Editorials and Perspectives: Special Feature
Summary of the British Transplantation Society Guidelines for the Prevention and Management of CMV Disease After Solid Organ Transplantation
Andrews, Peter A.1,4; Emery, Vincent C.2; Newstead, Chas3
1 SW Thames Renal & Transplantation Unit, St. Helier Hospital, Surrey, United Kingdom.
2 Department of Virology, UCL Medical School, London, United Kingdom.
3 Department of Nephrology, St. James's University Hospital, Leeds, United Kingdom.
The authors received no support for the writing of the BTS guideline or this paper based on it. They declare no conflicts of interest in the writing of this paper. For completeness, comprehensive declarations of interest declared in the guideline document are reproduced as follows: Dr. C.G. Newstead received honoraria for lectures and teaching and expenses for travel and accommodation to attend scientific meetings from Fujisawa (now Astellas), Novartis, Roche, and Wyeth (now Pfizer), most recently more than 4 years ago. He received honoraria in the past for contributions to Advisory Boards for both Roche and Wyeth (Pfizer), but none for more than 10 years. After election to the Council of the BTS and Chair of the Standards Committee more than 10 years ago, he declined invitations to contribute to Advisory Boards. His research and that of close collaborators has been in part sponsored by the above named companies and eight different Foundations. Prof. V.C. Emery received honoraria for lectures and teaching and expenses for travel and accommodation to attend scientific meetings from Roche and Viropharma. He received honoraria for participation in advisory boards for Elan Pharmaceuticals, Novartis, Roche, and Viropharma. Dr. P.A. Andrews received travel and meeting expenses, but did not receive lecture fees or contribute to Advisory Boards from Astellas, Novartis, Pfizer, or Roche.
4 Address correspondence to: Dr. P.A. Andrews, Department of Nephrology, SW Thames Renal & Transplantation Unit, St. Helier Hospital, Surrey SM5 1AA, UK.
All authors contributed to the BTS guideline document and to this summary of the guideline. All have reviewed and approved the final document.
Received 19 July 2011. Revision requested 8 August 2011.
Accepted 1 September 2011.
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.
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 (1). Developed by a working group of the British Transplantation Society, the last date of formal literature review was October 2010, although additional references were included during the review process. The guideline has been extensively revised since the previous edition in 2005 and has used the GRADE system to rate the strength of evidence and the strength of recommendations (2). This approach is consistent with that adopted by Kidney Disease Improving Global Outcomes in its recent guidance relating to renal transplantation and also with guidelines from the European Best Practice Committee and the UK Renal Association (3–5). Complementing previous guidance published by the American Society of Transplantation/American Society of Transplant Surgeons, Kidney Disease Improving Global Outcomes and the Transplantation Society (6), they thus represent the most up-to-date synthesis of the evidence in this rapidly evolving field.
Diagnosis and Prevention of Cytomegalovirus Disease
After primary infection, cytomegalovirus (CMV) establishes life-long latency. One challenge in the transplant recipient is therefore the differentiation of patients with active CMV infection who are at risk of tissue invasive CMV disease from those who have subclinical infection. In this review, we use the term latent to define a state of virus infection in which the full replication cycle of the virus is not occurring, whereas active infection is defined as a state where there is evidence of virus undergoing a complete replication cycle and producing new infectious virions. Active infection can be further characterized into asymptomatic infection (no obvious signs of pathologic symptoms), viral syndrome (fever >38°C for 2 days of unexplained origin and one of leucopenia, myalgia, or arthralgia), and CMV disease (histopathological evidence of CMV, CMV retinitis diagnosed by an ophthalmologist, or CMV in the CSF indicative of CNS disease).
The frequency of CMV disease varies markedly depending on the definition used and the intensity of immunosuppression. Approximately 8% of renal, 29% of liver, 25% of heart, and 39% of lung transplant recipients experience symptomatic infection (7).
CMV load, used as a surrogate marker of CMV replication, has been shown in many studies to be a dominant risk factor for CMV disease. Increased experience and the availability of commercial assays have now allowed polymerase chain reaction (PCR) diagnosis and monitoring to be offered on a routine basis (8, 9), with real-time PCR offering highly reproducible and rapid data on viral load (10). The objective of modern management is to avoid patients reaching a clinical endpoint of CMV syndrome or tissue invasive disease.
Two approaches are in common use to minimize the impact of CMV infection or reactivation in solid organ transplantation: universal or targeted anti-CMV prophylaxis; and pre-emptive anti-CMV therapy. In some units, both approaches are used, depending on the donor/recipient CMV status, organs transplanted, and intensity of immunosuppression. The following sections summarize the evidence for the most commonly adopted strategies.
