Intervention Review

You have free access to this content

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 Kidney and Transplant 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, Centre for Kidney Research, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia. 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

 
Characteristics of included studies [ordered by study ID]
Brennan 1997a Kidney

Methods
  • Study design: parallel RCT
  • Follow-up period: 12.3 to 18.2 months


Participants
  • Country: USA
  • Setting: University
  • CMV status: D/R+; D+/R-
  • Kidney transplant recipients: 1st transplant (48); 2nd transplant (3)
  • Number: 39
  • Mean age ± SD: treatment group (48 ± 2.6 years); control group (47 ± 3.2 years)


InterventionsTreatment group

  • Pre-emptive IV ganciclovir 5 mg/kg every 12 hours for 3 weeks


Control group

  • Deferred ganciclovir (same schedule)


Outcomes
  1. CMV disease
  2. Acute rejection
  3. All-cause mortality
  4. Graft loss
  5. Adverse events


Notes
  • Method for detection of CMV infection: qualitative PCR for CMV DNA; shell vial culture; serology


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation reported but method not specified

Allocation concealment (selection bias)High riskAuthors reported that patients allocated according to last digit of medical record number (odd and even numbers)

Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded as some patients received IV medications while other received no treatment. The interpretation of clinical symptoms could be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskOutcome analysis was likely performed by the study investigators.

Incomplete outcome data (attrition bias)
All outcomes
Low risk3 patients excluded but this was unlikely to influence results

Selective reporting (reporting bias)Low riskAll outcomes specified in methods are reported

Other biasLow riskSupported by grant from Missouri Kidney Program

Gerna 2008 Liver

Methods
  • Study design: parallel RCT
  • Follow-up period: 24 months


Participants
  • Country: Italy
  • Setting: NS
  • CMV status: D+/R+, D+/R-
  • Paediatric liver transplant patients
  • Number: 21
  • Median age; range: treatment group (11 months; 2 months to 11 years); control group (19 months; 6 months to 6 years)


InterventionsTreatment group

  • Pre-emptive ganciclovir 5 mg/kg twice/d when positive CMV DNAemia occurred


Control group

  • Prophylactic ganciclovir 5 mg/kg twice/d for 30 days then pre-emptive IV ganciclovir 5 mg/kg twice/d when positive CMV DNAemia occurred


Outcomes
  1. CMV infection
  2. Acute rejection
  3. Time to development of CMV


Notes
  • Method for detection of CMV infection: qualitative PCR for CMV DNA >100,000 copies/mL for pre-emptive therapy; viral assay pp65-antigenaemia for prophylaxis


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation reported but method not specified

Allocation concealment (selection bias)Unclear riskAuthors did not report method used to conceal allocation of patients

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen labelled and the interpretation of clinical symptoms could be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskOutcome was likely dependent on the study investigators as the study was open labelled.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data

Selective reporting (reporting bias)High riskAll outcomes specified in methods were reported; however, outcomes of interest were not reported: graft loss, graft function, adverse effects of medications and other infections

Other biasLow riskTrial stopped early due to ethical reasons. No significant difference between the groups led to the conclusion that prophylactic treatment of patients would be unethical due to unjustified treatment.

Jung 2001 Kidney

Methods
  • Study design: parallel RCT
  • Follow-up period: 12 months


Participants
  • Country: Germany
  • Setting: NS
  • CMV status: D/R+, D+/R-, D-/R-
  • Kidney transplant recipients (1st transplant only)
  • Number: 70
  • Mean age: NS


InterventionsTreatment group

  • Pre-emptive oral ganciclovir 3000 mg/d for 14 days or until test negative


Control group

  • Prophylactic oral ganciclovir 3000 mg/d for 90 days starting at week 2 after transplant


Outcomes
  1. CMV disease
  2. CMV infection
  3. Acute rejection
  4. All-cause mortality
  5. Graft loss
  6. Adverse events


