Review of Cytomegalovirus Infection Findings With Mammalian Target of Rapamycin Inhibitor-Based Immunosuppressive Therapy in De Novo Renal Transplant Recipients

Review of Cytomegalovirus Infection Findings With Mammalian Target of Rapamycin Inhibitor-Based Immunosuppressive Therapy in De Novo Renal Transplant Recipients: Cytomegalovirus (CMV) infection and disease are major complications in the renal transplant recipient. The occurrence of CMV is associated with acute rejection, allograft dysfunction, significant end-organ disease, and mortality. Several clinical studies have indicated that the use of certain immunosuppressive drugs can delay the reconstitution of CMV-specific cell-mediated immune responses, thereby leading to uncontrolled CMV replication. Accumulating evidence indicates, however, that the use of the mammalian target of rapamycin (mTOR) inhibitors, sirolimus, and everolimus, may decrease the incidence and severity of CMV infection in renal transplant recipients. The purpose of this article is to review CMV infection data from randomized clinical trials that investigated the use of sirolimus- and everolimus-based treatment regimens in de novo renal transplantation. The mTOR inhibitor clinical trials included were primarily identified using biomedical literature database searches, with additional studies added at the authors’ discretion. This review will summarize these studies to discuss whether mTOR inhibitor-based immunosuppressive therapy can reduce the magnitude of CMV-related complications in the de novo renal transplantation setting.

CMV Late Phase-Induced mTOR Activation Is Essential for Efficient Virus Replication in Polarized Human Macrophages

CMV Late Phase-Induced mTOR Activation Is Essential for Efficient Virus Replication in Polarized Human Macrophages

Successful outcome of ganciclovir-resistant cytomegalovirus infection in organ transplant recipients after conversion to mTOR inhibitors

Successful outcome of ganciclovir-resistant cytomegalovirus infection in organ transplant recipients after conversion to mTOR inhibitors:

Summary

Ganciclovir-resistant (GanR) cytomegalovirus (CMV) infection after organ transplantation is emerging as a significant therapeutic challenge. We report two cases of GanR CMV infection successfully managed by switching immunosuppression from calcineurin inhibitors to an mTOR inhibitor-based regimen. This salvage therapy should be considered when other options are not available.

Clinical Utility of Cytomegalovirus Cell-Mediated Immunity in Transplant Recipients With Cytomegalovirus Viremia

Clinical Utility of Cytomegalovirus Cell-Mediated Immunity in Transplant Recipients With Cytomegalovirus Viremia: Background. A CD8+ T-cell response to cytomegalovirus (CMV) has been associated with control of viral replication. Assessment shortly after the onset of asymptomatic viremia could help significantly refine preemptive strategies.
Methods. We conducted a prospective study of organ transplant recipients who developed asymptomatic low-level viremia not initially requiring antiviral therapy. Cell-mediated immunity (CMI) was measured shortly after viremia onset and longitudinally using the Quantiferon-CMV assay. The primary outcome was the ability to predict spontaneous clearance versus virologic and/or clinical progression.

A Systematic Review and Meta-analysis of Prophylactic versus Pre-emptive Strategies for Preventing Cytomegalovirus Infection in Renal Transplant Recipients

A Systematic Review and Meta-analysis of Prophylactic versus Pre-emptive Strategies for Preventing Cytomegalovirus Infection in Renal Transplant Recipients:
Background: In kidney transplant (KT) recipients, CMV infection poses significant morbidity and mortality. Both prophylactic and pre-emptive approaches for preventing CMV infection have been utilized.
Objective: To compare the effectiveness of routine prophylaxis vs. pre-emptive treatment for preventing CMV disease after KT.
Methods: We conducted a systematic review and meta-analysis comparing the effectiveness of routine prophylaxis vs. pre-emptive treatment for preventing CMV disease after KT. Combining 4 comprehensive search terms (CMV, renal transplant, prophylaxis, pre-emptive); we searched PubMed, EMBASE, ISI Web of Science, and Cochrane Central Register from inception through January 2011. We also evaluated studies referenced in review articles and abstracts from meetings of major nephrology and transplant societies (2009–2011). Two authors independently extracted data and assessed methodological criteria. The primary outcome was the pooled estimate of the odds ratio (OR) of developing CMV infection. Secondary outcomes included OR of acute rejection, OR of graft loss and OR of death within first year of KT. Comprehensive Meta-analysis V2 software was used for data analysis.

