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

  1. Daniel S Owers1,
  2. Angela C Webster2,3,4,
  3. Giovanni FM Strippoli2,4,5,6,7,
  4. Kathy Kable8,
  5. Elisabeth M Hodson2,9,*

Editorial Group: Cochrane Renal Group

Published Online: 28 FEB 2013

Assessed as up-to-date: 16 JAN 2013

DOI: 10.1002/14651858.CD005133.pub3


How to Cite

Owers DS, Webster AC, Strippoli GFM, Kable K, Hodson EM. Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD005133. DOI: 10.1002/14651858.CD005133.pub3.

Author Information

  1. 1

    Australian National University, Australian National University Medical School, Canberra, ACT, Australia

  2. 2

    The University of Sydney, Sydney School of Public Health, Sydney, NSW, Australia

  3. 3

    The University of Sydney at Westmead, Centre for Transplant and Renal Research, Westmead Millennium Institute, Westmead, NSW, Australia

  4. 4

    The Children's Hospital at Westmead, Cochrane Renal Group, Centre for Kidney Research, Westmead, NSW, Australia

  5. 5

    University of Bari, Department of Emergency and Organ Transplantation, Bari, Italy

  6. 6

    Mario Negri Sud Consortium, Department of Clinical Pharmacology and Epidemiology, Santa Maria Imbaro, Italy

  7. 7

    Diaverum, Medical-Scientific Office, Lund, Sweden

  8. 8

    Westmead Hospital, Department of Renal Medicine and Transplantation, Westmead, NSW, Australia

  9. 9

    The Children's Hospital at Westmead, Centre for Kidney Research, Westmead, NSW, Australia

*Elisabeth M Hodson, elisabeth.hodson@health.nsw.gov.au.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 28 FEB 2013

SEARCH

 

Summary of findings    [Explanations]

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

 
Summary of findings for the main comparison. Pre-emptive medication for cytomegalovirus (CMV) viraemia compared to placebo/no treatment to prevent CMV disease in solid organ transplant recipients

Pre-emptive medication for CMV viraemia versus placebo/no treatment to prevent CMV disease in solid organ transplant recipients

Patient or population: solid organ transplant recipients with CMV viraemia
Settings: tertiary hospitals
Intervention: pre-emptive medication for CMV viraemia to prevent CMV disease
Comparison: placebo/no treatment

OutcomesIllustrative comparative risks* (95% CI)Risk ratio
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Placebo/no treatmentPre-emptive medication for CMV viraemia

All symptomatic CMV diseaseStudy population0.29
(0.11 to 0.8)
288 (6)⊕⊕⊝⊝
low1,2

295 per 100085 per 1000
(32 to 236)

Moderate

359 per 1000104 per 1000
(39 to 287)

CMV organ involvementStudy population0.41
(0.06 to 2.63)
217 (5)⊕⊕⊝⊝
low1,2

107 per 100044 per 1000
(6 to 282)

Moderate

48 per 100020 per 1000
(3 to 126)

Acute rejectionStudy population1.21
(0.69 to 2.12)
185 (3)⊕⊕⊝⊝
low1,2

172 per 1000208 per 1000
(119 to 365)

Moderate

191 per 1000231 per 1000
(132 to 405)

All-cause mortalityStudy population1.23
(0.35 to 4.3)
176 (3)⊕⊕⊝⊝
low1,2

45 per 100055 per 1000
(16 to 193)

Moderate

26 per 100032 per 1000
(9 to 112)

Graft lossStudy population0.28
(0.01 to 5.35)
36 (1)⊕⊝⊝⊝
very low1,2

95 per 100027 per 1000
(1 to 510)

Moderate

95 per 100027 per 1000
(1 to 508)

LeucopeniaStudy population1.54
(0.16 to 15.36)
114 (2)⊕⊕⊝⊝
low1,2

17 per 100026 per 1000
(3 to 260)

Moderate

24 per 100037 per 1000
(4 to 369)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative risk of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate

 ¹No studies used blinding of participants, investigators and outcome assessors and most reported unclear allocation concealment
²Small patient numbers

 Summary of findings 2 Pre-emptive medication compared to prophylaxis for cytomegalovirus (CMV) viraemia to prevent CMV disease in solid organ transplant recipients

 

Background

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

Description of the condition

Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality in solid organ transplant recipients, with up to 75% of patients developing or reactivating infection after transplantation (Fishman 2007). The risk of developing CMV is well established. CMV infection and disease are seen most commonly in CMV negative recipients of CMV seropositive organs and in recipients treated with anti-lymphocyte therapy (EBPG 2000). Recipients who have a positive serostatus for CMV, regardless of donor status, are at intermediate risk of developing or re-developing CMV; donor negative organs and negative serostatus recipients are at the lowest risk of infection (Fishman 2007).

CMV can lead to direct or indirect effects of infection. Direct effects include CMV syndrome (encompassing fever, myelosuppression, myalgia and arthralgia), tissue invasive CMV disease leading to hepatitis, gastroenteritis, pneumonitis and potentially any other organ or body tissue, and finally, mortality (Eid 2010). CMV infection may also be associated with indirect effects including acute and chronic organ rejection, graft loss, opportunistic infections other than CMV, and new onset diabetes mellitus (Eid 2010; Kotton 2010).

 

Description of the intervention

Pre-emptive therapy involves the detection of active CMV replication through routine surveillance using an appropriately sensitive and specific test (such as real-time polymerase chain reaction (PCR) or pp65 antigenaemia assay) with established thresholds for CMV infection. Once the CMV infection threshold has been reached, treatment with antiviral medications (valganciclovir or ganciclovir) is initiated with the aim of preventing progression to symptomatic CMV disease (Humar 2009).

 

How the intervention might work

The intervention aims to direct treatment to patients who are most at risk of developing CMV disease, rather than administering universal prophylaxis that would include some patients who would never develop CMV disease. By targeting higher risk patients it should be possible to direct therapy to those in need, to reduce the risk of adverse effects associated with long-term antiviral therapy, and possibly, to lower the cost of therapy. Pre-emptive therapy may also reduce the numbers of patients who develop late onset CMV disease after prophylaxis is ceased (Eid 2010).

 

Why it is important to do this review

Pre-emptive treatment of recipients with CMV viraemia detected on surveillance has been advocated as an alternative to antiviral prophylaxis because only recipients who develop CMV infection, and are thus 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 and of late onset CMV disease, which has been reported as increasing in frequency in solid organ transplant recipients (Arthurs 2007; Arthurs 2008; Eid 2010; Kotton 2010). Late onset CMV disease is seen in about 10% of patients given 12 weeks of oral ganciclovir prophylaxis but is rare following pre-emptive regimens.

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 (Limaye 2000). This could result in the development of specific immune responses which are important in the prevention of future episodes of CMV disease.

Pre-emptive therapy appears particularly attractive in recipients at low risk of CMV disease such as CMV positive recipients of kidney transplants who are not receiving antibody immunosuppression because their risk of CMV disease is only about 7% (Waiser 1998). However, pre-emptive therapy relies on the timely availability of sensitive and reliable methods for detecting CMV viraemia so that treatment based on identifying CMV infection can be initiated before CMV disease develops. Furthermore, the cost of screening may be higher than prophylaxis even though the cost of antiviral medication is lower (Eid 2010). Pre-emptive therapy potentially exposes patients to periods of CMV infection and possibly indirect effects of CMV infection. Moreover, treatment method relies on the patient's compliance with regular screening and easy access to a transplant centre if treatment is required.

Prophylaxis is currently the predominant intervention used to prevent CMV disease. Routine antiviral prophylaxis is associated with an increased risk of adverse effects of medications, the development of CMV resistance and late onset CMV disease when prophylaxis is discontinued and is costly (Arthurs 2008; Emery 2001; Hart 2001). Prophylaxis for all organ transplant recipients (except CMV negative recipients of CMV negative donors) means that a proportion of patients will receive potentially harmful medications when they were not destined to develop CMV disease.

In view of the actual and potential advantages and disadvantages of pre-emptive therapy and of prophylaxis to prevent CMV disease, a systematic review was warranted to ascertain the efficacy of pre-emptive therapy and the relative benefits and harms of these therapies for preventing CMV disease in solid organ transplant recipients.

This Cochrane systematic review should be considered in conjunction with the Cochrane review Antiviral therapy for preventing CMV disease in solid organ transplants recipients (Hodson 2013) which looked at the benefits and harms of prophylaxis with antiviral medications to prevent CMV disease. Hodson 2013 includes 37 studies (4342 participants). Prophylaxis with ganciclovir, valaciclovir or aciclovir (19 studies, 1981 participants) significantly reduced the risk of CMV disease, CMV infection and all-cause mortality compared with placebo or no specific therapy. In direct comparison studies, ganciclovir was significantly more effective than aciclovir (7 studies, 1113 participants). Valganciclovir was as effective as ganciclovir (1 study, 364 participants) and extended duration valganciclovir significantly reduced the risk of CMV disease compared with three months (2 studies, 454 participants).

 

Objectives

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

The aim of this review was to evaluate the benefits and harms of pre-emptive treatment of CMV viraemia to prevent CMV disease, all-cause mortality and the 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. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Criteria for considering studies for this review

 

Types of studies

We included randomised controlled trials (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

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

 

Types of interventions

We included RCTs of pre-emptive treatment compared with placebo or standard care, pre-emptive treatment compared with 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.

 

Types of outcome measures

The effects of these interventions were tested on the following outcomes:

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

For the purpose of analysis, pre-emptive treatment was defined as routine testing for CMV viraemia using any test and commencing antiviral treatment if viraemia was detected. Prophylaxis was defined as the regular administration of an appropriate antiviral medication for a period of time immediately post transplantation.

Other definitions for the meta-analysis were comparable with those reported previously by Ljungman 2002. CMV infection was defined as isolation of CMV in any tissue or body fluid by an appropriately sensitive and specific test. CMV DNAemia was defined as detection of CMV DNA in whole blood, plasma, peripheral blood leukocytes or buffy coat specimens by an appropriately sensitive and specific technique such as real time polymerase chain reaction (RT-PCR). CMV disease was defined as CMV infection together with CMV syndrome (fever and bone marrow suppression) and/or tissue invasive CMV confirmed on histopathology.

 

Search methods for identification of studies

 

Original review (2005)

We searched the following resources without language restriction.

  • The Cochrane Renal Group's Specialised Register
  • The Cochrane Central Register of Controlled Trials (CENTRAL in The Cochrane Database of Systematic Reviews issue 2, 2005).
  • MEDLINE (1966 to February 2005).
  • EMBASE (1980 to February 2005).