Notes
  • Method for detection of CMV infection: pp65 antigenaemia > 2 positive cell/20 x 104; PCR for CMV DNA > 400 copies/mL5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation reported but method not specified

Allocation concealment (selection bias)Unclear riskAuthors did not report method used to conceal allocation of patients

Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded as no placebo was given to the pre-emptive group. The interpretation of clinical symptoms could be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskOutcome analysis was likely performed by the study investigators and assessment of the outcome could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data

Selective reporting (reporting bias)Low riskAll outcomes specified in methods are reported

Other biasUnclear riskNo sponsorship of trial was stated

Khoury 2006 Kidney

Methods
  • Study design: parallel RCT
  • Follow-up period: 12 months


Participants
  • Country: USA
  • Setting: University
  • CMV status: D/R+, D+/R-, D-/R-
  • Kidney transplant recipients
  • Number: 99
  • Mean age ± SD: treatment group (47.5 ± 14.96 years); control group (51.9 ± 13.91 years)


InterventionsTreatment group

  • Pre-emptive oral valganciclovir 900 mg twice/d for at least 21 days or until test negative


Control group

  • Prophylactic oral valganciclovir 900 mg/d for 100 days after transplantation


Outcomes
  1. CMV disease
  2. CMV infection
  3. All-cause mortality
  4. Graft loss
  5. Other infections
  6. Acute rejection
  7. Pharmacoeconomics
  8. Time to development of CMV


Notes
  • Method for detection of CMV infection: quantitative PCR on whole blood for CMV DNAemia with a cut off value of > 2000 copies/mL


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomised by computer program with 1:1 block design

Allocation concealment (selection bias)Low riskClinical pharmacist allocation

Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded as pre-emptive group was not given placebo. The interpretation of clinical symptoms could be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskOutcome analysis was likely performed by the study investigators

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data

Selective reporting (reporting bias)Low riskAll outcomes specified in methods are reported and all outcomes of importance were included

Other biasHigh riskRoche supplied research support and the antiviral medication

Kliem 2008 Kidney

Methods
  • Study design: parallel RCT
  • Follow-up period: 48 months


Participants
  • Country: Germany
  • Setting: Multicentre
  • CMV status: D/R+, D+/R-, D-/R-
  • Kidney transplant recipients
  • Number: 148
  • Mean age ± SD: treatment group (50.9 ± 12.4 years); control group (48.3 ± 12.4 years)


InterventionsTreatment group

  • Pre-emptive IV ganciclovir 5 mg/kg twice/d for at least 10 days or until test was < 100 copies CMV DNA/mL on two successive tests


Control group

  • Prophylactic oral ganciclovir 1000 mg/d for 90 days within 48 hours following transplantation (for those who could not tolerate oral therapy temporary prophylaxis was provided as ganciclovir 5 mg/kg twice daily)


Outcomes
  1. CMV disease
  2. CMV infection
  3. All-cause mortality
  4. Graft loss
  5. Acute rejection
  6. Graft function
  7. Adverse events
  8. Time to development of CMV


Notes
  • Method for detection of CMV infection: quantitative PCR on whole blood for CMV DNAemia with a cut off value of > 400 copies/mL


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomised to either treatment group centrally by phone

Allocation concealment (selection bias)Low riskCentral allocation

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen labelled. The interpretation of clinical symptoms could be influenced by blinding.

Blinding of outcome assessment (detection bias)
All outcomes
High riskOutcome analysis was likely performed by the study investigators

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data

Selective reporting (reporting bias)Low riskAll outcomes specified in methods are reported, however, outcome of infections not reported, however, it is unlikely that this would affect study outcome

Other biasHigh riskSupport from Roche Pharma AG

Authors; Kliem, Fricke, Burg and Radermacher received honoraria for speaking and providing advice to Roche Pharma AG