Valganciclovir Prophylaxis Versus Preemptive Therapy in Cytomegalovirus-Positive Renal Allograft Recipients: 1-Year Results of a Randomized Clinical Trial

Valganciclovir Prophylaxis Versus Preemptive Therapy in Cytomegalovirus-Positive Renal Allograft Recipients: 1-Year Results of a Randomized Clinical Trial: Background. Cytomegalovirus (CMV) prevention can be achieved by prophylaxis or preemptive therapy. We performed a prospective randomized trial to determine whether renal transplant recipients with a positive CMV serostatus (R+) had a higher rate of CMV infection and disease after transplantation when treated preemptively for CMV infection, compared with primary valganciclovir prophylaxis.
Methods. Prophylaxis was 2×450 mg oral valganciclovir/day for 100 days; preemptive patients were monitored by CMV-polymerase chain reaction (PCR), and after a positive PCR test received 2×900 mg valganciclovir/day for at least 14 days followed by secondary prophylaxis. Valganciclovir dosage was adjusted according to renal function. Patients are followed up for 5 years and initial 12-month data are presented. Two hundred and ninety-six recipients were analyzed (168 donor/recipient seropositive [D+/R+], 128 donor seronegative/recipient seropositive [D−/R+]; 146 receiving prophylaxis and 150 preemptive therapy).
Results. Overall, CMV infection (asymptomatic CMV viral load ≥400 CMV DNA copies/mL proven by CMV-PCR) was significantly higher in recipients under preemptive therapy (38.7% vs. 11.0%, P<0.0001), with the highest incidence in D+/R+ preemptive patients (53.8% vs. 15.6%, P<0.0001). D+/R+ recipients with preemptive therapy also had the highest rate of CMV disease (CMV syndrome and tissue-invasive disease that was clinically diagnosed and biopsy proven) (19.2% vs. 4.4%, P=0.003). Renal function assessed by creatinine clearance was similar for both groups. Graft loss occurred in 7 vs. 4 patients on preemptive versus prophylactic therapy (P>0.05). Tolerability was similar for both treatment groups.
Conclusions. Oral valganciclovir prophylaxis significantly reduces CMV infection and disease, particularly for D+/R+ patients. Hence, our study supports routine prophylaxis for all D+/R+ recipients.

Valganciclovir Prophylaxis Versus Preemptive Therapy in Cytomegalovirus-Positive Renal Allograft Recipients: 1-Year Results of a Randomized Clinical Trial

Valganciclovir Prophylaxis Versus Preemptive Therapy in Cytomegalovirus-Positive Renal Allograft Recipients: 1-Year Results of a Randomized Clinical Trial: Background. Cytomegalovirus (CMV) prevention can be achieved by prophylaxis or preemptive therapy. We performed a prospective randomized trial to determine whether renal transplant recipients with a positive CMV serostatus (R+) had a higher rate of CMV infection and disease after transplantation when treated preemptively for CMV infection, compared with primary valganciclovir prophylaxis.
Methods. Prophylaxis was 2x450 mg oral valganciclovir/day for 100 days; preemptive patients were monitored by CMV-polymerase chain reaction (PCR), and after a positive PCR test received 2x900 mg valganciclovir/day for at least 14 days followed by secondary prophylaxis. Valganciclovir dosage was adjusted according to renal function. Patients are followed up for 5 years and initial 12-month data are presented. Two hundred and ninety-six recipients were analyzed (168 donor/recipient seropositive [D+/R+], 128 donor seronegative/recipient seropositive [D-/R+]; 146 receiving prophylaxis and 150 preemptive therapy).

Epidemiology of Cytomegalovirus Infection After Pancreas Transplantation

Epidemiology of Cytomegalovirus Infection After Pancreas Transplantation: Background. Epidemiology of cytomegalovirus (CMV) infection has not been comprehensively studied after all three types of pancreas transplant (PT) including simultaneous pancreas-kidney transplantation (SPK), pancreas transplantation alone (PTA), and pancreas after kidney transplantation (PAK).
Methods. We evaluated incidence, risk factors, and outcomes of CMV infection after pancreas transplant at our center from January 1, 1998, to December 31, 2009.

