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Cochrane Database of Systematic Reviews

Intervenciones antivirales para pacientes con un trasplante hepático e infección recurrente del injerto debido al virus de la hepatitis C

Información

DOI:
https://doi.org/10.1002/14651858.CD006803.pub4Copiar DOI
Base de datos:
  1. Cochrane Database of Systematic Reviews
Versión publicada:
  1. 04 diciembre 2013see what's new
Tipo:
  1. Intervention
Etapa:
  1. Review
Grupo Editorial Cochrane:

  1. Grupo Cochrane de Hepatobiliar

Copyright:
  1. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

  • Kurinchi Selvan Gurusamy

    Correspondencia a: Department of Surgery, Royal Free Campus, UCL Medical School, London, UK

    [email protected]

  • Emmanuel Tsochatzis

    Sheila Sherlock Liver Centre, Royal Free Hampstead NHS Foundation Trust and UCL Institute of Liver and Digestive Health, London, UK

  • Clare D Toon

    Division of Surgery & Interventional Science, University College London, London, UK

  • Elias Xirouchakis

    GI and Hepatology, Athens Medical Group, Hospital P. Faliro, Athens, Greece

  • Andrew K Burroughs

    Sheila Sherlock Liver Centre, Royal Free Hampstead NHS Foundation Trust, London, UK

  • Brian R Davidson

    Department of Surgery, Royal Free Campus, UCL Medical School, London, UK

Contributions of authors

KS Gurusamy wrote the review, assessed the trials for inclusion, and extracted data on included trials.
E Tsochatzis, C Toon, and E Xirouchakis extracted the data on included trials.
AK Burroughs and BR Davidson critically commented on the review and provided advice for improving the review.
All authors agreed to the final version.

Sources of support

Internal sources

  • None, Other.

External sources

  • Hellenic Association for the Study of the Liver, Greece.

    Dr E Tsochatzis receives an educational grant for his research in the UK.

Declarations of interest

None known.

Acknowledgements

To the Cochrane Hepato‐Biliary Group for the support that they have provided.
Dr Bujar Osmani, who contributed to the previous version of this Cochrane review.

Peer Reviewers: Jason Vanatta, USA; Ryan Groeschl, USA.
Contact Editor: Davor Stimac, Croatia.

This project was funded by the National Institute for Health Research.
Disclaimer of the Department of Health: 'The views and opinions expressed in the review are those of the authors and do not necessarily reflect those of the National Institute for Health Research (NIHR), National Health Services (NHS), or the Department of Health'.

Version history

Published

Title

Stage

Authors

Version

2013 Dec 04

Antiviral interventions for liver transplant patients with recurrent graft infection due to hepatitis C virus

Review

Kurinchi Selvan Gurusamy, Emmanuel Tsochatzis, Clare D Toon, Elias Xirouchakis, Andrew K Burroughs, Brian R Davidson

https://doi.org/10.1002/14651858.CD006803.pub4

2010 Jan 20

Antiviral therapy for recurrent liver graft infection with hepatitis C virus

Review

Kurinchi Selvan Gurusamy, Emmanuel Tsochatzis, Elias Xirouchakis, Andrew K Burroughs, Brian R Davidson

https://doi.org/10.1002/14651858.CD006803.pub3

2009 Jan 21

Antiviral therapy for recurrent liver graft infection with hepatitis C virus

Review

Kurinchi Selvan Gurusamy, Bujar Osmani, Elias Xirouchakis, Andrew K Burroughs, Brian R Davidson

https://doi.org/10.1002/14651858.CD006803.pub2

2007 Oct 17

Antiviral therapy for recurrent liver graft infection with hepatitis C virus

Protocol

Kurinchi Selvan Gurusamy, Kumarakrishnan Samraj, Brian R Davidson

https://doi.org/10.1002/14651858.CD006803

Differences between protocol and review

The outcomes have been divided into primary and secondary outcomes, and ordered by clinical importance. The outcomes retransplantation and graft rejection have now been clearly defined as those occurring after the start of therapy. Liver decompensation has been added as an additional primary outcome as this is an important clinical outcome that can be influenced by treatment. The outcomes initial poor function, primary graft non‐function, intensive therapy unit stay, and hospital stay have been removed as these events and outcomes are prior to the start of the treatment and hence are redundant.

Differences between first review and update

  1. We updated the search and identified one new trial (Lodato 2008). Also, a previously included trial, which was available only as an abstract, was published as full text (Nair 2008), and we used the information from the full text for this update of the review.