Koetz 2001 Kidney

Methods
  • Study design: parallel RCT
  • Follow-up period: 3 months


Participants
  • Country: Germany
  • Setting: University
  • CMV status: D/R+, D+/R-
  • Kidney and liver transplant recipients
  • Number: 12
  • Mean age: NS


InterventionsTreatment group

  • Pre-emptive IV ganciclovir 2 x 5 mg/kg/d for 2 weeks


Control group

  • Placebo: 0.9% NaCl for 2 weeks


Outcomes
  1. CMV disease and syndrome


Notes
  • Method for detection of CMV infection: pp65 antigenaemia > 5 positive cells/20 x 104


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation reported but method not specified

Allocation concealment (selection bias)Unclear riskAuthors did not report method used to conceal allocation of patients

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskAuthors reported study as double blind but did not state methods

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported and unclear whether outcome assessors were blinded to treatment groups

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data

Selective reporting (reporting bias)High riskAll outcomes specified in methods were reported; however, outcomes of interest not reported included death, graft loss, graft function and acute rejection

Other biasUnclear riskNo sponsorship of trial was stated

Paya 2002 Liver

Methods
  • Study design: parallel RCT
  • Follow-up period: 4 months


Participants
  • Country: USA
  • Setting: University
  • CMV status: D/R+, D+/R-
  • Liver transplant recipients (1st transplant only)
  • Number: 69
  • Median age; range: treatment group (54 years; 23 to 67 years); control group (50 years; 26 to 67 years)


InterventionsTreatment group

  • Pre-emptive oral ganciclovir 1000 mg 3 times daily for 8 weeks


Control group

  • Placebo


Outcomes
  1. CMV disease
  2. Acute rejection
  3. Other infections


Notes
  • Method for detection of CMV infection: qualitative PCR for CMV DNA


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation occurred via predetermined randomisation chart

Allocation concealment (selection bias)Low riskAllocation performed by unblinded pharmacist

Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants and study personnel were blinded and oral placebo treatment was visually identical to oral ganciclovir

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported and unclear whether outcome assessors were blinded to treatment groups.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data

Selective reporting (reporting bias)High riskOutcomes of interest not reported: Death and graft loss

Other biasHigh riskRoche pharmaceuticals supplied oral ganciclovir

Queiroga 2003 Kidney

Methods
  • Study design: parallel RCT
  • Follow-up period: 6 months


Participants
  • Country: Brazil
  • Setting: NS
  • CMV status: D/R+, D+/R-, D-/R-
  • Kidney transplant recipients
  • Number: 34
  • Mean age: NS


InterventionsTreatment group

  • Pre-emptive oral ganciclovir (dose/route not specified)


Control group

  • Ganciclovir 750 g 3 times/d for 90 days


Outcomes
  1. CMV disease
  2. CMV infection
  3. All-cause mortality
  4. Graft loss


Notes
  • Method for detection of CMV infection: pp65 antigenaemia > 3 positive cell/30 x 104


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation reported but method not specified

Allocation concealment (selection bias)Unclear riskAuthors did not report method used to conceal allocation of patients

Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded as placebo was not given to pre-emptive group. The interpretation of clinical symptoms could be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskOutcome analysis was likely performed by the study investigators

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data

Selective reporting (reporting bias)High riskAll outcomes specified in methods were reported; however, acute rejection was not reported

Other biasUnclear riskNo sponsorship of trial was stated

Rayes 2001 Liver

Methods
  • Study design: parallel RCT
  • Follow-up period: 4 months


Participants
  • Country: Germany
  • Setting: University
  • CMV status: D/R+, D+/R-, D-/R-
  • Liver transplant recipients
  • Number: 60
  • Mean age ± SE: treatment group (53 ± 2 years); control group (49 ± 2 years)


InterventionsTreatment group

  • Pre-emptive oral ganciclovir 1000 mg x 3 times/d for 14 days


Control group

  • No treatment (treatment given when CMV disease presented)


Outcomes
  1. CMV disease and syndrome
  2. CMV infection
  3. Acute rejection
  4. Adverse events
  5. All-cause mortality


