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Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients

  1. Giovanni FM Strippoli1,*,
  2. Elisabeth M Hodson2,
  3. Cheryl A Jones3,
  4. Jonathan C Craig4

Editorial Group: Cochrane Renal Group

Published Online: 17 FEB 2010

Assessed as up-to-date: 9 NOV 2005

DOI: 10.1002/14651858.CD005133.pub2

Database Title

Additional Information

How to Cite

Strippoli GFM, Hodson EM, Jones CA, Craig JC. Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD005133. DOI: 10.1002/14651858.CD005133.pub2.

Author Information

  1. 1

    c) Diaverum Medical Scientific office, d) Mario Negri Sud Consortium, Italy, a) School of Public Health, University of Sydney, b) Cochrane Renal Group, Westmead, NSW, Australia

  2. 2

    School of Public Health, The University of Sydney, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, NSW, Australia

  3. 3

    The University of Sydney, Discipline of Paediatrics and Child Health, Westmead, Sydney, NSW, Australia

  4. 4

    (b) School of Public Health, The University of Sydney, (a) Cochrane Renal Group, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, NSW, Australia

*Giovanni FM Strippoli, a) School of Public Health, University of Sydney, b) Cochrane Renal Group, c) Diaverum Medical Scientific office, d) Mario Negri Sud Consortium, Italy, Locked Bag 4001, Westmead, NSW, 2145, Australia. Giovanni.Strippoli@diaverum.com. strippoli@negrisud.it.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 17 FEB 2010

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality in solid organ transplant recipients. CMV infection may directly result in CMV disease (fever, leucopenia and thrombocytopenia with or without specific organ dysfunction) and indirectly affect the host's immune response contributing to acute rejection, graft loss and onset of other opportunistic infections (Hart 2001). Before antiviral prophylaxis was widely used, CMV disease occurred in 7% to 32% of solid organ transplant recipients with the lowest risk in kidney recipients and the highest in heart-lung recipients. In all patient groups, CMV infection and disease are most common in CMV negative recipients of CMV seropositive organs and in recipients treated with antilymphocyte therapy (EBPG 2000).

A recent systematic review of randomised controlled trials (RCTs) has demonstrated that CMV prophylaxis with antiviral agents given unselectively to solid organ transplant recipients prevents CMV disease and death due to CMV disease and is associated with lower incidence of opportunistic infections (Hodson 2005a). Routine antiviral prophylaxis has however many potential problems, such as leucopenia and neurological dysfunction, development of CMV resistance, cost, and the occurrence of late CMV disease when prophylaxis is discontinued (Emery 2001; Hart 2001). Alternatives to antiviral prophylaxis include administration of antiviral agents during antilymphocyte antibody therapy (Hibberd 1992), surveillance and treatment with antiviral agents when viraemia is detected (pre-emptive therapy) or standard care based upon regular clinical assessment with treatment of symptomatic CMV infection (CMV disease) when it occurs. The use of pre-emptive regimens has been advocated on the basis of reduced toxicity and costs through targeting patients at high risk for CMV disease. These regimens rely on the timely availability of sensitive and reliable methods for detecting CMV viraemia, in order to predict subsequent disease in time to be influenced by antiviral therapy.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

The aim of this study was to evaluate the benefits and harms of pre-emptive treatment of CMV viraemia to prevent CMV disease, all cause mortality and indirect effects of CMV infection (acute rejection, graft loss, opportunistic infections) in solid organ transplant recipients and to assess the comparative effects of pre-emptive treatment regimens and routine CMV prophylaxis with antiviral medications.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Criteria for considering studies for this review

 

Types of studies

We included RCTs and quasi-RCTs (trials in which allocation was obtained by alternation, alternate medical records, date of birth or other predictable methods) only.

 

Types of participants

Trials enrolling any type of solid organ transplant recipient, adult or paediatric, were included.

 

Types of interventions

We included RCTs of pre-emptive treatment versus placebo or standard care, pre-emptive treatment versus non specific antiviral prophylaxis and different pre-emptive treatment regimens (different antiviral agents used for pre-emptive treatment, different doses, different routes of administration) in solid organ transplant recipients. Pre-emptive treatment was defined as routine testing for CMV viraemia using any test and commencing anti-viral treatment if viraemia was detected.

 

Types of outcome measures

The effect of these intervention was tested on the following outcomes:

  • all-cause mortality
  • death due to CMV disease
  • time to development of CMV disease
  • graft loss
  • acute rejection
  • other infections
  • adverse effects of medications

CMV disease was defined as CMV infection together with CMV syndrome (fever, leucopenia, thrombocytopenia, malaise) and/or CMV organ involvement confirmed by histopathology.

 

Search methods for identification of studies

Electronic searches ( Table 1 - Electronic search strategies) were performed in MEDLINE (1966 to February 2005), EMBASE (1980 to February 2005), the Cochrane Central Registry of Controlled Trials (CENTRAL - in The Cochrane Library, issue 2, 2005) and the Cochrane Renal Group's specialised register. We adopted an optimally search strategy for identification of RCTs developed by the Cochrane Collaboration for MEDLINE (Dickersin 1994) and EMBASE (Lefebvre 1996) combined with subject headings and text words for CMV infection and disease, solid organ transplant recipients (kidney, liver, heart, lung, combined liver-kidney, combined kidney-pancreas and combined heart-lung) and antiviral medications including acyclovir, valacyclovir, ganciclovir, valganciclovir and foscarnet. We also searched reference lists of review articles, relevant trials and abstracts of scientific meetings (American Society of Nephrology and European Renal Association-European Dialysis and Transplantation Association (1995-2005)).

 

Data collection and analysis

This systematic review was undertaken by four authors (GS, EH, CJ, JC). The titles and abstracts were screened by EH and CJ, who discarded studies that were not applicable, however studies and reviews that might include relevant data or information on trials were retained initially and their full-text version analysed. GS and EH independently assessed retrieved abstracts and, if necessary the full text, to determine which studies satisfied the inclusion criteria. Data extraction was carried out by the same authors independently using standard data extraction forms. It was planned that studies reported in non-English language journals (if any) would be translated before assessment. Where more than one publication of one trial existed, only the publication with the most complete data was included. Any further information required from the original author was requested by written correspondence and any relevant information obtained in this manner was included in the review. Disagreements were resolved in consultation with JC.