Universal Anti-CMV Prophylaxis
In this approach, subgroups of “at-risk” patients are offered prophylactic antiviral therapy for a defined period posttransplantation, at doses designed to prevent disease. Therapy is usually offered to donor positive/recipient negative for previous CMV infection (D+/R−) combinations to prevent primary infection, less commonly to D+R+ combinations to minimize reactivation of latent virus and infection with new genotypes, and occasionally to donor negative/ recipient positive for previous CMV infection (D−/R+) combinations to prevent reactivation.
A number of antiviral agents have been shown to be effective. Agents currently in use include ganciclovir (oral and intravenous preparations), valaciclovir, and valganciclovir. Some centers use CMV immune globulin, especially for D+/R− heart and heart-lung transplantation. A summary of current organ-specific recommendations is given in Table 1.
The major change in clinical practice since the second edition of the guidelines is that most units involved in solid organ transplantation use valganciclovir rather than intravenous ganciclovir as first-line CMV prophylaxis. Recent evidence regarding the use of this agent will therefore be considered in some detail.
The key licensing data came from a randomized double-blind multicenter study that recruited 364 adult CMV-negative recipients of CMV-positive solid organ transplants randomized 2:1 to valganciclovir or oral ganciclovir prophylaxis (11, 12). Treatment started within 10 days of transplantation and continued until 100 days after surgery. The frequency of CMV disease in the first 6 months was 17.2% in the valganciclovir compared with 18.4% in the ganciclovir-treated group. After 6 months, CMV disease occurred in 5% of the valganciclovir and 3.2% of the ganciclovir- treated group. At the end of the 3-month prophylactic period, the incidence of ganciclovir-resistant CMV strains was low at 0% for the valganciclovir and 1.9% in patients who had received oral ganciclovir (13).
The evidence base for CMV prophylaxis is suboptimal and varies according to the organ transplanted. Most data show oral valganciclovir and intravenous ganciclovir to be broadly equivalent, but the absence of comparative trial data makes intravenous ganciclovir a preferred option in many transplant situations. A pragmatic approach balances the limited evidence base against clinical experience. Although the Federal Drug Authority has not licensed oral valganciclovir for CMV prophylaxis in liver transplantation, accumulating evidence and expert opinion means that most liver transplant units in the United States and United Kingdom now use such prophylaxis. Similarly, although the best available evidence supports the use of intravenous ganciclovir for prophylaxis in simultaneous kidney-pancreas and cardiac transplantation, many units use oral valganciclovir to avoid the costs and inconvenience of hospital admission or home intravenous antiviral therapy.
The length of posttransplant prophylaxis has been mainly studied in renal transplantation. The IMPACT study was a double-blind, randomized, controlled study that compared 326 D+/R− renal transplant recipients randomized 1:1 to 200 days prophylaxis with valganciclovir versus 100 days prophylaxis followed by 100 days treatment with placebo (14). The rate of biopsy-proven acute rejection was not significantly different, the rates of graft loss were low, and renal function was equal in the two groups. The rate of other opportunist infections was significantly higher in the 100-day treatment arm, but this was almost entirely due to an increase in infections seen in the first 50 days. It is biologically implausible to ascribe this difference to drug therapy (or placebo) that was not due to start for another 50 days. The rate of CMV viremia at 12 months was 51% in the 100-day arm and 37% in the 200-day treatment arm (P<0.05). The primary efficacy parameter was the proportion of patients who developed “CMV syndrome” or tissue invasive CMV within the first 52 weeks. “CMV syndrome” was defined as CMV viremia with at least one of fever, malaise, leucopenia, thrombocytopenia, or hepatitis. This definition of CMV syndrome and that of tissue invasive disease was congruent with that recommended by American authorities (15). In contrast to most studies, however, the authors of this study chose to define CMV disease as a combination of tissue-invasive CMV or CMV syndrome defined earlier (14). Using this broadened definition of disease, “CMV disease” was seen at 1 year in 16% of the 200-day treatment group versus 37% of the 100-day treatment group (P<0.0001), of which 97.6% was “CMV syndrome.” Three patients experienced tissue invasive disease (all gastrointestinal), two in the 100-day treatment group and one in the 200-day treatment group (not significant).
When deciding whether doubling the length of prophylaxis with valganciclovir achieved a clinically useful risk- benefit ratio, one key assessment is how worthwhile it might be to approximately halve the rate of CMV disease, as defined by these authors. Of the CMV syndrome observed, which represented 97.6% of all CMV recorded, 45 of 59 cases in the 100-day group and 20 of 24 cases in the 200-day group were rated by the local investigator as of mild-to-moderate severity. The local clinicians decided to treat 57 of 59 of those with CMV syndrome in the 100-day group and all 24 patients with CMV syndrome in the 200-day group. This indicates that the local clinicians thought that the level of ill health justified treatment in these cases and implies that they believed it was better to treat at this stage rather than wait until the patients' condition had potentially worsened.
