The Experts below are selected from a list of 279 Experts worldwide ranked by ideXlab platform
Michael Boeckh - One of the best experts on this subject based on the ideXlab platform.
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a novel therapeutic Cytomegalovirus dna vaccine in allogeneic haemopoietic stem cell transplantation a randomised double blind placebo controlled phase 2 trial
Lancet Infectious Diseases, 2012Co-Authors: Michael Boeckh, Mohamed A Kharfandabaja, Marissa B Wilck, Amelia Langston, Mary K Wloch, Don F Guterwill, Larry R Smith, Alain RollandAbstract:Summary Background Cytomegalovirus reactivation occurs within 6 months in 60–70% of Cytomegalovirus-seropositive patients after allogeneic haemopoietic stem-cell transplantation (HSCT), mainly due to immunosuppression associated with the procedure. Pre-emptive antiviral therapy reduces incidence of Cytomegalovirus disease but can be toxic. To reduce the potential for disease and subsequent need for such antiviral drugs, we aimed to assess safety and efficacy of a Cytomegalovirus therapeutic DNA vaccine compared with placebo. Methods In this exploratory double-blind, placebo-controlled, parallel group, phase 2 trial, up to 80 donor–recipient pairs and 80 unpaired recipients undergoing allogeneic HSCT were planned for enrolment at 16 transplant centres in the USA. Eligible recipients were Cytomegalovirus-seropositive, 18–65 years old, without high-risk primary disease, T-cell depletion, previous vaccination for Cytomegalovirus, or autoimmune diseases. We randomly allocated participants in both parallel groups in a 1:1 ratio to receive a Cytomegalovirus therapeutic DNA vaccine (TransVax; Vical, San Diego, CA, USA) or placebo before conditioning and at 1, 3, and 6 months after transplantation. The vaccine contains plasmids encoding Cytomegalovirus glycoprotein B and phosphoprotein 65 formulated with poloxamer CRL1005 and benzalkonium chloride. Randomisation was done by sequential allocation based on Pocock and Simon's method, and stratified by site, donor–recipient HLA matching status, and donor's Cytomegalovirus serostatus. The primary outcome was the occurrence rate of clinically significant viraemia resulting in initiation of Cytomegalovirus-specific antiviral therapy in the per-protocol assessable population. We assessed rates of adverse events in all participants who received at least one dose of vaccine or placebo. This study is registered with ClinicalTrials.gov, number NCT00285259. Findings We randomly allocated 108 participants (94 HSCT recipients and 14 paired donors) between June 29, 2006, and Dec 11, 2009. Enrolment of the paired arm was halted in February 2008 for logistical reasons. Safety was assessed in all participants; the efficacy population was restricted to 74 unpaired recipients. Groups were balanced for demographic and clinical variables. 19 (48%) of 40 vaccine recipients required Cytomegalovirus-specific antiviral therapy, compared with 21 (62%) of 34 controls (p=0·145). However, during follow-up vaccine significantly reduced the occurrence and recurrence of Cytomegalovirus viraemia and improved the time-to-event for viraemia episodes compared with placebo. The vaccine was well-tolerated; only one participant discontinued after an allergic reaction. Incidence of common adverse events after HSCT (eg, graft-versus-host disease or secondary infections) did not differ between groups. Interpretation We show proof of concept for an immunotherapeutic Cytomegalovirus vaccine (TransVax) for clinically significant viraemia in the HSCT setting. The reported safety and efficacy outcomes support further development in a phase 3 trial, notwithstanding a lack of significant reduction in the use of Cytomegalovirus-specific antiviral therapy compared with placebo in this phase 2 trial. Funding Vical and US National Institute of Allergy and Infectious Diseases.
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emergence of ganciclovir resistant Cytomegalovirus disease among recipients of solid organ transplants
The Lancet, 2000Co-Authors: Ajit P Limaye, Lawrence Corey, David M Koelle, Connie L Davis, Michael BoeckhAbstract: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.
Elisabeth M Hodson - One of the best experts on this subject based on the ideXlab platform.