The quality of studies included was assessed independently by EH and GS without blinding to authorship or journal of publication using the checklist developed by the Cochrane Renal Group. Discrepancies were resolved by consensus and when necessary by discussion with JC. The quality items assessed were allocation concealment, blinding of investigators, participants and outcome assessors, intention-to-treat analysis and completeness of follow-up (Schulz 1995).

 

Quality checklist

 

Allocation concealment

  • Adequate: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study
  • Unclear: Randomisation stated but no information on method used is available
  • Inadequate: Method of randomisation used such as alternate medical record numbers or unsealed envelopes; any information in the study that indicated that investigators or participants could influence intervention group

 

Blinding

  • Blinding of investigators: Yes/no/not stated
  • Blinding of participants: Yes/no/not stated
  • Blinding of outcome assessor: Yes/no/not stated
  • Blinding of data analysis: Yes/no/not stated

The above are considered not blinded if the treatment group could be identified in > 20% of participants due to side effects of treatment or the treatment groups could be identified through different routes or frequency of administration of trial medications.

 

Intention-to-treat analysis

  • Yes: specifically reported by authors that intention-to-treat analysis was undertaken and this was confirmed on study assessment
  • No: not reported and lack of intention-to-treat analysis confirmed on study assessment (i.e. patients who were randomised but were not included in the analysis because they did not receive the study intervention, they withdrew from the study or were not included because of protocol violation).
  • Not stated: not reported and could be determined (Studies with 100% follow up of patients included so that patient exclusion after randomisation cannot be excluded)

 

Completeness of follow-up

Percentage of participants lost to follow-up or with no data for the primary outcome of effectiveness

 

Statistical assessment

Dichotomous outcomes were analysed using the risk ratio measure (RR) with its 95% confidence intervals (CI) while continuous outcomes were to be analysed using the mean difference (MD) and its 95% CI. Data were pooled where appropriate using a random-effects model to calculate a summary estimate of effect. Heterogeneity was formally tested using Cochran Q and the I² statistic (Higgin 2003). To determine whether there was any difference between study results due to plausible effect modifiers, subgroup analysis was planned provided that sufficient numbers of studies for analysis were identified. The analysis aimed to explore the effects of patient characteristics such as type of solid organ transplanted, type of intervention, dose and duration of intervention, level of pre-existent risk, timing and methods used for diagnosis of CMV infection, time to graft loss, HHV6/7 status, and quality of study on treatment effect.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

The combined search of MEDLINE, EMBASE, the specialist registry of the Cochrane Renal Group and CENTRAL identified 1930 articles. Of these, 1737 were excluded because they were not RCTs or were RCTs evaluating ineligible interventions (Figure 1- Flow chart of trial selection). Full-text assessment of 193 potentially eligible articles identified 10 trials (476 patients) (Brennan 97-Kidney; Jung 01-Kidney; Koetz 01-Kidney; Paya 02-Liver; Queiroga 03-Kidney; Rayes 01-Liver; Sagedal 03-kidney; Singh 00-Liver; Singh 94-Liver; Yang 98-Kidney). Four trial authors responded to queries about uncertainties on study methods (Singh 00-Liver; Singh 94-Liver; Jung 01-Kidney; Brennan 97-Kidney).

 FigureFigure 1. Flow-chart indicating the number of citations retrieved by individual searches and the final number of included trials; reasons for exclusions are provided.

Three groups of interventions were studied. The first group included six trials (288 patients) which randomised patients to pre-emptive treatment or placebo (Brennan 97-Kidney; Koetz 01-Kidney; Paya 02-Liver; Rayes 01-Liver; Sagedal 03-kidney Yang 98-Kidney). For five of these trials (Koetz 01-Kidney; Paya 02-Liver; Rayes 01-Liver; Sagedal 03-kidney; Yang 98-Kidney), all transplant recipients were screened for CMV viraemia and the patients who developed viraemia were then randomised to receive pre-emptive treatment or placebo/standard care. In the sixth trial (Brennan 97-Kidney) recipients were randomised at transplant to receive pre-emptive treatment (screening and treatment of patients with positive viraemia) or standard care (treatment of symptomatic CMV infection when it developed). Screening was done at the time of transplantation and at weekly intervals thereafter. The second group consisted of three trials (151 patients) in which patients were randomised at transplant to viral surveillance and pre-emptive treatment on development of CMV viraemia or to non specific antiviral prophylaxis for 90 to 168 days (Queiroga 03-Kidney; Singh 94-Liver; Yang 98-Kidney). In the last included trial (Singh 00-Liver), patients who developed CMV viraemia, were randomised to receive oral or intravenous ganciclovir as pre-emptive treatment. Follow-up duration of all studies ranged from 3 to 18 months.

 

Risk of bias in included studies

Quality assessment of trials was problematic because many details were difficult to ascertain or not provided (see Characteristics of included studies).

 

Allocation concealment

Allocation concealment was adequate in only one trial (Paya 02-Liver), clearly inadequate (last digit of date of birth) in one trial (Brennan 97-Kidney) and unclear in all others.

 

Blinding

Outcome assessors were not stated as blinded in any of the trials. Blinding of participants and investigators was used in two trials (Koetz 01-Kidney; Paya 02-Liver).

 

Intention-to-treat analysis

Analysis was based on intention-to-treat in four trials (Koetz 01-Kidney; Paya 02-Liver; Rayes 01-Liver; Yang 98-Kidney).

 

Completeness of follow-up

The proportion of patients lost to follow-up was 0% for eight trials and unclear in two (Brennan 97-Kidney; Paya 02-Liver).

 

Effects of interventions

 

Pre-emptive treatment for CMV infection versus placebo or standard care

There were 1393 patients screened for entry to the six trials of pre-emptive treatment versus placebo or standard care. Of these 1035 patients were excluded (no CMV viraemia in 597, CMV viraemia below threshold for trial entry in 116, other reasons in 322) so that 358 patients were eligible for trial entry. However 64 (17.8%) developed CMV disease within the 0 to 10 day time gap between testing for viraemia and randomisation, and were thus excluded. The proportion of patients in each trial who developed CMV disease before CMV viraemia was detected varied from 0% to 32%. Six (1.7%) additional patients were excluded after randomisation for protocol violations so that 288 patients were evaluated.