  2. We updated the assessment of risk of bias according to the new methods of bias risk assessment in the updated version of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).

  3. Previously, the risk ratio in outcomes such as fibrosis improvement, where higher incidence of an event was beneficial, was entered in the same way as outcomes such as fibrosis worsening, where higher incidence of an event was harmful. This meant that the readers had to take extra care when interpreting the risk ratios. Now, the incidence of non‐event has been reported in beneficial outcomes so that all risk ratios of less than one indicate benefit of the experimental intervention and risk ratios of more than one indicate harm of the experimental intervention for all the outcomes in the review.

  4. For dichotomous variables in which there was only one trial included, we performed the Fisher's exact test. This is because of the potential for false estimates for risk ratio in RevMan 2008 in the presence of only one trial for the outcome.

Differences between first update and second update

  1. We have updated the methods according to the updated version of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

  2. We have added trial sequential analysis.

  3. We have identified five new trials and included them in the systematic review (Gane 2009; Aguilera 2011; Yedibela 2011; Belli 2012; Calmus 2012).

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Humans;

Study flow diagram.
Figuras y tablas -
Figure 1

Study flow diagram.

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Methodological quality graph: Review authors' judgements about each methodological quality item presented as percentages across all included studies.
Figuras y tablas -
Figure 2

Methodological quality graph: Review authors' judgements about each methodological quality item presented as percentages across all included studies.

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Methodological quality summary: Review authors' judgements about each methodological quality item for each included study.
Figuras y tablas -
Figure 3

Methodological quality summary: Review authors' judgements about each methodological quality item for each included study.

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Trial Sequential Analysis of mortality (ribavirin plus peg interferon versus peg interferon) 
 The diversity‐adjusted required information size (DARIS) was calculated to 16,594 patients, based on the proportion of patients in the control group with the outcome of 4.1%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z‐curve (blue line). After accruing 98 participants in two trials, only 0.59% of the DARIS has been reached. Accordingly, the Trial Sequential Analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, the conventional boundaries (dotted red line) have also not been crossed by the cumulative Z‐curve.
Figuras y tablas -
Figure 4

Trial Sequential Analysis of mortality (ribavirin plus peg interferon versus peg interferon)
The diversity‐adjusted required information size (DARIS) was calculated to 16,594 patients, based on the proportion of patients in the control group with the outcome of 4.1%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z‐curve (blue line). After accruing 98 participants in two trials, only 0.59% of the DARIS has been reached. Accordingly, the Trial Sequential Analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, the conventional boundaries (dotted red line) have also not been crossed by the cumulative Z‐curve.

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Trial Sequential Analysis of fibrosis worsening (ribavirin plus peg interferon versus control) 
 The diversity‐adjusted required information size (DARIS) was calculated to 4066 patients, based on the proportion of patients in the control group with the outcome of 65.1%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 88.93%. After accruing 126 participants in two trials, only 3.1% of the DARIS has been reached. Accordingly, the Trial Sequential Analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, the conventional boundaries (dotted red line) was no longer crossed by the cumulative Z‐curve after two trials although the conventional boundaries were crossed after the first trial.
Figuras y tablas -
Figure 5

Trial Sequential Analysis of fibrosis worsening (ribavirin plus peg interferon versus control)
The diversity‐adjusted required information size (DARIS) was calculated to 4066 patients, based on the proportion of patients in the control group with the outcome of 65.1%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 88.93%. After accruing 126 participants in two trials, only 3.1% of the DARIS has been reached. Accordingly, the Trial Sequential Analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, the conventional boundaries (dotted red line) was no longer crossed by the cumulative Z‐curve after two trials although the conventional boundaries were crossed after the first trial.

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Comparison 1 Intervention versus control, Outcome 1 Mortality.
Figuras y tablas -
Analysis 1.1

Comparison 1 Intervention versus control, Outcome 1 Mortality.

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Comparison 1 Intervention versus control, Outcome 2 Retransplantation after start of therapy.
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Analysis 1.2

Comparison 1 Intervention versus control, Outcome 2 Retransplantation after start of therapy.

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Comparison 1 Intervention versus control, Outcome 3 Treatment‐related serious adverse events (proportion).
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Analysis 1.3

Comparison 1 Intervention versus control, Outcome 3 Treatment‐related serious adverse events (proportion).

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Comparison 1 Intervention versus control, Outcome 4 Treatment‐related serious adverse events (number of serious adverse events).
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Analysis 1.4

Comparison 1 Intervention versus control, Outcome 4 Treatment‐related serious adverse events (number of serious adverse events).

