Intervention Review

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Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients

  1. Elisabeth M Hodson1,2,*,
  2. Maleeka Ladhani1,
  3. Angela C Webster2,3,4,
  4. Giovanni FM Strippoli2,4,5,6,7,
  5. Jonathan C Craig2,4

Editorial Group: Cochrane Kidney and Transplant Group

Published Online: 28 FEB 2013

Assessed as up-to-date: 11 JUL 2011

DOI: 10.1002/14651858.CD003774.pub4


How to Cite

Hodson EM, Ladhani M, Webster AC, Strippoli GFM, Craig JC. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD003774. DOI: 10.1002/14651858.CD003774.pub4.

Author Information

  1. 1

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

*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]
2VAL Study 2010 Kidney

Methods
  • Study design: parallel RCT
  • Time frame: November 2007 and ongoing
  • Follow-up period: 4 months (preliminary data); planned for 36 months
  • Loss to follow-up: 0%


Participants
  • Country: Czech Republic
  • Setting: tertiary single centre
  • Kidney transplant recipients aged ≥ 18 years; D/R+, D+/R-, D-/R-


Treatment group 1

  • Number: 19
  • Mean age ± SD: 46 ± 14 years
  • Sex (M/F): 13/6


Treatment group 2

  • Number: 17
  • Mean age ± SD: 47 ± 10 years
  • Sex (M/F): 10/7


Exclusion criteria

  • Unknown or D-/R- serology; systemic antiviral drug intake within 2 weeks; active viral infection; significant leukopenia or thrombocytopenia; participation in another study; allergy to study medications


InterventionsTreatment group 1

  • VGCV: 900 mg orally/d for 12 weeks


Treatment group 2

  • VACV: 2000 mg 4 times/d for 12 weeks


Co-interventions

  • CSA, TAC, MMF, prednisone, ALG 1/19 valganciclovir, 5/17 valaciclovir


Outcomes
  1. CMV disease
  2. CMV infection: CMV DNA by PCR
  3. Graft loss
  4. Acute rejection
  5. Adverse effects


NotesPreliminary results at 4 months only. Full data to be analysed when all patients have completed 12 months. Information on results and randomisation sequence obtained from authors


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers table, block randomisation (1:1 ratio, blocks of 4)

Allocation concealment (selection bias)Low riskSealed envelopes opened after patient enrolled

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen label. Lack of blinding could influence clinical assessment of symptoms of possible CMV disease

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen label. Lack of blinding could influence clinical assessment of symptoms of possible CMV disease

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFull data on follow-up not yet reported

Selective reporting (reporting bias)Unclear riskFull data on outcomes not yet reported

Other biasLow riskGrants from Ministry of Health

Ahsan 1997 Kidney

Methods
  • Study design: parallel RCT
  • Time frame: March 1995 to December 1995
  • Follow-up period: 9 months
  • Loss to follow-up: 0%


Participants
  • Country: USA
  • Setting: tertiary single centre
  • Kidney transplant recipients; D/R+, D+/R-, D-/R-; if diabetic or receiving OKT-3


Treatment group

  • Number: 22
  • Mean age ± SEM: 50.4 ± 2.3 years
  • Sex (M/F): 10/11
  • CD/LD: 18/3


Control group

  • Number: 22
  • Mean age ± SEM: 47.6 ± 2.1 years
  • Sex (M/F): 12/11
  • CD/LD: 7/15


Exclusion criteria: NS


InterventionsTreatment group

  • GCV: 750 mg orally twice/d for 12 weeks starting day 1


Control group

  • No treatment


Co-interventions

  • CSA, AZA, prednisone, OKT-3 (CD recipients)


Outcomes
  1. CMV disease
  2. CMV infection: CMV culture, IgM3
  3. All-cause mortality
  4. Death due to CMV disease
  5. Acute rejection
  6. Graft loss
  7. Opportunistic infections


Notes
  1. Exclusions post randomisation but pre-intervention: none
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised generated code with 4 patients in each block

Allocation concealment (selection bias)Unclear riskRandomisation stated but no information provided

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen label study. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen label study. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskOne patient excluded but reason unlikely to be related to true outcome

Selective reporting (reporting bias)High riskIncomplete reporting of adverse effects

Other biasUnclear riskNo information about pharmaceutical sponsorship

Badley 1997 Liver

Methods
  • Study design: parallel RCT
  • Time frame: January 1991 to June 1994
  • Follow-up period: 1 year
  • Loss to follow-up: 0%


Participants
  • Country: USA
  • Setting: tertiary multicentre
  • First liver transplant


Treatment group

  • Number: 83
  • Age range: 16 to 68 years
  • Sex (M/F): 50/33


Control group

  • Number: 84
  • Age range: 16 to 68 years
  • Sex (M/F): 46/38


Exclusion criteria

  • Allergy to GCV/ACV; creatinine > 3 mg/dL or GFR < 10; stage 3/4 coma post-transplant; existing CMV infection


InterventionsTreatment group

  • GCV: 5 mg/kg IV twice/d for 14 days starting first day post-transplant
  • ACV: 800 mg orally 4 times/d to 120 days


Control group

  • ACV: 800 mg orally 4 times/d to 120 days


Co-interventions

  • CSA, AZA (one centre), prednisone


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive organ disease
  4. CMV infection: CMV culture
  5. All-cause mortality
  6. Acute rejection
  7. Opportunistic infections
  8. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: 3 excluded
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Block randomisation scheme was used to generate a series of 150 randomly selected treatment assignments for each transplant centre"

Allocation concealment (selection bias)Low riskPatient randomisation and all statistical analyses were performed at coordinating centre

Blinding of participants and personnel (performance bias)
All outcomes
High riskMedications schedules differ between intervention groups. Assessment of primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskMedications schedules differ between intervention groups. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskThree patients excluded but exclusions unlikely to be related to outcomes

Selective reporting (reporting bias)High riskNo graft loss reported

Other biasLow riskStudy carried out under NIH contracts

Balfour 1989 Kidney

Methods
  • Study design: parallel RCT
  • Time frame: August 1985 to May 1988
  • Follow-up period: 1 year
  • Loss to follow-up: 6% at 1 year, 0% at 6 months


Participants
  • Country: USA
  • Setting: tertiary single centre
  • Cadaveric kidney transplant recipients > 10 years


Treatment group

  • Number: 53
  • Median age (range): 43 years (15 to 67)
  • Sex (M/F): 36/17


Control group

  • Number: 51
  • Median age (range): 42 years (17 to 68)
  • Sex (M/F): 34/17


Exclusion criteria

  • Intolerance of ACV


InterventionsTreatment group

  • ACV: 800 mg orally 4 times/d for 12 weeks starting day of transplant


Control group

  • Placebo: 1 tablet 4 times/d for 12 weeks starting day of transplant


Co-interventions

  • CSA, AZA, prednisone


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive organ disease
  4. CMV infection: CMV culture, rising CMV antibody
  5. All-cause mortality
  6. Death due to CMV disease
  7. Acute rejection
  8. Graft loss
  9. Opportunistic infections
  10. Adverse events


Notes
  1. Exclusions post randomisation but pre-intervention: none reported
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation scheme generated by computer program

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo controlled. Placebo tablets identical in appearance to acyclovir

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPlacebo controlled. Placebo tablets identical in appearance to acyclovir

Incomplete outcome data (attrition bias)
All outcomes
Low risk14 patients (6 intervention, 8 placebo) excluded but reasons unlikely to be related to true outcome

Selective reporting (reporting bias)Low riskAll expected outcomes reported

Other biasLow riskReport partial support from NIH, Minnesota Medical Foundation and Burroughs Wellcome

Barkholt 1999 Liver

Methods
  • Study design: parallel RCT
  • Time frame: May 1993 to December 1994
  • Follow-up period: 3 months
  • Loss to follow-up: 0%


Participants
  • Country: Sweden
  • Setting: tertiary single centre
  • Liver transplant recipients; all CMV serostatus


Treatment group

  • Number: 28
  • Mean age ± SD: 41 ± 17 years
  • Sex (M/F): 16/12


Control group

  • Number: 27
  • Mean age± SD: 47 ± 15 years
  • Sex (M/F): 12/15


Exclusion criteria

  • Age < 6 years; HIV infection; CMV therapy in previous 4 weeks


InterventionsTreatment group

  • ACV: 800 mg (1 tablet) orally 4 times/d for 12 weeks starting 6 hours pre-transplant


Control group

  • Placebo: 1 tablet orally 4 times/d for 12 weeks starting 6 hours pre-transplant


Co-interventions

  • CSA, AZA, prednisone


Outcomes
  1. CMV disease
  2. CMV infection: CMV culture, CMV DNA, IgM
  3. All-cause mortality
  4. Death due to CMV disease
  5. Acute rejection
  6. Graft loss
  7. Opportunistic infections
  8. Adverse reactions


Notes
  1. Exclusions post randomisation but pre-intervention: 5
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo controlled

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPlacebo controlled. Patients with verified CMV infection were withdrawn from study drug without breaking the code

Incomplete outcome data (attrition bias)
All outcomes
Low risk5 excluded (3 given acyclovir outside study; 2 under 6 years) but reasons unlikely to be related to true outcome

Selective reporting (reporting bias)Low riskAll expected outcomes reported

Other biasHigh riskSupported by Wellcome Research Laboratories

Brennan 1997 Kidney

Methods
  • Study design: parallel RCT
  • Time frame: NS
  • Follow-up period: 6 months
  • Loss to follow-up: 0%


Participants
  • Country: USA
  • Setting: tertiary single centre
  • Kidney transplant recipients; D/R+, D+/R- recipients


Treatment group

  • Number: 19
  • Mean age ± SEM: 50.6 ± 2.8 years
  • Sex (M/F): 13/6


Control group

  • Number: 23
  • Mean age ± SEM: 44.2 ± 3.0 years
  • Sex (M/F): 5/18


Exclusion criteria

  • D-/R- recipients


InterventionsTreatment group

  • GCV: 1000 mg orally 3 times/d for 12 weeks starting at transplant


Control group

  • No treatment except ACV low dose to prevent Herpes simplex


Co-interventions

  • CSA, AZA, prednisone, ATG


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive organ disease
  4. CMV infection: CMV DNA
  5. All-cause mortality
  6. Acute rejection
  7. Opportunistic infections
  8. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskOdd and even numbers according to last digit of medical record number. Information obtained from authors

Allocation concealment (selection bias)High riskOdd and even numbers according to last digit of medical record number. Information obtained from authors

Blinding of participants and personnel (performance bias)
All outcomes
High riskMedications differ between intervention groups. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskMedications differ between intervention groups. Primary outcome of CMV disease could be influenced by lack of blinding

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

Selective reporting (reporting bias)High riskIncomplete outcome reporting. No report of graft loss

Other biasHigh riskHoffman-La Roche Laboratory pharmaceutical sponsorship

Cohen 1993 Liver

Methods
  • Study design: parallel RCT
  • Time frame: NS
  • Follow-up period: 18 months
  • Loss to follow-up: 0%


Participants
  • Country: UK
  • Setting: tertiary single centre
  • Liver transplant recipients; D/R+, D+/R-


Treatment group

  • Number: 33
  • Mean age: 42.4 years
  • Sex (M/F): 15/18


Control group

  • Number: 32
  • Mean age: 46.3 years
  • Sex (M/F): 16/16


Exclusion criteria

  • Acute kidney injury; multiple organ system failure; D-/R- recipients


InterventionsTreatment group

  • GCV: 5 mg/kg IV twice/d for 14 days starting on day 14


Control group

  • No treatment


Co-interventions

  • CSA, AZA, prednisone


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive organ disease
  4. CMV infection: CMV culture, IgM
  5. All-cause mortality
  6. Death due to CMV disease
  7. Acute rejection
  8. Graft loss
  9. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"65 patients were randomised in a distribution determined by random numbers"

Allocation concealment (selection bias)Low riskInformation obtained from authors that method used would not allow investigator/participant to know allocation before participant entered study

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen label study. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen label study. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients completed follow-up

Selective reporting (reporting bias)High riskIncomplete reporting of outcomes. No or limited report on other infections or adverse effects

Other biasUnclear riskNo report on pharmaceutical sponsorship

Conti 1995 Kidney

Methods
  • Study design: parallel RCT
  • Time frame: January 1992 to January 1994
  • Follow-up period: 12 months
  • Loss to follow-up: 0%


Participants
  • Country: USA
  • Setting: tertiary single centre
  • Kidney transplant recipients; D/R+; receiving ALG for induction or rejection


Treatment group

  • Number: 22
  • Mean age: 43 years
  • Sex (M/F): 11/11


Control group

  • Number: 18
  • Mean age: 45 years
  • Sex (M/F): 12/6


Exclusion criteria: NS


InterventionsTreatment group

  • GCV: 5 mg/kg/d IV during ALG therapy (median 10 days) starting on first day of ALG


Control group

  • No treatment


Co-interventions

  • CSA, AZA, prednisone, ALG


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive organ disease
  4. All-cause mortality
  5. Acute rejection
  6. Graft loss
  7. Opportunistic infections
  8. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Patients were randomly assigned" but method of sequence generation not stated

Allocation concealment (selection bias)Unclear risk"Patients were randomly assigned" but no information provided on method used

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants in control group received no specific intervention. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskParticipants in control group received no specific intervention. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients evaluated

Selective reporting (reporting bias)High riskIncomplete reporting of outcomes. No report or limited reporting of CMV infection/adverse effects

Other biasUnclear riskSupported in part by grant from National Kidney Foundation. No report on pharmaceutical sponsorship

Duncan 1993 Lung

Methods
  • Study design: parallel RCT
  • Time frame: NS
  • Follow-up period: 1 year
  • Loss to follow-up: 0%


Participants
  • Country: USA
  • Setting: tertiary single centre
  • Lung transplant recipients; D/R+, D+/R-; neutrophils > 1000/mm³, creatinine > 2.5 mg/dL


Treatment group

  • Number: 13
  • Age: 41.8 ± 9.6 years (mean ± SD)
  • Sex (M/F): 9/4


Control group

  • Number: 12
  • Age: 45.6 ± 8.4 years
  • Sex (M/F): 7/5


Exclusion criteria

  • D-/R-


InterventionsTreatment group

  • GCV: 5 mg/kg 4 times/d IV x 14 days starting day 7; 5 mg/kg/d IV for days 21 to 28; 5 mg/kg IV 5 times/wk to day 90


Control group

  • GCV: 5 mg/kg 4 times/d IV x 14 days starting day 7; 5 mg/kg/d IV for days 21 to 28
  • ACV: 800 mg orally 4 times/d to day 90


Co-interventions

  • CSA, AZA


Outcomes
  1. CMV tissue invasive disease
  2. CMV infection: CMV culture of bronchial lavage
  3. All-cause mortality
  4. Death due to CMV disease
  5. Obliterative bronchiolitis
  6. Graft loss
  7. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided other than that patients were stratified according to CMV serostatus and type of transplant

Allocation concealment (selection bias)Unclear riskSaid to be "randomly assigned" but no other information provided

Blinding of participants and personnel (performance bias)
All outcomes
High riskMedications differ between intervention groups. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskMedications differ between intervention groups. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskConsecutive lung transplant recipients randomised. Results from all reported.