Compared with placebo or standard care, pre-emptive treatment significantly reduced the risk of CMV disease ( Analysis 1.1, 6 trials, 288 patients: RR 0.29, 95% CI 0.11 to 0.80). The heterogeneity (I² = 53.7%, P = 0.06) was explained by the trial of Brennan 97-Kidney, which was the only trial in which transplant recipients were randomised to screen (and treat) for CMV viraemia versus no screening, rather than randomising patients with CMV viraemia to treatment or not. Removing this study resulted in homogenous results (I² = 0.0%, P = 0.54). There was no significant difference for the outcome of CMV disease in trials that used oral compared to trials that used intravenous ganciclovir preparations (P = 0.93 for interaction).

For the outcomes of CMV organ involvement or CMV associated symptoms ( Analysis 1.2,  Analysis 1.3), the summary estimates favoured treatment but the confidence intervals were wide. There was also no significant difference in the risks of acute rejection ( Analysis 1.4), all-cause mortality ( Analysis 1.5.1), graft loss ( Analysis 1.5.2), leucopenia ( Analysis 1.7.1) or renal dysfunction ( Analysis 1.7.2), with no significant variation in treatment effect for any these outcomes when trials using oral and intravenous ganciclovir regimens were considered separately.

 

Pre-emptive treatment for CMV viraemia versus anti-viral prophylaxis

One hundred and fifty one patients entered three trials comparing pre-emptive treatment with prophylaxis. CMV viraemia developed in 26% to 76% patients in the pre-emptive group and 0% to 42% in the prophylaxis group. The risk for CMV disease did not differ significantly between pre-emptive treatment with oral or intravenous ganciclovir and prophylaxis with oral acyclovir or ganciclovir ( Analysis 2.1, 3 trials, 151 patients: RR 0.42, 95% CI 0.07 to 2.65). There was also no significant difference in the risk of acute rejection ( Analysis 2.2), all-cause mortality ( Analysis 2.3.1) or graft loss ( Analysis 2.3.2). A significantly lower risk was observed for leukopenia ( Analysis 2.2.04, 2 trials, 117 patients: RR 0.12. 95% CI 0.01 to 0.96) but no differences were found in the risk of neurological dysfunction ( Analysis 2.4.02) or renal dysfunction ( Analysis 2.4.3).

 

Oral versus intravenous ganciclovir for pre-emptive treatment of CMV viraemia (comparison 03)

Twenty two (31%) of 72 liver transplant recipients undergoing surveillance developed CMV viraemia and entered a trial comparing oral and intravenous ganciclovir for pre-emptive treatment. There were no significant differences in the risk of CMV disease ( Analysis 3.1), all-cause mortality ( Analysis 3.2) or other infections ( Analysis 3.3) between the two regimens.

 

Other outcomes

No data were available on the outcomes of death due to CMV disease or the time to development of CMV disease for any comparison.

Subgroup analyses according to organ transplanted, CMV serostatus, antiviral medication, duration of treatment, timing and methods used for diagnosis of CMV infection, time to graft loss, HHV6/7 status or methodological quality were not possible because of the small number of trials and enrolled patients.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

This systematic review shows that pre-emptive treatment of solid organ transplant recipients after screen detection of CMV viraemia, is significantly more effective than placebo or standard care in reducing the risk of CMV disease. No significant differences in the risks of all-cause mortality, acute rejection, graft loss, other infections, leucopenia or renal dysfunction were demonstrated between pre-emptive therapy and placebo or standard care. The six trials of pre-emptive treatment versus placebo or standard care only evaluated a total of 288 patients for the primary outcome of CMV disease. Tests and thresholds used to detect CMV viraemia were different across the trials but results were generally consistent. Fewer patients were evaluated for other outcomes and confidence intervals around observed treatment effects were so wide that other benefits (or harms) of pre-emptive therapy cannot be excluded. The only available trial of oral versus IV pre-emptive regimens showed no significant difference in the risk of CMV disease. It should be emphasised that oral ganciclovir, which was the basis for three of the included analyses, is no longer available.

Comparative data of the effects of pre-emptive therapy versus routine prophylaxis was even more sparse and so there remains considerable uncertainty about the relative effects of these two interventions. Only three trials involving 151 patients are available, with most data provided by one trial (Jung 01-Kidney). Of the two other relevant trials, one is confounded by the use of an inferior antiviral agent (acyclovir) in the prophylaxis arm compared with ganciclovir in the pre-emptive arm (Singh 94-Liver).

Pre-emptive treatment of recipients with CMV viraemia detected on surveillance has been advocated as an alternative to antiviral prophylaxis because only recipients at high risk of CMV disease are treated. This approach exposes patients to a lower risk of adverse effects of medications and may reduce the risk of the emergence of resistant strains of CMV, which are now being described in solid organ transplant recipients (Limaye 2000). It has been argued that pre-emptive treatment in CMV negative recipients of CMV positive organs allows controlled viral replication to occur before antiviral medications are administered. This could result in the development of specific immune responses which are important in the prevention of future episodes of so called "late" CMV disease, a condition which is seen in about 10% of patients given 12 weeks of oral ganciclovir prophylaxis but has been only found rarely with pre-emptive regimens (Limaye 2000). Pre-emptive therapy appears particularly attractive in recipients at low risk of CMV disease such as CMV positive recipients of renal transplants not receiving antibody immunosuppression, whose risk of CMV disease is about 7% (Waiser 1998).

There are important arguments against the use of pre-emptive therapy rather than current standard care - routine prophylaxis with antiviral medications to prevent CMV disease (Hart 2001; Paya 02-Liver). Compared with the sparse data supporting pre-emptive treatment from six trials of 288 patients, the trial-basis for routine antiviral prophylaxis is substantial, arising from 19 trials of 1981 patients (Hodson 2005a; Hodson 2005b). Prophylaxis has been shown to reduce CMV disease by about 60% (RR = 0.42), with tight confidence intervals (0.34 to 0.52), strong evidence of statistically significant benefit (P < 0.0001), and considerable homogeneity of results across all trials (I² = 12.6%, where only one of the point estimates of the 19 trials did not favour prophylaxis) (Hodson 2005a; Hodson 2005b). The data favouring pre-emptive therapy is much less convincing. The confidence intervals are much wider (0.11 to 0.80), the level of statistical significance is lower (P = 0.02), and there was evidence of heterogeneity across the trials (I² = 53.7%, with one of the six trials not favouring pre-emptive therapy). Perhaps more importantly antiviral prophylaxis has been shown to reduce not only CMV disease but also CMV-related mortality, all-cause mortality, and clinically important disease caused by opportunistic infections. This has not been demonstrated for pre-emptive therapy.