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antiviral medications to prevent Cytomegalovirus disease and early death in recipients of solid organ transplants a systematic review of randomised controlled trials
The Lancet, 2005Co-Authors: Elisabeth M Hodson, Cheryl A Jones, Angela C Webster, Giovanni F M Strippoli, Peter G Barclay, Kathy KableAbstract:Summary Background Antiviral prophylaxis is commonly used in recipients of solid-organ transplants with the aim of preventing the clinical syndrome associated with Cytomegalovirus infection. We undertook a systematic review to investigate whether this approach affects risks of Cytomegalovirus disease and death. Methods Randomised controlled trials of prophylaxis with antiviral medications for Cytomegalovirus disease in solid-organ-transplant recipients were identified. Data were combined in meta-analyses by a random-effects model. Findings Compared with placebo or no treatment, prophylaxis with aciclovir, ganciclovir, or valaciclovir significantly reduced the risks of Cytomegalovirus disease (19 trials, 1981 patients; relative risk 0·42 [95% CI 0·34–0·52]), Cytomegalovirus infection (17 trials, 1786 patients; 0·61 [0·48–0·77]), and all-cause mortality (17 trials, 1838 patients; 0·63 [0·43–0·92]), mainly owing to lower mortality from Cytomegalovirus disease (seven trials, 1300 patients; 0·26 [0·08–0·78]). Prophylaxis also lowered the risks of disease caused by herpes simplex or zoster virus, bacterial infections, and protozoal infections, but not fungal infection, acute rejection, or graft loss. Meta-regression showed no significant difference in the risk of Cytomegalovirus disease or all-cause mortality by organ transplanted or Cytomegalovirus serostatus; no conclusions were possible for Cytomegalovirus-negative recipients of negative organs. In trials of direct comparisons, ganciclovir was more effective than aciclovir in preventing Cytomegalovirus disease. Valganciclovir and intravenous ganciclovir were as effective as oral ganciclovir. Interpretation Prophylaxis with antiviral medications reduces the risk of Cytomegalovirus disease and associated mortality in recipients of solid-organ transplants. This approach should be used routinely in Cytomegalovirus-positive recipients and in Cytomegalovirus-negative recipients of organs positive for the virus.
Margaret L Green - One of the best experts on this subject based on the ideXlab platform.
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Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre emptive therapy a retrospective cohort study
The Lancet Haematology, 2016Co-Authors: Margaret L Green, Wendy Leisenring, Christopher T Mast, Brenda M Sandmaier, Mohamed L Sorror, Sonia GoyalAbstract:Summary Background Although Cytomegalovirus viral load is commonly used to guide pre-emptive therapy in the post-transplantation setting, few data are available correlating viraemia with clinical endpoints. We therefore investigated the association between Cytomegalovirus viral load and mortality in the first year after haemopoietic stem cell transplantation. Methods In this retrospective cohort study, we included patients from the Fred Hutchinson Cancer Research Center, WA, USA, who received an allogeneic haemopoietic stem cell transplantation between Jan 1, 2007, and Feb 28, 2013, were Cytomegalovirus seropositive or had a seropositive donor, and underwent weekly plasma Cytomegalovirus monitoring by PCR through to day 100 post-transplantation. Cox proportional hazards models were used to estimate the association of Cytomegalovirus viral load at different thresholds with overall mortality by 1 year post-transplantation, adjusting for the use of pre-emptive therapy and other factors such as neutropenia, and graft-versus-host disease. Findings Of the 1037 patients initially selected for inclusion in this cohort, 87 (8%) patients were excluded because of missing Cytomegalovirus testing and 24 (2%) were excluded because of their participation in Cytomegalovirus prophylaxis trials. In the remaining 926 patients included in this study, the cumulative overall mortality was 30·0% (95% CI 26·9–33·0) 1 year after haemopoietic stem cell transplantation. 95 patients developed Cytomegalovirus disease; death was directly attributable to Cytomegalovirus disease in three (1%) of 263 patients who died in the first year after transplantation. A Cytomegalovirus viral load of 250 IU/mL or greater was associated with increased risk of early (day 0–60 post-transplantation) death (adjusted hazard ratio [HR] 19·8, 95% CI 9·6–41·1). The risk was attenuated after day 60 (adjusted HR 1·8, 95% CI 1·3–2·3). Similar associations were noted for higher Cytomegalovirus viral load thresholds. Interpretation Cytomegalovirus viraemia is associated with an increased risk of overall mortality in the first year after haemopoietic stem cell transplantation, independent of the use of pre-emptive therapy, and with evidence of a positive dose-response relationship. These data indicate the suitability of viral load as a surrogate clinical endpoint for clinical trials for Cytomegalovirus vaccines, biologics, and drugs. Funding Merck and Co, National Institutes of Health.
Cheryl A Jones - One of the best experts on this subject based on the ideXlab platform.
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Primary and secondary Cytomegalovirus in pregnancy
The Obstetrician and Gynaecologist, 2009Co-Authors: Fergus P. Mccarthy, Cheryl A Jones, Shelley Rowlands, Michelle L. GilesAbstract:• Cytomegalovirus is the commonest cause of congenital viral infection in developed countries. • Infection is asymptomatic in 90% of individuals. • Forty percent of pregnant women with primary infection transmit it to their fetus. • Ten percent of infants with congenital Cytomegalovirus display clinical manifestations at birth and are at risk of neurological sequelae. • While routine antenatal testing is not currently recommended, congenital infection remains a significant obstetric management problem. Learning objectives: • To learn about the incidence, diagnosis and sequelae of Cytomegalovirus in pregnancy. • To become familiar with treatment options for the management of congenital Cytomegalovirus. Ethical issues: • Should practitioners recommend routine Cytomegalovirus screening in pregnancy? • Is a randomised controlled trial necessary before offering treatment with hyperimmune globulin for congenital Cytomegalovirus? Please cite this article as: McCarthy FP, Jones C, Rowlands S, Giles M. Primary and secondary Cytomegalovirus in pregnancy. The Obstetrician & Gynaecologist 2009;11:96–100.