Selective reporting (reporting bias)High riskIncomplete outcome reporting. No or limited reporting of CMV disease, acute rejection, opportunistic infections

Other biasUnclear riskNo report of pharmaceutical sponsorship

Egan 2002 Heart

Methods
  • Study design: parallel RCT
  • Time frame: September 1994 to February 1998
  • Follow-up period: 6 months
  • Loss to follow-up: 0%


Participants
  • Country: UK
  • Setting: tertiary single centre
  • Heart transplant recipients; D/R+


Treatment group

  • Number: 14
  • Mean age (range): 51.6 years (39 to 63)
  • Sex (M/F): 11/1


Control group

  • Number: 13
  • Mean age (range): 50.4 years (31 to 62)
  • Sex (M/F): 10/3


Exclusion criteria

  • Active herpes infection; required other antiviral agents


InterventionsTreatment group

  • VACV: 2000 mg orally 4 times/d for 90 days starting within 72 hours of transplant


Control group

  • ACV: 200 mg orally 4 times/d for 90 days starting within 72 hours of transplant for herpes simplex


Co-interventions

  • CSA, AZA, prednisone, ATG


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive organ disease
  4. CMV infection: CMV antigenaemia, culture
  5. All-cause mortality
  6. Death due to CMV disease
  7. Acute rejection
  8. Graft loss
  9. Opportunistic infections
  10. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: none
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Computer generated randomization schedule (block size 4)"

Allocation concealment (selection bias)Low risk"Allocation by opening sealed envelopes corresponding to patient number in sequence"

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskControl group given low dose acyclovir to "maintain double blind by effective prophylaxis of herpes simplex outbreaks" but no information that acyclovir and valacyclovir tablets were indistinguishable

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskControl group given low dose acyclovir to "maintain double blind by effective prophylaxis of herpes simplex outbreaks" but no information that acyclovir and valacyclovir tablets were indistinguishable

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll enrolled patients were included in the analysis including 2 patients randomised in error

Selective reporting (reporting bias)Low riskAll expected outcomes reported

Other biasHigh riskFunding provided by Glaxo Wellcome Research and Development

Flechner 1998 Kidney

Methods
  • Study design: parallel RCT
  • Time frame: April 1996 to December 1997
  • Follow-up period: 6 to 27 months
  • Loss to follow-up: 0%


Participants
  • Country: USA
  • Setting: tertiary single centre
  • Kidney transplant recipients > 18 years and < 101 kg; D/R+, D+/R-


Treatment group

  • Number: 40
  • Mean age: 47.9 years
  • Sex (M/F): 30/10


Control group

  • Number: 39
  • Mean age: 50.2 years
  • Sex (M/F): 31/8


Exclusion criteria

  • D-/R-; Allergy to GCV/ACV; AIDS; WBC < 3000; platelets < 100,000; previous viral hepatitis


InterventionsTreatment group

  • GCV: 1000 mg orally 3 times/d for 84 days starting on day 1


Control group

  • ACV: 800 mg orally 4 times/d for 84 days starting on day 1


Co-interventions

  • CMV IgG given to D+/R- recipients in each group; CSA, AZA (⅓), MMF (⅔), OKT-3


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive organ disease
  4. CMV infection: CMV culture
  5. All-cause mortality
  6. Death due to CMV disease
  7. Acute rejection
  8. Opportunistic infections


Notes
  1. Exclusions post-randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated list. Information provided by authors

Allocation concealment (selection bias)Low riskCentral research coordinator

Blinding of participants and personnel (performance bias)
All outcomes
High riskMedications differ between intervention groups. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskMedications differ between intervention groups. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants were followed to death/graft loss or June 1998

Selective reporting (reporting bias)High riskIncomplete outcome reporting. No report of graft loss

Other biasUnclear riskNo information provided about pharmaceutical sponsorship

Gane 1997 Liver

Methods
  • Study design: parallel RCT
  • Time frame: December 1993 to April 1995
  • Follow-up period: 1 year
  • Loss to follow-up: 0%


Participants
  • Country: USA, Europe
  • Setting: tertiary multicentre
  • Primary liver transplant recipients aged > 18 years; D/R+, D+/R-


Treatment group

  • Number: 150
  • Mean age ± SD: 46.8 ± 11.6 years
  • Sex (M/F): 92/58


Control group

  • Number: 154
  • Mean age ± SD: 48.1 ± 10.9 years
  • Sex (M/F): 82/72


Exclusion criteria

  • Multiple organ transplant; D-/R- (2 patients inadvertently randomised and included in analysis); unable to take oral medications; neutrophils < 1000; platelets < 25,000; creatinine > 300


InterventionsTreatment group

  • GCV: 1000 mg (4 tablets) orally 3 times/d until day 98 starting within 10 days of transplant


Control group

  • Matching placebo: 4 tablets orally 3 times/d until day 98 starting within 10 days of transplant


Co-interventions

  • CSA, TAC (52 patients), ALG (61 patients)


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive organ disease
  4. CMV infection: CMV antigenaemia, IgM, CMV culture
  5. All-cause mortality
  6. Death due to CMV disease
  7. Acute rejection
  8. Graft loss
  9. Opportunistic infection
  10. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear risk"Randomised trial" but no further information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low riskMatching placebo capsules

Blinding of outcome assessment (detection bias)
All outcomes
Low riskMatching placebo capsules

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete 12 month data available on all participants

Selective reporting (reporting bias)Low riskAll expected outcomes reported

Other biasHigh riskGrant support from Roche Global Development

Gavalda 1997 Liver

Methods
  • Study design: parallel RCT
  • Time frame: June 1991 to November 1993
  • Follow-up period: 12 months
  • Loss to follow-up: 0%


Participants
  • Country: Spain
  • Setting: tertiary single centre
  • Primary liver transplant recipient; D/R+


Treatment group

  • Number: 37
  • Median age (range): 57 years (34 to 66)
  • Sex (M/F): 25/12


Control group

  • Number: 36
  • Median age (range): 54 years (20 to 65)
  • Sex (M/F): 23/13


Exclusion criteria

  • Second transplant recipients


InterventionsTreatment group

  • ACV: 400 mg orally 5 times/d for 16 weeks starting 3 to 30 days (median 7 days) post-transplant


Control group

  • No treatment


Co-interventions
CSA, prednisone


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive organ disease
  4. CMV infection: CMV culture
  5. All-cause mortality
  6. Opportunistic infections
  7. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear risk"Randomized study" but no other information provided

Blinding of participants and personnel (performance bias)
All outcomes
High riskControl group received no medication. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskControl group received no medication. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskConsecutive adult recipients enrolled. 7 did not complete study. All included in analysis

Selective reporting (reporting bias)High riskIncomplete outcome reporting. No or limited reporting of acute rejection, adverse effects

Other biasUnclear riskNo information provided on pharmaceutical sponsorship

Green 1997 Liver

Methods
  • Study design: parallel RCT
  • Time frame: July 1992 to March 1994
  • Follow-up period: 1 year
  • Loss to follow-up: 0%


Participants
  • Country: USA
  • Setting: tertiary single centre
  • First liver transplant recipients aged < 18 years


Treatment group

  • Number: 24
  • Mean age: 4.9 years
  • Sex (M/F): NS


Control group

  • Number: 24
  • Mean age: 4.3 years
  • Sex (M/F): NS


Exclusion criteria

  • Multi-organ recipients


InterventionsTreatment group

  • GCV: 5 mg/kg twice/d IV for 14 days starting day 1
  • ACV: 800 mg/m² orally 4 times/d to 1 year


Control group

  • GCV: 5 mg/kg twice/d IV for 14 days starting day 1


Co-interventions

  • TAC, prednisone


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive tissue disease
  4. CMV infection: CMV culture
  5. All-cause mortality
  6. Opportunistic infections


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStratified according to donor/recipient serostatus. Method not reported.

Allocation concealment (selection bias)Unclear risk"A randomized trial" but no further information provided

Blinding of participants and personnel (performance bias)
All outcomes
High riskControl group received no medication after initial two weeks of ganciclovir therapy. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskControl group received no medication after initial two weeks of ganciclovir therapy. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients enrolled in study were included in analysis

Selective reporting (reporting bias)High riskIncomplete reporting of outcomes. No or limited reporting of acute rejection, graft loss, adverse effects

Other biasUnclear riskStudy ended following interim analysis which showed no benefit of prolonged course of acyclovir and families requesting that their children receive acyclovir rather than enter trial. No information provided on pharmaceutical sponsorship

Hertz 1998 Heart/lung

Methods
  • Study design: parallel RCT
  • Time frame: January 1993 to January 1996
  • Follow-up period: 1 year
  • Loss to follow-up: 0%


Participants
  • Country: USA
  • Setting: tertiary single centre
  • Lung or heart/lung transplant recipients; D/R+; D+/R-


Treatment group

  • Number: 35
  • Mean age ± SD: 46.4 ± 11.4 years
  • Sex (M/F): 15/20


Control group

  • Number: 37
  • Mean age ± SD: 49.1 ± 8.7 years
  • Sex (M/F): 14/23


Exclusion criteria

  • D-/R-


InterventionsTreatment group

  • GCV: 5 mg/kg twice/d IV on days 8 to 21; 5 mg/kg IV 3 times/wk to 90 days


Control group

  • GCV: 5 mg/kg twice/d IV on days 8 to 21; 5 mg/kg IV daily to 90 days


Co-interventions

  • CSA, AZA, prednisone


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV tissue invasive disease
  4. CMV infection: CMV culture of bronchial lavage
  5. All-cause mortality
  6. Death due to CMV disease
  7. Opportunistic infections
  8. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear risk"Randomized trial" in title but no information provided

Blinding of participants and personnel (performance bias)
All outcomes
High riskDifferent interventions given to groups. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskDifferent interventions given to groups. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskOne patient unable to complete therapy but included in analyses

Selective reporting (reporting bias)High riskIncomplete outcome reporting. No or limited reporting of graft loss, adverse effects

Other biasUnclear riskNo information provided about pharmaceutical sponsorship

Hibberd 1995 Kidney

Methods
  • Study design: parallel RCT
  • Time frame: November 1990 to September 1992
  • Follow-up period: 6 months
  • Loss to follow-up: 1.8% (2 lost at 32 days and 78 days)


Participants
  • Country: USA
  • Setting: tertiary multicentre
  • Kidney transplant recipients; receiving ALG preparations for induction or treatment of rejection; D/R+


Treatment group

  • Number: 64
  • Mean age ± SEM: 44.2 ± 1.62 years
  • Sex (M/F): 36/28


Control group

  • Number: 49
  • Mean age ± SEM: 42.8 ± 1.99 years
  • Sex (M/F): 33/16


Exclusion criteria

  • Aged < 20 years; pregnant; multi-organ recipient; treatment with other antiviral agent


InterventionsTreatment group

  • GCV: 2.5 mg/kg/d IV during ALG therapy (median duration 9 days) starting within 24 hours of first dose of ALG


Control group

  • No treatment


Co-interventions

  • CSA, AZA, prednisone, ALG or OKT-3


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive organ disease
  4. CMV infection: CMV culture
  5. All-cause mortality
  6. Death due to CMV disease
  7. Graft loss
  8. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Separate randomization lists for each center" but no other information available

Allocation concealment (selection bias)Unclear risk"Patients were randomly assigned" but no other information available

Blinding of participants and personnel (performance bias)
All outcomes
High risk"Investigators at each site knew which patients received the study drug". Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High risk"Investigators at each site knew which patients received the study drug". Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants included in the analyses

Selective reporting (reporting bias)High riskIncomplete outcome reporting. No or limited reporting of acute rejection, adverse effects

Other biasHigh riskSupported in part by a grant from Ortho Pharmaceutical Corporation. Ganciclovir provided by Syntex Laboratories Inc

IMPACT 2010 Kidney

Methods
  • Study design: parallel RCT
  • Time frame: March 2006 to August 2008 (final data collection date for primary outcome measure)
  • Follow-up period: 24 months
  • Loss to follow-up: 6/326 did not receive experimental therapy. 103 subsequently withdrew from treatment but all who received at least one dose of medication and underwent post randomisation safety assessment were included in ITT analysis for safety. All who received at least one dose of therapy and were D+/R- were included in efficacy study