The successful use of a pre-emptive regimen also requires a readily available, rapid, sensitive and specific surveillance test for early identification of CMV viraemia. Currently there are no universally agreed criteria for the level of viraemia that requires treatment or for the most appropriate surveillance test. There remains controversy over the thresholds for pp65 antigenaemia that require treatment as indicated by the different cut-off levels used in the trials reported in this systematic review (see table of included studies). Quantitative PCR for viral load may prove more valuable in directing pre-emptive therapy (Humar 1999) but so far this has only been tested in one trial (Jung 01-Kidney). Unless the surveillance test is performed frequently and with results available rapidly, patients may develop CMV disease before pre-emptive therapy can be initiated. In the six trials comparing pre-emptive treatment with placebo or no therapy, 64/358 (17.8%) screened patients were excluded because they developed CMV disease in the 0 to 10-day gap between testing and randomisation suggesting that the surveillance tests in use were inadequate to predict the population requiring treatment. In routine clinical care it is likely that the observed benefits of pre-emptive therapy are lower than in the setting of published trials, because patients who develop CMV disease cannot be legitimately excluded as they can in trials, and represent pre-emptive "failures".

Given that prophylaxis requires giving antiviral medications to all recipients (except CMV negative recipients of CMV negative donors), and pre-emptive therapy means restricting antiviral medications to patients with CMV viraemia, it is implausible that pre-emptive therapy could be better than prophylaxis in preventing disease, unless the dose of antiviral medication administered was higher in pre-emptive treatment and there was a strong relationship with dose and effectiveness (which has not been demonstrated). At best non-inferiority could be achieved only, with reduction in effect associated with increasing false negative rate of the CMV detection test, and rapidity of disease progression from viraemia to syndrome relative to frequency of testing. Any advantages of pre-emptive therapy compared with prophylaxis could only be found in cost reduction and reduction in adverse events with fewer patients treated. Finally there is increasing evidence that CMV infection may have immune-modulating effects and may increase the risk of opportunistic infections, allograft dysfunction and graft loss (Hart 2001; Sagedal 03-kidney). Treating recipients only when CMV viraemia is detected may reduce disease but may not reduce these immuno-modulating effects.

Few guidelines, including the British Transplantation Society (BTC 2004), the Caring for Australians with Renal Impairment (CARI 2004) and the Infectious Diseases Society of America (IDSA 2005), address the use of pre-emptive therapy and these are largely outdated. In particular, our findings are not consistent with the recommendations of the Infectious Diseases Society of America, which advocates pre-emptive therapy in preference to prophylaxis in liver transplant recipients.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

 

Implications for practice

Our systematic review demonstrates that pre-emptive treatment for CMV viraemia has been shown to reduce the risk of CMV disease in solid organ transplant recipients, but the trial data are very sparse, and patient benefits limited, compared with current practice which is routine antiviral prophylaxis for all (except sero-negative recipients of sero-negative donors). Pre-emptive treatment is a promising strategy for preventing CMV disease and minimising cost and unnecessary exposure to agents with potentially serious adverse effects.

 
Implications for research

A well designed and adequately powered trial is required to compare three months of prophylactic therapy using an anti-CMV viral medication with pre-emptive therapy for patients who develop viraemia. Such a trial should be powered to allow assessment of direct and indirect effects of CMV infection, adverse effects of medications and resource utilisation and have sufficient follow-up to assess graft loss and mortality.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

This review has been co-published with Transplantation (Strippoli 2006).
We are indebted to Narelle Willis, Co-ordinator of the Cochrane Renal Group, Linda Heslop and Ruth Mitchell, Trial Search Co-ordinators of the Cochrane Renal Group, and Sandra Puckeridge of the Centre for Kidney Research for their assistance in the conduct of this study.
The authors would like to thank Dr Jayant Kalpoe, Mr Geoff McDonnell, Dr Petra Macaskill and Dr Chas Newstead for their editorial advice during the preparation of this review.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
Download statistical data

 
Comparison 1. Pre-emptive medication for CMV viraemia versus placebo or standard care
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 All symptomatic CMV disease6288Risk Ratio (M-H, Random, 95% CI)0.29 [0.11, 0.80]
 2 CMV organ involvement5217Risk Ratio (M-H, Random, 95% CI)0.41 [0.06, 2.63]
 3 CMV associated symptoms5217Risk Ratio (M-H, Random, 95% CI)0.28 [0.06, 1.21]
 4 Acute rejection3185Risk Ratio (M-H, Random, 95% CI)1.21 [0.69, 2.12]
 5 All-cause mortality and graft loss3Risk Ratio (M-H, Random, 95% CI)Subtotals only
    5.1 All-cause mortality
3176Risk Ratio (M-H, Random, 95% CI)1.23 [0.35, 4.30]
    5.2 Graft loss
136Risk Ratio (M-H, Random, 95% CI)0.28 [0.01, 5.35]
 6 Other infections1Risk Ratio (M-H, Random, 95% CI)Totals not selected
 7 Adverse effects2Risk Ratio (M-H, Random, 95% CI)Subtotals only
    7.1 Leucopenia
2114Risk Ratio (M-H, Random, 95% CI)1.54 [0.16, 15.36]
    7.2 Renal dysfunction
136Risk Ratio (M-H, Random, 95% CI)0.93 [0.18, 4.92]

 
Comparison 2. Pre-emptive medication versus prophylaxis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 All symptomatic CMV disease3151Risk Ratio (M-H, Random, 95% CI)0.42 [0.07, 2.65]
 2 Acute rejection1Risk Ratio (M-H, Random, 95% CI)Totals not selected
 3 All-cause mortality and graft loss3Risk Ratio (M-H, Random, 95% CI)Subtotals only
    3.1 All-cause mortality
3151Risk Ratio (M-H, Random, 95% CI)1.86 [0.61, 5.72]
    3.2 Graft loss
3151Risk Ratio (M-H, Random, 95% CI)1.03 [0.10, 10.34]
 4 Adverse effects2Risk Ratio (M-H, Random, 95% CI)Subtotals only
    4.1 Leucopenia
2117Risk Ratio (M-H, Random, 95% CI)0.12 [0.01, 0.96]
    4.2 Neurological dysfunction
2117Risk Ratio (M-H, Random, 95% CI)0.17 [0.02, 1.35]
    4.3 Renal dysfunction
147Risk Ratio (M-H, Random, 95% CI)0.35 [0.01, 8.11]

 
Comparison 3. Oral versus IV ganciclovir
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 All symptomatic CMV disease1Risk Ratio (M-H, Random, 95% CI)Totals not selected
 2 All-cause mortality1Risk Ratio (M-H, Random, 95% CI)Totals not selected
 3 Other infections1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Last assessed as up-to-date: 9 November 2005.

