The Experts below are selected from a list of 25941 Experts worldwide ranked by ideXlab platform
Mark D. Pescovitz - One of the best experts on this subject based on the ideXlab platform.
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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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Pharmacodynamics of oral Ganciclovir and valGanciclovir in solid organ transplant recipients.
Transplantation, 2005Co-Authors: Hugh Wiltshire, Carlos V. Paya, Mark D. Pescovitz, Atul Humar, Edward A. Dominguez, Kenneth Washburn, Emily A. Blumberg, Barbara D. Alexander, Richard B. Freeman, Nigel HeatonAbstract:BACKGROUND A randomized, double-blind study was conducted to evaluate the pharmacokinetics of Ganciclovir following oral administration of Ganciclovir or valGanciclovir for prophylaxis of cytomegalovirus (CMV) disease in solid organ transplant recipients (n = 240/372). METHODS The correlations between individual exposure to Ganciclovir during prophylaxis, with CMV viremia incidence during and after treatment, CMV disease up to 12 months posttransplant, and hematological toxicity were assessed. RESULTS Mean daily areas under the curve (AUCs) of Ganciclovir from valGanciclovir and oral Ganciclovir were 46.3 +/- 15.2 and 28.0 +/- 10.9 microg.h/ml (mean +/- SD), respectively. Viremia was suppressed during prophylaxis when exposure to Ganciclovir was 40-50 microg.h/ml, AUCs typical of those achieved in valGanciclovir-treated patients. The development of viremia 1 month after ending prophylaxis was also reduced with higher Ganciclovir AUC (median predicted incidence, 20% and 10% at AUCs of 33 and 50 microg h/ml, respectively). The development of CMV disease within 1 year of transplant was 17.6% and independent of prophylactic exposure to Ganciclovir. There was only a weak tendency to increased neutropenia and leukopenia with higher Ganciclovir exposure. CONCLUSIONS The greater systemic exposure to Ganciclovir delivered by valGanciclovir was associated with delayed development of viremia. There was only a weak association between AUC and hematological toxicity.
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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.
Michael Boeckh - One of the best experts on this subject based on the ideXlab platform.
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emergence of Ganciclovir resistant cytomegalovirus disease among recipients of solid organ transplants
The Lancet, 2000Co-Authors: Ajit P Limaye, David M Koelle, Connie L Davis, Michael Boeckh, Lawrence CoreyAbstract:Summary Background Concerns have been raised about emergence of Ganciclovir resistance as a result of the advent of both routine oral Ganciclovir prophylaxis and highly potent immuno-suppression. We retrospectively assessed the occurrence of Ganciclovir-resistant cytomegalovirus disease among transplant recipients who had received oral Ganciclovir prophylaxis and highly potent immunosuppression. Methods We studied 240 recipients of liver, kidney, or pancreas transplants. Antiviral susceptibility testing of blood cytomegaloviral isolates was done when patients failed to respond to intravenous Ganciclovir treatment for symptomatic cytomegalovirus infection. Portions of the UL97 gene associated with Ganciclovir resistance were sequenced in cytomegalovirus isolates with phenotypic resistance to Ganciclovir. Findings Ganciclovir-resistant cytomegalovirus disease developed in five (7%) of 67 seronegative recipients of cytomegalovirus-seropositive organs (D+/R−) compared with none of 173 seropositive recipients (p=0·002). Among the 25 (10·4%) patients who developed cytomegalovirus disease within 1 year after transplantation, five had Ganciclovir-resistant cytomegalovirus disease. Among D+/R− transplant recipients, Ganciclovir-resistant cytomegalovirus disease was more common among the group receiving the most potent immunosuppression—ie, recipients of kidney and pancreas or pancreas alone (four of 19) compared with all other transplant recipients (one of 48, p=0·02). Ganciclovir-resistant cytomegalovirus disease was diagnosed at a median of 10 months after transplantation (range 7–12) after lengthened exposure to Ganciclovir, was associated with previously described mutations of the UL97 gene, and led to serious clinical complications. Interpretation Ganciclovir-resistant cytomegalovirus is an important cause of late morbidity among D+/R− transplant recipients who have had lengthened exposure to Ganciclovir and have received highly potent immunosuppression. Strategies to reduce this complication, especially among D+/R− patients, are warranted.