Notes
  • Method for detection of CMV infection: pp65 antigenaemia > 1 positive cell/1 x 104; qualitative PCR for CMV DNA


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation reported but method not specified

Allocation concealment (selection bias)Unclear riskAuthors did not report method used to conceal allocation of patients

Blinding of participants and personnel (performance bias)
All outcomes
High riskDifferent treatment schemes oral versus intravenous therefore not blinded. The interpretation of clinical symptoms could be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskOutcome analysis was likely performed by the study investigators

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data

Selective reporting (reporting bias)Low riskAll outcomes specified in methods are reported and all outcomes of importance were included

Other biasUnclear riskNo sponsorship of trial was stated

Reischig 2008 Kidney

Methods
  • Study design: parallel RCT
  • Primary follow-up period: 12 months. 4 year follow-up data


Participants
  • Country: Czech Republic
  • Setting: University
  • CMV status: D/R+, D+/R-, D-/R-
  • Kidney transplant recipients
  • Number: 70
  • Mean age ± SD: treatment (50 ± 13 years); control group: 48 ± 12 years)


InterventionsTreatment group

  • Pre-emptive oral valganciclovir 900 mg twice/d for at least 14 days or until test negative


Control group

  • Prophylactic oral valaciclovir 2 g 4 times/d for 3 months starting 1 to 7 days post transplantation


Outcomes
  1. CMV disease
  2. CMV infection
  3. All-cause mortality
  4. Graft loss5. Other infections
  5. Acute rejection
  6. Time to development of CMV
  7. Adverse events


Notes
  • Method for detection of CMV infection: quantitative PCR on whole blood for CMV DNAemia with a cut off value of > 2000 copies/mL


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation occurred 1:1 to either group via a random number table

Allocation concealment (selection bias)Unclear riskAuthors did not report method used to conceal allocation of patients

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen labelled. The interpretation of clinical symptoms could be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskOutcome analysis was likely performed by the study investigators

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data

Selective reporting (reporting bias)Low riskAll outcomes specified in methods are reported and all outcomes of importance were included

Other biasLow riskStudy was supported by an award from the Ministry of Education, Youth and Physical Training of the Czech Republic

Sagedal 2003 Kidney

Methods
  • Study design: parallel RCT
  • Follow-up period: 12 months


Participants
  • Country: Norway
  • Setting: University
  • CMV status: D/R+, D+/R-
  • Kidney transplant recipients (1st transplant only)
  • Number: 80
  • Mean age; range: treatment group (55 years; 22 to 79); control group (56 years; 21 to 78)


InterventionsTreatment group

  • Pre-emptive oral ganciclovir 100 mg x 3 times/d (duration not specified)


Control group

  • No treatment


Outcomes
  1. CMV syndrome and disease
  2. Acute rejection
  3. All-cause mortality
  4. Serum creatinine


Notes
  • Method for detection of CMV infection: pp65 antigenaemia > 1 positive cell/10 x 104


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation reported but method not specified

Allocation concealment (selection bias)Unclear riskAuthors did not report method used to conceal allocation of patients

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-labelled. The interpretation of clinical symptoms could be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskOutcome analysis was likely performed by the study investigators

Incomplete outcome data (attrition bias)
All outcomes
Low riskInfection other than CMV were not reported past 12 weeks, however, this would not affect the study outcomes

Selective reporting (reporting bias)Low riskAll outcomes specified in methods are reported and all outcomes of importance were included

Other biasHigh riskTrial was supported by grants from the Research Council of Norway and Hofmann-La Roche, Norway

Gancicolvir was supplied by F. Hoffmann La-Roche AG

Singh 1994 Liver

Methods
  • Study design: parallel RCT
  • Follow-up period: 6 months


Participants
  • Country: USA
  • Setting: University
  • CMV status: D/R+, D+/R-, D-/R-
  • Liver transplant recipients: 1st transplant (44); 2nd transplant (3)
  • Number: 47
  • Mean age; range: treatment group (49 years; 22 to 66); control group (45 years; 21 to 69)