DateEventDescription
19 January 2010AmendedContact details updated.


 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Protocol first published: Issue 1, 2005
Review first published: Issue 1, 2006

DateEventDescription
13 August 2009AmendedContact details updated.
14 October 2008AmendedConverted to new review format.


 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

  • Giovanni FM Strippoli: design, conduct, data-analysis, reporting
  • Elisabeth M Hodson: design, conduct, data-analysis, reporting
  • Cheryl Jones: reporting
  • Jonathan C Craig: design, data-analysis, reporting

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

None declared

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Internal sources

  • Australia-Europe Endeavour Scholarship, 2005, Australia.
  • University of Sydney Program Grant PhD Scholarship, Australia.

 

External sources

  • No sources of support supplied

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
Brennan 97-Kidney {published data only}
  • Brennan DC, Garlock KA, Lippmann BA, Buller RS, Gaudreault-Keener M, Lowell JA, et al. Control of cytomegalovirus-associated morbidity in renal transplant patients using intensive monitoring and either preemptive or deferred therapy. Journal of the Amercian Society of Nephrology 1997;8(1):118-25. [MEDLINE: 9013456]
  • Brennan DC, Garlock KA, Lippmann BJ, Buller RS, Gaudreault-Keener M, Lowell JA, et al. Polymerase chain reaction-triggered preemptive or deferred therapy to control cytomegalovirus-associated morbidity and costs in renal transplant patients. Transplantation Proceedings 1997;29(1-2):809-11. [MEDLINE: 9123536]
Jung 01-Kidney {published data only}
  • Jung C, Engelmann E, Borner K, Offermann G. Preemptive oral ganciclovir therapy versus prophylaxis to prevent symptomatic cytomegalovirus infection after kidney transplantation. Transplantation Proceedings 2001;33(7-8):3621-3. [MEDLINE: 11750538]
Koetz 01-Kidney {published data only}
  • Koetz AC, Delbruch R, Furtwangler A, Hufert FT, Neumann-Haefelin D, Kirste G, et al. Cytomegalovirus pp65 antigen-guided preemptive therapy with ganciclovir in solid organ transplant recipients: a prospective double-blind, placebo-controlled study. Transplantation 2001;72(7):1325-7. [MEDLINE: 11602864]
Paya 02-Liver {published data only}
  • Paya CV, Wilson JA, Espy MJ, Sia IG, DeBernardi MJ, Smith TF, et al. Preemptive use of oral ganciclovir to prevent cytomegalovirus infection in liver transplant patients: a randomized, placebo-controlled trial. The Journal of Infectious Diseases 2002;185(7):854-60. [MEDLINE: 11920308]
Queiroga 03-Kidney {published data only}
  • Queiroga M, Castro MC, Araujo LM, Alves CF, Kakehashi E, Panutti C, et al. A prospective, randomized controlled trial comparing oral ganciclovir with weekly-monitored CMV-antigenemia in renal transplant patients with a high-risk for CMV infection [abstract]. American Journal of Transplantation 2003;3(Suppl 5):511. [CENTRAL: CN-00447308]
Rayes 01-Liver {published data only}
  • Rayes N, Seehofer D, Schmidt CA, Oettle H, Muller AR, Steinmuller T, et al. Prospective randomized trial to assess the value of preemptive oral therapy for CMV infection following liver transplantation. Transplantation 2001;72(5):881-5. [MEDLINE: 11571454]
Sagedal 03-kidney {published data only}
  • Sagedal S, Nordal KP, Hartmann A, Midvedt K, Foss A, Asberg A, et al. Pre-emptive therapy of CMVpp65 antigen positive renal transplant recipients with oral ganciclovir: a randomized, comparative study. Nephrology Dialysis Transplantation 2003;18(9):1899-908. [MEDLINE: 12937241]
Singh 00-Liver {published data only}
  • Sing N, Paterson DL, Gayowsky T, Wagener MM, Marino IR. Cytomegalovirus antigenemia directed pre-emptive prophylaxis with oral versus I.V. ganciclovir for the prevention of cytomegalovirus disease in liver transplant recipients. Transplantation 2000;70(5):717-22. [MEDLINE: 11003347]
Singh 94-Liver {published data only}
  • Sing N, Yu VL, Mieles L, Wagener MM, Miner RC, Gayowsky T. High-dose acyclovir compared with short-course preemptive ganciclovir therapy to prevent cytomegalovirus disease in liver transplant recipients. Annals of Internal Medicine 1994;120(5):375-81. [MEDLINE: 8304654]
Yang 98-Kidney {published data only}
  • Yang CW, Kim YO, Kin YS, Kin SY, Moon IS, Ahn HJ, et al. Clinical course of cytomegalovirus (CMV) viremia with and without ganciclovir treatment in CMV-seropositive kidney transplant recipients. American Journal of Nephrology 1998;18(5):373-8. [MEDLINE: 9730559]