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Comparison 1 Intervention versus control, Outcome 5 Graft rejection requiring retransplantation after start of therapy.
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Analysis 1.5

Comparison 1 Intervention versus control, Outcome 5 Graft rejection requiring retransplantation after start of therapy.

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Comparison 1 Intervention versus control, Outcome 6 Graft rejection requiring medical treatment.
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Analysis 1.6

Comparison 1 Intervention versus control, Outcome 6 Graft rejection requiring medical treatment.

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Comparison 1 Intervention versus control, Outcome 7 Graft rejection (others with unknown treatment).
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Analysis 1.7

Comparison 1 Intervention versus control, Outcome 7 Graft rejection (others with unknown treatment).

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Comparison 1 Intervention versus control, Outcome 8 Fibrosis worsening.
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Analysis 1.8

Comparison 1 Intervention versus control, Outcome 8 Fibrosis worsening.

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Summary of findings for the main comparison. Antiviral therapy for recurrent liver graft infection with hepatitis C virus (mortality)

Mortality

Patient or population: Participants with recurrent liver graft infection with hepatitis C virus.
Settings: Secondary or tertiary setting.
Intervention: Various interventions.
Comparison: Various controls.

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Intervention

Peg interferon vs.control

62 per 1000

30 per 1000
(3 to 318)

RR 0.48
(0.05 to 5.09)

65
(1 study)

⊕⊝⊝⊝
very low1,2

The assumed risk was the control group risk.

Peg interferon plus ribavirin vs.control

63 per 1000

189 per 1000
(8 to 1000)

RR 3
(0.13 to 70.53)

54
(1 study)

⊕⊝⊝⊝
very low1,2

Since there were no deaths in the control group, the assumed risk was the control group risk in a different trial included in this review.

Ribavirin plus peg interferon vs.peg interferon

41 per 1000

20 per 1000
(2 to 212)

RR 0.5
(0.05 to 5.2)

98
(2 studies)

⊕⊝⊝⊝
very low1,2

The assumed risk was the control group risk.

Interferon vs.control

63 per 1000

105 per 1000
(5 to 1000)

RR 1.67
(0.08 to 33.75)

12
(1 study)

⊕⊝⊝⊝
very low1,2

Since there were no deaths in the control group, the assumed risk was the control group risk in a different trial included in this review.

Interferon plus ribavirin vs.control

42 per 1000

12 per 1000
(0 to 281)

RR 0.29
(0.01 to 6.74)

52
(1 study)

⊕⊝⊝⊝
very low1,2

The assumed risk was the control group risk.

Ribavirin vs.interferon

There were no deaths in either group.

Not estimable

30
(1 study)

⊕⊝⊝⊝
very low1,2

‐

Ribavirin vs.placebo

There were no deaths in either group.

Not estimable

77
(1 study)

⊕⊝⊝⊝
very low1,2

‐

*The basis for the assumed risk is provided in the comments section. 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; peg: pegylated; 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.

1 The trial(s) was (were) of high risk of bias.
2 The confidence intervals overlapped 1 and either 0.75 or 1.25 or both. The number of events in the intervention and control group was fewer than 300.

Figuras y tablas -
Summary of findings for the main comparison. Antiviral therapy for recurrent liver graft infection with hepatitis C virus (mortality)
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Summary of findings 2. Antiviral therapy for recurrent liver graft infection with hepatitis C virus (retransplantation)

Retransplantation

Patient or population: Participants with recurrent liver graft infection with hepatitis C virus.
Settings: Secondary or tertiary setting.
Intervention: Various interventions.
Comparison: Various controls.

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Intervention

Retransplantation after start of therapy ‐ ribavirin vs.placebo

No retransplantation in either group

Not estimable

77
(1 study)

⊕⊝⊝⊝
very low1,2

Retransplantation after start of therapy ‐ interferon vs.control

10 per 1000

17 per 1000
(1 to 338)

RR 1.67
(0.08 to 33.75)

12
(1 study)

⊕⊝⊝⊝
very low1,2

There was no retransplantation in the control group. So, we used an assumed risk of 1%.

*The basis for the assumed risk is provided in the comments section. 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.

1 The trial(s) was (were) of high risk of bias.
2 The confidence intervals overlapped 1 and either 0.75 or 1.25 or both. The number of events in the intervention and control group was fewer than 300.