InterventionsTreatment group

  • Pre-emptive IV ganciclovir 5 mg/kg twice/d x 7 days


Control group

  • Oral acyclovir 800 mg x 4 times/d x 24 weeks


Outcomes
  1. CMV syndrome and disease
  2. All-cause mortality
  3. Graft loss
  4. Adverse events


Notes
  • Method for detection of CMV infection: shell vial culture; EIA (titre > 0.79 positive)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation was stratified by CMV serostatus of donor and recipient. Randomisation process by blocks of 4

Allocation concealment (selection bias)Unclear riskAuthors did not report method used to conceal allocation of patients

Blinding of participants and personnel (performance bias)
All outcomes
High riskNot reported, however, different medications and administration routes were used therefore it was considered not to be blinded. The interpretation of clinical symptoms could be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskOutcome analysis was likely performed by the study investigators

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data

Selective reporting (reporting bias)High riskAll outcomes specified in methods were reported; however, acute rejection was not reported

Other biasUnclear riskNo sponsorship of trial was stated

Singh 2000 Liver

Methods
  • Study design: parallel RCT
  • Follow-up period: 3 months


Participants
  • Country: USA
  • Setting: University
  • CMV status: D/R+, D+/R-, D-/R-
  • Liver transplant recipients
  • Number: 22
  • Mean age: Treatment group (50.9 years); control group (49.9 years)


InterventionsTreatment group

  • Pre-emptive oral ganciclovir 2000 mg 3 times/d for 2 weeks, then 1000 mg 3 times/d for 4 weeks


Control group

  • Pre-emptive ganciclovir IV 5 mg/kg every 12 hours for 7 days


Outcomes
  1. CMV disease and syndrome
  2. All-cause mortality
  3. Other infections
  4. Adverse events
  5. Cost analysis


Notes
  • Method for detection of CMV infection: pp65 antigenaemia > 1 positive cell/20 x 104


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation reported but method not specified

Allocation concealment (selection bias)Unclear riskAuthors did not report method used to conceal allocation of patients

Blinding of participants and personnel (performance bias)
All outcomes
High riskNot reported. However, different administration routes were used and considered not to be blinded. The interpretation of clinical symptoms could be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskOutcome analysis was likely performed by the study investigators

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data

Selective reporting (reporting bias)High riskAll outcomes specified in methods were reported; however, graft loss and acute rejection were not reported

Other biasUnclear riskNo sponsorship of study was stated

Witzke 2012 Kidney

Methods
  • Study design: parallel RCT
  • Follow-up period: 12 months


Participants
  • Country: Germany/Austria
  • Setting: Multicentre
  • CMV status: D+/R+, D-/R+
  • Kidney transplant recipients
  • Number: 296
  • Mean age ± SD: treatment group (54.2 ± 12.0 years); control group (51.1 ± 13.6 years)


InterventionsTreatment group

  • Pre-emptive oral valganciclovir 900 mg twice/d for at least 14 days or until test negative (< 400 copies/mL) with prophylaxis period consisting of 450 mg valganciclovir twice/d for 28 days


Control group

  • Prophylactic oral valganciclovir 900 mg twice/d for 100 days initiated within 14 days post transplantation


Outcomes
  1. CMV disease and syndrome
  2. CMV infection
  3. Other infections
  4. Adverse events
  5. All-cause mortality
  6. Acute rejection
  7. Graft loss


Notes
  • Method for CMV detection was RT-PCR with cut off value > 400 copies/mL


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod of randomisation not specified

Allocation concealment (selection bias)Low risk1:1 central allocation via phone

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-labelled. The interpretation of clinical symptoms could be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskOutcome analysis was likely performed by the study investigators.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data