The Trials Search Co-ordinator ensured that all relevant studies had been identified. Additional studies were located through article reference lists and from abstracts from international meetings.

 

Review update (2013)

For this update, we searched the Cochrane Renal Group's Specialised Register (to 16 January 2013) through contact with the Trials' Search Co-ordinator using search terms relevant to this review.

The Cochrane Renal Group’s Specialised Register contains studies identified from:

  1. Quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
  2. Weekly searches of MEDLINE OVID SP
  3. Handsearching of renal-related journals and the proceedings of major renal conferences
  4. Searching of the current year of EMBASE OVID SP
  5. Weekly current awareness alerts for selected renal journals
  6. Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the specialised register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available from the Specialised Register section of information about the Cochrane Renal Group.

See Appendix 1 for search terms used in strategies for this review.

 

Data collection and analysis

This systematic review was originally undertaken by four authors (GS, JC, EH, CJ) and was published in The Cochrane Database of Systematic Reviews in 2005 (Strippoli 2005). This update was undertaken by five authors (DO, AW, GS, KK, EH).

 

Selection of studies

Two authors independently screened titles and abstracts retrieved from the searches and identified those studies that met the inclusion criteria. This process favoured over-selection in order to include all relevant studies. The full article was retrieved if uncertainty existed or when the abstract was not available. Any disagreement with article selection was resolved through discussion and consultation.

 

Data extraction and management

Two authors independently extracted data from eligible studies using standardised data extraction forms. Studies reported in foreign language journals were translated before data extraction. Participant characteristics (number, age, sex, co-morbidities), interventions (type of treatment, dose, duration, co-interventions) and primary and secondary outcome measures were recorded. Authors were contacted to obtain missing information on allocation concealment. Any discrepancies in data extraction were resolved in discussion. Where results of a study were published more than once, the most complete data were extracted from all sources and used in the analysis only once.

 

Assessment of risk of bias in included studies

The following items were independently assessed by two authors using the risk of bias assessment tool (Higgins 2011; Appendix 2).

  • Was there adequate sequence generation (selection bias)?
  • Was allocation adequately concealed (selection bias)?
  • Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?
    • Participants and personnel
    • Outcome assessors
  • Were incomplete outcome data adequately addressed (attrition bias)?
  • Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
  • Was the study apparently free of other problems that could put it at a risk of bias?

 

Measures of treatment effect

Dichotomous outcomes were expressed as risk ratios (RR) with 95% confidence intervals (CI). Risk differences (RD) with 95% CI were calculated for adverse effects. Continuous outcomes were calculated as mean differences (MD) with 95% CI.

 

Unit of analysis issues

If available, data for the first period of cross-over studies were to be included in meta-analyses; otherwise, cross-over studies were reported in the text only.

 

Dealing with missing data

Study authors were contacted for information on sequence generation, allocation concealments and for missing data. Where missing data were few and not thought likely to influence results, the available data were analysed.

 

Assessment of heterogeneity

Heterogeneity was analysed using a Chi² test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.

 

Assessment of reporting biases

This updated review included all studies identified in the Cochrane Renal Group's Specialised Register, which is revised regularly with published and unpublished reports identified in congress proceedings. This reduces the risk of publication bias. All reports of a single study were reviewed to ensure that all outcomes were reported to reduce the risk of selection bias.

 

Data synthesis

Data were pooled using a random-effects model to calculate a summary estimate of effect.

 

Subgroup analysis and investigation of heterogeneity

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.

 

Sensitivity analysis

Where a study's results differed considerably from other studies in a meta-analysis, exclusion of the study was investigated to determine whether this altered the result of the meta-analysis.

 

Results

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

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies.

 

Results of the search

The literature search for the original review consisted of a combined search of MEDLINE, EMBASE, the Cochrane Central Registry of Controlled Trials (CENTRAL) and the Cochrane Renal Group's Specialised Register. There were 1930 articles identified. Of these, 1737 were excluded because they were not RCTs or were RCTs that evaluated ineligible interventions. Full-text assessment of 193 potentially eligible articles identified 10 studies (14 reports; 476 participants) (Brennan 1997a Kidney; Jung 2001 Kidney; Koetz 2001 Kidney; Paya 2002 Liver; Queiroga 2003 Kidney; Rayes 2001 Liver; Sagedal 2003 Kidney; Singh 2000 Liver; Singh 1994 Liver; Yang 1998 Kidney). Four study authors responded to queries about uncertainties on study methods (Brennan 1997a Kidney; Jung 2001 Kidney; Singh 2000 Liver; Singh 1994 Liver).

For this update, only the Cochrane Renal Group's Specialised Register was searched. This is updated continuously and contains all new kidney and related studies, reports and articles. The search identified 20 reports of nine studies. Of the nine studies, five were new studies of pre-emptive therapy versus prophylaxis (Gerna 2008 Liver; Khoury 2006 Kidney; Kliem 2008 Kidney; Reischig 2008 Kidney; Witzke 2012 Kidney). Two additional reports were identified in the search but had already been included in the original review (Singh 1998; Yang 1996). A further two studies (Qiu 2008 Kidney; Tian 2005 Kidney) were identified from a systematic review of RCTs conducted by Zhang 2011. Further assessment of these studies, including contact with the authors facilitated through the Chinese Cochrane Centre, indicated that participants were not randomised, hence these studies were excluded. One study author responded to queries about uncertainties on study methods (Khoury 2006 Kidney).

There are three ongoing studies that are potentially relevant to this review (NCT00372229; NCT00966836; NCT01552369). When concluded these studies will be assessed for inclusion in a future update of this review. Another study relevant to this review was also identified for inclusion (Scott 2011 Liver), however, more information has been requested from the authors before the study can be included in meta analysis.

The combined search results are presented in Figure 1.

 FigureFigure 1. Combined search results for the original and updated reviews. Reasons for exclusions are provided in text

 

Included studies

The combined updated study data included 1098 participants from 15 studies. Three intervention rationales were investigated by these studies.

One rationale involved randomising participants at transplant to receive viral surveillance and pre-emptive treatment on development of CMV viraemia versus prophylaxis with antiviral medications for 30 to 168 days (8 studies, 785 participants: Gerna 2008 Liver; Jung 2001 Kidney; Khoury 2006 Kidney; Kliem 2008 Kidney; Queiroga 2003 Kidney; Reischig 2008 Kidney; Singh 1994 Liver; Witzke 2012 Kidney). (This was the only rationale in previous iterations of this review to which new study data were added for this update).

A second rationale involved randomising participants to pre-emptive treatment or to placebo or no specific therapy (6 studies, 291 participants: Brennan 1997a Kidney; Koetz 2001 Kidney; Paya 2002 Liver; Rayes 2001 Liver; Sagedal 2003 Kidney; Yang 1998 Kidney). In five of these studies (Koetz 2001 Kidney; Paya 2002 Liver; Rayes 2001 Liver; Sagedal 2003 Kidney; Yang 1998 Kidney), all transplant recipients were screened for CMV viraemia. Study participants who developed viraemia were then randomised to receive pre-emptive treatment or placebo/standard care. In the study by Brennan 1997a Kidney, transplant recipients were randomised at transplant to receive pre-emptive treatment (screening and treatment of those with positive viraemia) or standard care (treatment of symptomatic CMV infection when it developed). Screening occurred at the time of transplantation and at weekly intervals thereafter.

The third rational type was applied in a study by Singh 2000 Liver. It investigated 22 patients who developed CMV viraemia, and were randomised to receive oral or intravenous ganciclovir as pre-emptive treatment.

All studies investigated ganciclovir or valganciclovir. Six studies compared ganciclovir with placebo or delayed treatment (Brennan 1997a Kidney; Koetz 2001 Kidney; Paya 2002 Liver; Rayes 2001 Liver; Sagedal 2003 Kidney; Yang 1998 Kidney); five compared pre-emptive ganciclovir with prophylactic ganciclovir (Gerna 2008 Liver; Jung 2001 Kidney; Kliem 2008 Kidney; Queiroga 2003 Kidney; Singh 2000 Liver); two compared pre-emptive valganciclovir with prophylactic valganciclovir (Khoury 2006 Kidney; Witzke 2012 Kidney); one study compared pre-emptive valganciclovir with prophylactic valaciclovir (Reischig 2008 Kidney); and one compared pre-emptive ganciclovir with prophylactic aciclovir (Singh 1994 Liver).

Follow-up duration of all studies ranged from three to 18 months.

 

Excluded studies

Overall, we excluded 1976 studies. The 2005 review excluded 1916 reports, 33 reports were assessed and excluded in 2010, and 27 reports in this update. Most exclusions were made following assessment of title and abstract appraisal. The most common reasons for exclusion were for non-randomisation of participants or were for RCTs that investigated interventions outside the inclusion criteria for this review.

 

Risk of bias in included studies

Assessing risk of bias was problematic because many details were difficult to ascertain or not provided (see Characteristics of included studies). Study authors were contacted for clarification of study outcomes where reporting was inadequate (see Figure 2; Figure 3).

 FigureFigure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
 FigureFigure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study

 

Allocation

Allocation concealment was considered to be at low risk of bias in four studies (Khoury 2006 Kidney; Kliem 2008 Kidney; Paya 2002 Liver; Witzke 2012 Kidney); while the remaining studies did not report methods used to conceal the randomisation process.

Risk of bias in random sequence generation bias was considered low in five studies (Khoury 2006 Kidney; Kliem 2008 Kidney; Paya 2002 Liver; Reischig 2008 Kidney; Singh 1994 Liver). While the majority of other papers reported randomisation of patients, the method used to generate a random sequence was not reported. The risk of bias in random sequence generation was high in one study (Brennan 1997a Kidney) (last digit of medical number).

 

Blinding

Blinding of participants and personnel was reported in Koetz 2001 Kidney and Paya 2002 Liver. However, only Paya 2002 Liver provided detailed information to indicate that the study was at low risk of performance bias. Neither study reported blinding or provided information on whether outcome assessors were blinded to intervention groups. Of the 15 included studies, five (Gerna 2008 Liver; Kliem 2008 Kidney; Reischig 2008 Kidney; Sagedal 2003 Kidney; Witzke 2012 Kidney) were reported to be open-label. These, and the remaining eight studies, were assessed as being at high risk of bias for performance and detection bias because interpretation of the clinical outcome of CMV disease by clinical features could be affected by lack of blinding of participants, investigators and outcome assessors.