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
Ahsan 1997 {published data only}
  • Ahsan N, Holman MJ, Yang HC. Efficacy of oral ganciclovir in prevention of cytomegalovirus infection in post-kidney transplant patients. Clinical Transplantation 1997;11(6):633-9. [MEDLINE: 9408699]
Ahsan 1998 {published data only}
  • Ahsan N, Holman MJ, Sonderbye L, Langhoff E, Yang HC. Oral ganciclovir in the prevention of cytomegalovirus infection in post kidney transplant "CMV at risk" recipients: a controlled, comparative study of two regimens (750 mg Bid and 500 mg Bid). Transplantation Proceedings 1998;30(4):1383-5. [MEDLINE: 9636560]
Arbo 2000 {published data only}
  • Arbo MD, Snydman DR, Wong JB, Goldberg HS, Schmid CH, Pauker SG. Cytomegalovirus immune globulin after liver transplantation: a cost-effectiveness analysis. Clinical Transplantation 2000;14(1):19-27. [MEDLINE: 10693631]
    Direct Link:
Badley 1997 {published data only}
  • Badley AD, Seaberg EC, Porayko MK, Wiesner RH, Keating MR, Wilhelm MP, et al. Prophylaxis of cytomegalovirus infection in liver transplantation: A randomized trial comparing a combination of ganciclovir and acyclovir to acyclovir. Transplantation 1997;64(1):66-73. [MEDLINE: 9233703]
Balfour 1989 {published data only}
  • Balfour HH, Jr, Chace BA, Stapleton JT, Simmons RL, Fryd DS. A randomized, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. New England Journal of Medicine 1989;320(21):1381-7. [MEDLINE: 2541335]
  • Balfour Jr HH, Bean B, Mitchell CD. Acyclovir in immunocompromised patients with cytomegalovirus disease. A controlled trial at one institution. American Journal of Medicine 1982;73(1A):241-8. [MEDLINE: 6285715]
Barkholt 1999 {published data only}
  • Barkholt L, Lewensohn-Fuchs I, Ericzon BG, Tyden G, Andersson J. High-dose acyclovir prophylaxis reduces cytomegalovirus disease in liver transplant patients. Transplant Infectious Disease 1999;1(2):89-97. [MEDLINE: 11428976]
    Direct Link:
Cohen 1993 {published data only}
  • Cohen AT, O'Grady JG, Sutherland S, Sallie R, Tan K-C, Williams R. Controlled trial of prophylactic versus therapeutic use of ganciclovir after liver transplantation in adults. Journal of Medical Virology 1993;40(1):5-9. [MEDLINE: 8390559]
    Direct Link:
Conti 1995 {published data only}
Dickinson 1996 {published data only}
  • Dickinson BI, Gora-Harper ML, McCraney SA, Gosland M. Studies evaluating high-dose acyclovir, intravenous immune globulin, and cytomegalovirus hyperimmunoglobulin for prophylaxis against cytomegalovirus in kidney transplant recipients. Annals of Pharmacotherapy 1996;30(12):1452-64. [MEDLINE: 8968459]
Duncan 1994 {published data only}
  • Duncan SR, Grgurich WF, Iacono AT, Burckart GJ, Yousem SA, Paradis IL, et al. A comparison of ganciclovir and acyclovir to prevent cytomegalovirus after lung transplantation. American Journal of Respiratory & Critical Care Medicine 1994;150(1):146-52. [MEDLINE: 8025741]
Egan 2002 {published data only}
  • Egan JJ, Carroll KB, Yonan N, Woodcock A, Crisp A. Valacyclovir prevention of cytomegalovirus reactivation after heart transplantation: a randomized trial. Journal of Heart & Lung Transplantation 2002;21(4):460-6. [MEDLINE: 11927223]
Falagas 1997 {published data only}
  • Falagas ME, Snydman DR, Ruthazer R, Griffith J, Werner BG, Freeman R, et al. Cytomegalovirus immune globulin (CMVIG) prophylaxis is associated with increased survival after orthotopic liver transplantation. The Boston Center for Liver Transplantation CMVIG Study Group. Clinical Transplantation 1997;11(5 Pt 1):432-7. [MEDLINE: 9361936]
Fehir 1989 {published data only}
  • Fehir KM, Decker WA, Samo T, Young JB, Lederer E, Lawrence EC. Immune globulin (GAMMAGARD) prophylaxis of CMV infections in patients undergoing organ transplantation and allogeneic bone marrow transplantation. Transplantation Proceedings 1989;21(1 Pt 3):3107-9. [MEDLINE: 2539691]
Fishman 2000 {published data only}
  • Fishman JA, Doran MT, Volpicelli SA, Cosimi AB, Flood JG, Rubin RH. Dosing of intravenous ganciclovir for the prophylaxis and treatment of cytomegalovirus infection in solid organ transplant recipients. Transplantation 2000;69(3):389-94. [MEDLINE: 10706048]
Flechner 1998 {published data only}
  • Flechner SM, Avery RK, Fisher R, Mastroianni BA, Papajcik DA, O'Malley KJ, et al. A randomized prospective controlled trial of oral acyclovir versus oral, ganciclovir for cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Transplantation 1998;66(12):1682-8. [MEDLINE: 9884259]
Gane 1997 {published data only}
  • Gane E, Saliba F, Valdecasas GJ, O'Grady J, Pescovitz MD, Lyman S, et al. Randomised trial of efficacy and safety of oral ganciclovir in the prevention of cytomegalovirus disease in liver-transplant recipients. The Oral Ganciclovir International Transplantation Study Group. Lancet 1997;350(9093):1729-33. [MEDLINE: 9413463]
Gavalda 1997 {published data only}
  • Gavalda J, De Otero J, Murio E, Vargas V, Rossello J, Calico I, et al. Two grams daily of oral acyclovir reduces the incidence of cytomegalovirus disease in CMV-seropositive liver transplant recipients. Transplant International 1997;10(6):462-5. [MEDLINE: 9428121]
    Direct Link:
Gerna 2003 {published data only}
  • Gerna G, Baldanti F, Lilleri D, Parea M, Torsellini M, Castiglioni B, et al. Human cytomegalovirus pp67 mRNAemia versus pp65 antigenemia for guiding preemptive therapy in heart and lung transplant recipients: a prospective, randomized, controlled, open-label trial. Transplantation 2003;75(7):1012-9. [MEDLINE: 12698090]
Green 1997 {published data only}
  • Green M, Kaufmann M, Wilson J, Reyes J. Comparison of intravenous ganciclovir followed by oral acyclovir with intravenous ganciclovir alone for prevention of cytomegalovirus and Epstein- Barr virus disease after liver transplantation in children. Clinical Infectious Diseases 1997;25(6):1344-9. [MEDLINE: 9431375]
Hertz 1988 {published data only}
  • Hertz MI, Jordan C, Savik SK, Fox JMK, Park S, Bolman II RM, et al. Randomized trial of daily versus three-times-weekly prophylactic ganciclovir after lung and heart-lung transplantation. Journal of Heart & Lung Transplantation 1988;17(9):913-20. [MEDLINE: 9773865]
Hibberd 1995 {published data only}
  • Hibberd PL, Tolkoff-Rubin NE, Conti D, Stuart F, Thistlethwaite JR, Neylan JF, et al. Preemptive ganciclovir therapy to prevent cytomegalovirus disease, in cytomegalovirus antibody-positive renal transplant recipients. A randomized controlled trial. Annals of Internal Medicine 1995;123(1):18-26. [MEDLINE: 7762909]
Jurim 1996 {published data only}
  • Jurim O, Martin P, Winston DJ, Shackleton C, Holt C, Feller J, et al. Failure of ganciclovir prophylaxis to prevent allograft reinfection following orthotopic liver transplantation for chronic hepatitis B infection. Liver Transplantation & Surgery 1996;2(5):370-4. [MEDLINE: 9346678]
    Direct Link:
Kim 2000 {published data only}
King 1999 {published data only}
Kletzmayr 1996 {published data only}
  • Kletzmayr J, Kotzmann H, Popow-Kraupp T, Kovarik J, Klauser R. Impact of high-dose oral acyclovir prophylaxis on cytomegalovirus (CMV) disease in CMV high-risk renal transplant recipients. Journal of the American Society of Nephrology 1996;7(2):325-30. [MEDLINE: 8785404]
Kletzmayr 2000 {published data only}
  • Kletzmayr J, Kreuzwieser E, Watkins-Riedel T, Berlakovich G, Kovarik J, Klauser R. Long-term oral ganciclovir prophylaxis for prevention of cytomegalovirus infection and disease in cytomegalovirus high-risk renal transplant recipients. Transplantation 2000;70(8):1174-80. [MEDLINE: 11063336]