Selective reporting (reporting bias)Low riskAll outcomes specified in methods are reported and all outcomes of importance were included

Other biasHigh riskValgancicolvir was supplied by Roche Pharma AG, Germany

Yang 1998 Kidney

Methods
  • Study design: parallel RCT
  • Follow-up period: 6 months


Participants
  • Country: South Korea
  • Setting: University
  • CMV status: D/R+
  • Kidney transplant recipients
  • Number: 31
  • Mean age: NS


InterventionsTreatment group

  • Pre-emptive IV ganciclovir 5 mg/kg twice/d for 2 weeks


Control group

  • No treatment


Outcomes
  1. CMV syndrome and disease
  2. CMV infection


Notes
  • Method for detection of CMV infection: pp65 antigenaemia > 1 positive cell/5 x 104; CMV IgM index > 0.500


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation reported but method not specified

Allocation concealment (selection bias)Unclear riskAuthors did not report method used to conceal allocation of patients

Blinding of participants and personnel (performance bias)
All outcomes
High riskNot reported. However, no placebo was given to the untreated control group. This would enable investigators to identify participant's groups. The interpretation of clinical symptoms could be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskOutcome analysis was likely performed by the study investigators

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data

Selective reporting (reporting bias)High riskAll outcomes specified in methods were reported; however, death, graft loss and acute rejection outcomes were not reported

Other biasLow riskStudy was supported by a research grant from the Clinical Research fund (BKB) of the Catholic Medical Centre

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Ahsan 1997 KidneyProphylaxis RCT

Ahsan 1998Not RCT (sequential)

Arbo 2000Economic evaluation of previous study

Badley 1997 LiverProphylaxis RCT

Balfour 1989 KidneyProphylaxis RCT

Barkholt 1999 LiverProphylaxis RCT

Brennan 1997b KidneyNot a pre-emptive study and primary outcome was herpes virus (HHV-7) infection

Cohen 1993 LiverProphylaxis RCT

Conti 1995 KidneyProphylaxis RCT

Denny 2002Not an RCT

Devolder 2010Ineligible intervention

Dickinson 1996IgG to prevent CMV

Duncan 1993 LungProphylaxis RCT

Egan 2002 HeartProphylaxis RCT

Euro-SPK 2005RCT comparing tacrolimus and cyclosporin

Falagas 1997Included both non-randomised patients and patients from a previous study

Fehir 1989Non-randomised patients included

Ferreira 2004CMV data from several studies comparing immunosuppressive regimens

Fishman 2000Retrospective study

Flechner 1998 KidneyProphylaxis RCT

Gane 1997 LiverProphylaxis RCT

Gavalda 1997 LiverProphylaxis RCT

Gerna 2003Qualitative molecular assay for detection of a late (pp67) HCMV mRNA versus quantitative antigenaemia

Gerna 2007Evaluation of cytomegalovirus DNAemia versus pp65-antigenaemia

Green 1997 LiverProphylaxis RCT

Greger 1988Comparison of immunosuppression regimes

Griffiths 2010Ineligable intervention (haematopoetic stem cell transplant recipients)

Hecht 1988Case reports of patients treated with ganciclovir

Hertz 1998 Heart/LungProphylaxis RCT

Hibberd 1995 KidneyProphylaxis RCT

IMPACT Study 2010 TXProphylaxis RCT

Jurim 1996Subgroup of previous study; outcome hepatitis B

Kim 2000Economic evaluation of previous study

King 1999IgG versus antiviral to prevent CMV

Kletzmayr 1996 KidneyProphylaxis RCT

Kletzmayr 2000Not RCT; historical controls

Leray 1995 KidneyProphylaxis RCT

Lowance 1999 KidneyProphylaxis RCT

Lumbreras 1993Not RCT; historical controls

MacDonald 1991Ineligible intervention

Macdonald 1995 HeartProphylaxis RCT

Marker 1980Intervention study. Included both randomised and non-randomised participants