 

Incomplete outcome data

Brennan 1997a Kidney had missing outcome data due to losses to follow-up. However, this was considered unlikely to influence the results of this study. Bias due to incomplete outcome data was considered low for all other studies.

 

Selective reporting

Bias through selective reporting was considered a low risk in eight studies (Brennan 1997a Kidney; Jung 2001 Kidney; Khoury 2006 Kidney; Kliem 2008 Kidney; Rayes 2001 Liver; Reischig 2008 Kidney; Sagedal 2003 Kidney; Witzke 2012 Kidney). In the remaining seven, selective reporting bias was considered high as they did not report outcomes of importance for this review. In the study of Gerna 2008 Liver graft loss, adverse effects and opportunistic infections were not reported. In the studies by Koetz 2001 Kidney and Yang 1998 Kidney all-cause mortality, graft loss and acute rejection were not reported. In Paya 2002 Liver, all-cause mortality and graft loss were not reported. Acute rejection was not reported in either Queiroga 2003 Kidney or Singh 1994 Liver, and Singh 2000 Liver did not report graft loss or acute rejection.

 

Other potential sources of bias

Five studies reported pharmaceutical sponsorship (Khoury 2006 Kidney; Kliem 2008 Kidney; Paya 2002 Liver; Sagedal 2003 Kidney; Witzke 2012 Kidney) and were judged as high risk of bias. Several other studies reported sponsorship from educational and government organisations (Brennan 1997a Kidney; Gerna 2008 Liver; Reischig 2008 Kidney; Yang 1998 Kidney). These studies were considered to be at low risk of bias. The remaining studies did not state any form of sponsorship and their risk of bias was unclear (Jung 2001 Kidney; Koetz 2001 Kidney; Queiroga 2003 Kidney; Rayes 2001 Liver; Singh 1994 Liver; Singh 2000 Liver).

 

Effects of interventions

See:  Summary of findings for the main comparison Pre-emptive medication for cytomegalovirus (CMV) viraemia compared to placebo/no treatment to prevent CMV disease in solid organ transplant recipients;  Summary of findings 2 Pre-emptive medication compared to prophylaxis for cytomegalovirus (CMV) viraemia to prevent CMV disease in solid organ transplant recipients

 

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

There were 1393 patients screened for entry to the six studies 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 study entry in 116, other reasons in 322) so that 358 patients were eligible for study entry. However, 64 patients (17.8%) developed CMV disease within the 0 to 10 day time gap between testing for viraemia and randomisation, and thus were excluded. The proportion of patients in each study who developed CMV disease before CMV viraemia was detected varied from 0% to 32%. In addition, six (1.7%) other 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 studies, 288 participants): RR 0.29, 95% CI 0.11 to 0.80). The heterogeneity (I² = 54%, P = 0.06) was explained by the study undertaken by Brennan 1997a Kidney, which was the only study in which transplant recipients were randomised to screen (and treat) for CMV viraemia versus no screening, rather than randomising participants with CMV viraemia to treatment or not. Removing this study resulted in homogenous results (I² = 0%, P = 0.54). There was no significant difference for the outcome of CMV disease in studies that used oral ganciclovir compared with studies that used intravenous ganciclovir preparations (P = 0.93 for interaction).

For the outcomes of CMV organ involvement ( Analysis 1.2 (5 studies, 217 participants): RR 0.41, 95% CI 0.06 to 2.63) or CMV associated symptoms ( Analysis 1.3 (5 studies, 217 participants): RR 0.28, 95% CI 0.06 to 1.21), the summary estimates favoured treatment, but the CIs were wide. There was also no significant difference in the risks of acute rejection ( Analysis 1.4 (3 studies, 185 participants): RR 1.21, 95% CI 0.69 to 2.12), all-cause mortality ( Analysis 1.5.1 (3 studies, 176 participants): RR 1.23, 95% CI 0.35 to 4.30), graft loss ( Analysis 1.5.2 (1 study, 36 participants): 0.28, 95% CI 0.01 to 5.35), leucopenia ( Analysis 1.7.1 (2 studies, 114 participants): RR 1.54, 95% CI 0.16 to 15.36), or kidney dysfunction ( Analysis 1.7.2 (1 study, 36 participants): RR 0.93, 95% CI 0.18 to 4.92). There was no significant variation in treatment effect for any these outcomes when studies that used oral and intravenous ganciclovir regimens were considered separately.

 

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

Symptomatic CMV disease occurred at rates between 0% and 28.7% in the pre-emptive group and 0% and 29.2% in the prophylaxis group. The risk of developing CMV disease was not significantly different among groups ( Analysis 2.1 (7 studies, 753 participants): RR 1.02; 95% CI 0.43 to 2.44).

There was considerable heterogeneity among the seven studies (I² = 67%). Of these, two favoured pre-emptive therapy and two favoured prophylaxis. Removal of studies by Khoury 2006 Kidney and Singh 1994 Liver from the analysis, which both favoured pre-emptive therapy, decreased heterogeneity considerably (I² = 26%) and a clinically significant result favouring prophylaxis was observed (5 studies, 608 participants: RR 2.19, 95% CI 1.3 to 4.23). Investigation of the Singh 1994 Liver study indicated that an inferior agent (aciclovir) was used in the prophylaxis arm compared with a superior agent (ganciclovir) in the pre-emptive arm (Hodson 2013) which may have exerted a favourable influence on pre-emptive treatment. Investigation of the Khoury 2006 Kidney study did not yield any substantial differences to account for the reduction in heterogeneity.

It was found that alternately excluding the two studies (Kliem 2008 Kidney; Witzke 2012 Kidney) that favoured prophylaxis, the relative risk supported pre-emptive therapy, although the result was not significant (5 studies, 319 participants: RR 0.42; 95% CI 0.16 to 1.11).

CMV infection was significantly more common in the pre-emptive group compared with the prophylaxis group ( Analysis 2.2 (7 studies, 727 participants): RR 2.06, 95% CI 1.44 to 2.96). However, there was considerable heterogeneity (1² = 71%).

There was no significant difference observed between the pre-emptive and prophylaxis groups for all-cause mortality ( Analysis 2.3.1 (7 studies, 753 participants): RR 1.19, 95% CI 0.56 to 2.51), graft loss ( Analysis 2.3.2 (7 studies, 753 participants): RR 1.07, 95% CI 0.41 to 2.82), and acute rejection ( Analysis 2.4 (6 studies, 693 participants): RR 1.23, 95% CI 0.75 to 2.03). No heterogeneity existed among the studies for all-cause mortality. Some degree of heterogeneity existed in the graft loss analysis (I² = 41%) and acute rejection (I² = 44%) analyses. Heterogeneity was considerably diminished (I² = 14%) in the graft loss analysis when Jung 2001 Kidney was excluded. The only differences observed between Jung 2001 Kidney and all other studies were a later start for prophylaxis and a higher dose of oral ganciclovir (3000 mg/d compared with 1500 mg to 2000 mg/d).

Heterogeneity was abolished entirely in the acute rejection analysis when the study by Witzke 2012 Kidney was excluded from the analysis. The only difference that existed between the Witzke 2012 Kidney study and others was the non-inclusion of high risk transplant recipients (D+/R-).

No significant difference was identified between pre-emptive therapy and prophylaxis for infections other than CMV including bacterial ( Analysis 2.5.1 (2 studies, 168 participants): RR 0.89, 95% CI 0.55 to 1.43), viral ( Analysis 2.5.2 (1 study, 70 participants): RR 1.57, 95% CI 0.92 to 2.70), and fungal infections ( Analysis 2.5.3 (1 study, 70 participants): RR 1.89, 95% CI 0.18 to 19.89).

Leucopenia was significantly less common in patients who underwent pre-emptive therapy compared with prophylaxis ( Analysis 2.6.1 (6 studies, 729 participants): RR 0.42, 95% CI 0.20 to 0.90). Some heterogeneity existed among the studies (I² = 45%) which was considerably diminished when the Kliem 2008 Kidney study was excluded from the analysis (I² = 15%). No identifiable differences in the Kliem 2008 Kidney study were observed in comparison with others in this subgroup analysis. No significant difference was observed for neurological dysfunction between the therapies ( Analysis 2.6.2 (3 studies, 187 participants): RR 0.58, 95% CI 0.17 to 1.96).

In general, other adverse effects were poorly reported in eight pre-emptive therapy versus prophylaxis studies; one study (Reischig 2008 Kidney) provided most of the data ( Analysis 2.6).

Serostatus stratification of CMV disease was reported in two studies (Khoury 2006 Kidney; Reischig 2008 Kidney). No significant differences in symptomatic CMV disease or CMV infection were observed between pre-emptive treatment and prophylaxis for high risk transplant recipients (D+/R-) ( Analysis 2.7). For lower risk transplant recipients (D+ or D-/R+), there was no significant difference in symptomatic CMV disease ( Analysis 2.8.1) but CMV infection was significantly less common in recipients receiving prophylaxis ( Analysis 2.8.2 (2 studies, 129 participants): RR 2.07, 95% CI 1.25 to 3.42).

 

Oral versus intravenous ganciclovir for pre-emptive treatment of CMV viraemia

We found that 22/72 (31%) liver transplant recipients undergoing surveillance developed CMV viraemia and entered a study comparing oral and intravenous ganciclovir for pre-emptive treatment (Singh 2000 Liver). 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 regimens.

 

Other outcomes

No data were available on the outcomes of death due to CMV disease. The time to development of CMV disease outcome was reported in four studies (Gerna 2008 Liver; Khoury 2006 Kidney; Kliem 2008 Kidney; Reischig 2008 Kidney). Moreover, the different methods of measurement used to report these outcomes (median, mean and frequencies) prevented meta-analysis.

Subgroup analyses according to organ transplanted, 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 studies and enrolled patients.

 

Discussion

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

Summary of main results

This review identified eight studies that compared pre-emptive with prophylactic therapy (784 patients) and six studies that compared pre-emptive therapy versus placebo or standard care (288 patients) where the primary outcome was CMV disease. Tests and thresholds used to detect CMV viraemia were different across the studies, but results were generally consistent. Confidence intervals were wide across most outcomes, indicating considerable imprecision ( Summary of findings for the main comparison;  Summary of findings 2). Fewer patients were evaluated for other outcomes, and CIs around observed treatment effects were so wide that other benefits (or harms) of pre-emptive therapy could not be excluded.