Participants
  • Countries: 65 transplant centres in 13 countries
  • Setting: tertiary multicentre
  • Kidney transplant recipients


Treatment group 1

  • Number: 156
  • Mean age ± SD: 47 ± 13.5 years
  • Sex (M/F): 116/40


Treatment group 2

  • Number: 164
  • Mean age ± SD: 48.5 ± 13.8 years
  • Sex (M/F): 119/45


Exclusion criteria

  • CMV disease; HIV; hepatitis B; hepatitis C at enrolment; received CMV IgG in previous 1 month; multi-organ transplant


InterventionsTreatment group 1

  • 200 days group
    • VGCV: 900 mg/d orally for 200 days started as soon as able to tolerate oral medications and by 10 days post-transplant


Treatment group 2

  • 100 days group
  • VGCV: 900 mg/d orally for 100 days started as soon as able to tolerate oral medications and by 10 days post-transplant followed by placebo orally for 100 days


Co-interventions

  • Induction therapy with ATG (52, 52) or IL2Ra (79, 72)


Outcomes
  1. CMV disease
  2. CMV infection: CMV DNA by PCR, CMV antigenaemia
  3. All-cause mortality
  4. Acute rejection
  5. Graft loss
  6. Opportunistic infections
  7. Adverse effects
  8. Death due to CMV disease
  9. Ganciclovir resistant mutations


NotesFurther Information sought from the authors on sequence generation and allocation concealment but no response obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Patients randomized sequentially in a 1:1 ratio at each study centre in the order in which they were enrolled". No other information provided

Allocation concealment (selection bias)Low riskCentral randomisation

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind. Placebo and active drug "were indistinguishable"

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Study investigators, site staff and sponsors were fully blinded to treatment allocation until after analysis of the primary endpoint"

Incomplete outcome data (attrition bias)
All outcomes
Low riskITT analysis. Patients excluded who did not receive at least one dose of medication but only 8 patients excluded and numbers unlikely to influence true outcome

Selective reporting (reporting bias)Low riskAll expected outcomes reported

Other biasHigh riskFunded by F Hoffman-La-Roche. Medical writers funded by sponsors. "There is an agreement between the Principal Investigators and the Sponsor that restricts the principal investigators' rights to discuss or publish trial results after the trial is completed"

Kletzmayr 1996 Kidney

Methods
  • Study design: parallel RCT
  • Time frame: NS
  • Follow-up period: 1 year
  • Loss to follow-up: 5.6%


ParticipantsCountry: Austria

  • Setting: tertiary single centre
  • Kidney transplant recipients; D+/R-


Treatment group

  • Number: 22
  • Mean age ± SD: 46 ± 14 years
  • Sex (M/F): 17/5


Control group

  • Number: 10
  • Mean age ± SD: 44 ± 13 years
  • Sex (M/F): 7/3


Exclusion criteria: NS


InterventionsTreatment group

  • ACV: 800 mg 3 times/d orally for 3 months starting first post-op day


Control group

  • No treatment


Co-interventions

  • CSA, AZA, prednisone


Outcomes
  1. CMV disease
  2. CMV infection: CMV antigenaemia, CMV culture, IgM
  3. All-cause mortality
  4. Acute rejection
  5. Graft loss


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Patients randomized... in a 2:1 ratio". No information on sequence generation provided

Allocation concealment (selection bias)Unclear risk"Patients were randomly assigned". No information provided on method

Blinding of participants and personnel (performance bias)
All outcomes
High riskControl group received no specific treatment. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskControl group received no specific treatment. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low risk4/36 excluded from analysis

Selective reporting (reporting bias)High riskIncomplete outcome reporting. No or limited reporting of opportunistic infections/adverse effects

Other biasUnclear riskNo information provided on pharmaceutical sponsorship

Leray 1995 Kidney

Methods
  • Study design: parallel RCT
  • Time frame: January 1991 to July 1994
  • Follow-up period: Unclear
  • Loss to follow-up: 0%


Participants
  • Country: France
  • Setting: tertiary single centre
  • Kidney transplant recipients; D+/R-


Treatment group

  • Number: 13
  • Age: NS
  • Sex (M/F): NS


Control group

  • Number: 10
  • Age: NS
  • Sex (M/F): NS


Exclusion criteria: NS


InterventionsTreatment group

  • GCV: 5 mg/kg IV twice/d for 14 days starting 14 days post-transplant


Control group

  • No treatment


Co-interventions

  • CSA, AZA, prednisone, ALG


Outcomes
  1. CMV disease
  2. CMV infection: CMV antigenaemia, CMV culture, IgM
  3. Acute rejection
  4. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: none reported
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear risk"On day 14 patients were randomized". No other information provided

Blinding of participants and personnel (performance bias)
All outcomes
High riskControl group received no specific therapy. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskControl group received no specific therapy. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear if any patients were excluded from analysis

Selective reporting (reporting bias)Unclear riskAbstract only available

Other biasUnclear riskNo information provided on sponsorship

Lowance 1999 Kidney

Methods
  • Study design: parallel RCT
  • Time frame: July 1992 to December 1996
  • Follow-up period: 12 months
  • Loss to follow-up: 0%


Participants
  • Country: USA/Europe
  • Setting: tertiary multicentre
  • Kidney transplant recipients; D/R+, D+/R-


Treatment group

  • Number: 306; D/R+ (204); D+/R- (102)
  • Mean age ± SD: D/R+ (43.6 ± 13.1 years); D+/R- (40.3 ± 14.2 years)
  • Sex (M/F): D/R+ 153/51; D+/R- 60/42


Control group

  • Number: 310; D/R+ (204); D+/R- (106)
  • Mean age ± SD: D/R+ (45.1 ± 13 years); D+/R- (45.6 ± 13.5 years)
  • Sex (M/F): D/R+ 124/80; D+/R- 65/41


Exclusion criteria

  • D-/R-; active herpes infection; antiviral therapy in previous 2 months


InterventionsTreatment group

  • VACV: 2000 mg orally 4 times/d for 90 days starting within 3 days of transplant


Control group

  • Placebo: orally 4 times/d for 90 days starting within 3 days of transplant


Co-interventions

  • CSA, AZA, TAC (6), MMF (7), ATG or ALG (251), OKT-3 (102)


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive organ disease
  4. CMV infection: CMV culture
  5. All-cause mortality
  6. Death due to CMV disease
  7. Acute rejection
  8. Opportunistic infections
  9. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Randomly assigned in 1:1 ratio according to study site". No other information provided

Allocation concealment (selection bias)Unclear risk"Randomly assigned" but method of allocation unstated

Blinding of participants and personnel (performance bias)
All outcomes
Low riskMatching placebo tablets

Blinding of outcome assessment (detection bias)
All outcomes
Low riskMatching placebo tablets

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients included in intention to treat analysis

Selective reporting (reporting bias)High riskNot all expected outcomes reported. No graft loss data reported

Other biasHigh riskSupported by Glaxo Wellcome. Employees included as authors

Macdonald 1995 Heart

Methods
  • Study design: parallel RCT
  • Time frame: NS
  • Follow-up period: 12 months
  • Loss to follow-up: 0%


Participants
  • Country: Australia
  • Setting: tertiary single centre
  • Heart transplant recipients; D/R+, D+/R-


Treatment group

  • Number: 28
  • Mean age ± SD: 48 ± 15 years
  • Sex (M/F): 24/4


Control group

  • Number: 28
  • Mean age ± SD: 45 ± 15 years
  • Sex (M/F): 25/3


Exclusion criteria

  • D-/R-


InterventionsTreatment group

  • GCV: 5 mg/kg IV 3 times/wk for 6 weeks starting pre-transplant


Control group

  • Placebo: IV 3 times/wk for 6 weeks starting pre-transplant


Co-interventions

  • CSA, AZA, prednisone, ATG


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive organ disease
  4. CMV infection: CMV culture
  5. All-cause mortality
  6. Opportunistic infections
  7. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTable of random numbers. Separate randomisation sequences were used according to serostatus

Allocation concealment (selection bias)Unclear riskMethod of allocation not stated

Blinding of participants and personnel (performance bias)
All outcomes
Low riskMatching placebo administered to control group

Blinding of outcome assessment (detection bias)
All outcomes
Low riskMatching placebo administered to control group

Incomplete outcome data (attrition bias)
All outcomes
Low riskConsecutive patients enrolled and all included in analysis

Selective reporting (reporting bias)High riskIncomplete outcome reporting. No report of graft loss

Other biasUnclear riskNo report on pharmaceutical sponsorship

Martin 1994 Liver

Methods
  • Study design: parallel RCT
  • Time frame: February 1991 to August 1991
  • Follow-up period: 24 weeks
  • Loss to follow-up: 0%


Participants
  • Country: USA
  • Setting: tertiary single centre
  • Liver transplant recipients aged > 18 years


Treatment group

  • Number: 68
  • Mean age ± SD: 48.1 ± 13.2 years
  • Sex (M/F): 43/25


Control group

  • Number: 71
  • Mean age ± SD: 47 ± 12.9 years


Sex (M/F): 35/36

Exclusion criteria

  • Fulminant hepatic failure; stage 3/4 hepatic coma; hepatic malignancies with pre-operative chemotherapy


InterventionsTreatment group

  • GCV: 5 mg/kg twice/d IV for 14 days starting 2 days post-transplant
  • ACV: 800 mg orally 4 times/d to 10 weeks


Control group

  • ACV: 800 mg orally 4 times/d for 10 weeks starting 2 days post-transplant


Co-interventions

  • TAC


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive tissue disease
  4. CMV infection: CMV culture, IgM
  5. All-cause mortality
  6. Acute rejection
  7. Graft loss
  8. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: none
  2. Stop or end point: NS
  3. Four excluded after randomisation (active CMV (1), death from sepsis (2), unable to take medication (1)) and one randomised to ganciclovir given acyclovir and analysed in acyclovir group


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Fixed block randomization scheme (block size = 4)"

Allocation concealment (selection bias)Unclear riskNo information provided on allocation

Blinding of participants and personnel (performance bias)
All outcomes
High riskGroups received different medications by different routes. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskGroups received different medications by different routes. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low risk4/143. Missing outcome data unlikely to be related to true outcome

Selective reporting (reporting bias)High riskDid not report opportunistic infections

Other biasUnclear riskNo information on pharmaceutical sponsorship provided

Merigan 1992 Heart

Methods
  • Study design: parallel RCT
  • Time frame: NS
  • Follow-up period: 120 days
  • Loss to follow-up: 0%


Participants
  • Country: USA
  • Setting: tertiary multicentre
  • Heart transplant recipients; D/R+, D+/R-.


Treatment group

  • Number: 76
  • Mean age ± SEM: 47.1 ± 1.55 years
  • Sex (M/F): 68/8


Control group

  • Number: 73
  • Mean age ± SEM: 47.6 ± 1.4 years
  • Sex (M/F): 63/10


Exclusion criteria

  • D-/R-; combined heart-lung transplant recipients; antiviral agents in previous 7 days; WBC < 1500; platelets < 50,000; GFR < 10 or > 400


InterventionsTreatment group

  • GCV: 5 mg/kg IV twice/d for 14 days starting on day 1 post-transplant but delay for 2 to 7 days in 21%


Control group

  • Placebo: IV twice/d for 14 days starting on day 1 post-transplant but delay for 2 to 7 days in 23%


Co-interventions

  • CSA, AZA, prednisone, OKT-3


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive organ disease
  4. CMV infection: CMV culture
  5. All-cause mortality
  6. Opportunistic infections
  7. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: Study stopped after interim assessment after 80 patients enrolled when difference between treatment groups evident


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Stratified at randomization according to their CMV serostatus". Otherwise no information provided

Allocation concealment (selection bias)Unclear riskPatients were... randomly assigned". No information provided on allocation

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPatients in control group received infusions of placebo medication

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPatients in control group received infusions of placebo medication

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients included in analysis

Selective reporting (reporting bias)High riskIncomplete outcome reporting. No report of graft loss

Other biasHigh riskSupported by Public Health Service grant and by grant from Syntex Corporation (employees included as authors)

Nafar 2005 Kidney

Methods
  • Study design: parallel RCT
  • Time frame: September 2001 to November 2001
  • Follow-up period: 12 months
  • Loss to follow-up: 0%


Participants
  • Country: Iran
  • Setting: tertiary single centre
  • Kidney transplant recipients; D+/R+; ATG required for rejection; second transplant; deceased donor transplant
  • Mean age ± SD: 37.8 ± 9.8 years


Treatment group

  • Number: 16 (17 entered the study)
  • Age: NS
  • Sex (M/F): 11/5


Control group

  • Number: 14 (17 entered study)
  • Age: NS
  • Sex (M/F): 9/5


Exclusion criteria: NS


InterventionsTreatment group

  • GCV: 1000 mg oral 3 times/d for 3 months


Control group

  • GCV: 5 mg/kg/d IV for 2 weeks


Co-interventions

  • ATG for induction or rejection; other immunosuppression NS


Outcomes
  1. CMV disease
  2. CMV viraemia: CMV antigenaemia
  3. Acute rejection
  4. Adverse effects
  5. Kidney function at 12 months


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. One patient from treatment group excluded following graft loss; 3 excluded from control group (graft loss 1, pre-existing CMV antigenaemia, refusal to be followed).
  3. Stop or end point: NS
  4. Additional data requested from authors: none


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information available

Allocation concealment (selection bias)Unclear risk"Randomized prospective trial" in title but no other information provided

Blinding of participants and personnel (performance bias)
All outcomes
High riskDifferent interventions given to groups. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskDifferent interventions given to groups. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
High risk4/34 excluded. 3 excluded from !V ganciclovir arm

Selective reporting (reporting bias)High riskDrug toxicity and side effects not reported