The impact of this study on clinical practice has varied across transplant centers in the United Kingdom, with some moving to a universal policy of 200 days of CMV prophylaxis in the D+/R− group, others continuing with a policy of 100 days of prophylaxis with a longer period for patients following treatment of rejection or at a perceived higher infective risk. This may reflect reluctance to extrapolate from a single study in which a nonstandard definition of disease was adopted, together with concerns regarding the cost of additional therapy.
A study supported by the drug manufacturer examined the cost-effectiveness of extended therapy in the United States and indicated that such treatment reduced the incidence of CMV disease (syndrome) at a cost of $15,000 per QALY (16). Such economic analyses are subject to many input variables and should be treated with caution, and the results may not be generalizable to other health care systems. However, the Scottish Medicines Consortium recently accepted that extending valganciclovir prophylaxis to 200 days was probably cost- effective in CMV D+/R− transplants (17).
The recommended dose of valganciclovir is 900 mg once daily for patients with normal renal function, with reduction in dose at lower levels of GFR. A recent meta-analysis is pertinent (18). This described the comparative use of 900 mg vs. 450 mg of valganciclovir as prophylaxis against CMV in solid organ transplant recipients, with more than 1500 patients analyzed in each treatment arm. No difference was identified in the incidence of CMV using the lower dose of valganciclovir, but the 900 mg dose was associated with an increased risk of leukopenia (odds ratio 3.32; P<0.0002) and—surprisingly—an increased risk of rejection (odds ratio 2.56; P<0.005). These risks persisted after adjustment for the type of allograft, CMV control strategy, and immunosuppression. The interpretation of these data is not clear, but a linked editorial (19) recommends further study of the dose requirements for extended CMV prophylaxis, while noting the risk of an increased rate of antiviral resistance when using the lower drug dose.
The evidence base for prolonged CMV prophylaxis is more limited for lung than for renal transplantation. However, in a study published in 2010 involving 11 U.S. centers, 136 lung transplant recipients who had completed 3 months of valganciclovir prophylaxis were randomly assigned to treatment with valganciclovir or placebo for an additional 9 months (20). CMV infection defined as disease or positive viremia or bronchoalveolar lavage culture but not meeting the primary end point occurred in 32% of short-course vs. 4% of extended-course treatment (P<0.001), whereas total CMV infection occurred in 64% vs. 10%. There was no difference in other secondary endpoints which included acute rejection, opportunistic infection, ganciclovir resistance, and safety. In these guidelines, prolonged antiviral prophylaxis has been recommended in lung transplantation because of high infection rates and the observation that the lung seems to be particularly badly affected by CMV infection. More data would be welcome.
Pre-Emptive Anti-CMV Therapy
In this approach, which is largely confined to renal transplantation, patients undergo regular surveillance and are treated when judged to be at high risk of developing CMV disease. Treatment is usually with full-dose valganciclovir as the kinetics of decrease in viral load has been shown to be the same as for intravenous ganciclovir (21). A variety of markers for predicting future CMV disease have been described and results should be interpreted in terms of the rapid dynamics of CMV replication as the average doubling time is rapid (between 1 and 2 days) (22, 23). The absolute levels of viremia that are recommended as a threshold to start preemptive therapy will depend upon the assay used. For example, most real-time PCR assays (which are popular because of simplicity and high level of automation) report lower levels of viremia compared with the Hybrid Capture Assay. Ideally, units should establish the clinical significance of their local assay, although there is now a universal standard for CMV nucleic acid testing produced by NIBSC (United Kingdom), which should reduce interlaboratory variation and facilitate multicenter approaches to antiviral trials and patient management (24).
That preemptive therapy can be used to control CMV disease has been demonstrated in many studies and in several meta-analyses. For example, in a study of 52 asymptomatic renal transplant recipients, 23 (44%) had positive CMV PCR tests on at least one occasion. However, only 2 (8.6%) developed CMV disease. This study suggests that, in this population with this assay, a treatment strategy based on positive PCR alone would treat a significant number of patients who did not necessarily require it (25). The authors reported the important finding that none of the 29 patients who were continuously negative for CMV PCR developed CMV disease. Similar studies have demonstrated efficacy of preemptive therapy in renal (26), bone marrow (27), liver, and cardiac transplantation (28).