Summary of the British Transplantation Society Guidelines for the Prevention and Management of CMV Disease After Solid Organ Transplantation

Summary of the British Transplantation Society Guidelines for the Prevention and Management of CMV Disease After Solid Organ Transplantation: The third edition of the British Transplantation Society Guidelines for the Prevention and Management of CMV Disease after Solid Organ Transplantation was published in March 2011. This article summarizes the important changes and advances in management in this rapidly evolving field. The pros and cons of universal, or targeted anti-cytomegalovirus (CMV) prophylaxis, and pre-emptive anti-CMV therapy are discussed, especially with respect to advances in CMV polymerase chain reaction monitoring. The evidence for oral anti-CMV prophylaxis using valganciclovir is presented, together with a summary of the treatment of CMV disease and emerging fields such as CMV vaccination, CMV genotyping, and drug resistance.
(C) 2011 Lippincott Williams & Wilkins, Inc.

Clinical Utility of Molecular Surveillance for Cytomegalovirus After Antiviral Prophylaxis in High-Risk Solid Organ Transplant Recipients

Clinical Utility of Molecular Surveillance for Cytomegalovirus After Antiviral Prophylaxis in High-Risk Solid Organ Transplant Recipients: Background. Cytomegalovirus (CMV) disease after discontinuation of prophylaxis is a significant problem for CMV-seronegative recipients of CMV-seropositive organs (donor seropositive and recipient seronegative [D+/R-]). Virologic monitoring after prophylaxis has been proposed as a way to prevent late-onset disease.
Methods. We reviewed the efficacy of this strategy. CMV D+/R- organ transplant recipients received 3 to 6 months of antiviral prophylaxis, and then viral loads were performed weekly for 8 weeks. Preemptive antiviral therapy was initiated at a predefined threshold.

Impact of Cytomegalovirus Disease in D+/R– Kidney Transplant Patients Receiving 6 Months Low-Dose Valganciclovir Prophylaxis

Impact of Cytomegalovirus Disease in D+/R– Kidney Transplant Patients Receiving 6 Months Low-Dose Valganciclovir Prophylaxis:

Late-onset cytomegalovirus (CMV) disease remains common in CMV serology naïve kidney transplant patients of CMV serology positive organs (D+/R–) despite the use of antiviral prophylaxis. We studied clinical efficacy of 6-month low-dose valganciclovir (VGCV) prophylaxis, risk factors for late-onset CMV disease and its impact on kidney transplant outcomes. Between October 2005 and December 2009, 166 consecutive D+/R– kidney alone and simultaneous pancreas and kidney transplant patients received VGCV 450 mg daily for 6 months after transplantation. After a median follow-up of 3.2 years, 30 cases of CMV disease occurred within the first 2 years after transplantation with a cumulative incidence of 11.5 and 18.1% at 1 and 2 years, respectively.

Incidence and Outcomes of Ganciclovir-Resistant Cytomegalovirus Infections in 1244 Kidney Transplant Recipients

Incidence and Outcomes of Ganciclovir-Resistant Cytomegalovirus Infections in 1244 Kidney Transplant Recipients: "Background. Cytomegalovirus (CMV) infections in kidney transplant recipients are in most cases successfully treated with oral valganciclovir (VGCV). However, in a few percent of patients, mutations in the UL 97 or UL 54 gene lead to drug resistance.
Methods. We investigated the incidence and outcomes of ganciclovir-resistant CMV viremia in all 1244 kidney recipients transplanted at our center from 2004 through 2008. CMV DNAemia was monitored in all patients at least weekly, and patients who were positive were treated preemptively with VGCV (900 mg once daily).

Preemptive versus prophylactic protocol to prevent cytomegalovirus infection after renal transplantation: a meta-analysis and systematic review of randomized controlled trials

Preemptive versus prophylactic protocol to prevent cytomegalovirus infection after renal transplantation: a meta-analysis and systematic review of randomized controlled trials: "

L.-F. Zhang, Y.-T. Wang, J.-H. Tian, K.-H. Yang, J.-Q. Wang. Preemptive versus prophylactic protocol to prevent cytomegalovirus infection after renal transplantation: a meta-analysis and systematic review of randomized controlled trials. Transpl Infect Dis 2011. All rights reserved

Objective. This review was conducted to assess the efficacy of preemptive versus prophylactic protocols for the prevention and treatment of cytomegalovirus (CMV) infection and disease after renal transplantation.

Methods. PubMed, EMBASE, the Cochrane Library, SCI, the China Journal Full-text Database, the Chinese Biomedical Database, the Chinese Scientific Journals Full-text Database, and the CMA Digital Periodicals were searched to collect randomized controlled trials (RCTs) of preemptive versus prophylactic protocols for the prevention and treatment of CMV infections after renal transplantation (up to April 2010). Two reviewers independently extracted data using a designed extraction form. The quality of the included trials was evaluated according to the Cochrane Handbook. RevMan 5.0 software was used for data analysis.