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Cytomegalovirus pp65 antigenemia-guided early treatment with Ganciclovir versus Ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study
Blood, 1996Co-Authors: Michael Boeckh, Ted Gooley, David Myerson, Terri Cunningham, Gary Schoch, Raleigh A. BowdenAbstract:To determine whether cytomegalovirus (CMV) antigenemiaguided Ganciclovir treatment may be as effective, may require less treatment, and thus may cause less marrow toxicity than Ganciclovir administered at engraftment, 226 marrow transplant recipients were randomized at engraftment to receive placebo (antigenemia-Ganciclovir group) or Ganciclovir (Ganciclovir group) until day 100 in a double-blind study. In patients with antigenemia of 3 or more positive cells in 2 slides and/or viremia, study drug was discontinued and Ganciclovir was started for at least 3 weeks or until negative CMV antigenemia and resumed only if antigenemia recurred. More patients in the antigenemia-Ganciclovir group developed CMV disease before day 100 after transplantation compared with the Ganciclovir group (14% v 2.7%, P = .002). Of the 16 patients with CMV disease before day 100 in the antigenemia-Ganciclovir group, 10 (8.8%) had disease before or during the first episode of antigenemia and 6 (5.3%) developed disease after discontinuation of Ganciclovir. Untreated low-grade antigenemia progressed to CMV disease in 19% of patients with grade 3-4 compared with 0% of patients with grade 0-2 acute graft-versus-host disease (P = .04). There was no significant difference in CMV disease by day 180 after transplantation and thereafter. CMV-related death, transplant survival, and neutropenia were not significantly different between the groups. In the Ganciclovir group, more invasive fungal infections occurred (P = .03) and more Ganciclovir was used (P < .0001). Thus, delaying the start of Ganciclovir until highgrade antigenemia and discontinuing Ganciclovir based on negative antigenemia results in more CMV disease by day 100 than Ganciclovir administered at engraftment. However, Ganciclovir at engraftment is associated with more early invasive fungal infections and more late CMV disease resulting in similar survival rates.
Atul Humar - One of the best experts on this subject based on the ideXlab platform.
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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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Pharmacodynamics of oral Ganciclovir and valGanciclovir in solid organ transplant recipients.
Transplantation, 2005Co-Authors: Hugh Wiltshire, Carlos V. Paya, Mark D. Pescovitz, Atul Humar, Edward A. Dominguez, Kenneth Washburn, Emily A. Blumberg, Barbara D. Alexander, Richard B. Freeman, Nigel HeatonAbstract:BACKGROUND A randomized, double-blind study was conducted to evaluate the pharmacokinetics of Ganciclovir following oral administration of Ganciclovir or valGanciclovir for prophylaxis of cytomegalovirus (CMV) disease in solid organ transplant recipients (n = 240/372). METHODS The correlations between individual exposure to Ganciclovir during prophylaxis, with CMV viremia incidence during and after treatment, CMV disease up to 12 months posttransplant, and hematological toxicity were assessed. RESULTS Mean daily areas under the curve (AUCs) of Ganciclovir from valGanciclovir and oral Ganciclovir were 46.3 +/- 15.2 and 28.0 +/- 10.9 microg.h/ml (mean +/- SD), respectively. Viremia was suppressed during prophylaxis when exposure to Ganciclovir was 40-50 microg.h/ml, AUCs typical of those achieved in valGanciclovir-treated patients. The development of viremia 1 month after ending prophylaxis was also reduced with higher Ganciclovir AUC (median predicted incidence, 20% and 10% at AUCs of 33 and 50 microg h/ml, respectively). The development of CMV disease within 1 year of transplant was 17.6% and independent of prophylactic exposure to Ganciclovir. There was only a weak tendency to increased neutropenia and leukopenia with higher Ganciclovir exposure. CONCLUSIONS The greater systemic exposure to Ganciclovir delivered by valGanciclovir was associated with delayed development of viremia. There was only a weak association between AUC and hematological toxicity.
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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.
Baruch D. Kuppermann - One of the best experts on this subject based on the ideXlab platform.
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ORAL Ganciclovir FOR PATIENTS WITH CYTOMEGALOVIRUS RETINITIS TREATED WITH A Ganciclovir IMPLANT
New England Journal of Medicine, 1999Co-Authors: Daniel F Martin, Richard A Wolitz, Alan G Palestine, Baruch D. Kuppermann, Charles A RobinsonAbstract:Background The intraocular Ganciclovir implant is effective for local treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS), but it does not treat or prevent other systemic manifestations of cytomegalovirus infection. Methods Three hundred seventy-seven patients with AIDS and unilateral cytomegalovirus retinitis were randomly assigned to one of three treatments: a Ganciclovir implant plus oral Ganciclovir (4.5 g daily), a Ganciclovir implant plus oral placebo, or intravenous Ganciclovir alone. The primary outcome measure was the development of new cytomegalovirus disease, either contralateral retinitis or biopsy-proved extraocular disease. Results The incidence of new cytomegalovirus disease at six months was 44.3 percent in the group assigned to the Ganciclovir implant plus placebo, as compared with 24.3 percent in the group assigned to the Ganciclovir implant plus oral Ganciclovir (P=0.002) and 19.6 percent in the group assigned to intravenous Ganciclovir ...