The duration of preemptive antiviral therapy is important. The optimum length of treatment has not been determined, although some authors have recommended a minimum period of 4 weeks. It is logical to be guided by serial measurements of the viral load, and others have recommended treatment continue for 1, 2, or 4 weeks after the patient has tested negative for viral replication (29). There is no trial evidence to inform the required frequency of viral load estimation, but expert opinion and the kinetics of viral replication suggest that such assessment should be performed at least weekly.
The authors of a review of prophylaxis strategies for CMV in solid organ transplantation commented on what has been termed “targeted prophylaxis” in these guidelines and pointed out that “conventional prophylactic therapy has a large body of supportive controlled clinical studies demonstrating efficacy and cost-effectiveness. The strategy has the advantage of preventing other herpes viruses. There is some information to suggest that prophylactic therapy may benefit by reducing rejection” (30). The authors contrast preemptive therapy, pointing out “it is limited by reliance on intensive surveillance with significant logistic difficulties and requiring good patient compliance. There is ambiguity about the best surveillance method and the purported benefits of preemptive therapy, such as decreased cost, fewer adverse medication effects and less anti-viral resistance have not been proven in head to head clinical studies.” In the counterpoint article published simultaneously, the problems of prophylaxis were discussed (31). These include preventing antigen presentation to the immune system so that patients are at risk of developing disease once the drug is stopped and the risk of drug resistance. More recent reviews have advocated targeted prophylaxis (32), the advantages of preemptive therapy (33), and the possibility of different approaches in each serological combination (34, 35).
One theoretical concern with a preemptive approach is that it would not be expected to protect from the indirect effects of CMV infection, including any influence on late graft and patient survival (36). A recent randomized controlled study in kidney transplant patients compared preemptive therapy with prophylaxis with oral ganciclovir (37). These data suggest that graft survival at 4 years posttransplantation was significantly worse in patients who had been managed preemptively. More data are needed in this area but the suggestion is that prophylaxis interrupts initial organ amplification of CMV, and hence minimizes effects on the graft, both in the early period posttransplantation and also potentially in the longer term.
Both prophylaxis and preemptive therapy are effective at controlling CMV disease. Colleagues should discuss the practicalities with their local virologists and audit their agreed management strategy. The majority of UK units have adopted a targeted prophylaxis strategy.
Recent studies have seen considerable progress towards the “holy grail” of an effective CMV vaccine. In 2009, a phase 2 trial reported the use of a vaccine containing recombinant CMV glycoprotein B subunit antigen combined with MF59 adjuvant for the prevention of CMV infection in seronegative women of childbearing age. The primary end point was the time to CMV infection in the women and the vaccine was found to be 50% effective (95% confidence interval, 7–73) (38).
This is a rapidly evolving field and recent results of a phase 2 study in solid organ transplant patients with the same gB-MF59 vaccine have indicated that the vaccine is highly immunogenic in CMV-seronegative individuals and can boost immunity in CMV-seropositive individuals. In addition, in those patients who proceeded to transplantation, there were encouraging indications that vaccinated patients required less antiviral therapy and that the incidence of infection was reduced in the high-risk D+R− group (39). These results are encouraging and should stimulate the evaluation of further vaccines in solid organ transplant recipients and phase 3 studies of the gB-MF59 vaccine.
Treatment of CMV Disease
Intravenous ganciclovir has had a major impact on the mortality and morbidity of CMV disease in the transplant recipient (40, 41). Few would argue with the use of intravenous ganciclovir in this setting, although the only randomized placebo controlled trial, in bone marrow transplant patients with CMV gastroenteritis, did not show clinical benefit (42). Where there is fever and only trivial organ involvement, withdrawal of azathioprine or mycophenolate from a triple-drug regimen may the only adjustment required to the baseline immunosuppression. More commonly, if the patient is unwell or there is evidence of organ dysfunction, it is appropriate to reduce (by 50%) the dose of calcineurin inhibitor.
Early concerns about neutropenia coincident with ganciclovir treatment have become less of an issue with greater experience and the appreciation that marrow suppression is often due to CMV disease and responds to antiviral therapy (43, 44).
Intravenous administration of ganciclovir remains the route of choice when the patient is seriously unwell, or when oral drug absorption is uncertain or poorly tolerated. However, oral valganciclovir was of equal efficacy to intravenous ganciclovir for treating CMV disease in a mixed group of solid organ transplant recipients, three quarters of whom were renal transplant recipients (45). Substantial clinical experience in recent years has re-enforced that this is an appropriate treatment strategy, which has the advantage of being able to offer outpatient management for a proportion of patients.
Very high doses of intravenous hyperimmune globulin (0.5 g/kg body weight) have been used in conjunction with ganciclovir for the treatment of pneumonitis (46). It is not possible to evaluate the effectiveness of this treatment from the published literature, but the treatment is unlikely to have serious side effects and should be considered for life (or sight)-threatening disease.