Pre-emptive treatment using standard detection methods for CMV viraemia was 71% more effective than placebo or standard care in reducing the risk of CMV disease (RR 0.29, 95% CI 0.11 to 0.80). CMV organ involvement was 59% lower in the pre-emptive therapy regime compared with the placebo/standard care regime. However, the quality of evidence was low due to small patient numbers and lack of blinding across all studies. No significant differences in the risks of all-cause mortality, acute rejection, graft loss, other infections, leucopenia, or kidney dysfunction were demonstrated between pre-emptive therapy and placebo or standard care ( Summary of findings for the main comparison).

There was no significant difference in preventing CMV disease using pre-emptive versus prophylactic therapy. However, there was significant heterogeneity among studies so that superiority of one or other treatment could not be excluded. The major benefit observed for pre-emptive therapy was a 58% reduction in leucopenia compared with prophylaxis, while other adverse effects did not differ significantly, or were not reported. There were no significant differences in the risks of all-cause mortality, graft loss, acute rejection and infections other than CMV. There was also no significant difference observed between pre-emptive therapy and prophylaxis with regards to CMV disease in high risk solid organ transplant patients (D+/R-) ( Summary of findings 2).

Only one study of oral versus IV pre-emptive regimens was included in this review; it showed no significant difference in the risk of CMV disease between the groups.

It should be emphasised that oral ganciclovir, which was the basis for three of the included analyses, is no longer available and has been replaced by valganciclovir.

 

Overall completeness and applicability of evidence

Overall, the evidence from the 15 studies included in this review prevented confident conclusions to be made on the efficacy of pre-emptive therapy in preventing CMV disease, graft loss, acute rejection and all-cause mortality in comparison with placebo/no specific treatment or with prophylaxis. This was primarily due to a lack of adequately powered studies and low precision of the measured outcomes. There was also a lack of studies that compared pre-emptive therapy across a broad range of different transplanted organs; the highest representation was for kidney transplant recipients among the 15 studies included in this review.

Many studies did not address important outcomes, including adverse effects of medications. In contrast, the evidence base for routine prophylaxis compared with placebo/no specific therapy is substantial, arising from 19 studies of 1981 participants (Hodson 2005; Hodson 2013) which enabled more precise results to be derived.

Prophylaxis has been shown to reduce CMV disease by about 60% (RR = 0.42), with tight CIs (0.34 to 0.52), strong evidence of statistically significant benefit (P < 0.0001), and considerable homogeneity of results across all studies (I² = 13%, where only one of the point estimates of the 19 studies did not favour prophylaxis (Hodson 2005; Hodson 2013).

Antiviral prophylaxis has been shown to reduce CMV-related mortality, all-cause mortality, and clinically important disease caused by opportunistic infections.

Although both prophylaxis (Hodson 2013) and pre-emptive therapy significantly reduce CMV disease compared with placebo or no specific therapy in solid organ transplant recipients, this review has demonstrated that the available data evaluating pre-emptive therapy (6 studies; 288 participants) was of low quality (GRADE) compared with the high quality data (GRADE) evaluating antiviral prophylaxis (19 studies; 1981 participants).

There appeared to be little evidence that the use of medications now considered to be less effective than valganciclovir or ganciclovir (Humar 2009; Pescovitz 2007) influenced the results in studies comparing pre-emptive therapy with prophylaxis. Two studies (117 participants) of eight studies used aciclovir (Singh 1994 Liver) or valaciclovir (Reischig 2008 Kidney) in the prophylaxis arm of the studies. This would potentially favour pre-emptive therapy and could have contributed to the results of the Singh 1994 Liver study. All studies comparing pre-emptive therapy with placebo or no specific therapy used ganciclovir, which has been superseded by valganciclovir for prophylaxis or pre-emptive therapy. RCT data have shown no significant difference in efficacy for prophylaxis of CMV disease between ganciclovir and valganciclovir (Hodson 2005) so it can be presumed that valganciclovir would be more effective than placebo in prophylaxis or pre-emptive therapy studies, although this has not been formally tested in RCTs.

There was also substantial difference among studies with regard to CMV surveillance testing. The type of test used (pp65 antigenaemia assay or PCR DNA), the assays used, the frequency of surveillance (weekly to monthly), the cut-off values (DNA PCR > 400 to > 2000 copies/mL) to define CMV infection and the blood component used for testing were factors contributing to these differences. This large variability among studies further reduced confidence of drawing definite conclusions about the applicability of pre-emptive therapy for several reasons. Longer time intervals between surveillance tests potentially increases the chances of CMV infection not being detected so that the patient develops CMV disease before he or she can be entered in a study. This means that the proportion of preventable CMV disease patients in the pre-emptive arm may have erroneously increased. Lower cut-off values used for diagnosing CMV infection with more frequent testing could result in earlier detection of CMV infection and enable earlier initiation of therapy to prevent CMV disease and reduce the effects of indirect CMV infection. Alternatively, higher cut-off values with longer periods between tests could result in delayed therapy and potentially increase the number of preventable CMV disease cases. Finally, PCR testing needs consideration as to what component of blood is being tested; whole blood will often yield higher rates of CMV DNA compared to plasma (Humar 2009).

 

Quality of the evidence

This systematic review identified 15 studies of 1094 participants; of these, 784 participants were evaluated in studies that compared pre-emptive therapy with prophylaxis; and 288 were evaluated in studies that compared pre-emptive therapy with placebo/no specific treatment. The 15 studies failed to report all relevant outcomes, were frequently at high risk of bias, demonstrated imprecision and heterogeneity among studies which lowered the integrity of the meta-analysed results.

The poorly reported methods of randomisation and allocation concealment have prevented an accurate assessment of the risk of selection bias: only three studies adequately performed both. The lack of allocation concealment in these studies introduced the potential to overestimate outcome benefits (Hewitt 2005). The blinding of outcome assessors and personnel was poorly performed in most studies; only one reported blinding of participants and investigators. The blinding of outcome assessors was not conducted in any study because all study authors were judged to also be outcome assessors. Therefore, most included studies were at high risk of both performance and detection bias. The risk of attrition bias was considered to be low in all studies. Half of the studies did not include outcomes that were assessed to be important by the review authors.

Pre-emptive therapy compared with placebo/no specific therapy significantly reduced CMV disease (RR 0.29, 95% CI 0.11 to 0.80). However, CIs were wide (0.11 to 0.80), statistical significance was moderate (P = 0.02), and there was evidence of significant heterogeneity among studies (I² = 54%): two studies favoured pre-emptive therapy and two large studies favoured prophylaxis. Similarly, no significant difference was identified in the risk for CMV disease between pre-emptive therapy and prophylaxis (RR 1.02, 95% CI 0.43 to 2.44); CIs were wide, indicating considerable imprecision, and there was significant heterogeneity (I² = 63%).

Data for outcomes other than CMV disease were more limited. Particularly, we found that there was failure to report outcomes relating to adverse effects. We also found that low participant numbers and few events increased imprecision.

Only two studies stratified CMV disease and infection by the high risk serostatus D+/R- (Khoury 2006 Kidney; Reischig 2008 Kidney). Only 49 patients were available from these two studies which prevented comprehensive analysis. Such subset analysis required a larger sample size to enable accurate assessment of this high risk group.

Overall, the quality of the evidence was considered to be low or very low because of small numbers of enrolled participants, few events, significant heterogeneity, lack of blinding, and inadequate allocation concealment ( Summary of findings for the main comparison;  Summary of findings 2).

 

Potential biases in the review process

The search criteria, analysis, and data extraction were performed to a high standard (see Methods). Four reviewers independently performed the analysis and data extraction; any conflict was resolved by an independent party. This further decreased the risk of bias for the review. The search strategy for the review was thorough. The Cochrane Renal Group's Specialised Register includes complete listings of current studies and is regularly updated to include new studies and additional reports of existing studies from journals and conference reports.

It is possible that some studies may have been missed where the study report has only been published in abstract form in conference proceedings, which have not yet been handsearched.

Overall, this review and review search represent an up-to-date assessment of current pre-emptive therapy studies.

 

Agreements and disagreements with other studies or reviews

Zhang 2011 conducted a systematic review comparing pre-emptive therapy and prophylaxis in solid organ transplants, and consistent with our review findings, also found no significant difference in the risk of CMV disease, graft loss, acute rejection and mortality between pre-emptive therapy and prophylaxis. However, our review identified a 58% reduced risk of leucopenia in the pre-emptive therapy rationale which was not identified by Zhang 2011. The studies included in this review for pre-emptive treatment versus prophylaxis were mostly the same as those analysed by Zhang 2011; the exceptions were two Chinese studies included by Zhang 2011 that were excluded from our review on the basis that they were not RCTs (Qiu 2008 Kidney; Tian 2005 Kidney). Zhang 2011 did not include either the Gerna 2008 Liver transplant study in children or the liver transplant study by Singh 1994 Liver which were included in this review. This would account for numerical variations between these reviews, although much of the statistical outcomes remain the same.

A recent commentary on CMV in solid organ transplant recipients also suggested the need for more studies comparing pre-emptive therapy with prophylaxis to identify if pre-emptive therapy may increase the risk of the indirect effects of CMV infection (Humar 2009). This is in agreement with our findings where several studies did not report on outcomes relating to indirect effects of CMV infection. Our findings are consistent with recent guidelines from the British Transplantation Society (BTS 2011), Kidney Disease Improving Global Outcomes (KDIGO 2009) and Caring for Australians with Renal Impairment (CARI 2010). A summary of these guidelines are presented in  Table 1.

 

Authors' conclusions

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

 

Implications for practice

This systematic review identified no significant differences in efficacy between pre-emptive therapy and prophylaxis for preventing CMV disease, graft loss, and death in solid organ transplant recipients. However, study data remain sparse. The ability to ascertain true benefits and harms remains problematic when compared with prophylaxis due to heterogeneity between study results together with low sample sizes and event rates leading to imprecision.

Pre-emptive therapy has shown benefits over placebo and standard care. This review has identified an increased risk of CMV infection with pre-emptive therapy, which may have deleterious impacts on the indirect effects of CMV infection including graft loss, acute rejection, and infections other than CMV compared with prophylaxis. While no significant differences in meta-analyses could be demonstrated for these outcomes, heterogeneity around the results indicate that differences cannot be excluded. Furthermore, four year follow-up data reported by Reischig 2008 Kidney suggest that graft loss may be higher in patients treated with prophylaxis compared with pre-emptive therapy. Four year follow-up data for the much larger Witzke 2012 Kidney study are awaited.