Leray 1995 {published data only}
  • Leray H, Mourad G, Chong G, Segondy M, Mion C. Prophylactic treatment of cytomegalovirus primary infection with ganciclovir in renal transplant recipients. Transplantation Proceedings 1995;27(4):2448. [MEDLINE: 7652875]
Lowance 1998 {published data only}
  • Lowance D, Neumayer HH, Legendre CM, Squifflet JP, Kovarik J, Brennan PJ, et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. New England Journal of Medicine 1998;340(19):1462-70. [MEDLINE: 10320384]
Lumbreras 1993 {published data only}
  • Lumbreras C, Otero JR, Herrero JA, Gomez R, Lizasoain M, Aguado JM, et al. Ganciclovir prophylaxis decreases frequency and severity of cytomegalovirus disease in seropositive liver transplant recipients treated with OKT3 monoclonal antibodies. Antimicrobial Agents & Chemotherapy 1993;37(11):2490-2. [MEDLINE: 8285641]
Macdonald 1995 {published data only}
  • Macdonald PS, Keogh AM, Marshman D, Richens D, Harvison A, Kaan AM, et al. A double-blind placebo-controlled trial of low-dose ganciclovir to prevent cytomegalovirus disease after heart transplantation. Journal of Heart & Lung Transplantation 1995;14(1):32-8. [MEDLINE: 7727473]
Marker 1980 {published data only}
Merigan 1992 {published data only}
  • Merigan TC, Renlund DG, Keay S, Bristow MR, Starnes V, O'Connell JB, et al. A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation. New England Journal of Medicine 1992;326(18):1182-6. [MEDLINE: 1313549]
Moreno 1999 {published data only}
  • Moreno J, Montero JL, Gavilan F, Costan G, Herrero C, Cardenas M, et al. Open clinical trial with oral acyclovir for the prophylaxis of disease by Cytomegalovirus in low risk liver transplant recipients. Enfermedades Infecciosas y Microbiologia Clinica 1999;17(8):382-5. [MEDLINE: 10563084]
Mullen 1998 {published data only}
  • Mullen GM, Silver MA, Malinowska K, Lawless CE, Lichtenberg RC, Barath PC, et al. Effective oral ganciclovir prophylaxis against cytomegalovirus disease in heart transplant recipients. Transplantation Proceedings 1998;30(8):4110-2. [MEDLINE: 9865316]
Nakazato 1993 {published data only}
  • Nakazato PZ, Burns W, Moore P, Garcia-Kennedy R, Cox K, Esquivel C. Viral prophylaxis in hepatic transplantation: Preliminary report of a randomized trial of acyclovir and gancyclovir. Transplantation Proceedings 1993;25(2):1935-7. [MEDLINE: 7682357]
Paya 2004 {published data only}
  • Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. American Journal of Transplantation 2004;4(4):611-20. [MEDLINE: 15023154]
    Direct Link:
Pouteil-Noble 1996 {published data only}
  • Pouteil-Noble C, Megas F, Chapuis F, Bosshard S, Colin C, Hadj-Aissa A, et al. Cytomegalovirus prophylaxis by ganciclovir followed by high-dose acyclovir in renal transplantation: A randomized, controlled trial. Transplantation Proceedings 1996;28(5):2811. [MEDLINE: 8908072]
Reischig 2002 {published data only}
  • Reischig T, Jindra P, Mares J, Opatrny K, Jr, Treska V, Cechura M, et al. Valacyclovir for cytomegalovirus prophylaxis reduces the risk of acute renal allograft rejection: a randomized comparison of oral ganciclovir and valacyclovir [abstract]. American Journal of Transplantation 2004;4(Suppl 8):493.
  • Reischig T, Opatrny K, Jr, Bouda M, Treska V, Jindra P, Svecova MT, et al. A randomized prospective controlled trial of oral ganciclovir versus oral valacyclovir for prophylaxis of cytomegalovirus disease after renal transplantation. Transplant International 2002;15(12):615-22. [MEDLINE: 12478408]
    Direct Link:
Rondeau 1993 {published data only}
  • Rondeau E, Bourgeon B, Peraldi MN, Lang P, Buisson C, Schulte KM, et al. Effect of prophylactic ganciclovir on cytomegalovirus infection in renal transplant recipients. Nephrology Dialysis Transplantation 1993;8(9):858-62. [MEDLINE: 8255520]
Rostaing 1994 {published data only}
  • Rostaing L, Crespin A, Icart J, Lloveras JJ, Durand D, Martinet O, et al. Cytomegalovirus (CMV) prophylaxis by acyclovir in pre-transplant CMV-positive renal transplant recipients. Transplant International 1994;7 Suppl 1:331-5. [MEDLINE: 11271244]
    Direct Link:
Rubin 2000 {published data only}
  • Rubin RH, Kemmerly SA, Conti D, Doran M, Murray BM, Neylan JF, et al. Prevention of primary cytomegalovirus disease in organ transplant recipients with oral ganciclovir or oral acyclovir prophylaxis. Transplant Infectious Disease 2000;2(3):112-7. [MEDLINE: 11429021]
    Direct Link:
Saliba 1993 {published data only}
  • Saliba F, Eyraud D, Samuel D, David MF, Arulnaden JL, Dussaix E, et al. Randomized controlled trial of acyclovir for the prevention of cytomegalovirus infection and disease in liver transplant recipients. Transplantation Proceedings 1993;25(1 Pt 2):1444-5. [MEDLINE: 8382876]
Schnitzler 2000 {published data only}
  • Schnitzler MA, Metheney TG, Rueda JF, Woodward RS, Lowell JA, Singer GG, et al. A 3-year follow-up of pre-emptive vs deferred treatment of cytomegalovirus disease in renal transplantation. Clinical Drug Investigation 2000;19(5):367-74. [EMBASE: 2000190076]
Singh 1995 {published data only}
Singh 2002a {published data only}
  • Singh N. Delayed occurrence of cytomegalovirus disease in organ transplant recipients receiving antiviral prophylaxis: are we winning the battle only to lose the war?[erratum appears in Eur J Clin Microbiol Infect Dis. 2002 Dec;21(12):902.]. European Journal of Clinical Microbiology & Infectious Diseases 2002;21(9):643-6. [MEDLINE: 12373496]
Speich 1999 {published data only}
  • Speich R, Thurnheer R, Gaspert A, Weder W, Boehler A. Efficacy and cost effectiveness of oral ganciclovir in the prevention of cytomegalovirus disease after lung transplantation. Transplantation 1999;67(2):315-20. [MEDLINE: 10075601]
Turgeon 1998 {published data only}
  • Turgeon N, Fishman JA, Basgoz N, Tolkoff-Rubin NE, Doran M, Cosimi AB, et al. Effect of oral acyclovir or ganciclovir therapy after preemptive intravenous ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus seropositive renal and liver transplant recipients receiving antilymphocyte antibody therapy. Transplantation 1998;66(12):1780-6. [MEDLINE: 9884276]
Valantine 1999 {published data only}
  • Valantine HA, Gao S-Z, Menon SG, Renlund DG, Hunt SA, Oyer P, et al. Impact of prophylactic immediate posttransplant ganciclovir on development of transplant atherosclerosis: A post hoc analysis of a randomized, placebo-controlled study. Circulation 1999;100(1):61-6. [MEDLINE: 10393682]
Winston 1995 {published data only}
Winston 2003 {published data only}
  • Winston DJ, Busuttil RW. Randomized controlled trial of oral ganciclovir versus oral acyclovir after induction with intravenous ganciclovir for long-term prophylaxis of cytomegalovirus disease in cytomegalovirus-seropositive liver transplant recipients. Transplantation 2003;75(2):229-33. [MEDLINE: 12548129]
Winston 2004 {published data only}
  • Winston DJ, Busuttil RW. Randomized controlled trial of sequential intravenous and oral ganciclovir versus prolonged intravenous ganciclovir for long-term prophylaxis of cytomegalovirus disease in high-risk cytomegalovirus-seronegative liver transplant recipients with cytomegalovirus-seropositive donors. Transplantation 2004;77(2):305-8. [MEDLINE: 14742998]
Yang 1999 {published data only}
  • Yang HC, Holman MJ, Langhoff E, Dellock CA, Gupta M, Ulsh PJ, et al. A comparative study of 500 mg BID and 250 mg BID of prophylactic oral ganciclovir in post-kidney transplant 'CMV at risk' recipients. Transplantation Proceedings 1999;31(1-2):1125-6. [MEDLINE: 10083502]