The optimal duration of intravenous treatment after resolution of clinical signs is uncertain. Serial PCR of CMV DNA offers an objective measure of the degree of viremia and may help to guide the duration of treatment. In practice, the clinical response and PCR measurements are used and, at least 2 weeks full-dose treatment is recommended, with a longer duration of treatment if there is not a prompt fall in viral load (7).
There is a significant risk of relapse after successful treatment of CMV disease, with recurrent CMV disease reported in various organ recipients (47–49). In one study, in kidney and kidney/pancreas recipients, relapse was seen in approximately one third of patients after treatment of the initial episode with ganciclovir (50). The quantitative measurement of CMV viral load may allow the risk of relapse to be predicted (50). Secondary prophylaxis after treatment of disease is common practice, but deciding the duration of treatment is difficult. In general, prophylactic dose antiviral therapy is usually prescribed for 1 month after resolution of CMV disease following mild illness, and for 3 months after severe illness, although there are no randomized trials to inform this strategy (7).
Although viral resistance has been rarely reported in the transplant literature (51–53), this may reflect underreporting because of difficulties with the required cell culture assays. When PCR is used, between 5% and 20% drug resistance has been reported in solid organ transplant recipients (54, 55).
The intensity of immunosuppression is likely to play a part in the frequency of drug resistance. However, in the VICTOR study, the greatest risk for recurrent DNAemia was not drug resistance itself, but failure to clear virus from the plasma by day 21 (56).
In clinical practice, viral resistance is manifest by progressive disease despite full-dose antiviral therapy or a static or increasing viral load after drug treatment. Importantly, viral load is not a reliable indicator of drug resistance in the first weeks of treatment (57) because the natural kinetics of CMV replication before antiviral treatment mean that patients with a rapidly increasing viral load are more likely to show a transient increase in viral load in the first 5 to 7 days after therapy, before a decline is observed. This means that if the patient is recovering then increasing viral loads do not confirm a diagnosis of drug resistance.
Despite recent advances in technology, phenotypic assays are technically difficult and have a slow turnaround time. Although important for setting reference standards, especially for novel mutations of unknown significance, they are not practical to guide clinical care. However, genotypic assays can relatively rapidly detect gene mutations that are associated with both high- and low-grade resistance to ganciclovir, and mutations that confer various degrees of resistance to ganciclovir, foscarnet, and cidofovir (58).
Although there is no evidence beyond that of anecdotal clinical experience, the use of high-dose hyperimmune CMV globulin is likely to be at least safe (46) and its effectiveness (if any) presumably uninfluenced by drug-resistant mutations. However, it is not recommended as a single agent.
Cidofovir is a potential second-line therapy unless there is a UL54 genotype that confers both ganciclovir and cidofovir resistance (59). It has significant side effects including nephrotoxicity.
Foscarnet is reserved as second- or even third-line therapy partly because of significant risks of nephrotoxicity and electrolyte disturbances, especially an acute reduction in ionized calcium. There is a smaller risk of neurotoxicity, particularly grand mal convulsions. However, there is extensive clinical experience of the agent, mostly for treating patients with AIDS. It remains a valuable option in the presence of virus resistant to ganciclovir (60, 61). In high-risk clinical situations, consensus advice is to use combination treatment with ganciclovir and foscarnet (7).
There is some in vitro evidence that both sirolimus and leflunomide have an anti-CMV effect. Clinical anecdotes, which must be subject to publication bias, have indicated benefit from leflunomide in some cases (62, 63), but failure (in hemopoietic transplantation) in another (64). In general, mammalian target of rapamycin inhibitors seem to be associated with a reduction in CMV infection/disease (65), although it is likely that this may be secondary to their effects on CMV-specific T cells rather than by a direct antiviral effect. For the future, novel anti-CMV agents are in development, with maribavir and benzimidavir the most advanced (66, 67). The ability to restore CMV-specific T cells to the patient would also be highly attractive. There have been some research reports documenting the potential feasibility of transfer; however, this is likely at first to be only an option in hemopoietic transplantation (68).
The authors thank those who contributed to or commented on this and previous editions of the BTS Guidelines. They also thank the Council of the BTS for permission to produce this summary.
2. Uhlig K, Macleod A, Craig J, et al. Grading evidence and recommendations for clinical practice guidelines in nephrology. A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006; 70: 2058.
3. Kidney Disease Improving Global Outcomes (KDIGO) Transplant Work Group: KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9(S3): S1.
4. Berthoux F, Abramowicz D, Bradlet B, et al. European best practice guidelines for renal transplantation (Part 1). Nephrol Dial Transplant 2000; 15(suppl 7): 1.