Other biasUnclear riskNo information provided on pharmaceutical sponsorship

Nakazato 1993 Liver

Methods
  • Study design: parallel RCT
  • Time frame: August 1990 to November 1991
  • Follow-up period: 1 year
  • Loss to follow-up: 0%


Participants
  • Country: USA
  • Setting: tertiary single centre
  • Liver transplant recipients


Treatment group

  • Number: 52
  • Mean age ± SD: 38.7 ± 21.5 years
  • Sex (M/F): NS


Control group

  • Number: 52
  • Mean age ± SD: 34.9 ± 22.8 years
  • Sex (M/F): NS


Exclusion criteria: NS


InterventionsTreatment group

  • GCV: 5 mg/kg/d IV during inpatient periods in first 3 months post-transplant
  • ACV: 5 mg/kg/d oral to 3 months


Control group

  • ACV: 5 mg/kg/d IV during inpatient periods in first 3 months post-transplant
  • ACV: 5 mg/kg/d oral to 3 months


Co-interventions

  • IgG IV 200 mg/kg/d during inpatient periods in first 3 months post-transplant; CSA (81), TAC (23), prednisone


Outcomes
  1. CMV disease: CMV culture/histopathology and symptoms
  2. All-cause mortality
  3. Acute rejection
  4. Graft loss
  5. Opportunistic infections
  6. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear risk"Preliminary report of a randomized trial..." in title. Otherwise no information provided

Blinding of participants and personnel (performance bias)
All outcomes
High riskDifferent interventions given to groups. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskDifferent interventions given to groups. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients included in analyses

Selective reporting (reporting bias)High riskNo CMV infection or adverse effects reported

Other biasHigh riskSupported in part by Sandoz Pharmaceuticals

Palmer 2010 Lung

Methods
  • Study design: parallel RCT
  • Time frame: July 2003 to January 2007
  • Follow-up period: 13 months
  • Loss to follow-up: 45/136 withdrawn but all included in analysis


Participants
  • Country: USA
  • Setting/Design: tertiary multicentre (11 centres)
  • Single or double first lung transplant recipient; aged ≥ 18 years; adequate haematological, kidney and liver function; D/R+, D+/R-; received IV GCV for 2 weeks post-transplant; able to tolerate oral medications; negative PCR/bronchoscopy for CMV at baseline and at day 75 when randomisation occurred


Treatment group 1

  • Number: 70
  • Age (IQR): 56 (45 to 62) years
  • Sex (M/F): 29/41


Treatment group 2

  • Number: 66
  • Age (IQR): 55 (42 to 61) years
  • Sex (M/F): 38/28


Exclusion criteria

  • Re-transplant, on ventilator; current/previous GCV outside study; invasive fungal disease; using disallowed medications; previous severe reaction to GCV; diarrhoea; malabsorption; liver/kidney/haematological dysfunction


InterventionsTreatment group 1

  • 12 months group
    • IV GCV: for 2 weeks starting within 24 hours of transplant
    • Oral VGCV: 900 mg/d for 3 months
    • Oral VGCV: 900 mg/d for 9 months


Treatment group 2

  • 3 months group
    • IV GCV: for 2 weeks starting within 24 hours of transplant
    • Oral VGCV: 900 mg/d for 3 months
    • Placebo: for 9 months


Co-interventions

  • TAC 50/70 and 46/66. ALG 23/70 and 21/66


Outcomes
  1. CMV disease
  2. CMV infection: CMV-DNA by PCR on blood and/or broncholavage
  3. All-cause mortality (data from 1 centre)
  4. Acute rejection
  5. Opportunistic infections
  6. Adverse reactions


Notes
  • Information on absolute numbers with outcomes requested from investigators. Response received but information not available


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomised 1.1 stratified by site at 3 months. Computer-generated randomised list managed centrally

Allocation concealment (selection bias)Low riskRandomised at 3 months. Independent pharmacist dispensed medically centrally

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo controlled

Blinding of outcome assessment (detection bias)
All outcomes
Low riskBronchoscopies performed by investigators blinded to treatment group

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients included in analysis

Selective reporting (reporting bias)High riskIncomplete reporting of outcomes. Reports of deaths only available for one institution

Other biasHigh riskFunded by Roche Pharmaceuticals. All data analyses performed at Duke Clinical Research Institute

Pavlopoulou 2005 Kidney

Methods
  • Study design: parallel RCT
  • Time frame: April 1999 to September 2000
  • Follow-up period: 6 months
  • Loss to follow-up: 0%


Participants
  • Country: Greece
  • Setting: tertiary single centre
  • Kidney transplant recipient; D/R+, D+/R-


Treatment group

  • Number: 43
  • Mean age ± SD: 40.7 ± 12 years
  • Sex (M/F): 34/9


Control group

  • Number: 40
  • Mean age ± SD: 43.1 ± 15 years
  • Sex (M/F): 29/11


Exclusion criteria

  • Active herpes viral infection; antiviral therapy in previous 14 days


InterventionsTreatment group

  • VACV: 2000 mg oral 4 times/d starting within 72 hours of transplant for 3 months


Control group

  • GCV: 1000 mg oral 3 times/d starting within 72 hours of transplant for 3 months


Co-interventions

  • CSA or TAC, sirolimus (11), IL2R antagonists 23 (treatment) and 25 (control), ATG 4 (treatment) and 2 (control)


Outcomes
  1. CMV disease
  2. CMV infection: CMV-DNA
  3. All-cause mortality
  4. Acute rejection
  5. Opportunistic infections
  6. Adverse reactions
  7. Kidney function at 6 months


Notes
  1. Exclusions post randomisation but pre-intervention: NS
  2. Stop or end point: NS
  3. Additional data requested from authors: None


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskAssigned randomly in 1:1 ratio but no other information provided

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen label. Different interventions given to groups. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen label. Different interventions given to groups. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients included in analyses

Selective reporting (reporting bias)High riskIncomplete outcome reporting. Limited reporting of adverse effects

Other biasUnclear riskNo information provided on pharmaceutical sponsorship

Paya 2004 All

Methods
  • Study design: parallel RCT
  • Time frame: April 2000 to August 2001
  • Follow-up period: 12 months
  • Loss to follow-up: 0%


Participants
  • Country: USA/Europe/Canada/Australia
  • Setting: tertiary multicentre
  • Solid organ transplant recipient aged >12 years (liver, kidney, heart, kidney-pancreas); D+/R-; first transplant; adequate liver and kidney function


Treatment group

  • Number: 245
  • Mean age: 45.7 years
  • Sex (M/F): 179/66


Control group

  • Number: 127
  • Mean age: 45.3 years
  • Sex (M/F): 95/32


Exclusion criteria

  • Retransplant; history of CMV infection/disease; CMV therapy in previous 30 days; severe uncontrolled diarrhoea; malabsorption


InterventionsTreatment group

  • VGCV: 900 mg oral daily starting within 10 days of transplant for 100 days


Control group

  • GCV: 1000 mg oral 3 times/d starting within 10 days of transplant for 100 days


Co-interventions

  • Immunosuppression according to protocol of centre


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV tissue invasive disease
  4. CMV infection: CMV-DNA; infection confirmed in central lab
  5. All-cause mortality
  6. Death due to CMV disease
  7. Acute rejection
  8. Graft loss
  9. Opportunistic infections
  10. Adverse reactions


NotesExclusions post-randomisation but pre-intervention: 2 excluded from safety analysis as did not receive medication, 8 excluded from primary outcome analysis as not D+/R-


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskStratified according to organ transplanted and assigned in 2:1 ratio at each centre

Allocation concealment (selection bias)Low risk"Treatment randomization numbers were assigned by telephone via a central randomization center"

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-dummy. Placebo tablets given to both groups

Blinding of outcome assessment (detection bias)
All outcomes
Low riskEnd points adjudicated by independent (of sponsor and study) blinded Endpoint Committee

Incomplete outcome data (attrition bias)
All outcomes
Low riskITT population included 364/372 patients. Safety 370/372. Reasons for missing outcomes data unlikely to be related to true outcome

Selective reporting (reporting bias)Low riskExpected outcomes all reported

Other biasHigh riskStudy funded by Hoffman-La Roche

Pouteil-Noble 1996 Kidney

Methods
  • Study design: parallel RCT
  • Time frame: NS
  • Follow-up period: 6 months
  • Loss to follow-up: 0%


Participants
  • Country: France
  • Setting: tertiary single centre
  • Kidney transplant recipients; all CMV serostatus


Treatment group

  • Number: 24
  • Age: NS
  • Sex (M/F): NS


Control group

  • Number: 26
  • Age: NS
  • Sex (M/F): NS


Exclusion criteria: NS


InterventionsTreatment group

  • GCV: 5 mg/kg/d IV for 14 days starting on day of transplant
  • ACV: 800 mg oral 3 times/d from day 14 to 3 months


Control group

  • Placebo: given as for treatment arm


Co-interventions: NS


Outcomes
  1. CMV disease
  2. CMV infection: CMV culture, IgM
  3. All-cause mortality


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided except stratification for CMV serostatus

Allocation concealment (selection bias)Low riskAdequate allocation (information received from authors)

Blinding of participants and personnel (performance bias)
All outcomes
Low riskControl group received placebo

Blinding of outcome assessment (detection bias)
All outcomes
Low riskControl group received placebo

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients included in analyses

Selective reporting (reporting bias)Unclear riskAbstract only

Other biasUnclear riskWork supported by Wellcome Laboratories and Hospices Civils de Lyon

Reischig 2005 Kidney

Methods
  • Study design: parallel RCT
  • Time frame: April1999 to December 2000; January 2001 to January 2003
  • Follow-up period: 12 months
  • Loss to follow-up: 0%


Participants
  • Country: Czech Republic
  • Setting: tertiary single centre
  • Kidney transplant recipients; D/R+, D+/R-


Treatment group

  • Number: 35
  • Mean age ± SD: 45 ± 12 years
  • Sex (M/F): 26/9


Control group

  • Number: 36
  • Mean age ± SD: 48 ± 11 years
  • Sex (M/F): 25/11


Exclusion criteria

  • D-/R-; unknown CMV status; active CMV infection; treatment with antiviral agents; WBC < 4000; platelets < 150,000; allergy to study drugs


InterventionsTreatment group

  • VACV: 2000 mg oral 4 times/d starting within 3 days of transplant for 3 months


Control group

  • GCV: 1000 mg oral 3 times/d starting within 3 days of transplant for 3 months


Co-interventions

  • ACV low dose to prevent herpes simplex; CSA, MMF, prednisone, ATG or OKT-3 (9), anti-IL2R monoclonal antibody/sirolimus (6)


Outcomes
  1. CMV disease
  2. CMV infection: CMV-DNA, CMV antigenaemia, CMV culture
  3. All-cause mortality
  4. Acute rejection
  5. Graft loss
  6. Adverse reactions


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS
  3. Additional data requested from authors: data on quality assessment and results obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom number generator used. (Information from authors)

Allocation concealment (selection bias)Low riskAdequate allocation based on information from authors

Blinding of participants and personnel (performance bias)
All outcomes
High riskDifferent medication schedules in each group. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskDifferent medication schedules in each group. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskRandomised consecutive patients. All patients included in analyses

Selective reporting (reporting bias)High riskIncomplete outcome reporting. No data of opportunistic infections

Other biasLow risk"The study was independent and not funded by any commercial sources"

Rondeau 1993 Kidney

Methods
  • Study design: parallel RCT
  • Time frame: January 1990 to July 1992
  • Follow-up period: 3 months
  • Loss to follow-up: 0%


Participants
  • Country: France
  • Setting: tertiary multicentre
  • Kidney transplant recipients; D+/R-


Treatment group

  • Number: 17
  • Mean age ± SEM: 43.8 ± 2.9 years
  • Sex (M/F): 13/4


Control group

  • Number: 15
  • Mean age ± SEM: 43.5 ± 3.3 years
  • Sex (M/F): 6/9


Exclusion criteria

  • Living related donor transplant recipients; WBC < 1500; platelets < 50,000; treatment with another antiviral agent


InterventionsTreatment group

  • GCV: 5 mg/kg IV twice/d for 14 days starting day 14 post-transplant


Control group

  • No treatment


Co-interventions: NS


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive organ disease
  4. CMV infection: CMV culture, IgM
  5. All-cause mortality
  6. Acute rejection
  7. Graft loss


Notes
  1. Exclusions post randomisation but pre-intervention: None reported
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information available

Allocation concealment (selection bias)Unclear risk"On day 14 after transplantation, patients were randomized...". No further information available

Blinding of participants and personnel (performance bias)
All outcomes
High riskControl group received no specific therapy. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskControl group received no specific therapy. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients included in analyses

Selective reporting (reporting bias)High riskIncomplete outcome reporting. No or limited reporting of opportunistic infections/adverse effects

Other biasLow riskWork supported in part by grants from non-pharmaceutical sources

Rostaing 1994 Kidney

Methods
  • Study design: parallel RCT
  • Time frame: April 1992 to February 1993
  • Follow-up period: mean 12 months
  • Loss to follow-up: 0%


Participants
  • Country: France
  • Setting: tertiary single centre
  • Kidney transplant recipients; D/R+


Treatment group

  • Number: 19
  • Mean age ± SD: 50.4 ± 11.3 years
  • Sex (M/F): 13/6


Control group

  • Number: 18
  • Mean age ± SD: 45.1 ± 11.1 years
  • Sex (M/F): 14/4


Exclusion criteria

  • D+/R-; D-/R- recipients


InterventionsTreatment group

  • ACV: 6 mg/kg/d IV for 3 days starting day 1 then ACV 800 mg oral 4 times/d for 3 months