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
BTC 2004
  • British Transplantation Society. Guidelines for the prevention and management of cytomegalovirus disease after solid organ transplantation. 2nd Edition. London: British Transplantation Society, 2004.
CARI 2004
  • Pre-emptive treatment of cytomegalovirus. http://www.cari.org.au/Part_4_3_Pre_emptive_treatment_of_CMV_updated_070904.pdf (accessed June 2005).
Dickersin 1994
EBPG 2000
  • EBPG Expert Group on Renal Transplantation. The transplant recipient from initial transplant hospitalization to 1 year post transplant. Nephrology Dialysis Transplantation 2000;15(Suppl 7):52-85.
Emery 2001
  • Emery VC. Prophylaxis for CMV should not now replace pre-emptive therapy in solid organ transplantation. Reviews in Medical Virology 2001;11(2):83-6. [MEDLINE: 11262527]
    Direct Link:
Hart 2001
  • Hart GD, Paya CV. Prophylaxis for CMV should now replace pre-emptive therapy in solid organ transplantation. Reviews in Medical Virology 2001;11(2):73-81. [MEDLINE: 11262526]
    Direct Link:
Hibberd 1992
  • Hibberd PL, Tolkoff-Rubin NE, Cosimi AB, Schooley RT, Isaacson D, Doran M, et al. Symptomatic cytomegalovirus disease in cytomegalovirus antibody seropositive renal transplant recipient treated with OKT3. Transplantation 1992;53(1):68-72. [MEDLINE: 1310173]
Higgin 2003
Hodson 2005a
  • Hodson EM, Jones CA, Webster AC, Strippoli GF, Barclay BG, Kable K, et al. Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials. Lancet 2005;365(9477):2105-15. [MEDLINE: 15964447]
Hodson 2005b
  • Hodson EM, Barclay PG, Craig JC, Jones C, Kable K, Strippoli GFM, et al. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database of Systematic Reviews 2005, Issue 4. [DOI: ]
Humar 1999
  • Humar A, Gregson D, Caliendo AM, McGeer A, Malkan G, Krajden M, et al. Clinical utility of quantitative cytomegalovirus viral load determination for predicting cytomegalovirus disease in liver transplant recipients. Transplantation 1999;68(9):1305-11. [MEDLINE: 10573068]
IDSA 2005
  • Infectious Diseases Society of America. http://www.idsociety.org (accessed June 2005).
Lefebvre 1996
  • Lefebvre C, McDonald S. Development of a sensitive search strategy for reports of randomized controlled trials in EMBASE. Fourth International Cochrane Colloquium; 1996 Oct 20-24; Adelaide (Australia). 1996.
Limaye 2000
Schulz 1995
Waiser 1998
  • Waiser J, Budde K, Schreiber M, Korn K, Stenglein S, Drenckhahn JT, et al. Effectiveness of deferred therapy with ganciclovir in renal allograft recipients with cytomegalovirus disease. Transplantation Proceedings 1998;30(5):2083-5. [MEDLINE: 9723399]

References to other published versions of this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
Strippoli 2005
  • Strippoli GFM, Craig JC, Hodson EM, Jones C. Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients. Cochrane Database of Systematic Reviews 2005, Issue 1. [DOI: ]
Strippoli 2006
  • Strippoli GF, Hodson EM, Jones C, Craig JC. Preemptive treatment for cytomegalovirus viremia to prevent cytomegalovirus disease in solid organ transplant recipients. Transplantation 2006;81(2):139-45. [MEDLINE: 16436954]
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