This review highlights the need to standardise testing frequency and cut off levels for positive tests used in the surveillance testing for CMV infection which could reduce variability between institutions and in studies. A standardised method should test patients frequently (especially within the first six months post-transplant) and should have a low threshold for detection. The results should be immediately available to enable therapy to be commenced as soon as possible after the surveillance threshold is exceeded.

 
Implications for research

In view of the heterogeneity of results in currently available studies, further well designed and adequately powered studies are required to compare three or more months of prophylactic therapy using an anti-CMV viral medication with pre-emptive therapy for patients who develop viraemia. Such studies should be powered to enable assessment of direct and indirect effects of CMV infection, adverse effects of medications and resource utilisation have sufficient follow-up to assess graft loss and mortality, and include standardised thresholds and frequency of testing for CMV viraemia.

 

Acknowledgements

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

The original review was co-published in Transplantation (Strippoli 2006b).

We are indebted to Narelle Willis, Managing Editor of the Cochrane Renal Group, Linda Heslop, Gail Higgins 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 review.

The authors would like to thank the referees for their editorial advice during the preparation of this review.

We also gratefully acknowledge the contributions of authors of previous version of this review: Cheryl Jones and Jonathan Craig,

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. 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 Kidney 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 disease7753Risk Ratio (M-H, Random, 95% CI)1.02 [0.43, 2.44]

 2 CMV infection7727Risk Ratio (M-H, Random, 95% CI)2.06 [1.44, 2.96]

 3 All-cause mortality and graft loss7Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 All-cause mortality
7753Risk Ratio (M-H, Random, 95% CI)1.19 [0.56, 2.51]

    3.2 Graft loss
7753Risk Ratio (M-H, Random, 95% CI)1.07 [0.41, 2.82]

 4 Acute rejection6693Risk Ratio (M-H, Random, 95% CI)1.23 [0.75, 2.03]

 5 Other infections2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 Bacterial
2168Risk Ratio (M-H, Random, 95% CI)0.89 [0.55, 1.43]

    5.2 Viral
170Risk Ratio (M-H, Random, 95% CI)1.57 [0.92, 2.70]

    5.3 Fungal
170Risk Ratio (M-H, Random, 95% CI)1.89 [0.18, 19.89]

 6 Adverse effects6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 Leucopenia
6729Risk Ratio (M-H, Random, 95% CI)0.42 [0.20, 0.90]

    6.2 Neurological dysfunction
3187Risk Ratio (M-H, Random, 95% CI)0.58 [0.17, 1.96]

    6.3 Kidney dysfunction
147Risk Ratio (M-H, Random, 95% CI)0.35 [0.01, 8.11]

    6.4 Anaemia
2218Risk Ratio (M-H, Random, 95% CI)0.91 [0.48, 1.73]

    6.5 Thrombocytopenia
2218Risk Ratio (M-H, Random, 95% CI)1.16 [0.54, 2.48]

    6.6 Malignancy
170Risk Ratio (M-H, Random, 95% CI)0.32 [0.01, 7.48]

    6.7 Hypertension
170Risk Ratio (M-H, Random, 95% CI)1.07 [0.91, 1.27]

    6.8 Hypercholesterolaemia
170Risk Ratio (M-H, Random, 95% CI)0.80 [0.58, 1.10]

    6.9 Cardiac events
170Risk Ratio (M-H, Random, 95% CI)0.67 [0.24, 1.92]

    6.10 Neutropenia
3514Risk Ratio (M-H, Random, 95% CI)0.51 [0.27, 0.95]

 7 D+/R- serostatus2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    7.1 Symptomatic CMV
239Risk Ratio (M-H, Random, 95% CI)0.99 [0.12, 8.02]

    7.2 CMV infection
239Risk Ratio (M-H, Random, 95% CI)1.16 [0.71, 1.92]

 8 D+ or D-/R+ serostatus2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    8.1 Symptomatic CMV
2129Risk Ratio (M-H, Random, 95% CI)0.20 [0.02, 1.74]

    8.2 CMV infection
2129Risk Ratio (M-H, Random, 95% CI)2.07 [1.25, 3.42]

 
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

 

Appendices

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

Appendix 1. Electronic search strategies


DatabaseSearch terms

CENTRAL
  1. MeSH descriptor Cytomegalovirus, this term only in MeSH products
  2. MeSH descriptor Cytomegalovirus Infections explode all trees in MeSH products
  3. MeSH descriptor Cytomegalovirus Vaccines explode all trees
  4. cytomegalovirus* in All Fields in CENTRAL
  5. cmv* in All Fields in CENTRAL
  6. (#1 OR #2 OR #3 OR #4 OR #5)
  7. (organ or renal or kidney or heart or lung or liver or pancreas) adj transplant in All Fields in all products
  8. MeSH descriptor Organ Transplantation, this term only
  9. MeSH descriptor Heart Transplantation explode all trees
  10. MeSH descriptor Lung Transplantation explode all trees
  11. MeSH descriptor Kidney Transplantation, this term only
  12. MeSH descriptor Liver Transplantation, this term only
  13. MeSH descriptor Pancreas Transplantation, this term only
  14. (#7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13)
  15. (#6 AND #14)

MEDLINE (OVID SP)
  1. Cytomegalovirus/
  2. exp Cytomegalovirus Infections/
  3. Cytomegalovirus Vaccines/
  4. cytomegalovirus.tw.
  5. cmv.tw.
  6. or/1-5
  7. Organ Transplantation/
  8. exp Heart Transplantation/
  9. exp Lung Transplantation/
  10. Kidney Transplantation/
  11. Liver Transplantation/
  12. Pancreas Transplantation
  13. ((organ or renal or kidney or heart or lung or liver or pancreas) adj transplant$).tw
  14. or/6-12
  15. and/6,15

EMBASE (OVID SP)
  1. exp CYTOMEGALOVIRUS/
  2. Cytomegalovirus Infection/
  3. Cytomegalovirus Antibody/
  4. Cytomegalovirus Vaccine/
  5. cytomegalovirus.tw.
  6. CMV.tw.
  7. or/1-6
  8. exp organ transplantation/
  9. ((organ or renal or kidney or heart or lung or liver or pancreas) adj transplant$).tw.
  10. or/8-9
  11. 7 and 10



 

Appendix 2. Risk of bias assessment tool


Potential source of biasAssessment criteria

Random sequence generation

Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence
Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).

High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.

Unclear: Insufficient information about the sequence generation process to permit judgement.

Allocation concealment

Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment
Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web-based, and pharmacy-controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).

High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.

Unclear: Randomisation stated but no information on method used is available.

Blinding of participants and personnel

Performance bias due to knowledge of the allocated interventions by participants and personnel during the study
Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.

High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.

Unclear: Insufficient information to permit judgement

Blinding of outcome assessment

Detection bias due to knowledge of the allocated interventions by outcome assessors.
Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.

High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.

Unclear: Insufficient information to permit judgement

Incomplete outcome data

Attrition bias due to amount, nature or handling of incomplete outcome data.
Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.

High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.

Unclear: Insufficient information to permit judgement

Selective reporting

Reporting bias due to selective outcome reporting
Low risk of bias: The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).

High risk of bias: Not all of the study’s pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.

Unclear: Insufficient information to permit judgement

Other bias

Bias due to problems not covered elsewhere in the table
Low risk of bias: The study appears to be free of other sources of bias.

High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data-dependent process (including a formal-stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.

Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.



 

What's new

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

Last assessed as up-to-date: 16 January 2013.


DateEventDescription

16 January 2013New search has been performedFive studies identified and included

16 January 2013New citation required and conclusions have changedNew outcome data available



 

History

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

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


DateEventDescription

19 January 2010AmendedContact details updated.

13 August 2009AmendedContact details updated.

14 October 2008AmendedConverted to new review format.



 

Contributions of authors

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

2013 review update

  • DO, AW, GS, KK and EH contributed to the data extraction, quality assessment, data analysis and rewriting of the review update.

 

2005 review

  • EMH identified and extracted data from included studies, contacted authors, analysed and interpreted the results and wrote the manuscript.
  • CAJ conceived, designed and developed the protocol and search strategy for the review, identified and extracted data from included studies and participated in revision of the manuscript.
  • GFMS checked the analysis and interpretation of the results and participated in the revision of the manuscript.
  • KK identified and extracted data from included studies and participated in revision of the manuscript.
  • JCC conceived, designed and developed the protocol, analysed and interpreted the results and edited the drafting and revision of the manuscript.

 