Control group

  • No treatment


Co-interventions

  • CSA, AZA, prednisone, ATG


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive organ disease
  4. CMV infection: CMV culture
  5. All-cause mortality
  6. Acute rejection
  7. Graft loss
  8. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: None reported
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information available

Allocation concealment (selection bias)Unclear risk"The patients were randomized to receive either acyclovir or nothing..". No other information available

Blinding of participants and personnel (performance bias)
All outcomes
High riskControl group received no specific therapy. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskControl group received no specific therapy. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients included in analysis

Selective reporting (reporting bias)High riskNo data on opportunistic infections or adverse reactions

Other biasUnclear riskNo information provided about pharmaceutical sponsorship

Rubin 2002 All

Methods
  • Study design: parallel RCT
  • Time frame: November 1996 to January 1999
  • Follow-up period: 12 months
  • Loss to follow-up: 0% of evaluated patients


Participants
  • Country: USA
  • Setting: tertiary multicentre
  • First kidney, liver or heart transplant recipients aged >12 years; D+/R-


Treatment group

  • Number: 77
  • Mean age ± SD: 46 ± 13 years
  • Sex (M/F): 60/17


Control group

  • Number: 78
  • Mean age ± SD: 45 ± 12 years
  • Sex (M/F): 61/17


Exclusion criteria

  • D/R+; D-/R-


InterventionsTreatment group

  • GCV: 5 mg/kg/d IV for 5 to 10 days starting within 72 hours of transplant, then GCV 1000 mg oral 3 times/d to 12 weeks


Control group

  • GCV: 5 mg/kg/d IV for 5 to 10 days starting within 72 hours of transplant then ACV 400 mg oral 3 times/d to 12 weeks


Co-interventions

  • CSA (141), TAC (27), AZA (57), MMF (101), antibody therapy (56)


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive organ disease
  4. CMV infection: CMV antigenaemia, CMV culture
  5. All-cause mortality
  6. Acute rejection
  7. Opportunistic infections
  8. Adverse effects
  9. Time to CMV disease


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS
  3. 11 (5 acyclovir, 6 ganciclovir) were deemed unable to be evaluated: 7 did not qualify for protocol, 1 died, 3 lost to follow-up


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStratification for organ transplanted. Central randomisation. Otherwise no information available

Allocation concealment (selection bias)Low riskCentral randomisation

Blinding of participants and personnel (performance bias)
All outcomes
High riskPatients received different oral medications. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskPatients received different oral medications. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low risk11/166 excluded from analyses. Reasons for missing data unlikely to be related to true outcome

Selective reporting (reporting bias)High riskIncomplete reporting of outcomes. No report of graft loss

Other biasHigh riskFunded in part by a grant from F. Hoffman-LaRoche

Saliba 1993 Liver

Methods
  • Study design: parallel RCT
  • Time frame: February 1990 to February 1991
  • Follow-up period: 3 months
  • Loss to follow-up: 0%


Participants
  • Country: France
  • Setting/Design: tertiary single centre
  • Liver transplant recipients; D/R+


Treatment group

  • Number: 60
  • Mean age ± SD: 45.3 ± 12 years
  • Sex (M/F): 36/24


Control group

  • Number: 60
  • Mean age ± SD: 44.5 ± 13 years
  • Sex (M/F): 35/35


Exclusion criteria

  • D+/R-; D-/R- recipients


InterventionsTreatment group

  • ACV: 500 mg/m²/d IV for 10 days, then 800 mg oral 4 times/d to 3 months


Control group

  • No treatment


Co-interventions

  • CSA, AZA, prednisone


Outcomes
  1. CMV disease
  2. CMV infection: CMV culture
  3. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information available

Allocation concealment (selection bias)Low riskAdequate allocation concealment (information from authors)

Blinding of participants and personnel (performance bias)
All outcomes
High riskControl group received no specific therapy. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskControl group received no specific therapy. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskConsecutive recruitment. All patients included in analyses

Selective reporting (reporting bias)Unclear riskAbstract only

Other biasUnclear riskNo information provided on pharmaceutical sponsorship

Winston 1995 Liver

Methods
  • Study design: parallel RCT
  • Time frame: NS
  • Follow-up period: 4 months
  • Loss to follow-up: 0%


Participants
  • Country: USA
  • Setting: tertiary single centre
  • First liver transplant recipients aged > 12 years; all serologies


Treatment group

  • Number: 124
  • Mean age (range): 52 years (20 to 72)
  • Sex (M/F): 67/57


Control group

  • Number: 126
  • Mean age (range): 47 years (20 to 74)
  • Sex (M/F): 67/59


Exclusion criteria

  • Second transplants


InterventionsTreatment group

  • GCV: 6 mg/kg/d IV to day 30; GCV 6 mg/kg/d IV Monday to Friday to day 100


Control group

  • ACV: 10 mg/kg IV 8 hourly until discharge; ACV 800 mg oral 4 times/d to day 100


Co-interventions

  • CSA, TAC (38), AZA, prednisone


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV invasive organ disease
  4. CMV infection: CMV culture, isolation from any site
  5. All-cause mortality
  6. Death due to CMV disease
  7. Acute rejection
  8. Opportunistic infections
  9. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation stratified according to CMV status but no other information provided

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
High riskPatients given different medications by different routes. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskPatients given different medications by different routes. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients included in analyses

Selective reporting (reporting bias)Low riskAll expected outcomes reported

Other biasHigh riskSupported in part by non-pharmaceutical grants. Ganciclovir from Syntex Research

Winston 2003 Liver

Methods
  • Study design: parallel RCT
  • Time frame: NS
  • Follow-up period: 12 months
  • Loss to follow-up: 0%


Participants
  • Country: USA
  • Setting: tertiary single centre
  • Liver transplant recipients; D/R+


Treatment group

  • Number: 110
  • Mean age (range): 51 years (7 to 78)
  • Sex (M/F): 58/52


Control group

  • Number: 109
  • Mean age (range): 51 years (7 to 71)
  • Sex (M/F): 58/51


Exclusion criteria

  • D+/R-; D-/R- recipients


InterventionsTreatment group

  • GCV: 6 mg/kg/d IV to day 14 starting day of transplant; GCV 1000 mg oral 3 times/d to day 100


Control group

  • GCV: 6 mg/kg/d IV to day 14 starting day of transplant; ACV 800 mg oral 4 times/d to day 100


Co-interventions

  • CSA (58), TAC (164), AZA (128), MMF (85), prednisone


Outcomes
  1. CMV disease: CMV DNA, CMV culture
  2. CMV syndrome
  3. CMV tissue invasive disease
  4. All-cause mortality
  5. Death due to CMV disease
  6. Acute rejection
  7. Opportunistic infections
  8. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: Unclear
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear risk"Patients were assigned randomly" but no other information available

Blinding of participants and personnel (performance bias)
All outcomes
High riskDifferent interventions given to groups with different dose frequency. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskDifferent interventions given to groups with different dose frequency. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients included in analyses

Selective reporting (reporting bias)High riskIncomplete reporting of outcomes. No report of CMV infection and graft loss

Other biasHigh riskSupported in part by a research grant from Roche Laboratories

Winston 2004 Liver

Methods
  • Study design: parallel RCT
  • Time frame: June 1997 to April 2000
  • Follow-up period: 1 year
  • Loss to follow-up: 0%


Participants
  • Country: USA
  • Setting: tertiary single centre
  • Liver transplant recipients; D+/R-


Treatment group

  • Number: 32
  • Mean age (range): 49 years (13 to 67)
  • Sex (M/F): 24/8


Control group

  • Number: 32
  • Mean age (range): 46 years (6 to 73)
  • Sex (M/F): 23/9


Exclusion criteria

  • D/R+; D-/R-


InterventionsTreatment group

  • GCV: 6 mg/kg IV daily days 1 to 14; GCV 1000 mg oral 3 times/d on days 15 to 86


Control group

  • GCV: 6 mg/kg IV daily days 1 to 14; GCV 6 mg/kg IV Monday to Friday from days 15 to 86


Co-interventions

  • CSA (10), TAC (54), MMF (29), AZA (3), prednisone


Outcomes
  1. CMV disease
  2. CMV syndrome
  3. CMV tissue invasive disease
  4. All-cause mortality
  5. Opportunistic infections
  6. Adverse effects


Notes
  1. Exclusions post randomisation but pre-intervention: None
  2. Stop or end point: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information available

Allocation concealment (selection bias)Unclear risk"Randomized controlled trial" in title but no other information provided

Blinding of participants and personnel (performance bias)
All outcomes
High riskDifferent interventions given to groups. Primary outcome of CMV disease could be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskDifferent interventions given to groups. Primary outcome of CMV disease could be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients followed for 1 year or until death

Selective reporting (reporting bias)High riskIncomplete outcome reporting. No report of CMV infection, graft loss

Other biasUnclear riskSupported in part by research grant from Roche Laboratories

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Ahsan 1998Not RCT (sequential)

Arbo 2000Economic evaluation of previous study

Brennan 1997Pre-emptive study

Brennan 2001Review article

Devolder 2010Ineligible intervention. Compares different methods to encourage compliance

Dickinson 1996IgG to prevent CMV

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

Fehir 1989Nonrandomised patients included

Ferreira 2004Prospective study of different immunosuppressive regimens. Not RCT

Fishman 2000Retrospective study

Gerna 2003Diagnostic test systematic review

Gerna 2008Pre-emptive therapy compared with prophylaxis

Greger 1988Ineligible intervention

Griffiths 1997Review article

Griffiths 2010Study of pre-emptive therapy vs. monitoring

Grundmann 1986Ineligible intervention. CMV IgG

Hecht 1988Not an RCT

Huurman 2006RCT of ATG versus daclizumab, not antiviral medication

Jung 2001Pre-emptive study

Jurim 1996Subgroup of previous study; outcome hepatitis B

Khoury 2006Pre-emptive study

Kim 2000Economic evaluation of previous study

Kletzmayr 2000Not RCT. Historical controls

Kliem 2008Pre-emptive study

Koetz 2001Pre-emptive study

Kuypers 1999Review article

Laske 1991Review article

Laske 1992Review article

Luan 2009Retrospective study

Lumbreras 1993Not RCT. Historical controls

MacDonald 1991Ineligible intervention. CMV IgG

Marker 1980Treatment not prophylaxis of CMV disease

Martin 1993Review article

Martin 1994Review article

Martin 1995Review article

Mattes 2004Ineligible intervention. Comparing 2 pre-emptive regimens. Results cannot be separated for bone marrow and solid organ transplant recipients

McGavin 2001GCV review

Moreno 1999Not RCT

Mullen 1998Retrospective study

Murray 1997Pre-emptive study

Paya 2002Pre-emptive study

Pescovitz 2009Pharmacokinetic study

Pouteil 1991Study of influence of HLA on CMV infection within RCT of different immunosuppressive regimens

PROTECT Study 2010Comparing pre-emptive therapy with prophylaxis

Queiroga 2003Pre-emptive study

Rayes 2001Pre-emptive study

Reischig 2008Pre-emptive study

Sagedal 2003Pre-emptive study

Said 2007Appears to be sequential study not RCT

Schafers 1988Not RCT (sequential)

Schnitzler 2000Re-analysis of previous study (1992)

Singh 1994Pre-emptive study

Singh 1995Not RCT

Singh 2000Pre-emptive study

Snydman 1991aReview article

Snydman 1991bCompares results to previous study

Snydman 1994Compares results to previous study

Snydman 2001Historical controls

Speich 1999Not RCT (sequential)

Stratta 1992Non-randomised patients included

Tong 2002Not an RCT

Turgeon 1998Not RCT (sequential)

Valantine 1995IgG study

VICTOR Study 2007Treatment of CMV disease not prophylaxis

Yang 1998Pre-emptive study

Yang 1999Unable to determine if patients randomised

 
Characteristics of ongoing studies [ordered by study ID]
Villano 2010

Trial name or titleA randomized, double-blind study to assess the efficacy and safety of prophylactic use of maribavir versus oral ganciclovir for the prevention of cytomegalovirus disease in recipients of orthotopic liver transplants

Methods
  • Allocation: randomized
  • Endpoint classification: safety/efficacy study
  • Intervention model: parallel assignment
  • Masking: double blind (subject, caregiver, investigator)
  • Primary purpose: prevention

ParticipantsInclusion criteria

  • Male and female, ≥ 18 years
  • Orthotopic liver transplant recipient
  • Donor CMV seropositive / Recipient CMV seronegative
  • Enrolled within 10 days after liver transplant
  • Able to swallow tablets


Exclusion criteria

  • Multiple organ transplant
  • HIV infection
  • CMV disease
  • Use of other anti-CMV therapy at time of enrolment

Interventions
  • Maribavir: 100 mg twice a day for 14 weeks
  • Ganciclovir: 1000 mg 3 times/d for 14 weeks

Outcomes
  • CMV disease 6 months post-transplant
  • CMV disease 100 days and 12 months post-transplant
  • Incidence of CMV infection 100 days and 12 months post-transplant
  • Incidence of graft rejection 100 days and 12 months post-transplant
  • Incidence of retransplantation 100 days and 12 months post-transplant
  • Mortality 100 days and 12 months post-transplant

Starting dateJuly 2007

Contact informationStephen Villano, MD, Viropharma, Inc.