Figuras y tablas -
Summary of findings 2. Antiviral therapy for recurrent liver graft infection with hepatitis C virus (retransplantation)
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Comparison 1. Intervention versus control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mortality Show forest plot

8

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 Peg interferon versus no intervention control

1

65

Risk Ratio (M‐H, Fixed, 95% CI)

0.48 [0.05, 5.09]

1.2 Peg interferon plus ribavirin versus no intervention control

1

54

Risk Ratio (M‐H, Fixed, 95% CI)

3.0 [0.13, 70.53]

1.3 Ribavirin plus peg interferon versus peg interferon

2

98

Risk Ratio (M‐H, Fixed, 95% CI)

0.5 [0.05, 5.20]

1.4 Interferon versus no intervention control

1

12

Risk Ratio (M‐H, Fixed, 95% CI)

1.67 [0.08, 33.75]

1.5 Interferon plus ribavirin versus no intervention control

1

52

Risk Ratio (M‐H, Fixed, 95% CI)

0.29 [0.01, 6.74]

1.6 Ribavirin versus interferon

1

30

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.7 Ribavirin versus placebo

1

77

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Retransplantation after start of therapy Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Interferon versus no intervention control

1

12

Risk Ratio (M‐H, Fixed, 95% CI)

1.67 [0.08, 33.75]

2.2 Ribavirin versus placebo

1

77

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Treatment‐related serious adverse events (proportion) Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 Ribavirin plus peg interferon versus peg interferon

1

56

Risk Ratio (M‐H, Fixed, 95% CI)

3.4 [1.46, 7.94]

3.2 Ribavirin versus placebo

1

77

Risk Ratio (M‐H, Fixed, 95% CI)

5.55 [0.70, 43.95]

4 Treatment‐related serious adverse events (number of serious adverse events) Show forest plot

2

Rate Ratio (Fixed, 95% CI)

Subtotals only

4.1 Peg interferon versus no intervention control

1

65

Rate Ratio (Fixed, 95% CI)

1.15 [0.52, 2.57]

4.2 Ribavirin plus peg interferon versus peg interferon

1

42

Rate Ratio (Fixed, 95% CI)

1.20 [0.36, 3.96]

5 Graft rejection requiring retransplantation after start of therapy Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

5.1 Peg interferon plus ribavirin versus no intervention control

1

72

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.07, 15.38]

5.2 Interferon versus no intervention control

1

12

Risk Ratio (M‐H, Fixed, 95% CI)

1.67 [0.08, 33.75]

6 Graft rejection requiring medical treatment Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

6.1 Ribavirin plus peg interferon versus peg interferon

1

42

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.04, 2.95]

7 Graft rejection (others with unknown treatment) Show forest plot

5

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

7.1 Peg interferon versus no intervention control

1

65

Risk Ratio (M‐H, Fixed, 95% CI)

24.26 [1.50, 393.41]

7.2 Peg interferon plus ribavirin versus no intervention control

1

54

Risk Ratio (M‐H, Fixed, 95% CI)

3.0 [0.13, 70.53]

7.3 Ribavirin plus peg interferon versus peg interferon

1

56

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.07, 15.21]

7.4 Peg interferon (1.5 μg/kg/week) plus ribavirin versus peg interferon (0.5 μg/kg/week) plus ribavirin

1

13

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.5 Interferon plus ribavirin versus no intervention control

1

52

Risk Ratio (M‐H, Fixed, 95% CI)

2.59 [0.11, 60.69]

8 Fibrosis worsening Show forest plot

7

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

8.1 Peg interferon versus no intervention control

1

45

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.30, 2.19]

8.2 Peg interferon plus ribavirin versus no intervention control

2

126

Risk Ratio (M‐H, Fixed, 95% CI)

0.71 [0.51, 0.98]

8.3 Ribavirin plus peg interferon versus peg interferon

1

42

Risk Ratio (M‐H, Fixed, 95% CI)

2.0 [0.20, 20.41]

8.4 Amantadine plus peg interferon plus ribavirin versus peg interferon plus ribavirin

1

30

Risk Ratio (M‐H, Fixed, 95% CI)

0.75 [0.28, 2.02]

8.5 Interferon plus ribavirin versus no intervention control

1

52

Risk Ratio (M‐H, Fixed, 95% CI)

0.29 [0.01, 6.74]

8.6 Ribavirin versus interferon

1

30

Risk Ratio (M‐H, Fixed, 95% CI)

0.73 [0.28, 1.88]
Figuras y tablas -
Comparison 1. Intervention versus control
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