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

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

Editorial Group: Cochrane Renal Group

Published Online: 17 FEB 2010

Assessed as up-to-date: 9 NOV 2005

DOI: 10.1002/14651858.CD005133.pub2

Database Title

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How to Cite

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

Author Information

  1. 1

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

  2. 2

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

  3. 3

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

  4. 4

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

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

Publication History

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

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Characteristics of included studies [ordered by study ID]
Brennan 97-Kidney
MethodsCountry: USA
Setting: University
Randomisation method: not stated
Blinding:
-Participants: no
-Investigators: no
-Outcome assessors: not stated
-Data analysis: not stated
Intention to treat: no (stated and not performed)
Follow-up period: 12.3 - 18.2 months.
Participants51 patients
Mean age: 48 years
All solid organ (kidney) transplant recipients (48 first and 3 second transplant)
CMV status: D/R+, D+/R-
InterventionsTREATMENT GROUP
Pre-emptive IV ganciclovir 5 mg/kg/ every 12 hours for 3 weeks

CONTROL GROUP
Deferred ganciclovir (same schedule)
Outcomes1. CMV disease
2. Acute rejection
3. All-cause mortality
4. Graft loss
5. Toxicity
NotesMethod for detection of CMV infection: Qualitative PCR for CMV DNA; Shell vial culture; serology
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?NoC - Inadequate




Jung 01-Kidney
MethodsCountry: Germany
Setting: NA
Randomisation method: not stated
Blinding:
-Participants: no
-Investigators: no
-Outcome assessors: not stated
-Data analysis: not stated
Intention-to-treat: not stated
Follow-up period: 12 months
Participants70 patients
Mean age: NA
All solid organ (kidney) transplant recipients (first transplant only)
CMV status: D/R+, D+/R-, D-/R-
InterventionsTREATMENT GROUP
Pre-emptive oral ganciclovir 100 mg/d for 14 days or until test negative

CONTROL GROUP
Prophylactic oral ganciclovir 100 mg/d for 90 days starting at week 2 after transplant
Outcomes1. CMV disease
2. Acute rejection
3. All-cause mortality
4. Graft loss
5. Toxicity
NotesMethod for detection of CMV infection: pp65 antigenaemia > 2 +ve cell/20 x 10(4)
PCR for CMV DNA >400 copies/ml(5)
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear




Koetz 01-Kidney
MethodsCountry: Germany
Setting: University
Randomisation method: not stated
Blinding:
-Participants: yes
-Investigators: yes
-Outcome assessors: not stated
-Data analysis: not stated
Intention-to-treat: yes
Follow-up period: 3 months
Participants12 patients
Mean age: NA
All solid organ (kidney, liver) transplant recipients
CMV status: D/R+, D+/R-
InterventionsTREATMENT GROUP
Pre-emptive IV ganciclovir 2 x 5 mg/kg/d for 2 weeks

CONTROL GROUP
Placebo (0.9% NaCl for 2 weeks)
Outcomes1. CMV disease and syndrome
NotesMethod for detection of CMV infection: pp65 antigenaemia >5 +ve cell/20 x 10(4)
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear




Paya 02-Liver
MethodsCountry: USA
Setting: University
Randomisation method: pharmacy randomisation by randomisation chart
Blinding:
-Participants: yes
-Investigators: yes
-Outcome assessors: not stated
-Data analysis: not stated
Intention-to-treat: yes
Follow-up period: 4 months
Participants69 patients
Mean age: 50 (23-67) years
All solid organ (liver) transplant recipients (first transplant only)
CMV status: D/R+, D+/R-
InterventionsTREATMENT GROUP
Pre-emptive oral ganciclovir 1000 mg tid for 8 weeks

CONTROL GROUP
Placebo
Outcomes1. CMV disease
2. Acute rejection
3. Other infections
NotesMethod for detection of CMV infection: qualitative PCR for CMV DNA
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate




Queiroga 03-Kidney
MethodsCountry: Brazil
Setting: NA
Randomisation method not stated
Blinding:
-Participants: no
-Investigators: no
-Outcome assessors: not stated
-Data analysis: not stated
Intention-to-treat: no
Follow-up period: 6 months
Participants34 patients
Mean age: NA
All solid organ (kidney) transplant recipients
CMV status: D/R+, D+/R-, D-/R-
InterventionsTREATMENT GROUP
Pre-emptive oral ganciclovir (dose/route not specified)