NotesStudy completed 2009

 
Comparison 1. Antiviral prophylaxis versus placebo/no treatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 CMV disease and CMV infection in all treated patients19Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 All symptomatic CMV disease
191981Risk Ratio (M-H, Random, 95% CI)0.42 [0.34, 0.52]

    1.2 CMV syndrome
111570Risk Ratio (M-H, Random, 95% CI)0.41 [0.29, 0.57]

    1.3 CMV organ involvement
121628Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.55]

    1.4 Total CMV infection
171786Risk Ratio (M-H, Random, 95% CI)0.61 [0.48, 0.77]

 2 All symptomatic CMV disease stratified by antibody status17Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 CMV antibody +ve recipients
131348Risk Ratio (M-H, Random, 95% CI)0.34 [0.24, 0.50]

    2.2 CMV +ve donor / CMV -ve recipient
10423Risk Ratio (M-H, Random, 95% CI)0.52 [0.37, 0.73]

    2.3 CMV -ve donor / CMV -ve recipient
438Risk Ratio (M-H, Random, 95% CI)1.0 [0.09, 11.03]

    2.4 CMV +ve donor / CMV +ve recipient
5276Risk Ratio (M-H, Random, 95% CI)0.19 [0.09, 0.37]

    2.5 CMV -ve donor / CMV +ve recipient
5160Risk Ratio (M-H, Random, 95% CI)0.32 [0.11, 0.95]

 3 CMV disease in all patients by antiviral medication191981Risk Ratio (M-H, Random, 95% CI)0.42 [0.34, 0.52]

    3.1 Aciclovir
6421Risk Ratio (M-H, Random, 95% CI)0.45 [0.29, 0.69]

    3.2 Ganciclovir
11917Risk Ratio (M-H, Random, 95% CI)0.44 [0.34, 0.58]

    3.3 Valaciclovir
2643Risk Ratio (M-H, Random, 95% CI)0.30 [0.19, 0.49]

 4 CMV disease for different organ transplants191980Risk Ratio (M-H, Random, 95% CI)0.44 [0.35, 0.55]

    4.1 Kidney transplant recipients
111132Risk Ratio (M-H, Random, 95% CI)0.42 [0.31, 0.57]

    4.2 Liver transplant recipients
5616Risk Ratio (M-H, Random, 95% CI)0.49 [0.29, 0.84]

    4.3 Heart transplant recipients
3232Risk Ratio (M-H, Random, 95% CI)0.39 [0.25, 0.63]

 5 CMV disease and ganciclovir duration11Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 Six weeks or less
7478Risk Ratio (M-H, Random, 95% CI)0.49 [0.36, 0.68]

    5.2 More than 6 weeks
4439Risk Ratio (M-H, Random, 95% CI)0.33 [0.21, 0.53]

 6 ATG therapy and antiviral efficacy11Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 CMV disease in all treated patients
11666Risk Ratio (M-H, Random, 95% CI)0.43 [0.33, 0.55]

    6.2 All-cause mortality
10643Risk Ratio (M-H, Random, 95% CI)0.82 [0.33, 2.02]

 7 Immunosuppression without ATG induction and antiviral efficacy6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    7.1 CMV disease in all treated patients
6649Risk Ratio (M-H, Random, 95% CI)0.47 [0.29, 0.76]

    7.2 All-cause mortality
5529Risk Ratio (M-H, Random, 95% CI)0.63 [0.39, 1.00]

 8 Mortality due to CMV disease or other causes7Risk Ratio (M-H, Random, 95% CI)Subtotals only

    8.1 CMV disease
71300Risk Ratio (M-H, Random, 95% CI)0.26 [0.08, 0.78]

    8.2 Other causes
71300Risk Ratio (M-H, Random, 95% CI)0.71 [0.44, 1.17]

 9 All-cause mortality according to antiviral medication171838Risk Ratio (M-H, Random, 95% CI)0.63 [0.43, 0.92]

    9.1 Aciclovir
5301Risk Ratio (M-H, Random, 95% CI)0.67 [0.38, 1.20]

    9.2 Ganciclovir
10894Risk Ratio (M-H, Random, 95% CI)0.69 [0.29, 1.65]

    9.3 Valaciclovir
2643Risk Ratio (M-H, Random, 95% CI)0.50 [0.22, 1.15]

 10 All-cause mortality according to CMV status91026Risk Ratio (M-H, Random, 95% CI)0.74 [0.41, 1.32]

    10.1 CMV +ve recipients
7738Risk Ratio (M-H, Random, 95% CI)0.59 [0.30, 1.18]

    10.2 CMV -ve recipients of CMV +ve organs
4288Risk Ratio (M-H, Random, 95% CI)1.42 [0.44, 4.66]

 11 All-cause mortality for different organ transplants171838Risk Ratio (M-H, Random, 95% CI)0.63 [0.43, 0.92]

    11.1 Kidney transplant recipients
101109Risk Ratio (M-H, Random, 95% CI)0.49 [0.24, 1.00]

    11.2 Liver transplant patients
4497Risk Ratio (M-H, Random, 95% CI)0.63 [0.39, 1.00]

    11.3 Heart transplant recipients
3232Risk Ratio (M-H, Random, 95% CI)1.82 [0.39, 8.51]

 12 All-cause mortality and ganciclovir duration10Risk Ratio (M-H, Random, 95% CI)Subtotals only

    12.1 Six weeks or less
6455Risk Ratio (M-H, Random, 95% CI)0.91 [0.17, 4.92]

    12.2 More than 6 weeks
4439Risk Ratio (M-H, Random, 95% CI)0.62 [0.30, 1.30]

 13 Additional outcomes - all medications16Risk Ratio (M-H, Random, 95% CI)Subtotals only

    13.1 Graft loss
10825Risk Ratio (M-H, Random, 95% CI)0.74 [0.47, 1.17]

    13.2 Acute rejection
131420Risk Ratio (M-H, Random, 95% CI)0.90 [0.78, 1.05]

    13.3 Herpes simplex and H. zoster infection
91483Risk Ratio (M-H, Random, 95% CI)0.27 [0.19, 0.40]

    13.4 Invasive fungal infection
3189Risk Ratio (M-H, Random, 95% CI)0.58 [0.19, 1.73]

    13.5 Bacterial infection
3174Risk Ratio (M-H, Random, 95% CI)0.65 [0.44, 0.96]

    13.6 EBV-associated PTLD
2359Risk Ratio (M-H, Random, 95% CI)1.01 [0.11, 9.51]

    13.7 Protozoal infections
2114Risk Ratio (M-H, Random, 95% CI)0.31 [0.10, 0.99]

 14 Acute rejection according to method of diagnosis131420Risk Ratio (M-H, Random, 95% CI)0.90 [0.78, 1.05]

    14.1 Biopsy-proven acute rejection
5821Risk Ratio (M-H, Random, 95% CI)0.97 [0.71, 1.32]

    14.2 Clinical diagnosis of acute rejection or method not stated
8599Risk Ratio (M-H, Random, 95% CI)0.91 [0.76, 1.08]

 15 Valaciclovir - additional outcomes2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    15.1 Acute rejection in donor CMV +ve / recipient CMV -ve grafts
1208Risk Ratio (M-H, Random, 95% CI)0.51 [0.35, 0.74]

    15.2 Acute rejection in CMV +ve recipients
1408Risk Ratio (M-H, Random, 95% CI)0.84 [0.63, 1.10]

    15.3 Total with acute rejection
2643Risk Ratio (M-H, Random, 95% CI)0.81 [0.55, 1.19]

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

   16.1 Leucopenia with aciclovir
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    16.2 Kidney dysfunction with aciclovir
2159Risk Ratio (M-H, Random, 95% CI)1.14 [0.27, 4.70]

    16.3 Neurological dysfunction with aciclovir
155Risk Ratio (M-H, Random, 95% CI)10.62 [0.62, 183.26]

    16.4 Leucopenia with ganciclovir
3509Risk Ratio (M-H, Random, 95% CI)0.99 [0.37, 2.65]

    16.5 Kidney dysfunction with ganciclovir
3509Risk Ratio (M-H, Random, 95% CI)2.36 [0.91, 6.15]

    16.6 Neurological dysfunction with ganciclovir
3509Risk Ratio (M-H, Random, 95% CI)1.59 [0.98, 2.58]

    16.7 Leucopenia with valaciclovir
1616Risk Ratio (M-H, Random, 95% CI)1.05 [0.62, 1.78]

   16.8 Kidney dysfunction with valaciclovir
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    16.9 Neurological dysfunction with valaciclovir
1616Risk Ratio (M-H, Random, 95% CI)8.78 [2.69, 28.71]

 
Comparison 2. Effect of methodological quality on CMV disease in studies of prophylaxis versus placebo/no treatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Allocation concealment19Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Adequate
4262Risk Ratio (M-H, Random, 95% CI)0.50 [0.31, 0.79]

    1.2 Inadequate/unclear
151719Risk Ratio (M-H, Random, 95% CI)0.41 [0.33, 0.51]

 2 Blinding of participants/investigators19Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Blinding
51135Risk Ratio (M-H, Random, 95% CI)0.35 [0.25, 0.48]

    2.2 No blinding
14846Risk Ratio (M-H, Random, 95% CI)0.47 [0.37, 0.59]

 3 Intention-to-treat analysis (ITT)19Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 ITT undertaken
101569Risk Ratio (M-H, Random, 95% CI)0.38 [0.30, 0.48]

    3.2 ITT not undertaken
9412Risk Ratio (M-H, Random, 95% CI)0.47 [0.33, 0.68]

 4 CMV disease by time of outcome assessment or trial publication date19Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 Outcome at 9-12 months
81277Risk Ratio (M-H, Random, 95% CI)0.36 [0.22, 0.58]

    4.2 Outcome at 3-6 months
11704Risk Ratio (M-H, Random, 95% CI)0.46 [0.36, 0.58]

    4.3 Trials published before 1997
12821Risk Ratio (M-H, Random, 95% CI)0.48 [0.37, 0.63]

    4.4 Trials published in 1997 and later
71160Risk Ratio (M-H, Random, 95% CI)0.32 [0.24, 0.44]

 
Comparison 3. Effect of methodological quality on all-cause mortality in studies of prophylaxis versus placebo/no treatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Allocation concealment17Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Adequate
3142Risk Ratio (M-H, Random, 95% CI)0.26 [0.06, 1.20]

    1.2 Inadequate/unclear
141695Risk Ratio (M-H, Random, 95% CI)0.67 [0.45, 0.99]

 2 Blinding of participants and investigators17Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Blinding
51135Risk Ratio (M-H, Random, 95% CI)0.62 [0.39, 0.98]

    2.2 No blinding
12702Risk Ratio (M-H, Random, 95% CI)0.65 [0.33, 1.27]

 3 Intention-to-treat analysis (ITT)17Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 ITT undertaken
91448Risk Ratio (M-H, Random, 95% CI)0.62 [0.40, 0.98]

    3.2 ITT not undertaken
8389Risk Ratio (M-H, Random, 95% CI)0.65 [0.32, 1.29]

 4 All-cause mortality and time of outcome assessment or trial publication date17Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 Outcome at 9-12 months
101370Risk Ratio (M-H, Random, 95% CI)0.63 [0.40, 0.97]

    4.2 Outcome at 4-6 months
7468Risk Ratio (M-H, Random, 95% CI)0.64 [0.31, 1.33]

    4.3 Outcome in trials published before 1997
10678Risk Ratio (M-H, Random, 95% CI)0.71 [0.25, 2.08]

    4.4 Outcome in trials published in 1997 or later
71160Risk Ratio (M-H, Random, 95% CI)0.62 [0.41, 0.94]

 
Comparison 4. Ganciclovir versus aciclovir

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 CMV disease and CMV infection in all treated patients8Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 CMV disease in all patients
71113Risk Ratio (M-H, Random, 95% CI)0.37 [0.23, 0.60]

    1.2 CMV organ involvement
71034Risk Ratio (M-H, Random, 95% CI)0.28 [0.15, 0.49]

    1.3 CMV syndrome
61009Risk Ratio (M-H, Random, 95% CI)0.40 [0.16, 1.02]

    1.4 CMV infection
6815Risk Ratio (M-H, Random, 95% CI)0.44 [0.28, 0.67]

    1.5 CMV disease in patients treated with ganciclovir for 3 months
4703Risk Ratio (M-H, Random, 95% CI)0.28 [0.09, 0.82]

    1.6 CMV disease in patients treated with ganciclovir for 2-4 weeks then aciclovir
3410Risk Ratio (M-H, Random, 95% CI)0.38 [0.22, 0.64]

 2 CMV antibody +ve recipients6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 All symptomatic CMV disease
5722Risk Ratio (M-H, Random, 95% CI)0.27 [0.13, 0.55]

    2.2 CMV infection
5522Risk Ratio (M-H, Random, 95% CI)0.30 [0.16, 0.58]

 3 CMV +ve donors / CMV -ve recipients5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 All symptomatic CMV disease
5246Risk Ratio (M-H, Random, 95% CI)0.64 [0.41, 0.99]

    3.2 CMV infection
4228Risk Ratio (M-H, Random, 95% CI)0.63 [0.36, 1.09]

 4 CMV -ve donor / CMV -ve recipient3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 CMV disease
341Risk Ratio (M-H, Random, 95% CI)0.45 [0.07, 3.07]

 5 Effect of prophylaxis for different transplanted organs7Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 CMV disease in kidney transplant patients
2168Risk Ratio (M-H, Random, 95% CI)0.30 [0.07, 1.35]

    5.2 CMV disease in liver transplant patients
5791Risk Ratio (M-H, Random, 95% CI)0.37 [0.23, 0.59]

    5.3 CMV disease in heart or lung transplant patients
275Risk Ratio (M-H, Random, 95% CI)0.55 [0.10, 3.00]

    5.4 CMV infection in kidney transplant patients
2168Risk Ratio (M-H, Random, 95% CI)0.20 [0.04, 0.95]

    5.5 CMV infection in liver transplant patients
4572Risk Ratio (M-H, Random, 95% CI)0.42 [0.25, 0.73]

    5.6 CMV infection in heart or lung transplant patients
275Risk Ratio (M-H, Random, 95% CI)0.88 [0.50, 1.55]

 6 Death8Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 Death associated with CMV disease
6832Risk Ratio (M-H, Random, 95% CI)0.33 [0.07, 1.58]

