred at similar rates between the groups and the majority were rated mild-to-moderate in intensity and not related to study medication. In conclusion, this study demonstrates that extending Valganciclovir prophylaxis (900 mg once daily) to 200 days significantly reduces the incidence of CMV disease and viremia through to 12 months compared with 100 days' prophylaxis, without significant additional safety concerns associated with longer treatment. The number needed to treat to avoid one additional patient with CMV disease up to 12 months posttransplant is approximately 5.
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long term outcomes of cmv disease treatment with Valganciclovir versus iv ganciclovir in solid organ transplant recipients
American Journal of Transplantation, 2009Co-Authors: Anders Asberg, Mark D. Pescovitz, Atul Humar, Halvor Rollag, Alan G Jardine, H Mouas, Angelo A Bignamini, Huseyin Toz, I Dittmer, M MontejoAbstract:Though an important cause of morbidity and mortality in solid organ transplantation (SOT), the long-term outcomes of cytomegalovirus (CMV) disease treatment have not been well studied. In a randomized trial, 321 SOT recipients with CMV disease were followed 1 year after treatment with either twice daily intravenous ganciclovir or oral Valganciclovir (for 21 days) followed by once daily Valganciclovir until day 49 in all patients. Clinical and viral eradication of CMV disease was similar between groups. Clinical recurrence beyond day 49 was found in 15.1% and virological recurrence in 30.0%, no difference between groups (p > 0.77). In a multivariable logistic regression analysis, the only independent predictor for recurrence was failure to eradicate DNAemia by day 21 (clinical: OR 3.9 [1.3-11.3], p = 0.012; virological: OR 5.6 [2.5-12.6], p < 0.0001). Eight patients developed ganciclovir resistance, with no difference between groups (p = 0.62). Twenty patients (Valganciclovir: 11, ganciclovir: 9, p = 0.82) died, 12 due to infections, two involving CMV disease. There were no differences in long-term outcomes between treatment arms, further supporting the use of oral Valganciclovir for treatment of CMV disease. Persistent DNAemia at day 21, CMV IgG serostatus and development of resistance may be relevant factors for further individualization of treatment.
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cytomegalovirus resistance in solid organ transplant recipients treated with intravenous ganciclovir or oral Valganciclovir
Antiviral Therapy, 2009Co-Authors: Guy Boivin, Mark D. Pescovitz, Nathalie Goyette, Halvor Rollag, Alan G Jardine, Anders Asberg, Jane Ives, Anders Hartmann, Atul HumarAbstract:Background: The rate of cytomegalovirus (CMV) mutations conferring ganciclovir resistance was assessed in a trial comparing intravenous ganciclovir and oral Valganciclovir for treatment of CMV disease in solid organ transplant (SOT) recipients. Methods: Viral genes (UL97 and UL54) conferring ganciclovir resistance were amplified and sequenced from blood samples collected at days 0 (before therapy), 21 (end of induction) and 49 (end of maintenance). Results: The overall risk of developing a confirmed or probable ganciclovir resistance mutation during treatment was similar for patients treated with ganciclovir (2.3%) and Valganciclovir (3.6%; P=0.51). A persistent viral load at day 21 was associated with a significant risk of ganciclovir resistance by day 49 (odds ratio 11.83; P= 0 . 022 ). In multivariate analyses, presence of a confirmed ganciclovir resistance mutation was independently associated with virological failure (viral load ≥600 copies/ml) at days 21 and 49. One-third (3/9) of patients with confirmed CMV resistance mutations had recurrent CMV disease. The plasma half-life of confirmed ganciclovir-resistant UL97 mutants was significantly longer than that of wild-type strains, polymorphic variants and strains with mutations of unknown significance (P=0.045). Multiple UL54 mutations of unknown significance were found in clinical strains. Viral kinetic analysis of these latter strains revealed no effect (negative or positive) on in vivo viral fitness. Conclusions: Treatment with oral Valganciclovir or intravenous ganciclovir results in similar and low rates of resistance mutations in SOT recipients. Patients with drug-resistant CMV strains often have virological failure and might have unfavourable clinical outcomes.
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oral Valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients
American Journal of Transplantation, 2007Co-Authors: Anders Asberg, Mark D. Pescovitz, Atul Humar, Halvor Rollag, Alan G Jardine, H Mouas, D Sgarabotto, Murat Tuncer, I L Noronha, Anders HartmannAbstract:Intravenous ganciclovir is the standard treatment for cytomegalovirus disease in solid organ transplant recipients. Oral Valganciclovir is a more convenient alternative. In a randomized, international trial, recipients with cytomegalovirus disease were treated with either 900 mg oral Valganciclovir or 5 mg/kg i.v. ganciclovir twice daily for 21 days, followed by 900 mg daily Valganciclovir for 28 days. A total of 321 patients were evaluated (Valganciclovir [n = 164]; i.v. ganciclovir [n = 157]). The success rate of viremia eradication at Day 21 was 45.1% for Valganciclovir and 48.4% for ganciclovir (95% CI -14.0% to +8.0%), and at Day 49; 67.1% and 70.1%, respectively (p = NS). Treatment success, as assessed by investigators, was 77.4% versus 80.3% at Day 21 and 85.4% versus 84.1% at Day 49 (p = NS). Baseline viral loads were not different between groups and decreased exponentially with similar half-lives and median time to eradication (21 vs. 19 days, p = 0.076). Side-effects and discontinuations of assigned treatment (18 of 321 patients) were comparable. Oral Valganciclovir shows comparable safety and is not inferior to i.v. ganciclovir for treatment of cytomegalovirus disease in organ transplant recipients and provides a simpler treatment strategy, but care should be taken in extrapolating to organ transplant recipients not properly represented in the present study.