CONTROL GROUP
Ganciclovir 750g tds for 90 days
Outcomes1. CMV disease
2. All-cause mortality
3. Graft loss
NotesMethod for detection of CMV infection: pp65 antigenaemia > 3 +ve cell/30 x 10(4)
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear




Rayes 01-Liver
MethodsCountry: Germany
Setting: University
Randomisation method: not stated
Blinding:
-Participants: no
-Investigators: no
-Outcome assessors: not stated
-Data analysis: not stated
Intention-to-treat: yes
Follow-up period: 4 months
Participants60 patients
Mean age: 50 years
All solid organ (liver) transplant recipients
CMV status: D/R+, D+/R-, D-/R-
InterventionsTREATMENT GROUP
Pre-emptive oral ganciclovir 1000 mg x 3/d

CONTROL GROUP
No treatment
Outcomes1. CMV disease and syndrome
2. Total CMV infection
3. Acute rejection
4. Toxicity
NotesMethod for detection of CMV infection: pp65 antigenaemia >1 +ve cell/1 x 10(4); qualitative PCR for CMV DNA
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear




Sagedal 03-kidney
MethodsCountry: Norway
Setting: University
Randomisation method: not stated
Blinding:
-Participants: no
-Investigators: no
-Outcome assessors: not stated
-Data analysis: not stated
Intention-to-treat: no
Follow-up period: 12 months
Participants80 patients
Mean age: 56 years (range 21-79)
All solid organ (kidney) transplant recipients (first transplant only)
CMV status: D/R+, D+/R-
InterventionsTREATMENT GROUP
Pre-emptive oral ganciclovir 100 mg x 3/d

CONTROL GROUP
No treatment
Outcomes1. CMV syndrome and disease
2. Acute rejection
3. Mortality
4. Serum creatinine
NotesMethod for detection of CMV infection: pp65 antigenaemia >1 +ve cell/10 x 10(4)
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear




Singh 00-Liver
MethodsCountry: USA
Setting: University
Randomisation method: not stated
Blinding:
-Participants: no
-Investigators: no
-Outcome assessors: not stated
-Data analysis: not stated
Intention-to-treat: not stated
Follow-up period: 3 months
Participants22 patients
Mean age: 50 years
Solid organ (liver) transplant recipients
CMV status: D/R+, D+/R-, D-/R-
InterventionsTREATMENT GROUP
Pre-emptive oral ganciclovir 2000 mg tid for 2 weeks, then 1000 mg tid for 4 weeks

CONTROL GROUP
Pre-emptive ganciclovir IV 5 mg/kg every 12 hours for 7 days
Outcomes1. CMV disease and syndrome
2. All-cause mortality
3. Other infections
4. Toxicity
5. Cost analysis
NotesMethod for detection of CMV infection: pp65 antigenaemia >1 +ve cell/20 x 10(4)
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear




Singh 94-Liver
MethodsCountry: USA
Setting: University
Randomisation method: stratified randomisation by blocks of 4
Blinding:
-Participants: no
-Investigators: no
-Outcome assessors: not stated
-Data analysis: not stated
Intention-to-treat: not stated
Follow-up period: 6 months
Participants47 patients
Mean age: 45 (21-69) years
Solid organ (liver) first (n = 44) and second (n = 3) transplant recipients
CMV status: D/R+, D+/R-, D-/R-
InterventionsTREATMENT GROUP
Pre-emptive IV ganciclovir 5 mg/kg x 2/day x 7 days

CONTROL GROUP
Oral acyclovir 800 mg x 4/day x 24 weeks
Outcomes1. CMV syndrome and disease
2. All-cause mortality
3. Graft loss
4. Toxicity
NotesMethod for detection of CMV infection: Shell vial culture; EIA (titre > 0.79 +ve)
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear




Yang 98-Kidney
MethodsCountry: South Korea
Setting: University
Randomisation method: not stated
Blinding:
-Participants: no
-Investigators: no
-Outcome assessors: not stated
-Data analysis: not stated
Intention-to-treat: yes
Follow-up period: 6 months
Participants31 patients
Mean age: NA
Solid organ (kidney) transplant recipients
CMV status: D/R+
InterventionsTREATMENT GROUP
Pre-emptive IV ganciclovir 5 mg/kg bid for 2 weeks