    6.2 All-cause mortality
81138Risk Ratio (M-H, Random, 95% CI)1.13 [0.82, 1.58]

 7 Additional outcomes8Risk Ratio (M-H, Random, 95% CI)Subtotals only

    7.1 Acute rejection
61009Risk Ratio (M-H, Random, 95% CI)0.98 [0.87, 1.10]

    7.2 Graft loss
3268Risk Ratio (M-H, Random, 95% CI)0.55 [0.27, 1.13]

    7.3 Other viral infections
4740Risk Ratio (M-H, Random, 95% CI)0.81 [0.32, 2.01]

    7.4 Invasive fungal infections
3401Risk Ratio (M-H, Random, 95% CI)0.67 [0.40, 1.10]

    7.5 Bacterial infections
1167Risk Ratio (M-H, Random, 95% CI)1.10 [0.78, 1.53]

    7.6 Protozoal infections
1167Risk Ratio (M-H, Random, 95% CI)0.34 [0.01, 8.16]

    7.7 Obliterative bronchiolitis in lung transplant recipients
125Risk Ratio (M-H, Random, 95% CI)0.81 [0.42, 1.54]

    7.8 Leucopenia
6955Risk Ratio (M-H, Random, 95% CI)3.28 [1.48, 7.25]

    7.9 Kidney dysfunction
4661Risk Ratio (M-H, Random, 95% CI)0.96 [0.83, 1.10]

    7.10 Neurological dysfunction
2306Risk Ratio (M-H, Random, 95% CI)1.01 [0.24, 4.15]

 
Comparison 5. Ganciclovir / aciclovir versus ganciclovir

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 CMV disease and CMV infection in all treated patients1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    1.1 CMV disease
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.2 CMV infection
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 2 Death1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    2.1 All-cause mortality
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 3 Additional outcomes1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    3.1 EBV infection
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 
Comparison 6. Valganciclovir versus ganciclovir

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 CMV disease or infection in CMV donor +ve / recipient -ve1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    1.1 CMV disease by 6 months
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.2 CMV disease by 1 year
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.3 CMV syndrome by 6 months
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.4 CMV syndrome by 1 year
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.5 Tissue invasive CMV disease by 6 months
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.6 Tissue invasive CMV disease by 1 year
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.7 CMV disease in liver transplant recipients by 6 months
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.8 CMV disease in renal transplant recipients by 6 months
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.9 CMV disease in heart transplant recipients by 6 months
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.10 CMV disease in renal-pancreas transplant recipients by 6 months
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.11 CMV infection by 6 months
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.12 CMV infection by 1 year
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 2 Death1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    2.1 Death due to CMV disease
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.2 All-cause mortality
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 3 Additional outcomes1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    3.1 Acute rejection in all recipients
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.2 Graft loss
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.3 Opportunistic infections
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.4 Neutrophil count < 1000/mm³
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.5 Medications ceased because of neutropenia
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.6 Anaemia (< 80 g/L)
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.7 Thrombocytopenia
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.8 Tremor
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 
Comparison 7. Valaciclovir versus ganciclovir or valganciclovir

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 CMV disease and CMV infection in all treated patients3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 CMV disease
3188Risk Ratio (M-H, Random, 95% CI)0.74 [0.15, 3.75]

    1.2 CMV infection
3188Risk Ratio (M-H, Random, 95% CI)1.37 [0.78, 2.39]

    1.3 CMV disease in donor +ve or -ve/recipient +ve
163Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.4 CMV infection in donor +ve or -ve/recipient +ve
163Risk Ratio (M-H, Random, 95% CI)0.45 [0.09, 2.31]

    1.5 CMV disease in donor +ve/recipient -ve
112Risk Ratio (M-H, Random, 95% CI)0.33 [0.02, 6.86]

    1.6 CMV infection in donor +ve/recipient -ve
112Risk Ratio (M-H, Random, 95% CI)1.86 [0.86, 4.01]

 2 Death2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 All-cause mortality
2154Risk Ratio (M-H, Random, 95% CI)1.03 [0.15, 6.90]

 3 Additional outcomes3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Acute rejection
3188Risk Ratio (M-H, Random, 95% CI)0.91 [0.22, 3.73]

    3.2 Graft loss
2107Risk Ratio (M-H, Random, 95% CI)1.34 [0.23, 7.86]

    3.3 Leucopenia
169Risk Ratio (M-H, Random, 95% CI)1.03 [0.40, 2.62]

    3.4 Thrombocytopenia
169Risk Ratio (M-H, Random, 95% CI)0.63 [0.30, 1.33]

    3.5 Anaemia
168Risk Ratio (M-H, Random, 95% CI)0.5 [0.19, 1.31]

    3.6 Neurological dysfunction
169Risk Ratio (M-H, Random, 95% CI)1.54 [0.62, 3.87]

    3.7 Dose reduction or cessation for adverse effects
169Risk Ratio (M-H, Random, 95% CI)0.62 [0.25, 1.51]

    3.8 Other herpes virus infections
183Risk Ratio (M-H, Random, 95% CI)1.86 [0.18, 19.73]

    3.9 Non-viral infections
183Risk Ratio (M-H, Random, 95% CI)0.59 [0.44, 0.80]

 4 Renal function at end of study3Std. Mean Difference (IV, Random, 95% CI)Subtotals only

    4.1 Serum creatinine
3188Std. Mean Difference (IV, Random, 95% CI)-0.23 [-0.51, 0.06]

    4.2 Calculated GFR
169Std. Mean Difference (IV, Random, 95% CI)0.41 [-0.06, 0.89]

 
Comparison 8. Different ganciclovir regimens

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 IV doses given at different frequencies1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    1.1 CMV disease
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.2 CMV syndrome
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.3 Invasive CMV disease
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.4 CMV infection
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.5 All-cause mortality
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.6 Death due to CMV disease
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.7 Bacteraemia
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.8 Bronchiolitis obliterans syndrome
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.9 Leucopenia
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 2 Oral versus IV ganciclovir2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 CMV disease
294Risk Ratio (M-H, Random, 95% CI)0.57 [0.16, 2.05]

    2.2 CMV syndrome
294Risk Ratio (M-H, Random, 95% CI)0.48 [0.11, 2.11]

    2.3 CMV invasive organ disease
164Risk Ratio (M-H, Random, 95% CI)1.0 [0.07, 15.30]

    2.4 CMV infection
130Risk Ratio (M-H, Random, 95% CI)1.05 [0.41, 2.70]

    2.5 All-cause mortality
164Risk Ratio (M-H, Random, 95% CI)5.00 [0.62, 40.44]

    2.6 Acute rejection
294Risk Ratio (M-H, Random, 95% CI)0.85 [0.45, 1.59]

    2.7 Graft loss
134Risk Ratio (M-H, Random, 95% CI)1.0 [0.07, 14.72]

    2.8 Leucopenia due to ganciclovir
164Risk Ratio (M-H, Random, 95% CI)0.69 [0.35, 1.39]

    2.9 Medications ceased due to leucopenia
164Risk Ratio (M-H, Random, 95% CI)1.0 [0.27, 3.66]

 
Comparison 9. Extended duration compared with three months of valganciclovir

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 CMV disease2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 CMV disease at end of treatment
2454Risk Ratio (M-H, Random, 95% CI)0.20 [0.12, 0.35]

    1.2 CMV disease at 9 months
1310Risk Ratio (M-H, Random, 95% CI)0.39 [0.25, 0.60]

    1.3 CMV disease at 12 months
1318Risk Ratio (M-H, Random, 95% CI)0.44 [0.29, 0.66]

    1.4 CMV disease at 24 months
1318Risk Ratio (M-H, Random, 95% CI)0.55 [0.38, 0.79]

 2 CMV syndrome2454Risk Ratio (M-H, Random, 95% CI)0.39 [0.24, 0.64]

 3 CMV invasive disease2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Number at 12 months
2454Risk Ratio (M-H, Random, 95% CI)0.17 [0.02, 1.34]

    3.2 Number at 24 months
1318Risk Ratio (M-H, Random, 95% CI)0.70 [0.12, 4.14]

 4 CMV infection2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 CMV infection at end of treatment
2454Risk Ratio (M-H, Random, 95% CI)0.27 [0.10, 0.71]

    4.2 CMV infection at 9 months
1318Risk Ratio (M-H, Random, 95% CI)0.72 [0.56, 0.94]

    4.3 CMV infection at 12 months
1318Risk Ratio (M-H, Random, 95% CI)0.73 [0.57, 0.95]

 5 All-cause mortality1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    5.1 Number at 12 months
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    5.2 Number at 2 years
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 6 Graft loss1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    6.1 Number at 12 months
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    6.2 Number at 24 months
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 7 Acute rejection2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    7.1 Biopsy proved acute rejection < 100 days
1318Risk Ratio (M-H, Random, 95% CI)0.70 [0.32, 1.51]

    7.2 Biopsy proven acute rejection at 12 months
2454Risk Ratio (M-H, Random, 95% CI)0.64 [0.43, 0.95]

    7.3 Biopsy proven acute rejection at 24 months
1318Risk Ratio (M-H, Random, 95% CI)0.62 [0.35, 1.08]

 8 Other outcomes2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    8.1 Opportunistic infections
2456Risk Ratio (M-H, Random, 95% CI)0.71 [0.33, 1.57]

    8.2 Post-transplant diabetes mellitus
1244Risk Ratio (M-H, Random, 95% CI)1.17 [0.58, 2.36]

 9 Adverse effects2Risk Difference (M-H, Random, 95% CI)Subtotals only

    9.1 Total treatment related adverse effects
2456Risk Difference (M-H, Random, 95% CI)0.08 [-0.01, 0.16]

    9.2 Treatment related serious adverse effects
2456Risk Difference (M-H, Random, 95% CI)0.02 [-0.02, 0.07]

    9.3 Leukopenia
1320Risk Difference (M-H, Random, 95% CI)0.12 [0.01, 0.22]

    9.4 Leucopenia leading to VGCV cessation
1320Risk Difference (M-H, Random, 95% CI)0.04 [0.00, 0.07]

    9.5 Termination due to treatment related adverse effects
1136Risk Difference (M-H, Random, 95% CI)0.07 [-0.04, 0.18]

    9.6 Hospitalisations due to CMV disease
1418Risk Difference (M-H, Random, 95% CI)-0.10 [-0.17, -0.04]

    9.7 Hospitalisations due to adverse effects
1418Risk Difference (M-H, Random, 95% CI)0.04 [-0.05, 0.13]

    9.8 CMV mutations known to confer ganciclovir resistance
2208Risk Difference (M-H, Random, 95% CI)0.02 [-0.08, 0.11]

 
Summary of findings for the main comparison. Antiviral prophylaxis versus placebo/no treatment compared with use for preventing cytomegalovirus disease in solid organ transplant recipients

Antiviral prophylaxis versus placebo/no treatment compared with use for preventing cytomegalovirus disease in solid organ transplant recipients

Patient or population: solid organ transplant recipients
Settings: tertiary hospitals
Intervention: antiviral prophylaxis versus placebo/no treatment

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Antiviral prophylaxis versus placebo/no treatment

CMV disease and CMV infection in all treated patients: all symptomatic CMV diseaseStudy populationRR 0.42
(0.34 to 0.52)
1981
(19 studies)
⊕⊕⊕⊕
high

299 per 1000126 per 1000
(102 to 156)

Moderate

357 per 1000150 per 1000
(121 to 186)

CMV disease for different organ transplants: Kidney transplant recipientsStudy populationRR 0.42
(0.31 to 0.57)
1132
(11 studies)
⊕⊕⊕⊕
high

297 per 1000125 per 1000
(92 to 169)

Moderate

400 per 1000168 per 1000
(124 to 228)

CMV disease for different organ transplants: Liver transplant recipientsStudy populationRR 0.49
(0.29 to 0.84)
616
(5 studies)
⊕⊕⊕⊝
moderate

262 per 1000128 per 1000
(76 to 220)

Moderate

306 per 1000150 per 1000
(89 to 257)

CMV disease for different organ transplants: Heart transplant recipientsStudy populationRR 0.39
(0.25 to 0.63)
232
(3 studies)
⊕⊕⊕⊝
moderate

412 per 1000161 per 1000
(103 to 260)

Moderate

425 per 1000166 per 1000
(106 to 268)

Death associated with CMV diseaseStudy populationRR 0.26
(0.08 to 0.78)
1300
(7 studies)
⊕⊕⊕⊝
moderate²

23 per 10006 per 1000
(2 to 18)

Moderate

39 per 100010 per 1000
(3 to 30)

All-cause mortality according to antiviral medicationStudy populationRR 0.63
(0.43 to 0.92)
1838
(17 studies)
⊕⊕⊕⊕
high

71 per 100045 per 1000
(30 to 65)

Moderate

45 per 100028 per 1000
(19 to 41)

Graft loss: all medicationsStudy populationRR 0.74
(0.47 to 1.17)
825
(10 studies)
⊕⊕⊕⊝
moderate²

93 per 100069 per 1000
(44 to 109)

Moderate

117 per 100087 per 1000
(55 to 137)

Acute rejection: all medicationsStudy populationRR 0.9
(0.78 to 1.05)
1420
(13 studies)
⊕⊕⊕⊕
high

468 per 1000421 per 1000
(365 to 491)

Moderate

500 per 1000450 per 1000
(390 to 525)

Herpes simplex and Herpes zoster infection: all medicationsStudy populationRR 0.27
(0.19 to 0.4)
1483
(9 studies)
⊕⊕⊕⊕
high

281 per 100076 per 1000
(53 to 113)

Moderate

260 per 100070 per 1000
(49 to 104)

*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% confidence interval) is based on the assumed risk in the comparison group and the relative effect 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

 ₑOnly 7/19 studies reported on this outcome. Small numbers of events.
²Few studies and events.
 