Declarations of interest

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

None known.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. 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. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
Brennan 1997a 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 American 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]
  • Brennan DC, Garlock KA, Lippmann BJ, Buller RS, Gaudreault-Keener M, Lowell JA, et al. The prevalence of human herpesvirus-7 in renal transplant recipients is unaffected by oral or intravenous ganciclovir. Journal of Infectious Diseases 2000;18(5):1557-61. [MEDLINE: 10823753]
Gerna 2008 Liver {published data only}
  • Gerna G, Lilleri D, Callegaro A, Goglio A, Cortese S, Stroppa P, et al. Prophylaxis followed by preemptive therapy versus preemptive therapy for prevention of human cytomegalovirus disease in pediatric patients undergoing liver transplantation. Transplantation 2008;86(1):163-6. [MEDLINE: 18622294]
Jung 2001 Kidney {published and unpublished data}
  • 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]
  • Offermann G, Jung C. Preemptive oral ganciclovir therapy versus prophylaxis to prevent symptomatic cytomegalovirus infection after kidney transplantation [abstract no: 1094]. A Transplant Odyssey; 2001 Aug 20-23; Istanbul, Turkey. 2001.
Khoury 2006 Kidney {published data only}
  • Brennan DC, Hardinger KL, Bohl DL, Lockwood M, Torrence S, Schuessler R, et al. Preemptive vs prophylactic valganciclovir for CMV in renal transplantation: early results from a randomized, prospective trial. [abstract]. Journal of the American Society of Nephrology 2004;15(Oct):23A.
  • Khoury JA, Storch GA, Bohl DL, Schuessler RM, Torrence SM, Lockwood M, et al. Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients. American Journal of Transplantation 2006;6(9):2134-43. [MEDLINE: 16780548]
  • Spinner ML, Saab G, Casabar E, Bowman LJ, Storch GA, Brennan DC. Impact of prophylactic versus preemptive valganciclovir on long-term renal allograft outcomes. Transplantation 2010;90(4):412-8. [MEDLINE: 20555305]
Kliem 2008 Kidney {published data only}
  • Kliem V, Fricke L, Wollbrink T, Burg M, Radermacher J, Rohde F. Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: results of a randomized clinical trial. American Journal of Transplantation 2008;8(5):975-83. [MEDLINE: 18261177]
  • Radermacher J, Fricke L, Burg M, Mischak H, Rohde F, Kliem V. Influence of prophylactic compared with early ganciclovir treatment on graft survival in renal allograft recipients. [abstract]. Journal of the American Society of Nephrology 2006;17(Abstracts):111A.
Koetz 2001 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 2002 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. Journal of Infectious Diseases 2002;185(7):854-60. [MEDLINE: 11920308]
Queiroga 2003 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.
Rayes 2001 Liver {published data only}
  • Rayes N, Seehofer D, Oettle H, Schmidt CA, Neuhaus R, Steinmuller T, et al. Prospective randomised trial to assess the value of preemptive oral therapy for CMV-infection after OLT. [abstract]. XVIII International Congress of the Transplantation Society; 2000 Aug 27-Sep 1; Rome, Italy. 2000.
  • 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]
Reischig 2008 Kidney {published data only}
  • Reischig T, Hribova P, Jindra P, Hes O, Bouda M, Treska V, et al. Improved long-term renal allograft survival in preemptive valganciclovir therapy compared to valacyclovir prophylaxis for cytomegalovirus: results of randomized controlled trial [abstract no: O-145]. Transplant International 2011;24(Suppl 2).
  • Reischig T, Hribova P, Jindra P, Hes O, Bouda M, Treska V, et al. Long-term outcomes of pre-emptive valganciclovir compared with valacyclovir prophylaxis for the prevention of cytomegalovirus in renal transplantation. Journal of the American Society of Nephrology 2012;23(9):1588-97. [MEDLINE: 22917575]
  • Reischig T, Jindra P, Hes O, Svecova M, Klaboch J, Treska V. Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation. American Journal of Transplantation 2008;8(1):69-77. [MEDLINE: 17973956]
  • Reischig T, Jindra P, Klaboch J, Svecova M, Hes O, Treska V. Valacyclovir prophylaxis for cytomegalovirus is associated with reduced risk of acute renal allograft rejection compared to preemptive valganciclovir therapy. [abstract]. Transplant International 2007;20(Suppl 2):185.
  • Reischig T, Kielberger L, Jindra P. The economic impact of different regimens to prevent cytomegalovirus disease in renal transplant recipients. [abstract]. Transplant International 2009;22(Suppl 2):279.
  • Reischig T, Nemcova J, Vanecek T, Jindra P, Hes O, Bouda M, et al. Cytomegalovirus DNA in renal allograft biopsy specimens in transplant recipients managed by preemptive valganciclovir therapy or valacyclovir prophylaxis [abstract no: SA708]. World Congress of Nephrology; 2009 May 22-26; Milan, Italy. 2009.
  • Reischig T, Nemcova J, Vanecek T, Jindra P, Hes O, Bouda M, et al. Intragraft cytomegalovirus infection: a randomized trial of valacyclovir prophylaxis versus pre-emptive therapy in renal transplant recipients. Antiviral Therapy 2010;15(1):23-30. [MEDLINE: 20167988]
  • Reischig T, Nemcova J, Vanecek T, Jindra P, Hes O, Bouda M, et al. Preemptive valganciclovir therapy is not associated with increase in cytomegalovirus (CMV) DNA in renal allograft biopsy specimens compared with valacyclovir prophylaxis. [abstract]. Transplantation 2008;86(2S):131.
  • Reischig T, Nmcov J, Vanek T, Jindra P, Hes O, Bouda M, et al. Cytomegalovirus infection in the graft: Results of a randomised study comparing valacyclovir prophylaxis and preemptive treatment after renal transplantation [abstract]. Kidney & Blood Pressure Research 2010;33(4):324. [EMBASE: 70448142]
  • Reischig T, Nmcov J, Vanek T, Jindra P, Hes O, Bouda M, et al. Cytomegalovirus infection in the graft: Results of a randomised study comparing valacyclovir prophylaxis and preemptive treatment after renal transplantation [abstract]. Kidney & Blood Pressure Research 2010;33(4):324. [EMBASE: 70448142]
Sagedal 2003 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 1994 Liver {published data only}
  • Singh 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]
Singh 2000 Liver {published data only}
  • Singh 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 N, Yu VL, Gayowski T, Marino IR. CMV antigenemia directed preemptive prophylaxis with oral ganciclovir for the prevention of CMV disease in liver transplant recipients: a prospective, randomised, controlled trial. [abstract]. Transplantation 1998;65(12):S113.
Witzke 2012 Kidney {published data only}
  • Witzke O, Hauser IA, Bartels M, Wolf G, Wolters H, Nitschke M, et al. Valganciclovir prophylaxis versus preemptive therapy in cytomegalovirus-positive renal allograft recipients: 1-year results of a randomized clinical trial. Transplantation 2012;93(1):61-8. [MEDLINE: 22094954]
  • Witzke O, Nitschke M, Bartels M, Ott U, Hauser IA. CMV valganciclovir prophylaxis versus preemptive therapy after renal transplantation: one year results of a randomized clinical trial. [abstract]. Transplantation 2010;90(Suppl 2):186.
Yang 1998 Kidney {published data only}
  • Yang CW, An HJ, Kim YO, Shin YS, Chang YS, Bang BK. Indication of ganciclovir treatment during early cytomegalovirus (cmv) viremia in CMV seropositive recipients. a longitudinal study of CMV pp65 antigenemia (Ag) assay. [abstract]. Journal of the American Society of Nephrology 1996;7(9):1928.
  • 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. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
Ahsan 1997 Kidney {published data only}
  • Ahsan N, Holman MJ, Dhilon S, Ream L, Yang HC. Oral ganciclovir (CytoveneR) effectively prevents cytomegalovirus (CMV) infection in renal transplant patients [abstract]. Journal of the American Society of Nephrology 1996;7(9):1929.
  • 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 N, Holman MJ, Yang HC. Oral ganciclovir is effective in preventing CMV infection in renal transplant recipients. [abstract]. Nephrology 1997;3(Suppl 1):S70.
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}
Badley 1997 Liver {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]
  • Paya CV, Marin E, Keating M, Dickson R, Porayko M, Wiesner R. Solid organ transplantation: results and implications of acyclovir use in liver transplants. Journal of Medical Virology 1993;Suppl 1:123-7. [MEDLINE: 8245877]
Balfour 1989 Kidney {published data only}
  • Balfour HH. Prevention of cytomegalovirus disease in renal allograft recipients. Scandinavian Journal of Infectious Diseases - Supplement 1991;80:88-93. [MEDLINE: 1725064]
  • Balfour HH, 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 HH, Fletcher CV, Dunn D. Prevention of cytomegalovirus disease with oral acyclovir. Transplantation Proceedings 1991;23(2 Suppl 1):17-9. [MEDLINE: 1647558]
  • 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]
  • Fletcher CV, Englund JA, Edelman CK, Gross CR, Dunn DL, Balfour HH. Pharmacologic basis for high-dose oral acyclovir prophylaxis of cytomegalovirus disease in renal allograft recipients. Antimicrobial Agents & Chemotherapy 1991;35(5):938-43. [MEDLINE: 1649575]
Barkholt 1999 Liver {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]
Brennan 1997b Kidney {published data only}
  • Brennan DC, Garlock KA, Singer GG, Schnitzler MA, Lippmann BJ, Buller RS, et al. Prophylactic oral ganciclovir compared with deferred therapy for control of cytomegalovirus in renal transplant recipients. Transplantation 1997;64(12):1843-6. [MEDLINE: 9422429]
  • Brennan DC, Garlock KA, Singer GG, Schnizler MA, Lippmann BJ, Buller RS, et al. Prophylactic oral ganciclovir prevents cytomegalovirus infection and disease in renal transplant recipients. [abstract]. 16th Annual Meeting. American Society of Transplant Physicians (ASTP); 1997 May 10-14; Chicago (IL). 1997:87.
  • Brennan DC, Singer GG, Garlock KA, Schnitzler MA, Storch GA. Prophylactic oral ganciclovir prevents cytomegalovirus disease in renal transplant recipients. [abstract]. Nephrology 1997;3(Suppl 1):S197.
  • Brennan DC, Storch GA, Singer GG, Lee L, Rueda J, Schnitzler MA. The prevalence of human herpesvirus-7 in renal transplant recipients is unaffected by oral or intravenous ganciclovir. Journal of Infectious Diseases 2000;181(5):1557-61. [MEDLINE: 10823753]
  • Singer GG, Storch GA, Burton KG, Lippmann BJ, Buller RS, Gaudreault-Keener M, et al. Prophylactic oral ganciclovir prevents cytomegalovirus disease in high-risk renal transplant recipients. [abstract]. Journal of the American Society of Nephrology 1996;7(9):1941.
Cohen 1993 Liver {published data only}
Conti 1995 Kidney {published data only}