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Treatment of cytomegalovirus retinitis with a sustained-release Ganciclovir implant
New England Journal of Medicine, 1997Co-Authors: David C. Musch, Daniel F Martin, Judy F. Gordon, Matthew D. Davis, Baruch D. KuppermannAbstract:Background Sustained-release, intraocular implants that deliver Ganciclovir are an alternative method for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS). Methods We conducted a randomized study of 188 patients with AIDS and newly diagnosed cytomegalovirus retinitis. The patients were randomly assigned to treatment with an implant delivering 1 μg of Ganciclovir per hour, an implant delivering 2 μg of Ganciclovir per hour, or intravenous Ganciclovir. The primary outcome we studied was progression of cytomegalovirus retinitis. Results The median time to progression of retinitis was 221 days with the 1-μg-per-hour implant (75 eyes), 191 days with the 2-μg-per-hour implant (71 eyes), and 71 days with Ganciclovir administered intravenously (76 eyes; P
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treatment of cytomegalovirus retinitis with a sustained release Ganciclovir implant
The New England Journal of Medicine, 1997Co-Authors: David C. Musch, Daniel F Martin, Judy F. Gordon, Matthew D. Davis, Baruch D. KuppermannAbstract:Background Sustained-release, intraocular implants that deliver Ganciclovir are an alternative method for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS). Methods We conducted a randomized study of 188 patients with AIDS and newly diagnosed cytomegalovirus retinitis. The patients were randomly assigned to treatment with an implant delivering 1 μg of Ganciclovir per hour, an implant delivering 2 μg of Ganciclovir per hour, or intravenous Ganciclovir. The primary outcome we studied was progression of cytomegalovirus retinitis. Results The median time to progression of retinitis was 221 days with the 1-μg-per-hour implant (75 eyes), 191 days with the 2-μg-per-hour implant (71 eyes), and 71 days with Ganciclovir administered intravenously (76 eyes; P<0.001). The risk of progression of retinitis was almost three times as great among patients treated with intravenous Ganciclovir as among those treated with a Ganciclovir implant (risk ratio, 2.8; P<0.001)...
Nigel Heaton - One of the best experts on this subject based on the ideXlab platform.
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Pharmacodynamics of oral Ganciclovir and valGanciclovir in solid organ transplant recipients.
Transplantation, 2005Co-Authors: Hugh Wiltshire, Carlos V. Paya, Mark D. Pescovitz, Atul Humar, Edward A. Dominguez, Kenneth Washburn, Emily A. Blumberg, Barbara D. Alexander, Richard B. Freeman, Nigel HeatonAbstract:BACKGROUND A randomized, double-blind study was conducted to evaluate the pharmacokinetics of Ganciclovir following oral administration of Ganciclovir or valGanciclovir for prophylaxis of cytomegalovirus (CMV) disease in solid organ transplant recipients (n = 240/372). METHODS The correlations between individual exposure to Ganciclovir during prophylaxis, with CMV viremia incidence during and after treatment, CMV disease up to 12 months posttransplant, and hematological toxicity were assessed. RESULTS Mean daily areas under the curve (AUCs) of Ganciclovir from valGanciclovir and oral Ganciclovir were 46.3 +/- 15.2 and 28.0 +/- 10.9 microg.h/ml (mean +/- SD), respectively. Viremia was suppressed during prophylaxis when exposure to Ganciclovir was 40-50 microg.h/ml, AUCs typical of those achieved in valGanciclovir-treated patients. The development of viremia 1 month after ending prophylaxis was also reduced with higher Ganciclovir AUC (median predicted incidence, 20% and 10% at AUCs of 33 and 50 microg h/ml, respectively). The development of CMV disease within 1 year of transplant was 17.6% and independent of prophylactic exposure to Ganciclovir. There was only a weak tendency to increased neutropenia and leukopenia with higher Ganciclovir exposure. CONCLUSIONS The greater systemic exposure to Ganciclovir delivered by valGanciclovir was associated with delayed development of viremia. There was only a weak association between AUC and hematological toxicity.
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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.