Summary of findings 2. Ganciclovir versus aciclovir for preventing cytomegalovirus disease in solid organ transplant recipients

Ganciclovir versus aciclovir for preventing cytomegalovirus disease in solid organ transplant recipients

Patient or population: solid organ transplant recipients
Settings: tertiary hospitals
Intervention: ganciclovir versus aciclovir

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlGanciclovir versus aciclovir

CMV disease and CMV infection in all treated patients: CMV disease in all patientsStudy populationRR 0.37
(0.23 to 0.6)
1113
(7 studies)
⊕⊕⊕⊕
high

177 per 100066 per 1000
(41 to 106)

Moderate

226 per 100084 per 1000
(52 to 136)

Death associated with CMV diseaseStudy populationRR 0.33
(0.07 to 1.58)
832
(6 studies)
⊕⊕⊕⊝
moderate

10 per 10003 per 1000
(1 to 15)

Moderate

9 per 10003 per 1000
(1 to 14)

All-cause mortalityStudy populationRR 1.13
(0.82 to 1.58)
1138
(8 studies)
⊕⊕⊕⊝
moderate

103 per 1000117 per 1000
(85 to 163)

Moderate

109 per 1000123 per 1000
(89 to 172)

Acute rejectionStudy populationRR 0.98
(0.87 to 1.1)
1009
(6 studies)
⊕⊕⊕⊕
high

491 per 1000481 per 1000
(427 to 540)

Moderate

517 per 1000507 per 1000
(450 to 569)

Graft lossStudy populationRR 0.55
(0.27 to 1.13)
268
(3 studies)
⊕⊕⊝⊝
low

148 per 100081 per 1000
(40 to 167)

Moderate

167 per 100092 per 1000
(45 to 189)

Other viral infectionsStudy populationRR 0.81
(0.32 to 2.01)
740
(4 studies)
⊕⊕⊕⊝
moderate

35 per 100028 per 1000
(11 to 70)

Moderate

44 per 100036 per 1000
(14 to 88)

Invasive fungal infectionsStudy populationRR 0.67
(0.4 to 1.1)
401
(3 studies)
⊕⊕⊝⊝
low

149 per 1000100 per 1000
(60 to 164)

Moderate

51 per 100034 per 1000
(20 to 56)

*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% confidence interval) is based on the assumed risk in the comparison group and the relative effect 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

 ₑSmall number of events in limited number of studies.
 
Summary of findings 3. Valaciclovir versus ganciclovir or valganciclovir for preventing cytomegalovirus disease in solid organ transplant recipients

Valaciclovir versus ganciclovir or valganciclovir for preventing cytomegalovirus disease in solid organ transplant recipients

Patient or population: solid organ transplant recipients
Settings: known or unknown
Intervention: valaciclovir versus ganciclovir or valganciclovir

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlValaciclovir versus ganciclovir or valganciclovir

CMV disease and CMV infection in all treated patients: CMV diseaseStudy populationRR 0.74
(0.15 to 3.75)
188
(3 studies)
⊕⊕⊝⊝
low

32 per 100024 per 1000
(5 to 120)

Moderate

25 per 100019 per 1000
(4 to 94)

All-cause mortalityStudy populationRR 1.03
(0.15 to 6.9)
154
(2 studies)
⊕⊕⊝⊝
low

26 per 100027 per 1000
(4 to 182)

Moderate

28 per 100029 per 1000
(4 to 193)

Acute rejectionStudy populationRR 0.91
(0.22 to 3.73)
188
(3 studies)
⊕⊕⊝⊝
low

181 per 1000165 per 1000
(40 to 675)

Moderate

125 per 1000114 per 1000
(27 to 466)

Graft lossStudy populationRR 1.34
(0.23 to 7.86)
107
(2 studies)
⊕⊕⊝⊝
low

73 per 100097 per 1000
(17 to 572)

Moderate

56 per 100075 per 1000
(13 to 440)

*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% confidence interval) is based on the assumed risk in the comparison group and the relative effect 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

 ₑSmall numbers of patients.
 
Summary of findings 4. Extended duration compared with 3 months of valganciclovir compared with use for preventing cytomegalovirus disease in solid organ transplant recipients

Extended duration compared with 3 months of valganciclovir compared with use for preventing cytomegalovirus disease in solid organ transplant recipients

Patient or population: solid organ transplant recipients
Settings: known or unknown
Intervention: extended duration compared with three months of valganciclovir

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Extended duration compared with three months of valganciclovir

CMV disease at end of treatmentStudy populationRR 0.2
(0.12 to 0.35)
454
(2 studies)
⊕⊕⊕⊕
high

314 per 100063 per 1000
(38 to 110)

Moderate

316 per 100063 per 1000
(38 to 111)

CMV syndromeStudy populationRR 0.4
(0.27 to 0.6)
454
(2 studies)
⊕⊕⊕⊕
high

310 per 1000124 per 1000
(84 to 186)

Moderate

272 per 1000109 per 1000
(73 to 163)

CMV invasive disease: Number at 12 monthsStudy populationRR 0.23
(0.01 to 3.5)
454
(2 studies)
⊕⊕⊝⊝
low

66 per 100015 per 1000
(1 to 229)

Moderate

109 per 100025 per 1000
(1 to 381)

CMV infection at end of treatmentStudy populationRR 0.27
(0.1 to 0.71)
454
(2 studies)
⊕⊕⊕⊕
high

502 per 1000136 per 1000
(50 to 357)

Moderate

542 per 1000146 per 1000
(54 to 385)

Biopsy-proven acute rejection at 12 monthsStudy populationRR 0.99
(0.42 to 2.37)
454
(2 studies)
⊕⊕⊝⊝
low

183 per 1000182 per 1000
(77 to 435)

Moderate

192 per 1000190 per 1000
(81 to 455)

Opportunistic infectionsStudy populationRR 0.71
(0.33 to 1.57)
456
(2 studies)
⊕⊕⊝⊝
low

343 per 1000244 per 1000
(113 to 539)

Moderate

399 per 1000283 per 1000
(132 to 626)

Total treatment related adverse effectsStudy populationSee comment456
(2 studies)
⊕⊕⊕⊕
high
Risks were calculated from pooled risk differences

426 per 1000503 per 1000
(418 to 588)

Moderate

353 per 1000417 per 1000
(346 to 487)

*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% confidence interval) is based on the assumed risk in the comparison group and the relative effect 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

 ₑConsiderable heterogeneity between studies.
 
Table 1. Potential sources of variability: CMV disease and all-cause mortality

VariableCMV diseaseAll-cause mortality


Number of studiesRR (95% CI)P for interactionNumber of studiesRR (95% CI)P for interaction

Antiviral medication

  1. Aciclovir
  2. Ganciclovir
  3. Valaciclovir
  1. 6
  2. 11
  3. 2
  1. 0.45 (0.29 to 0.69)
  2. 0.44 (0.34 to 0.58)
  3. 0.30 (0.19 to 0.49)
0.43
  1. 5
  2. 10
  3. 2
  1. 0.67 (0.38 to 1.20)
  2. 0.69 (0.29 to 1.65)
  3. 0.50 (0.22 to 1.15)
0.85

Time to outcome assessment

  1. 3 to 6 months
  2. 9 to 12 months
  1. 11
  2. 8
  1. 0.46 (0.36 to 0.58)
  2. 0.36 (0.22 to 0.58)
0.37
  1. 7
  2. 10
  1. 0.63 (0.40 to 0.97)
  2. 0.64 (0.31 to 1.33)
0.83

Recipient CMV status

  1. Positive (donor +ve or -ve)¹
  2. Negative (donor +ve)²
  1. 13
  2. 10
  1. 0.34 (0.24 to 0.50)
  2. 0.52 (0.37 to 0.74)
0.12
  1. 7
  2. 4
  1. 0.59 (0.30 to 1.18)
  2. 1.42 (0.44 to 4.66)
0.23

Donor CMV status³

  1. Positive (recipients all +ve)
  2. Negative (recipients all +ve)
  1. 5
  2. 5
  1. 0.18 (0.09 to 0.36)
  2. 0.33 (0.11 to 0.95)
0.37
  1. No data
  2. No data
  1. No data
  2. No data
No data

Organ transplanted

  1. Kidney
  2. Liver
  3. Heart
  1. 11
  2. 5
  3. 3
  1. 0.42 (0.31 to 0.57)
  2. 0.49 (0.29 to 0.84)
  3. 0.39 (0.25 to 0.63)
0.93
  1. 10
  2. 4
  3. 3
  1. 0.49 (0.24 to 1.00)
  2. 0.64 (0.39 to 1.00)
  3. 1.82 (0.39 to 8.51)
0.13

Antibody therapy

  1. Yes
  2. No
  1. 11
  2. 6
  1. 0.43 (0.33 to 0.55)
  2. 0.47 (0.29 to 0.76)
0.74
  1. 10
  2. 5
  1. 0.81 (0.33 to 2.01)
  2. 0.63 (0.39 to 1.00)
0.93

Treatment durationª

  1. 6 weeks or less
  2. More than 6 weeks
  1. 7
  2. 4
  1. 0.49 (0.36 to 0.68)
  2. 0.33 (0.21 to 0.53)
0.72
  1. 6
  2. 4
  1. 0.91 (0.17 to 4.92)
  2. 0.62 (0.30 to 1.30)
0.15

Allocation concealment

  1. Adequate
  2. Unclear or inadequate
  1. 4
  2. 15
  1. 0.50 (0.31 to 0.79)
  2. 0.41 (0.33 to 0.51)
0.64
  1. 3
  2. 14
  1. 0.26 (0.06 to 1.20)
  2. 0.67 (0.45 to 0.99)
0.88

Blinding

  1. Yes
  2. No
  1. 5
  2. 14
  1. 0.35 (0.25 to 0.48)
  2. 0.47 (0.37 to 0.59)
0.18
  1. 5
  2. 12
  1. 0.62 (0.39 to 0.98)
  2. 0.65 (0.33 to 1.27)
0.97

Intention to treat

  1. Yes
  2. No
  1. 10
  2. 9
  1. 0.38 (0.30 to 0.48)
  2. 0.47 (0.33 to 0.68)
0.37
  1. 9
  2. 8
  1. 0.62 (0.40 to 0.98)
  2. 0.65 (0.32 to 1.29)
0.57

 ¹Studies in "positive" group included those in which recipients were positive for CMV with donor positive or negative for CMV.
²Studies in "negative" group included those in which CMV negative recipients received CMV positive organs.
³Studies in which recipients were CMV positive and the donors CMV positive (positive group) or negative (CMV negative group).
ªGanciclovir studies only.
 
Table 2. Summary of outcomes for antiviral medication versus placebo/no treatment

OutcomeAciclovir
Studies; RR (95% CI)
Ganciclovir
Studies; RR (95% CI)
Valaciclovir
Studies; RR (95% CI)
All medications
Studies; RR (95% CI)

Acute rejection4; 1.03 (0.78 to 1.36)7; 0.92 (0.70 to 1.21)2; 0.81 (0.51 to 1.28)^13; 0.90 (0.78 to 1.17)

Graft loss4; 0.77 (0.35 to 1.68)6; 0.73 (0.41 to 1.28)No data10; 0.74 (0.47 to 1.17)

Herpes simplex or zoster infections3; 0.30 (0.14 to 0.62)4; 0.25 (0.08 to 0.78)2; 0.28 (0.20 to 0.40)9; 0.27 (0.19 to 0.40)

Post-transplant lymphoproliferative disease1; 2.90 (0.12 to 68.2)1; 0.34 (0.01 to 8.33)No data2; 1.01 (0.11 to 9.51)

Bacterial infections1; 0.67 (0.33 to 1.38)1; 0.72 (0.44 to 1.17)1; 0.27 (0.07 to 1.05)3; 0.65 (0.44 to 0.96)

Fungal infections1; 1.30 (0.31 to 5.39)2; 0.28 (0.07 to 1.12)No data3; 0.58 (0.19 to 1.73)

Protozoal infectionsNo data2; 0.31 (0.01 to 0.99)No data2; 0.31 (0.01 to 0.99)

LeucopeniaªNo data3; 0.99 (0.37 to 2.65)1; 1.05 (0.62 to 1.78)

Creatinine > 200 µmol/Lª2; 1.14 (0.27 to 4.70)3; 2.36 (0.91 to 6.15)No data

Hallucinationsª1; 10.6 (0.62 to 183.3)1; 1.59 (0.98 to 2.58)1; 8.78 (2.69 to 28.7)

 ªPlacebo-controlled RCTs only.
^Heterogeneity of study results present.
 
Table 3. Effects of antiviral medication on CMV disease and all-cause mortality

Recipient groupWithout prophylaxis¹With prophylaxis²Number preventedNumber with harms³

CMV disease

  1. Kidneyª
  2. Kidneyª; liver^; heartª
  3. Liver, heartª; all^, antibody therapy included in immunosuppressive regimen
  1. 7/100
  2. 28/100
  3. 59/100
  1. 3/100
  2. 12/100
  3. 25/100
  1. 4/100
  2. 16/100
  3. 39/100
  1. 7/100
  2. 7/100
  3. 7/100

All-cause mortality

  1. Kidney
  2. Liver
  3. Heart or lung
  1. 6/100
  2. 20/100
  3. 24/100
  1. 4/100
  2. 13/100
  3. 15/100
  1. 2/100
  2. 7/100
  3. 9/100
  1. 7/100
  2. 7/100
  3. 7/100

 ¹Data from references.
²Calculated from summary estimates of RR (0.42 for prevention of CMV disease, 0.63 for all-cause mortality).
³Based on proportion of patients, treated with valaciclovir, who developed hallucinations.
ªDonor positive or negative for CMV; recipient negative.
^Donor positive recipient negative for CMV.