David W Kimberlin - One of the best experts on this subject based on the ideXlab platform.
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Valganciclovir for symptomatic congenital cytomegalovirus disease
The New England Journal of Medicine, 2015Co-Authors: David W Kimberlin, Pablo J Sanchez, Penny Jester, Amina Ahmed, Ravit Aravboger, Marian G Michaels, Negar Ashouri, Janet A Englund, Benjamin Estrada, Richard F JacobsAbstract:BackgroundThe treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time. MethodsWe conducted a randomized, placebo-controlled trial of Valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear (“best-ear” hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline. ResultsA total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and...
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treatment of congenital cytomegalovirus infection implications for future therapeutic strategies
Journal of Antimicrobial Chemotherapy, 2009Co-Authors: Lauren Nassetta, David W Kimberlin, Richard J WhitleyAbstract:Cytomegalovirus (CMV) infection is the most common cause of congenital infection in the developed world, occurring in ∼1% of all liveborns. Symptomatic disease occurs in 10% of all congenitally infected infants, resulting in a spectrum of clinical manifestations that include microcephaly, chorioretinitis, hepatosplenomegaly and sensorineural hearing loss, among others. Even those children who are asymptomatic at birth have a risk of hearing loss, with ∼8% experiencing this sequela. Overall, congenital CMV infection accounts for one-third of all cases of sensorineural hearing loss. The economic burden of disease exceeds $2 billion annually in the USA. Therefore, this infection has been the target for antiviral therapy. Studies performed by the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group (CASG) have evaluated ganciclovir for the treatment of symptomatic congenital CMV infection with central nervous system involvement. In a randomized, controlled clinical trial of ganciclovir treatment (6 mg/kg iv every 12 h for 6 weeks) brainstem-evoked responses were utilized as the primary endpoint and demonstrated stabilization of hearing both at 6 months and >1 year. Treatment was associated with neutropenia in over 60% of treated patients. Since ganciclovir must be given intravenously, studies with its prodrug, Valganciclovir, have been performed to assess pharmacokinetics and pharmacodynamics. Currently, a clinical trial of 6 weeks versus 6 months of Valganciclovir is being performed by the CASG. Notably, only intravenous ganciclovir and orally administered Valganciclovir have been used to treat congenital CMV infection. Hopefully, other drugs such as maribavir will be available for evaluation in this population.
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pharmacokinetic and pharmacodynamic assessment of oral Valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease
The Journal of Infectious Diseases, 2008Co-Authors: David W Kimberlin, Edward P Acosta, Pablo J Sanchez, James Homans, Richard F Jacobs, Jose R Romero, Sunil K Sood, Vish Agrawal, David Lang, Jill GriffinAbstract:Background. Intravenous ganciclovir administered for 6 weeks improves hearing outcomes in infants with symptomatic congenital cytomegalovirus (CMV) disease involving the central nervous system. Methods. Twenty-four subjects received antiviral therapy for 6 weeks. Serial pharmacokinetic assessments were performed after administration ofValganciclovir oral solution and of intravenous ganciclovir. Results. On the basis of a previous pharmacokinetic study of the use of intravenous ganciclovir in this population, a target AUC 12 (area under the concentration-time curve over a 12-h period) of 27 mg X h/L was defined. The median dose of oral Valganciclovir administered in the present trial was 16 mg/kg, which produced a geometric mean AUC 12 of 27.4 mg X h/L. The bioavailability of Valganciclovir was 41.1%. Of the 18 subjects who had detectable CMV in whole blood at baseline or during therapy, 11 had <4 log viral DNA copies/mL at baseline, and 7 had 3≥4 log viral DNA copies/mL at baseline; subjects who started the study with the higher viral burden experienced greater decreases in viral load but did not clear virus during the 42-day course of therapy. Neutropenia of grade 3 or 4 developed in 38% of subjects. Conclusions. In neonates with symptomatic congenital CMV disease, Valganciclovir oral solution provides plasma concentrations of ganciclovir comparable to those achieved with administration of intravenous ganciclovir. The results of the present study cannot be extrapolated to extemporaneously compounded liquid formulations of Valganciclovir.