6. Kidney Disease Improving Global Outcomes (KDIGO) Transplant Work Group: KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9(S3): S1.
7. Patel R, Snydman DR, Rubin RH, et al. Cytomegalovirus prophylaxis in solid organ transplant recipients. Transplantation 1996; 61: 1279.
8. Einsele H, Ehninger G, Hebart H, et al. Polymerase chain reaction monitoring reduces the incidence of cytomegalovirus disease and the duration and side effects of antiviral therapy after bone marrow transplantation. Blood 1995; 86: 2815.
9. Emery VC, Sabin CA, Cope AV, et al. Application of viral-load kinetics to identify patients who develop cytomegalovirus disease after transplantation. Lancet 2000; 355: 2032.
10. Piiparinen H, Höckerstedt K, Grönhagen-Riska C, et al. Comparison of two quantitative CMV PCR tests, Cobas Amplicor CMV Monitor and TaqMan assay, and pp65-antigenemia assay in the determination of viral loads from peripheral blood of organ transplant patients. J Clin Virol 2004; 30: 258.
11. Pescovitz MD, Paya C, Humar A, et al. Valganciclovir for prevention of CMV disease: 12 month follow up of a randomized trial of 364 D+/R− transplant recipients. Am J Transplant 2003; 3(S5): 299.
12. Paya C, Humar A, Dominguez E, et al. Valganciclovir Solid Organ Transplant Study Group. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 2004; 4: 611.
13. Boivin G, Goyette N, Gilbert C, et al. Valganciclovir prophylaxis is not associated with the emergence of cytomegalovirus UL97 and UL54 resistance mutations in solid organ transplant recipients: Results from a multicenter trial. Am J Transplant 2003: 3(S5): 431.
14. Humar A, Lebranchu Y, Vincenti F, et al. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant 2010; 10: 1228.
15. Humar A, Michaels M. AST ID Working Group on Infectious Disease Monitoring. American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant 2006; 6: 262.
16. Blumberg EA, Hauser IA, Stanisic S, et al. Prolonged prophylaxis with valganciclovir is cost effective in reducing posttransplant cytomegalovirus disease within the United States. Transplantation 2010; 90: 1420.
18. Kalil AC, Mindru C, Florescu DF. Effectiveness of valganciclovir 900 mg versus 450 mg for cytomegalovirus prophylaxis in transplantation: Direct and indirect treatment comparison meta-analysis. Clin Infect Dis 2011; 52: 313.
19. Avery RK. Low-dose valganciclovir for cytomegalovirus prophylaxis in organ transplantation: Is less really more? Clin Infect Dis 2011; 52: 322.
20. Palmer SM, Limaye AP, Banks M, et al. Extended valganciclovir prophylaxis to prevent cytomegalovirus after lung transplantation. A randomized controlled trial. Ann Intern Med 2010; 152: 761.
21. Mattes FM, Hainsworth EG, Hassan-Walker AF, et al. Kinetics of cytomegalovirus load decrease in solid-organ transplant recipients after preemptive therapy with valganciclovir. J Infect Dis 2005; 191: 89.
22. Buyck HC, Griffiths PD, Emery VC. Human cytomegalovirus (HCMV) replication kinetics in stem cell transplant recipients following anti-HCMV therapy. J Clin Virol 2010; 49: 32.
23. Emery VC, Hassan-Walker AF, Burroughs AK, et al. Human cytomegalovirus (HCMV) replication dynamics in HCMV-naive and -experienced immunocompromised hosts. J Infect Dis 2002; 185: 1723.
25. Benedetti E, Mihalov M, Asolati M, et al. A prospective study of the predictive value of polymerase chain reaction assay for cytomegalovirus in asymptomatic kidney transplant recipients. Clin Transplant 1998; 12: 391.
26. Sagedal S, Nordal KP, Hartmann A, et al. Pre-emptive therapy of CMV pp65 antigen positive renal transplant recipients with oral ganciclovir: A randomized, comparative study. Nephrol Dial Transplant 2003; 18: 1899.
27. Stocchi R, Szydlo R, Craddock C, et al. A comparison of prophylactic vs pre-emptive ganciclovir to prevent cytomegalovirus disease after T-depleted volunteer unrelated donor bone marrow transplantation. Bone Marrow Transplant 1999; 23: 705.
28. Knzle N, Petignat C, Francioli P, et al. Preemptive treatment approach to cytomegalovirus (CMV) infection in solid organ transplant patients: Relationship between compliance with the guidelines and prevention of CMV morbidity. Transpl Infect Dis 2000; 2: 118.
29. Ketteler M, Kunter U, Floege J. An update on herpes virus infection in graft recipients. Nephrol Dial Transplant 2003; 18: 1703.