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antiviral medications to prevent Cytomegalovirus disease and early death in recipients of solid organ transplants a systematic review of randomised controlled trials
The Lancet, 2005Co-Authors: Elisabeth M Hodson, Cheryl A Jones, Angela C Webster, Giovanni F M Strippoli, Peter G Barclay, Kathy KableAbstract:Summary Background Antiviral prophylaxis is commonly used in recipients of solid-organ transplants with the aim of preventing the clinical syndrome associated with Cytomegalovirus infection. We undertook a systematic review to investigate whether this approach affects risks of Cytomegalovirus disease and death. Methods Randomised controlled trials of prophylaxis with antiviral medications for Cytomegalovirus disease in solid-organ-transplant recipients were identified. Data were combined in meta-analyses by a random-effects model. Findings Compared with placebo or no treatment, prophylaxis with aciclovir, ganciclovir, or valaciclovir significantly reduced the risks of Cytomegalovirus disease (19 trials, 1981 patients; relative risk 0·42 [95% CI 0·34–0·52]), Cytomegalovirus infection (17 trials, 1786 patients; 0·61 [0·48–0·77]), and all-cause mortality (17 trials, 1838 patients; 0·63 [0·43–0·92]), mainly owing to lower mortality from Cytomegalovirus disease (seven trials, 1300 patients; 0·26 [0·08–0·78]). Prophylaxis also lowered the risks of disease caused by herpes simplex or zoster virus, bacterial infections, and protozoal infections, but not fungal infection, acute rejection, or graft loss. Meta-regression showed no significant difference in the risk of Cytomegalovirus disease or all-cause mortality by organ transplanted or Cytomegalovirus serostatus; no conclusions were possible for Cytomegalovirus-negative recipients of negative organs. In trials of direct comparisons, ganciclovir was more effective than aciclovir in preventing Cytomegalovirus disease. Valganciclovir and intravenous ganciclovir were as effective as oral ganciclovir. Interpretation Prophylaxis with antiviral medications reduces the risk of Cytomegalovirus disease and associated mortality in recipients of solid-organ transplants. This approach should be used routinely in Cytomegalovirus-positive recipients and in Cytomegalovirus-negative recipients of organs positive for the virus.
Kathy Kable - One of the best experts on this subject based on the ideXlab platform.
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antiviral medications to prevent Cytomegalovirus disease and early death in recipients of solid organ transplants a systematic review of randomised controlled trials
The Lancet, 2005Co-Authors: Elisabeth M Hodson, Cheryl A Jones, Angela C Webster, Giovanni F M Strippoli, Peter G Barclay, Kathy KableAbstract:Summary Background Antiviral prophylaxis is commonly used in recipients of solid-organ transplants with the aim of preventing the clinical syndrome associated with Cytomegalovirus infection. We undertook a systematic review to investigate whether this approach affects risks of Cytomegalovirus disease and death. Methods Randomised controlled trials of prophylaxis with antiviral medications for Cytomegalovirus disease in solid-organ-transplant recipients were identified. Data were combined in meta-analyses by a random-effects model. Findings Compared with placebo or no treatment, prophylaxis with aciclovir, ganciclovir, or valaciclovir significantly reduced the risks of Cytomegalovirus disease (19 trials, 1981 patients; relative risk 0·42 [95% CI 0·34–0·52]), Cytomegalovirus infection (17 trials, 1786 patients; 0·61 [0·48–0·77]), and all-cause mortality (17 trials, 1838 patients; 0·63 [0·43–0·92]), mainly owing to lower mortality from Cytomegalovirus disease (seven trials, 1300 patients; 0·26 [0·08–0·78]). Prophylaxis also lowered the risks of disease caused by herpes simplex or zoster virus, bacterial infections, and protozoal infections, but not fungal infection, acute rejection, or graft loss. Meta-regression showed no significant difference in the risk of Cytomegalovirus disease or all-cause mortality by organ transplanted or Cytomegalovirus serostatus; no conclusions were possible for Cytomegalovirus-negative recipients of negative organs. In trials of direct comparisons, ganciclovir was more effective than aciclovir in preventing Cytomegalovirus disease. Valganciclovir and intravenous ganciclovir were as effective as oral ganciclovir. Interpretation Prophylaxis with antiviral medications reduces the risk of Cytomegalovirus disease and associated mortality in recipients of solid-organ transplants. This approach should be used routinely in Cytomegalovirus-positive recipients and in Cytomegalovirus-negative recipients of organs positive for the virus.