  • Conti DJ, Freed BM, Singh TP, Gallichio M, Gruber SA, Lempert N, et al. Preemptive ganciclovir therapy in cytomegalovirus-seropositive renal transplants recipients. Archives of Surgery 1995;130(11):1217-22. [MEDLINE: 7487465]
Denny 2002 {published data only}
  • Denny RR, Asolati M, Dunn DL, Sutherland D, Gillingham KJ, Matas AJ. Potent immunosuppression, CMV prophylaxis, and CMV risk. [abstract]. Transplant 2002 - American Transplant Congress; 2002 Apr 26- May 1; Washington DC. 2002.
Devolder 2010 {published data only}
  • Devolder I. The influence of intensive education and coaching on compliance for oral ganciclovir in the prophylaxis of CMCV: an open randomised trial. http://clinicaltrials.gov/ct2/show/NCT00566072 (accessed 10 January 2013).
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 1993 Lung {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 Heart {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]
Euro-SPK 2005 {published data only}
  • Kuypers D, Malaise J, Saudek F, Steurer W, Arbogast H, EUROSPK Study Group. CMV infections in primary simultaneous pancreas-kidney (SPK) transplantation: results at 1 year of a large multicenter trial. [abstract]. American Journal of Transplantation 2003;3(Suppl 5):293.
  • Langrehr J, Malaise J, Tyden G. CMV infections in primary simultaneous pancreas-kidney (SPK) transplantation: results at 1 year of a large multicenter trial. [abstract]. XIXth International Congress of the Transplantation Society; 2002 Aug 25-30; Miami (FL). 2002.
  • Malaise J, Kuypers D, Arbogast H, EUROSPK Study Group. CMV infections in primary simultaneous pancreas-kidney (SPK) transplantation: results at 1 year of a large multicenter trial. [abstract]. Nephrology Dialysis Transplantation 2003;18(Suppl 4):803-4.
  • Malaise J, Ricart MJ, Moreno A, Crespo M, Fernandez-Cruz L, Van OD, et al. Cytomegalovirus infection in simultaneous pancreas-kidney transplantation. Transplantation Proceedings 2005;37(6):2848-50. [MEDLINE: 16182830]
  • Ricart MJ, Malaise J, Moreno A, Crespo M, Fernandez-Cruz L, Euro-SPK Study Group. Cytomegalovirus: occurrence, severity, and effect on graft survival in simultaneous pancreas-kidney transplantation. Nephrology Dialysis Transplantation 2005;20(Suppl 2):ii25-32. [MEDLINE: 15814546]
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]
  • Falagas ME, Snydman DR, Werner B, Griffith J, Ruthazer R, Rohrer R, et al. Cytomegalovirus immune globulin (CMVIG) prophylaxis is associated with increased survival after orthotopic liver transplantation. [abstract]. 16th Annual Meeting. American Society of Transplant Physicians (ASTP); 1997 May 10-14; Chicago (IL). 1997:148.
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]
Ferreira 2004 {published data only}
  • Ferreira A, Felipe CR, Motegi SA, Hosaka BA, Tamura MK, Kamura LA, et al. Relationship between immunosuppression and subsequent development of CMV disease. [abstract]. 3rd International Congress on Immunosuppression; 2004 Dec 8-11; San Diego, (CA). 2004.
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 Kidney {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]
  • Flechner SM, O'Malley K, Fisher R, Mastroianni B, Papajcik D, Avery R, et al. A randomized prospective trial of oral acyclovir vs oral ganciclovir for CMV prophylaxis in high risk kidney transplant recipients. [abstract]. Transplantation 1998;65(12):S187.
Gane 1997 Liver {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]
  • Saliba F, Bismuth H, Gane E, Valdecasas G, O'Grady J, Behrend M, et al. A randomized double blind versus placebo multicenter study of efficacy and tolerance of oral ganciclovir in the prevention of cytomegalovirus disease in hepatic transplanted patients. Gastroenterologie Clinique et Biologique 1997;21(2 bis):A157.
Gavalda 1997 Liver {published data only}
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]
Gerna 2007 {published data only}
  • Gerna G, Baldanti F, Torsellini M, Minoli L, Vigano M, Oggionnis T, et al. Evaluation of cytomegalovirus DNAaemia versus pp65-antigenaemia cutoff for guiding preemptive therapy in transplant recipients: a randomized study. Antiviral Therapy 2007;12(1):63-72. [MEDLINE: 17503749]
Green 1997 Liver {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]
  • Green M, Reyes J, Nour B, Beatty D, Kaufman M, Wilson J, et al. Randomized trial of ganciclovir followed by high-dose oral acyclovir vs ganciclovir alone in the prevention of cytomegalovirus disease in pediatric liver transplant recipients: preliminary analysis. Transplantation Proceedings 1994;26(1):173-4.
Greger 1988 {published data only}
  • Greger B, Schareck WD, Busing M, Mellert J, Muller GH, Hopt UT, et al. Are the risks of viral infections increased in kidney transplant patients receiving triple-drug therapy?. Transplantation Proceedings 1988;20(1 Suppl 1):466-8. [EMBASE: 1988111944]
Griffiths 2010 {unpublished data only}
  • Griffiths PD. Determining a viral load threshold for treating cytomegalovirus (CMV). http://clinicaltrials.gov/ct2/show/NCT00947141 (accessed 10 January 2013).
Hecht 1988 {published data only}
  • Hecht DW, Snydman DR, Crumpacker CS, Werner BG, Heinze-Lacey B. Ganciclovir for treatment of renal transplant-associated primary cytomegalovirus pneumonia. Journal of Infectious Diseases 1988;157(1):187-90. [MEDLINE: 2826608]
Hertz 1998 Heart/Lung {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 Kidney {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]
IMPACT Study 2010 TX {published data only}
  • Blumberg E, Hauser I, Gahlemann CG, Berenson KL, Jardine A, Humar A. Cost-effectiveness model to evaluate 200-day vs 100-day valganciclovir (Valcyte®) prophylaxis to reduce CMV disease incidence post-transplant. [abstract]. American Journal of Transplantation 2010;10(Suppl 4):126.
  • Chou S, Marousek G, Boivin G, Goyette N, Farhan M, Ives JA, et al. Recombinant phenotyping of cytomegalovirus sequence variants detected after 200 or 100 days of valganciclovir prophylaxis. Transplantation 2010;90(12):1409-13. [MEDLINE: 21030903]
  • Elston R, Bovin G, Goyette N, Voulgari A, Ives J, Farhan M. The IMPACT Study: genotypic analysis of cytomegalovirus UL54 and UL97 genes derived from patients receiving 100 or 200 days of valganciclovir (Valcyte®) prophylaxis. [abstract]. American Journal of Transplantation 2010;10(Suppl 4):208.
  • Humar A, IMPACT ISC, Peeters P, Abramowicz D, Humar A, Lebranchu Y, et al. Response to questions regarding the design and results of the IMPACT trial. American Journal of Transplantation 2011;11(1):177-8. [MEDLINE: 21199360]
  • Humar A, Lebranchu Y, Vincenti F, Blumberg E, Punch J, Limaye A, et al. Long term results of the IMPACT study: 200 vs 100 days of valganciclovir prophylaxis in kidney transplant recipients. [abstract]. American Journal of Transplantation 2010;10(Suppl 4):143.
  • Humar A, Lebranchu Y, Vincenti F, Blumberg EA, Punch JD, Limaye AP, et al. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. American Journal of Transplantation 2010;10(5):1228-37. [MEDLINE: 20353469]
  • Humar A, Lebranchu Y, Vincenti F, Punch J, Abramowicz D, Blumberg E, et al. The Impact Study: Valganciclovir prophylaxis for until 200 days post-transplant in high risk kidney recipients substantially reduces the incidence of CMV disease. [abstract]. American Journal of Transplantation 2009;9(Suppl 2):248.
  • Humar A, Limaye AP, Blumberg EA, Hauser IA, Vincenti F, Jardine AG, et al. Extended valganciclovir prophylaxis in D+/R- kidney transplant recipients is associated with long-term reduction in cytomegalovirus disease: two-year results of the IMPACT study. Transplantation 2010;90(12):1427-31. [MEDLINE: 21197713]
  • Humar A, Peeters P, Abramowicz D, Humar A, Lebranchu Y, IMPACT Investigators Study Group. Response to questions regarding the design and results of the IMPACT trial. American Journal of Transplantation 2011;11(2):177-8. [MEDLINE: 21199360]
  • Kalil AC, Sun J, Florescu DF. IMPACT trial results should not change current standard of care of 100 days for cytomegalovirus prophylaxis. American Journal of Transplantation 2011;11(1):18-21. [MEDLINE: 21199346]
  • Kalil AC, Sun J, Florescu DF. IMPACT trial results should not change current standard of care of 100 days for cytomegalovirus prophylaxis. American Journal of Transplantation 2011;11(1):18-21. [MEDLINE: 21199346]
  • Welker H, Farhan M, Humar A, Washington C. Ganciclovir pharmacokinetic parameters do not change when extending valganciclovir cytomegalovirus prophylaxis from 100 to 200 days. Transplantation 2010;90(12):1414-9. [MEDLINE: 21076372]
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]
Kim 2000 {published data only}
King 1999 {published data only}
Kletzmayr 1996 Kidney {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 J, Kotzmann H, Popow-Kraupp T, Kovarik J, Klauser R. Oral acyclovir in prevention of CMV disease in high-risk renal transplant recipients. [abstract]. ISN XIII International Congress of Nephrology; 1995 Jul 2-6; Madrid, Spain. 1995:375.
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 Kidney {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 1999 Kidney {published data only}
  • Legendre CM, Norman DJ, Keating MR, Maclaine GD, Grant DM. Valaciclovir prophylaxis of cytomegalovirus infection and disease in renal transplantation: an economic evaluation. Transplantation 2000;70(10):1463-8. [MEDLINE: 11118091]
  • Lowance D, Legendre C, Neumayer H, Norman D, Coggon G, Lee I, et al. Valaciclovir reduces the incidence of cytomegalovirus disease and acute graft rejection in CMV-seronegative recipients of a seropositive cadaveric renal allograft. [abstract]. Transplantation 1998;65(12):S18.
  • 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]
  • Squifflet J, Mendez R. Valaciclovir reduces the incidence of cytomegalovirus disease in CMV-seropositive renal allograft recipients. [abstract]. 16th Annual Meeting. American Society of Transplant Physicians (ASTP); 1997 May 10-14; Chicago (IL). 1997:87.
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 1991 {published data only}
  • MacDonald AS, Belitsky P, Cohen A, Lee S. Cytomegalovirus disease prophylaxis in seronegative recipients of kidneys from seropositive donors by combination of cytomegalovirus-hyperimmune globulin and low-dose acyclovir. Transplantation Proceedings 1991;23(1 Pt 2):1355-6. [MEDLINE: 1846463]
Macdonald 1995 Heart {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}
Mattes 2004 {published data only}
  • Mattes FM, Hainsworth EG, Geretti AM, Nebbia G, Prentice G, Potter M, et al. A randomized, controlled trial comparing ganciclovir to ganciclovir plus foscarnet (each at half dose) for preemptive therapy of cytomegalovirus infection in transplant recipients. Journal of Infectious Diseases 2004;189(8):1355-61. [MEDLINE: 15073671]
Merigan 1992 Heart {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]
Murray 1997 {published data only}