30. Hart GD, Paya CV. Prophylaxis for CMV should now replace pre-emptive therapy in solid organ transplantation. Rev Med Virol 2001; 11: 73.
31. Emery VC. Prophylaxis for CMV should not now replace pre-emptive therapy in solid organ transplantation. Rev Med Virol 2001; 11: 83.
32. Snydman DR. The case for cytomegalovirus prophylaxis in solid organ transplantation. Rev Med Virol 2006; 16: 289.
33. Singh N. Antiviral drugs for cytomegalovirus in transplant recipients: Advantages of preemptive therapy. Rev Med Virol 2006; 16: 281.
34. Baillie GM. Prevention of cytomegalovirus disease in solid organ transplant patients: Prophylactic versus preemptive therapy. Am J Health Syst Pharm 2006; 63(19 suppl 5): S10.
35. Fishman JA, Emery V, Freeman R, et al. Cytomegalovirus in transplantation—Challenging the status quo. Clin Transplant 2007; 21: 149.
36. Sagedal S, Hartmann A, Nordal KP, et al. Impact of early cytomegalovirus infection and disease on long-term recipient and kidney graft survival. Kidney Int 2004; 66: 329.
37. Kliem V, Fricke L, Wollbrink T, et al. Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: Results of a randomized clinical trial. Am J Transplant 2008; 8: 975.
38. Pass RF, Zhang C, Evans A, et al. Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med 2009; 360: 1191.
39. Griffiths PD, Stanton A, McCarrell E, et al. Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: A phase 2 randomised placebo-controlled trial. Lancet 2011; 377: 1256.
40. Dunn DL, Mayoral JL, Gillingham KJ, et al. Treatment of invasive cytomegalovirus disease in solid organ transplant patients with ganciclovir. Transplantation 1991; 51: 98.
41. Harbison MA, De Girolami PC, Jenkins RL, et al. Ganciclovir therapy of severe cytomegalovirus infections in solid-organ transplant recipients. Transplantation 1988; 46: 82.
42. Reed EC, Wolford JL, Kopecky KJ, et al. Ganciclovir for the treatment of cytomegalovirus gastroenteritis in bone marrow transplant patients. A randomized, placebo- controlled trial. Ann Intern Med 1990; 112: 505.
43. Reed EC. Treatment of cytomegalovirus pneumonia in transplant patients. Transplant Proc 1991; 23(S1): 8–12.
44. Emanuel D, Cunningham I, Jules-Elysee K, et al. Cytomegalovirus pneumonia after bone marrow transplantation successfully treated with the combination of ganciclovir and high dose intravenous immunoglobulin. Ann Intern Med 1988; 109: 777.
45. Asberg A, Humar A, Rollag H, et al. VICTOR Study Group. Oral valganciclovir is non-inferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 2007; 7: 2106.
46. George MJ, Snydman DR, Werner BG, et al. Use of ganciclovir plus cytomegalovirus immune globulin to treat CMV pneumonia in orthotopic liver transplant recipients. Transplant Proc 1993; 25: 22.
47. Falgas ME, Snydman DR, Griffith J, et al. Clinical and epidemiological predictors of recurrent cytomegalovirus disease in orthotopic liver transplant recipients. Clin Infect Dis 1997; 25: 314.
48. van den Berg AP, van Son WJ, Haagsma EB, et al. Prediction of recurrent cytomegalovirus disease after treatment with ganciclovir in solid-organ transplant recipients. Transplantation 1993; 55: 847.
49. Manez R, Kusne G, Green M, et al. Incidence and risk factors associated with the development of cytomegalovirus disease after intestinal transplantation. Transplantation 1995; 59: 1010.
50. Humar A, Uknis M, Carlone-Jambor C, et al. Cytomegalovirus disease recurrence after ganciclovir treatment in kidney and kidney-pancreas transplant recipients. Transplantation 1999; 67: 94.
51. Boivin G, Erice A, Crane DD, et al. Ganciclovir susceptibilities of cytomegalovirus (CMV) isolates from solid organ transplant recipients with CMV viraemia after antiviral prophylaxis. J Infect Dis 1993; 168: 332.
52. Slavin MA, Bindra RR, Gleaves CA, Pettinger MB, Bowden RA. Ganciclovir sensitivity of cytomegalovirus at diagnosis and during treatment of cytomegalovirus pneumonia in marrow transplant recipients. Antimicrob Agents Chemother 1993; 36: 1360.
53. Jordan A, Bhorade SM, Lurain NS, et al. Emergence of ganciclovir resistant cytomegalovirus in lung transplant recipients. Transplant 2001, Chicago, IL, May 11–16, 2001.