Mattes 2004Included non-solid organ transplants in analysis

Merigan 1992 HeartProphylaxis RCT

Moreno 1999Not RCT

Mullen 1998Retrospective study

Murray 1997Economic evaluation of CMV treatments

Nakazato 1993 LiverProphylaxis RCT

Palmer 2010Prophylaxis RCT

Paya 2004 AllProphylaxis RCT

Pescovitz 2009Prophylaxis RCT

Pouteil 1991HLA compatibility with CMV infection

Pouteil-Noble 1996 KidneyProphylaxis RCT

Qiu 2008 KidneyNot an RCT

Reischig 2005 KidneyProphylaxis RCT

Rondeau 1993 KidneyProphylaxis RCT

Rostaing 1994 KidneyProphylaxis RCT

Rubin 2002 AllProphylaxis RCT

Saliba 1993 LiverProphylaxis RCT

Schnitzler 2000Re-analysis of previous study (1992)

Singh 1995Not RCT

Singh 2002Prophylaxis RCT

Speich 1999Not RCT; sequential enrolment

Tian 2005 KidneyNot RCT

Tong 2002Primary outcome was herpes virus (HHV-7) infection

Turgeon 1998Not RCT; sequential enrolment

Valantine 1999Post hoc analysis

VICTOR Study 2007Treatment study. Assessed genetic polymorphism impact on CMV infection and other herpes virus co-infections

Villano 2010Prophylaxis RCT

Winston 1995 LiverProphylaxis RCT

Winston 2003 LiverProphylaxis RCT

Winston 2004 LiverProphylaxis RCT

Yang 1999Unable to determine if participants were randomised

 
Characteristics of studies awaiting assessment [ordered by study ID]
Scott 2011 Liver

MethodsOpen label RCT, sequentially numbered envelopes.

Participants1. Male or female > 16 years of age
2. Patients undergoing liver transplantation
3. Single or multi-organ transplant
4. Patients meet transplant criteria
5. Chronic liver disease or fulminant hepatic failure
6. Able to give written informed consent

InterventionsHigh risk group and prophylaxis group are assigned to receive 900mg (two 450mg tablets) of valganciclovir (Valcyte) once daily for 3 months commenced within 72 hrs after liver transplantation and monitored regularly for CMV infection/disease. Dose will be changed based on creatinine clearance.

Pre- Emptive group Monitored regularly for CMV infection only. If this occurs patients will be given 5 mg/kg intravenously over one hour, of ganciclovir (GCV) twice daily for 2 weeks CMV infection is determined on testing with Qualitative Polymerease chain reaction (PCR)
Valganciclovir doses as per creatinine clearance:
Creatinine clearance >/=60 ml/min900mg daily
Creatinine clearance 40-59 ml/min 450mg daily
Creatinine clearance 25-39 ml/min450mg second daily
Creatinine clearance 10-24 ml/min450 mg twice weekly

OutcomesPrimary incidence of CMV infection and disease

Assess viral characteristics of infection

Antiviral resistant CMV

Incidence of opportunistic viral infections

Drug efficacy

NotesUnfunded

 
Characteristics of ongoing studies [ordered by study ID]
NCT00372229

Trial name or titleA randomized trial comparing valcyte CMV prophylaxis versus pre-emptive therapy after renal transplantation using proteomics for monitoring of graft alteration

MethodsOpen label RCT

ParticipantsUnknown

InterventionsValganciclovir CMV prophylaxis for 100 days versus valganciclovir pre-emptive therapy

OutcomesCMV infection

CMV disease

Graft loss

Starting dateMay 2006

Contact information

Notes

NCT00966836

Trial name or titlePrevention of transplant atherosclerosis with everolimus and anti-cytomegalovirus therapy