CONTROL GROUP
No treatment
Outcomes1. CMV syndrome and disease
2. CMV infection
NotesMethod for detection of CMV infection: pp65 antigenaemia > 1 +ve cell/5 x 10(4); CMV IgM index > 0.500
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear
 D/R+ = donor unknown, recipient CMV +ve
D+/R- = donor CMV +ve, recipient CMV -ve
D-/R- = donor CMV -ve, recipient CMV -ve
tid = three times a day
tds = to be taken three times a day
bid = twice per day


 
Characteristics of excluded studies [ordered by study ID]
StudyReason for exclusion
Ahsan 1997Prophylaxis RCT
Ahsan 1998Not RCT (sequential)
Arbo 2000Economic evaluation of previous trial
Badley 1997Prophylaxis RCT
Balfour 1989Prophylaxis RCT
Barkholt 1999Prophylaxis RCT
Cohen 1993Prophylaxis RCT
Conti 1995Prophylaxis RCT
Dickinson 1996IgG to prevent CMV
Duncan 1994Prophylaxis RCT
Egan 2002Prophylaxis RCT
Falagas 1997Included both non-randomised patients and patients from a previous trial
Fehir 1989Non-randomised patients included
Fishman 2000Retrospective study
Flechner 1998Prophylaxis RCT
Gane 1997Prophylaxis RCT
Gavalda 1997Prophylaxis RCT
Gerna 2003Qualitative molecular assay for detection of a late (pp67) HCMV mRNA versus quantitative antigenemia
Green 1997Prophylaxis RCT
Hertz 1988Prophylaxis RCT
Hibberd 1995Prophylaxis RCT
Jurim 1996Subgroup of previous trial - outcome Hepatitis B
Kim 2000Economic evaluation of previous study
King 1999IgG versus antiviral to prevent CMV
Kletzmayr 1996Prophylaxis RCT
Kletzmayr 2000Not RCT - historical controls
Leray 1995Prophylaxis RCT
Lowance 1998Prophylaxis RCT
Lumbreras 1993Not RCT - historical controls
Macdonald 1995Prophylaxis RCT
Marker 1980Included both randomised and non-randomised patients
Merigan 1992Prophylaxis RCT
Moreno 1999Not RCT
Mullen 1998Retrospective study
Nakazato 1993Prophylaxis RCT
Paya 2004Prophylaxis RCT
Pouteil-Noble 1996Prophylaxis RCT
Reischig 2002Prophylaxis RCT
Rondeau 1993Prophylaxis RCT
Rostaing 1994Prophylaxis RCT
Rubin 2000Prophylaxis RCT
Saliba 1993Prophylaxis RCT
Schnitzler 2000Re-analysis of previous study (1992)
Singh 1995Not RCT
Singh 2002aProphylaxis RCT
Speich 1999Not RCT - sequential
Turgeon 1998Not RCT - sequential
Valantine 1999Post hoc analysis
Winston 1995Prophylaxis RCT
Winston 2003Prophylaxis RCT
Winston 2004Prophylaxis RCT
Yang 1999Unable to determine if patients randomised


 
Comparison 1. Pre-emptive medication for CMV viraemia versus placebo or standard care
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 All symptomatic CMV disease6288Risk Ratio (M-H, Random, 95% CI)0.29 [0.11, 0.80]
 2 CMV organ involvement5217Risk Ratio (M-H, Random, 95% CI)0.41 [0.06, 2.63]
 3 CMV associated symptoms5217Risk Ratio (M-H, Random, 95% CI)0.28 [0.06, 1.21]
 4 Acute rejection3185Risk Ratio (M-H, Random, 95% CI)1.21 [0.69, 2.12]
 5 All-cause mortality and graft loss3Risk Ratio (M-H, Random, 95% CI)Subtotals only
    5.1 All-cause mortality
3176Risk Ratio (M-H, Random, 95% CI)1.23 [0.35, 4.30]
    5.2 Graft loss
136Risk Ratio (M-H, Random, 95% CI)0.28 [0.01, 5.35]
 6 Other infections1Risk Ratio (M-H, Random, 95% CI)Totals not selected
 7 Adverse effects2Risk Ratio (M-H, Random, 95% CI)Subtotals only
    7.1 Leucopenia
2114Risk Ratio (M-H, Random, 95% CI)1.54 [0.16, 15.36]
    7.2 Renal dysfunction
136Risk Ratio (M-H, Random, 95% CI)0.93 [0.18, 4.92]
 