  • Murray BM, Blas S. Cost comparison of two approaches to the management of CMV infection in renal transplant recipients. [abstract]. Journal of the American Society of Nephrology 1997;8(Program & Abstracts):695A.
Nakazato 1993 Liver {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 ganciclovir. Transplantation Proceedings 1993;25(2):1935-7. [MEDLINE: 7682357]
Palmer 2010 {published data only}
  • Finlen Copeland CA, Davis WA, Snyder LD, Banks M, Avery R, Palmer SM. Reduced lifetime incidence of cytomegalovirus with extended prophylaxis: Long-term follow up from a randomized controlled trial. [abstract]. Journal of Heart and Lung Transplantation 2011;30(4 Suppl 1):S42. [EMBASE: 70383484]
  • Palmer SM, Limaye AP, Banks M, Gallup D, Chapman J, Lawrence EC, et al. Extended valganciclovir prophylaxis to prevent cytomegalovirus after lung transplantation: a randomized, controlled trial. Annals of Internal Medicine 2010;152(12):761-9. [MEDLINE: 20547904]
Paya 2004 All {published data only}
  • Boivin G, Goyette N, Gilbert C, Roberts N, Macey K, Paya C, et al. Absence of cytomegalovirus-resistance mutations after valganciclovir prophylaxis, in a prospective multicenter study of solid-organ transplant recipients. Journal of Infectious Diseases 2004;189(9):1615-8. [MEDLINE: 15116297]
  • Freeman RB, Macey K, Paya C, Pescovitz MD, Humar A, Dominquez E, et al. Risk factors for cytomegalovirus (CMV) disease: results from a multicenter randomized trial of valganciclovir (VGC). [abstract]. American Journal of Transplantation 2003;3(Suppl 5):391.
  • Humar A, Mazzulli T, Moussa G, Razonable RR, Paya CV, Pescovitz MD, et al. Clinical utility of cytomegalovirus (CMV) serology testing in high-risk CMV D+/R- transplant recipients. American Journal of Transplantation 2005;5(5):1065-70. [MEDLINE: 15816887]
  • 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]
  • Pescovitz M, Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, et al. Valganciclovir for prevention of CMV disease: 12 month follow up of a randomized trial of 364 D+/R- transplant recipients. [abstract]. American Journal of Transplantation 2003;3(Suppl 5):299. [CENTRAL: CN-00465838]
  • Wiltshire H, Hirankarn S, Farrell C, Paya C, Pescovitz MD, Humar A, et al. Pharmacokinetic profile of ganciclovir after its oral administration and from its prodrug, valganciclovir, in solid organ transplant recipients. Clinical Pharmacokinetics 2005;44(5):495-507. [MEDLINE: 15871635]
  • Wiltshire H, Paya CV, Pescovitz MD, Humar A, Dominguez E, Washburn K, et al. Pharmacodynamics of oral ganciclovir and valganciclovir in solid organ transplant recipients. Transplantation 2005;79(11):1477-83. [MEDLINE: 15940035]
Pescovitz 2009 {published data only}
Pouteil 1991 {published data only}
  • Pouteil-Noble C, Betuel H, Raffaele P, Megri K, Louvier C, Lefrancois N, et al. Influence of HLA compatibility on cytomegalovirus infection in kidney transplantation. Presse Medicale 1991;20(40):2022-4. [MEDLINE: 1662376]
Pouteil-Noble 1996 Kidney {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]
  • Pouteil-Noble C, Megas F, Chapuis F, Colul C, Bosshard S, Hadj-Aissa A, et al. Is CMV prophylaxis by ganciclovir-high dose acyclovir worthwhile in renal transplantation? A randomized, controlled, clinical and economical trial. [abstract]. ISN XIII International Congress of Nephrology; 1995 Jul 2-6; Madrid, Spain. 1995:343.
Qiu 2008 Kidney {published data only}
  • Qiu J, Chen L-Z, Li J, et al. Prospective study of preemptive prophylaxis strategy combined with recipient’ risk-factors to prevent CMV disease after kidney transplantation. China Journal of Organ Transplantation 2008;29(5):294-7.
Reischig 2005 Kidney {published data only}
  • Reischig T, Bouda M, Opatrny K Jr, Treska V, Jindra P, Svecova M. Oral ganciclovir versus valacyclovir for prophylaxis of cytomegalovirus disease in renal transplant recipients. [abstract]. XIXth International Congress of the Transplantation Society; 2002 Aug 25-30; Miami (FL). 2002.
  • Reischig T, Jindra P, Mares J, Cechura M, Svecova M, Hes O, et al. Valacyclovir for cytomegalovirus prophylaxis reduces the risk of acute renal allograft rejection. Transplantation 2005;79(3):317-24. [MEDLINE: 15699762]
  • Reischig T, Jindra P, Mares J, Cechura M, Svecova M, Opatrny K Jr, et al. Valacyclovir for cytomegalovirus prophylaxis reduces the risk of acute renal allograft rejection: a randomized comparison with oral ganciclovir and deferred therapy. [abstract]. Transplantation 2004;78(2 Suppl):483.
  • 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, Jindra P, Svecova M, Kormunda S, Opatrny K, Treska V. The impact of cytomegalovirus disease and asymptomatic infection on acute renal allograft rejection. Journal of Clinical Virology 2006 Jun;36(2):146-51. [MEDLINE: 16531113]
  • Reischig T, Jindra P, Svecova M, Opatrny K, Treska V. The impact of cytomegalovirus disease and asymptomatic infection on acute renal allograft infection. [abstract]. American Journal of Transplantation 2005;5(Suppl 11):382.
  • Reischig T, Kielberger L, Jindra P. The economic impact of different regimens to prevent cytomegalovirus disease in renal transplant recipients. [abstract]. Transplant International 2009;22(Suppl 2):279.
  • Reischig T, Opatrny JK, Treska V, Mares J, Jindra P, Svecova M. Prospective comparison of valacyclovir and oral ganciclovir for prevention of cytomegalovirus disease in high-risk renal transplant recipients. Kidney & Blood Pressure Research 2005;28(4):218-25. [MEDLINE: 16043964]
  • 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]
Rondeau 1993 Kidney {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]
  • Rondeau E, Bourgeon B, Peraldi MN, Lang P, Buisson C, Schulte KM, et al. Prophylaxis of CMV disease by ganciclovir (DHPG) in seronegative recipients of renal allograft from seropositive donors. Transplant International 1992;5(Suppl 1):S30-1. [MEDLINE: 14621725]
  • Rondeau E, Bourgeon B, Peraldi MN, Lang P, Buisson C, Schulte KM, et al. Prophylaxis of cytomegalovirus infections with ganciclovir in kidney transplant recipients. Presse Medicale 1992;21(41):1979-80. [MEDLINE: 1338225]
Rostaing 1994 Kidney {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]
Rubin 2002 All {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]
Saliba 1993 Liver {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 2002 {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?. 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]
Tian 2005 Kidney {published data only}
  • Tian X-H, XueW-J, Ding X-M, et al. Preemptive therapy for prevention and treatment of cytomegalovirus disease after renal transplantation. Journal of the Fourth Military Medical University 2005;26(18):1695-7.
Tong 2002 {published data only}
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]
VICTOR Study 2007 {published data only}
  • Asberg A, Humar A, Jardine AG, Rollag H, Pescovitz MD, Mouas H, et al. Long-term outcomes of CMV disease treatment with valganciclovir versus IV ganciclovir in solid organ transplant recipients. American Journal of Transplantation 2009;9(5):1205-13. [MEDLINE: 19422345]
  • Asberg A, Humar A, Rollag H, Jardine AG, Mouas H, Pescovitz MD, et al. Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. American Journal of Transplantation 2007;7(9):2106-13. [MEDLINE: 17640310]
  • Asberg A, Jardine AG, Bignamini AA, Rollag H, Pescovitz MD, Gahlemann CC, et al. Effects of the intensity of immunosuppressive therapy on outcome of treatment for CMV disease in organ transplant recipients. American Journal of Transplantation 2010;10(8):1881-8. [MEDLINE: 20486914]
  • Asberg A, Pescovitz MD, Humar A, Jardine AG, Rollag H, Mouas H, et al. Oral valganciclovir and intravenous ganciclovir results in comparable long-term outcomes in transplant recipients with CMV disease: the VICTOR study. [abstract]. Transplantation 2008;86(2S):222.
  • Boivin G, Goyette N, Rollag H, Jardine AG, Pescovitz MD, Asberg A, et al. Cytomegalovirus resistance in solid organ transplant recipients treated with intravenous ganciclovir or oral valganciclovir. Antiviral Therapy 2009;14(5):697-704. [MEDLINE: 19704173]
  • Humar A, Asberg A, Kumar D, Hartmann A, Moussa G, Jardine A, et al. An assessment of herpesvirus co-infections in patients with CMV disease: correlation with clinical and virologic outcomes. American Journal of Transplantation 2009;9(2):374-81. [MEDLINE: 19120074]
  • Manual O, Emery V, Asberg A, Hartmann A, Pescovitz M, Pang X, et al. A prospective study of viral genetic polymorphisms in CMV glycoprotein B and their association with clinical and virologic outcomes in patients with CMV disease: results from the VICTOR Study. [abstract]. Transplantation 2008;86(2S):221.
  • Manuel O, Asberg A, Pang X, Rollag H, Emery VC, Preiksaitis JK, et al. Impact of genetic polymorphisms in cytomegalovirus glycoprotein B on outcomes in solid-organ transplant recipients with cytomegalovirus disease. Clinical Infectious Diseases 2009;49(8):1160-6. [MEDLINE: 19751151]
  • Pescovitz M, Hartmann A, Humar A, Rollag H, Jardine AG, Bignamini AA, et al. Management of post transplant CMV disease: lessons learned from the VICTOR trial. [abstract]. American Journal of Transplantation 2008;8(Suppl 2):183.
Villano 2010 {unpublished data only}
  • Villano SA. Maribavir versus oral ganciclovir for the prevention of cytomegalovirus (CMV) disease in liver transplant recipients. http://clinicaltrials.gov/ct2/show/NCT00497796 (accessed 10 January 2013).
Winston 1995 Liver {published data only}
Winston 2003 Liver {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 Liver {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]

References to ongoing studies

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
NCT00372229 {unpublished data only}
  • Hoffmann-La Roche. A study of Valcyte (valganciclovir) CMV prophylaxis after renal transplantation. http://clinicaltrials.gov/ct2/show/NCT00372229 (accessed 10 January 2013).
NCT00966836 {unpublished data only}
  • Potena L, Grigioni F. Prevention of Transplant Atherosclerosis With Everolimus and Anti-cytomegalovirus Therapy (PROTECT). http://clinicaltrials.gov/ct2/show/NCT00966836 (accessed 10 January 2013).
NCT01552369 {unpublished data only}
  • Singh N. Prophylaxis Versus Preemptive Therapy for the Prevention of CMV in Liver Transplant Recipients (CAPSIL). http://clinicaltrials.gov/ct2/show/NCT01552369 (accessed 10 Janaury 2013).

Additional references

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
Arthurs 2007
Arthurs 2008
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References to other published versions of this review

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
Strippoli 2005
  • Strippoli GF, 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: 10.1002/14651858.CD005133]
Strippoli 2006a
Strippoli 2006b
  • 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]