MethodsOpen label RCT

ParticipantsEstimated 100

InterventionsPre-emptive strategy with valganciclovir plus everolimus

Prophylaxis with valganciclovir plus mycophenolate

Prophylaxis with valganciclovir plus everolimus

Pre-emptive mycophenolate

OutcomesCMV infection

Starting dateApril 2009

Contact informationLuciano Potena, MD PhD

Francesco Grigioni, MD PhD

Notes

NCT01552369

Trial name or titleProphylaxis versus preemptive therapy for the prevention of CMV in high-risk R-D+ liver transplant recipients

MethodsSingle blind (outcome assessors), RCT

ParticipantsEstimated 180

InterventionsProphylaxis with valganciclovir for 100 days post transplantation versus subjects monitored with CMV PCR testing and given valganciclovir therapy only if PCR is positive. Therapy is stopped after second negative PCR test

OutcomesCMV disease

All-cause mortality

Starting dateJuly 2012

Contact informationPrincipal Investigator: Nina Singh, MD

Notes

 
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

 
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

Pre-emptive medication versus prophylaxis for CMV viraemia 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: prophylaxis

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

Assumed riskCorresponding risk

ProphylaxisPre-emptive medication

All symptomatic CMV diseaseStudy population1.02
(0.43 to 2.44)
753 (7)⊕⊕⊝⊝
low1,2

106 per 1000108 per 1000
(45 to 258)

Moderate

88 per 100090 per 1000
(38 to 215)

All-cause mortalityStudy population1.19
(0.56 to 2.51)
753 (7)⊕⊕⊝⊝
low1,3

33 per 100039 per 1000
(18 to 82)

Moderate

29 per 100035 per 1000
(16 to 73)

Graft lossStudy population1.07
(0.41 to 2.82)
753 (7)⊕⊕⊝⊝
low1,3

51 per 100055 per 1000
(21 to 145)

Moderate

55 per 100059 per 1000
(23 to 155)

Acute rejectionStudy population1.23
(0.75 to 2.03)
693 (6)⊕⊕⊝⊝
low1,3

165 per 1000203 per 1000
(124 to 334)

Moderate

166 per 1000204 per 1000
(125 to 337)

LeucopeniaStudy population0.42
(0.2 to 0.9)
729 (6)⊕⊕⊕⊝
moderate1

238 per 1000100 per 1000
(48 to 214)

Moderate

207 per 100087 per 1000
(41 to 186)

D+/R- serostatus: symptomatic CMVStudy population0.99
(0.12 to 8.02)
39 (2)⊕⊝⊝⊝
very low1,3

150 per 1000149 per 1000
(18 to 1000)

Moderate

94 per 100093 per 1000
(11 to 754)

D+ or D-/R+ serostatus: symptomatic CMVStudy population0.21
(0.02 to 1.76)
93 (2)⊕⊝⊝⊝
very low1,3

87 per 100018 per 1000
(2 to 153)

Moderate

85 per 100018 per 1000
(2 to 150)

*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 reported blinding of participants, investigators or outcome assessors and most did not report adequate allocation concealment
²Significant heterogeneity between studies
³Small numbers of events
 
Table 1. Summary of CMV guidelines for solid organ transplant recipients

 The Kidney Disease Improving Global Outcomes (KDIGO 2009)Caring for Australians with Renal Impairment (CARI 2010)British Transplant Society (BTS 2011)

Current recommendations to prevent CMV diseaseValganciclovir or IV ganciclovir prophylaxis for at least 3 months post renal transplantation and for 6 weeks post T-cell depleting immunosuppression.

No prophylaxis is required for renal transplant patients who are CMV seronegative and receive a seronegative transplant
Valganciclovir, valaciclovir or IV ganciclovir for prophylaxis for 3 months. This is extended to 6 months for high risk patients (D+/R-).

No prophylaxis is required for transplant recipients who are CMV seronegative and receive a seronegative transplant
Valganciclovir or IV ganciclovir for prophylaxis 100 days post transplantation.

No prophylaxis is required for renal or liver transplant patients who are seropositive for CMV and do not receive T-cell depleting immunosuppression