54. Li F, Kenyon KW, Kirby KA, Fishbein DP, et al. Incidence and clinical features of ganciclovir-resistant cytomegalovirus disease in heart transplant recipients. Clin Infect Dis 2007; 45: 439.
55. Lurain NS, Bhorade SM, Pursell KJ, et al. Analysis and characterization of antiviral drug-resistant cytomegalovirus isolates from solid organ transplant recipients. J Infect Dis 2002; 186: 760.
56. Asberg A, Humar A, Jardine AG, et al. VICTOR Study Group. Long-term outcomes of CMV disease treatment with valganciclovir versus IV ganciclovir in solid organ transplant recipients. Am J Transplant 2009; 9: 1205.
57. Nichols WG, Corey L, Gooley T, et al. Rising pp65 antigenemia during preemptive anticytomegalovirus therapy after allogeneic hematopoietic stem cell transplantation: Risk factors, correlation with DNA load, and outcomes. Blood 2001; 97: 867.
58. Lurain NS, Chou S. Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev 2010; 23: 689.
59. Chou SW. Cytomegalovirus drug resistance and clinical implications. Transpl Infect Dis 2001; 3(S2): 20.
60. Erice A. Resistance of human cytomegalovirus to antiviral drugs. Clin Microbiol Rev 1999; 12: 286.
61. Rubin RH. Prevention and treatment of cytomegalovirus disease in heart transplant patients. J Heart Lung Transplant 2000; 19: 731.
62. Levi ME, Mandava N, Chan LK, et al. Treatment of multidrug-resistant cytomegalovirus retinitis with systemically administered leflunomide. Transpl Infect Dis 2006; 8: 38.
63. Mossad SB, Avery RK. Second look at leflunomide “failure” to control cytomegalovirus infection in the setting of renal failure. Transpl Infect Dis 2007; 9: 260; author reply 260.
64. Battiwalla M, Paplham P, Almyroudis NG, et al. Leflunomide failure to control recurrent cytomegalovirus infection in the setting of renal failure after allogeneic stem cell transplantation. Transpl Infect Dis 2007; 9: 28.
65. Delgado JF, Manito N, Almenar L, et al. Risk factors associated with cytomegalovirus infection in heart transplant patients: A prospective, epidemiological study. Transpl Infect Dis 2011; 13: 136. doi: 10.1111/j. 1399-3062.2010.00573.x.
66. Steininger C. Novel therapies for cytomegalovirus disease. Recent Pat Antiinfect Drug Discov 2007; 2: 53.
67. Eid AJ, Razonable RR. New developments in the management of cytomegalovirus infection after solid organ transplantation. Drugs 2010; 70: 965.
68. Peggs KS. Adoptive T cell immunotherapy for cytomegalovirus. Expert Opin Biol Ther 2009; 9: 725.
This article has been cited 10 time(s).
Clinical Infectious DiseasesAn International Multicenter Performance Analysis of Cytomegalovirus Load TestsClinical Infectious Diseases
Clinical Infectious DiseasesThe Long Road Toward Standardization of Viral Load Testing for CytomegalovirusClinical Infectious Diseases
Expert Opinion on PharmacotherapyValganciclovir: therapeutic role in pediatric solid organ transplant recipientsExpert Opinion on Pharmacotherapy
Clinical ImmunologyCMV driven CD8(+) T-cell activation is associated with acute rejection in lung transplantationClinical Immunology
Journal of Medical VirologyHigh risk of cytomegalovirus infection following solid organ transplantation despite prophylactic therapyJournal of Medical Virology
Journal of Clinical MicrobiologyFully Automated Quantification of Cytomegalovirus (CMV) in Whole Blood with the New Sensitive Abbott RealTime CMV Assay in the Era of the CMV International StandardJournal of Clinical Microbiology
Liver TransplantationOccult Cytomegalovirus Cholangitis as a Potential Cause of Cholestatic Complications After Orthotopic Liver Transplantation? A Study of Cytomegalovirus DNA in BileLiver Transplantation
InfectionSuccessful ganciclovir treatment of primary cytomegalovirus infection containing the UL97 mutation N510S in an intestinal graft recipientInfection
Journal of Antimicrobial ChemotherapyEfficacy of a strategy for discontinuing pre-emptive ganciclovir therapy after a negative cytomegalovirus antigenaemia test result in seropositive kidney transplant recipientsJournal of Antimicrobial Chemotherapy
British Journal of HaematologyManagement of cytomegalovirus infection in haemopoietic stem cell transplantationBritish Journal of Haematology
Cytomegalovirus; Guideline; Transplantation; Valganciclovir
© 2011 Lippincott Williams & Wilkins, Inc.