Comparison 2. Pre-emptive medication versus prophylaxis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 All symptomatic CMV disease3151Risk Ratio (M-H, Random, 95% CI)0.42 [0.07, 2.65]
 2 Acute rejection1Risk Ratio (M-H, Random, 95% CI)Totals not selected
 3 All-cause mortality and graft loss3Risk Ratio (M-H, Random, 95% CI)Subtotals only
    3.1 All-cause mortality
3151Risk Ratio (M-H, Random, 95% CI)1.86 [0.61, 5.72]
    3.2 Graft loss
3151Risk Ratio (M-H, Random, 95% CI)1.03 [0.10, 10.34]
 4 Adverse effects2Risk Ratio (M-H, Random, 95% CI)Subtotals only
    4.1 Leucopenia
2117Risk Ratio (M-H, Random, 95% CI)0.12 [0.01, 0.96]
    4.2 Neurological dysfunction
2117Risk Ratio (M-H, Random, 95% CI)0.17 [0.02, 1.35]
    4.3 Renal dysfunction
147Risk Ratio (M-H, Random, 95% CI)0.35 [0.01, 8.11]
 
Comparison 3. Oral versus IV ganciclovir
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 All symptomatic CMV disease1Risk Ratio (M-H, Random, 95% CI)Totals not selected
 2 All-cause mortality1Risk Ratio (M-H, Random, 95% CI)Totals not selected
 3 Other infections1Risk Ratio (M-H, Random, 95% CI)Totals not selected
 
Table 1. Electronic search strategies
DatabaseSearch terms
CENTRAL#1. CYTOMEGALOVIRUS explode all trees (MeSH)
#2. CYTOMEGALOVIRUS INFECTIONS explode all trees (MeSH)
#3. CYTOMEGALOVIRUS VACCINES explode all trees (MeSH)
#4. cytomegalovirus
#5. cmv
#6. (#1 or #2 or #3 or #4 or #5)
#7. ORGAN TRANSPLANTATION explode all trees (MeSH)
#8. BONE TRANSPLANTATION explode all trees (MeSH)
#9. (#7 and (not #8))
#10. ((renal near transplant*) or (kidney near transplant*) or (heart near transplant*) or (lung near transplant*) or (liver near transplant*) or (pancreas near transplant*))
#11. (#9 or #10)
#12. (#6 and #11)
MEDLINE1. Cytomegalovirus/
2. exp Cytomegalovirus Infections/
3. Cytomegalovirus Vaccines/
4. cytomegalovirus.tw.
5. cmv.tw.
6. or/1-5
7. exp Organ Transplantation/
8. 7 not Bone Transplantation/
9. ((organ or renal or kidney or heart or lung or liver or pancreas) adj transplant$).tw.
10. or/8-9
11. 6 and 10
12. randomized controlled trial.pt.
13. controlled clinical trial.pt.
14. randomized controlled trials/
15. random allocation/
16. double blind method/
17. single blind method/
18. or/12-17
19. animal/ not (animal/ and human/)
20. 18 not 19
21. clinical trial.pt.
22. exp clinical trials/
23. (clinic$ adj25 trial$).ti,ab.
24. cross-over studies/
25. (crossover or cross-over or cross over).tw.
26. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab.
27. placebos/
28. placebo$.ti,ab.
29. random$.ti,ab.
30. research design/
31. or/21-30
32. 31 not 19
33. 20 or 32
34. 11 and 33
EMBASE1. exp CYTOMEGALOVIRUS/
2. Cytomegalovirus Infection/
3. Cytomegalovirus Antibody/
4. Cytomegalovirus Vaccine/
5. cytomegalovirus.tw.
6. CMV.tw.
7. or/1-6
8. exp organ transplantation/
9. ((organ or renal or kidney or heart or lung or liver or pancreas) adj transplant$).tw.
10. or/8-9
11. 7 and 10
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